Pharmaceutical compositions and respective delivery methods

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with pharmaceutical composition, containing suspension, which includes mixture of hydrophobic medium and solid form, where solid form contains therapeutically effective quantity of octreotide and, at least, one salt of fatty acid with medium chain length, which has chain length from 6 to 14 carbon atoms, and matrix-forming polymer, selected from dextran and polyvinylpyrrolidone (PVP), with salt of fatty acid with medium chain length being present in composition in amount of 10% by weight or more. Group of inventions also deals with capsule, containing said composition, intended for peroral introduction; method of obtaining said pharmaceutical composition.

EFFECT: group of inventions relates to improvement of octreotide bioavailability.

100 cl, 39 ex, 10 dwg, 45 tbl

 

PRIORITY CLAIMS

This application claims the priority application United States serial number 61/097,716, filed September 17, 2008, application United States serial number 61/141,686, filed December 31, 2008, and the application of the United States, serial number 61/161,387, filed March 18, 2009, the full disclosure of which is incorporated herein by reference.

AREA of TECHNOLOGY

The invention relates, mainly, pharmaceutical compositions, to improve methods of delivery, e.g., oral delivery, and methods of using such compositions.

The LEVEL of TECHNOLOGY

Technological practices that promote the efficient penetration of the target substance through a biological barrier, are of great interest in biotechnology and medicine. For example, such techniques can be applied to transport of various substances through a biological barrier, adjustable tight connections (i.e., mucous epithelium, including the intestinal epithelium and airway epithelium, and vascular endothelium, including the blood-brain barrier, the nasal septum, the cornea and other membranes of the eyes and the membranes of the genitourinary system). In particular, there is great interest in oral delivery of therapeutic agents to avoid the use of more invasive and�resources introduction and, therefore, improving convenience for patients and adherence to therapy.

Used various carriers for drug delivery, including liposomes, lipid or polymeric nanoparticles and microemulsions. They improve the bioavailability of certain drugs by oral administration, mainly due to the protective effect they may possess.

However, for most of the relevant drugs, bioavailability remains very low and does not reach the minimum therapeutic purposes.

Consequently, there is a need for efficient, specific, noninvasive means low-risk, targeted at different biological barriers for non-invasive delivery of various therapeutic agents such as peptides and polypeptides, macromolecules drugs and other therapeutic agents, which include molecules of small size, with low bioavailability.

Summary of the INVENTION

The authors of this invention have found that the absorption of certain therapeutic agents in a subject can be improved when administered in a composition described herein. For example, therapeutic agent that is administered in a composition in accordance with one or more embodiments, demonstrates improved bioavailability (DB) compared � the same therapeutic agent, which is administered in a similar way, but in composition, containing salts of fatty acids with medium chain length, as described herein, or containing fewer salts of fatty acids with medium chain length, described in this description. This improvement relative DB can be above at least about 1,5, 2, 3, 5, 10, 50 or 100 times In some aspects, the composition described herein, improves the absorption of a therapeutic agent in the gastrointestinal tract (GIT), which, as a rule, is characterized by low or no bioavailability and/or absorption when administered orally. These therapeutic agents may have low or no bioavailability, for example, in aqueous solution and in other dosage forms for oral administration, known in this field. At least in one aspect of the composition as described herein, improves the bioavailability by increasing the permeability of the partition/barrier of the gastrointestinal tract relative to the molecules of the drug. For example, the composition described herein, can assist in the absorption of penetrating through a partition/barrier of the gastrointestinal tract is mainly by breaking the tight connection between the epithelial cells of the gastrointestinal tract, although it may also operate through transcellular absorption.

The authors of this Fig�plants have developed a way to create a pharmaceutical composition (bulk dosage form of the drug), which comprises preparing a water-soluble composition containing a therapeutically effective amount of at least one therapeutic agent and salts of fatty acids of medium length (and other ingredients - see below), drying (e.g., by lyophilization) water soluble composition to obtain a solid powder, and suspending the lyophilized material (solid powder) to hydrophobic (fatty) environment, preferably castor oil or glyceryltrinitrate (including other ingredients, such as PVP and surfactants and viscosity modifiers - see below), to obtain a suspension, containing in solid form therapeutic agent and a salt of fatty acids of medium length, thereby creating bulk dosage form of the drug, which must contain at least 10% by weight of salts of fatty acids of medium length. The solid form may contain particles (e.g., consists mainly of particles, or consists of particles). Particles can be produced by lyophilization or by granulation. Bulk form of the drug may be subsequently encapsulated in capsules that are coated, sensitive to pH and can be used for oral administration. Standard manufacturing process of the claimed drug�Noi form shown in Fig.1, where insulin is presented as an example of active pharmaceutical ingredient (API), and a salt of a fatty acid with an average chain length is octanoate sodium (Na-C8), which is also called capricolum sodium.

The present invention demonstrates the delivery of the drug in the intestine, which is a model for oral delivery, and thence into the blood, with high bioavailability.

Thus, in one aspect of the invention describes an arrangement. The composition includes a therapeutic agent and a salt of fatty acid of medium length, combined substantially in a hydrophobic environment, preferably in castor oil, in which a therapeutic agent and a salt of fatty acid with an average chain length in solid form, for example, in solid form, such as a particle obtained by drying from an aqueous medium, for example, by lyophilization from aqueous environment, and in which the fatty acid salt medium length is 10 mass% or more, preferably 12-15%, for example, about 12%, about 13%, about 14% or about 15%, or about 16%, or about 17%, and where the composition includes other ingredients (as described in this description), but contains almost no "membrane-thinning means." "Membrane-thinning means" are different linear, branched, aromatic and cyclic alcohols, the average length�; in particular, geraniol and octanol.

Presents the composition of the invention are emulsions. Almost all submitted compositions are oil suspensions, and the amount of water in the compositions is very small; a few presents compositions that are not suspensions, include a large number (about 78%) octanoic acid and are solutions.

In the compositions according to the invention, a therapeutic agent and a salt of fatty acid of medium length are in direct contact with mainly hydrophobic environment. For example, a powder comprising a therapeutic agent and a salt of fatty acids with medium chain length, covered with a shell, immersed or suspended, mainly in the hydrophobic environment.

During the process of production of the aquatic environment, which includes a therapeutic agent and a salt of fatty acid of medium length, as well as other ingredients, dried (e.g., by lyophilization) to obtain the hydrophilic fraction, which is a powder (e.g., a solid form comprising a plurality of particles) and the particle of the powder includes all the ingredients, i.e., a therapeutic agent and a salt of fatty acids with medium chain length are simultaneously in the same particle. The solid form can be, for example, the granulated particle or lyophilized�lysed particle.

In some embodiments, a therapeutic agent selected from the group consisting of peptides, polysaccharides, polyp of cleotides, and molecules of small size. A therapeutic agent can be a protein. For example, therapeutic agent can be insulin. In other embodiments, therapeutic agent is a polynucleotide, for example, coupling of DNA or RNA. In some embodiments, therapeutic agent is a small molecule size, the poorly soluble drug or a high degree of crystalline drug. A therapeutic agent can be a growth hormone. In at least one embodiment, therapeutic agent is teriparatide. In some embodiments, a therapeutic agent can be leuprolide or alendronate or octreotide.

In some embodiments, the composition contains a lot of salts of fatty acids with medium chain length and their derivatives. For example, the solid particle may further contain a variety of salts of fatty acids with medium chain length and their derivatives.

In some embodiments, the salt of a fatty acid with an average chain length selected from the group consisting of hexanoate sodium, heptanoate sodium, octanoate sodium, nonanoate sodium, sodium decanoate, undecanoate sodium, dodecanoate sodium, tridecanoate n�try and tetradecanoate sodium or combinations thereof. In accordance with one or more embodiments the composition contains dodecanoate sodium, tridecanoate sodium and tetradecanoate sodium. In some embodiments, the fatty acid of medium length is octanoate sodium, and octanoate sodium is present in a concentration of more than 10%, for example, about 11% to about 50%, of the mass.

In some embodiments, the substantially hydrophobic environment includes the triglyceride. For example, the triglyceride may be selected from the group consisting of glyceryltrinitrate, glycerylmonostearate, glycerylmonostearate and glyceryltrinitrate.

In some embodiments, the substantially hydrophobic environment includes mineral oil, castor oil, olive oil, corn oil, coconut oil, peanut oil, soybean oil, cottonseed oil, sesame oil or canola oil, or a combination thereof.

In some embodiments, the water soluble composition comprises the fatty acid salt is of medium length, and hydrophobic environment includes corresponding fatty acid with an average chain length; in some specific embodiments, the salt of a fatty acid with an average chain length is salt octanoic acid, such as octanoic sodium, and fatty acid with an average chain length is octanoic acid.

In some embodiments, the water-soluble composition comprising a salt of fatty acid�you medium length and hydrophobic environment includes corresponding monoglyceride medium length or corresponding triglyceride of medium length, or a combination thereof; in some specific embodiments, the salt of fatty acids of medium length sodium is octanoate and monoglyceride is glycerylmonostearate and triglyceride is glyceryltrinitrate.

In some embodiments, the composition further includes one or more fillers. Fillers may be a salt, for example, MgCl2or a compound containing an amine, or mannitol. In some embodiments, the filler is in the same solid form therapeutic agent.

In some embodiments, the filler is a stabilizer. The inventors unexpectedly found that despite the fact that polyvinylpyrrolidone (PVP), in particular PVP-12, known in this area as a stabilizer in the compositions according to the invention it serves to enhance the effect of the permeability enhancer at the absorption of a therapeutic agent.

In some embodiments, the composition further includes one or more surface-active compounds. For example, the surfactant may be selected from the group consisting of sorbitan monopalmitate (span 40®), polyoxyethylenesorbitan of monooleate (tween 80), lecithin and glycerylmonostearate (GMOs), In one or several�lcih embodiments, the surfactant comprises from about 0.1% to 6% by weight of the composition. In preferred embodiments, the composition is a dosage form for oral administration. For example, the composition can be filled hard or soft gelatin capsule. In some embodiments, the composition may be in the form of suppositories. In accordance with one or more embodiments, the composition may be in the form of melting enema (fleet enema),

In some embodiments, the bioavailability of the drug when administered to a subject is at least 1.5-2% compared with parenteral (subcutaneous or intravenous) introduction In some embodiments, the composition when administered to a subject provides more than 2%, 3%, 5%, 10% or more 20% or more 30% absorption of therapeutic agents across a biological barrier, the resulting levels of absorption are therapeutic levels required for investigational indications for use.

In one aspect, the invention describes a method of treating disorders in a subject. The method comprises administering to a subject any one of the compositions described in this specification.

In some embodiments, the composition is administered orally. In other embodiments, the composition is administered rectally, sublingually or buccally.

In some embodiments, the disorder may be anemia, In accordance with one or more embodiments the disease is osteoporosis RA�disorder can be a female infertility In other embodiments, the disorder is stunting or growth hormone deficiency. At least, in one embodiment, the disorder is HIV-related decrease in body weight or cachexia, acromegaly or diabetes.

In some embodiments, therapeutic agent is octreotide, and disorder is acromegaly, abnormal peristalsis of the gastrointestinal tract, gastroparesis, diarrhea, or portal hypertension.

In some embodiments, the method may include encapsulating the suspension in the form of capsules. The method may further include coating of the capsule shell.

In some embodiments, the method can include providing instructions for administration of the capsule to a subject. The instructions may be associated with the introduction of the capsule to a subject any of the symptoms described in this description.

In one aspect of the invention characterizes the capsules are provided with instructions for administration of the capsule to a subject any of the symptoms described in this description.

Other aspects, variants and advantages of these aspects and options provided as examples, are discussed in detail below. In addition, it should be understood that the foregoing information and further detailed description are only examples illustrating various aspects and variants, and designed to provide an overview or framework for understanding the nature and character of the claimed aspects and options. When�agamya drawings are included for the purpose of providing illustration and understanding of the various aspects and options they are included and form part of this specification Figures, along with the rest of the specification, serve to explain the principles and operations of the described and claimed aspects and options.

Throughout this application various publications, including U.S. patents listed by reference to the author and year and patents and applications - room Disclosure of publications, patents and patent applications in their entirety, thus, incorporated by reference in this application to more fully describe the state of the field of the invention

BRIEF DESCRIPTION of FIGURES

Various aspects of at least one of the options discussed below with reference to the accompanying figures. In the figures, which are not intended to draw to scale, each identical or nearly identical component that is illustrated with various figures, presented in the form of a symbol. For the sake of clarity, not every component may be labeled in every drawing. Figures are given for the purpose of illustration and explanation of the results and are not intended to define the limits of the invention. In the figures

Fig.1 shows the manufacturing process of the composition of the dosage form of insulin in accordance with one or more embodiments, as described in the accompanying examples;

Fig.2-5 represent the data monsters�Noemie in the accompanying Examples 3-6,

Fig.6 represents the data referred to in the accompanying Example 8,

Fig.7 represents the transmissivity values for the marker of molecular weight referred to in the accompanying Example 33,

Fig.8 represents the value of the period constant, referred to in the accompanying Example 34, and

Fig.9 and 10 shows the data related to the introduction of octreotide monkeys mentioned in the accompanying Example 35.

DETAILED DESCRIPTION

Composition described herein, can be administered to a subject to provide enhanced bioavailability of therapeutic agents.

The pharmaceutical composition

The pharmaceutical composition described in the present description, contain a therapeutic agent and a salt of fatty acids with medium chain length, which are in direct contact or in connection with substantially hydrophobic environment. For example, a therapeutic agent and a fatty acid with an average chain length or its derivatives can be coated, suspended, spraying or immersing in a largely hydrophobic environment, to form a suspension. The compositions according to the invention are emulsions. Almost all compositions are oil suspensions, and the amount of water in the compositions is negligible; a few of the songs are not suspensions contain a large amount (about 78%) octanoic acid and are the solutions that are determined visually. The suspension may be a liquid slurry containing solids or semi-liquid suspension containing solid (ointment).

Many of the compositions described in this description, contain the slurry, which contains a mixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of a therapeutic agent and at least one salt of fatty acids with medium chain length, and wherein the salt of a fatty acid with an average chain length present in the composition in an amount of 10% or more by mass. The solid form may contain particles (e.g., consisting mainly of particles, or consist of particles). The particle can be obtained by lyophilization or by granulation. In some embodiments, preferably after grinding, 90% (V/V) of the particles have a size of less than 130 microns, and 50% (V/V) of the particles have a size less than 45 microns.

Connection cargo is a therapeutic agent (e.g., insulin) or test compound (for example, high molecular weight dextran), which are made as described in this description, in the form of compositions by

invention.

The authors of this invention have paid special attention to ensure that in the compositions according to the invention only t� fillers, are acknowledged to are safe, based on the available data regarding safety of use in humans, as well as data security and regulatory advice on the use of animals (for example, fillers, having the status of an harmless - GRAS). Some compositions according to the invention can contain other types of fillers (for example, do not have GRAS status). In some embodiments, the compositions of the invention contain such a number of fillers, which is within the maximum daily dose as specified in the relevant data available for each specific filler.

Salt of a fatty acid with an average chain length may generally contribute to or increase the permeability and/or absorption of a therapeutic agent. In some embodiments, salts of fatty acids with medium chain length contain derivatives of salts of fatty acids with medium chain length. Therapeutic agent and a salt of fatty acid with an average chain length is in solid form, e.g., in the form of solid particles, such as freeze-dried particle, granular particle, pellet or microsphere In preferred embodiments, therapeutic agent and a salt of fatty acids with medium chain length are in the same solid form, for example, in the same particle. In the Dr�many embodiments, therapeutic agent and a salt of fatty acid with an average chain length can be in separate solid forms, for example, each one in a separate particle. Composition described herein, in substantially do not contain any "membrane-thinning of funds" such as linear, branched, aromatic and cyclic alcohols with an average chain length, in particular, geraniol and octanol. For example, the compositions preferably do not contain membrane-thinning means, but some options may include, for example, less than 1%, or less than 0.5%, or less than 0.1% by weight membrane-thinning of funds.

Unlike emulsions, where water is the main element in the formula for the compositions described herein, are in solid form, such as a particle containing a therapeutic agent, which is then linked to a hydrophobic (oily) environment. The amount of water in the compositions is typically less than 3% by weight, typically less than 2% or about 1% or less by mass.

The compositions described in this description are the suspensions that contain a mixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of a therapeutic agent and at least one salt of fatty acids with medium chain length. The solid form can be a particle (for example, consist mainly of particles, or consist of particles). The particle can be obtained by lyophilization �whether granulation. Salt of fatty acids with medium chain length is usually present in the compositions described herein, in an amount of 10% or more by mass. In some embodiments, the salt of a fatty acid with an average chain length present in the composition in an amount of 10% -50%, preferably 11%-18%, or approximately 11%-17% or 12%-16% or 12%-15% or 13%-16% or 13%-15% or 14%-16%, or 14% -15% or 15%-16%, or more preferably 15% or 16% by weight, and a fatty acid with an average chain length has a chain length of from 6 to about 14 carbon atoms, preferably 8, 9 or 10 carbon atoms.

In some embodiments, the compositions described above, the solid form that contains a therapeutic agent, also contains a stabilizer (e.g., a stabilizer of protein structure). The stabilizers of protein structure are compounds that stabilize protein structure in aqueous or anhydrous conditions, or which can reduce or prevent aggregation of a therapeutic agent, for example, during the drying process, such as lyophilization or other processing stage. Stabilizers patterns can be polyanionic molecules, such as phytic acid, polyvalent ions such as Ca, Zn or Mg, sugars such as the disaccharide (e.g., trehalose, maltose), or oligo - or polysaccharide such as dextrin or dextran, or sugar SP�mouth, such as mannitol, or an amino acid such as glycine, or poly-molecules such as spermine, or surfactants, such as polyoxyethylenesorbitan monooleate (tween 80) or planilla acid. Uncharged polymers, such as mannitol, methylcellulose and polyvinyl alcohol, are also suitable stabilizers.

Despite the fact that polyvinylpyrrolidone (PVP) is known in this area as a stabilizer, the inventors unexpectedly found that the compositions according to the invention described in this description, PVP, especially PVP-12, is designed to enhance the effect of permeability enhancers on a synergistic basis; in addition, increased levels of PVP-12 to 10% resulted in increasing the level of absorption of therapeutic agent in the blood in connection with the improved activity of the dosage form. The inventors have demonstrated that dextran has a similar (but less pronounced) effect as PVP. Other matrices formed by polymers have the same effect.

In some embodiments, for example, when therapeutic agent is a small molecule size, filler can be added, for example mannitol or glycine.

In some embodiments, the compositions described herein, therapeutic agent is a protein, polypeptide, �eptid, glycosaminoglycans, a small molecule size, polysaccharide or polynucleotide, including, such as octreotide, growth hormone, parathyroid hormone, amino acids of parathyroid hormone 1-34 [PTH (1-34), which has the name of teriparatide], low molecular weight heparin or fondaparinux, and others. low Molecular weight heparins defined as a salt of heparin with an average molecular weight less than 8000 Da and for which at least 60% of all chains have a molecular weight of less than 8000 Da.

In a specific embodiment, the compositions described herein, fatty acid salt is octanoate sodium, and a hydrophobic medium is castor oil; in another specific embodiment, the composition further comprises glycerylmonostearate and sorbitan monopalmitate or glycerylmonostearate and glyceryltrinitrate, and polyoxyethylenesorbitan monooleate; in another specific embodiment, the composition further comprises glyceryltrinitrate, lecithin, utilizabilitate and at least one stabilizer. In specific embodiments, therapeutic agent is octreotide, growth hormone, parathyroid hormone, teriparatide, interferon-alpha (IFN-α), low molecular weight heparin, fondaparinux, siRNAs, somatostatin and their analogues (agonists), including peptidomimetics, ecstatic, vancomycin or gentamicin.

A therapeutic agent

Pharmaceutical co�position, described in this description may be applied with various therapeutic agents (also called active pharmaceutical ingredients = APIs). In some embodiments, the pharmaceutical composition contains a lot of therapeutic agents (effectors), a Therapeutic agent can be in the same solid form (e.g., in the same particle), or any of therapeutic agents may be in separate solid form (for example, every one of them in different particles). In some embodiments, therapeutic agent is in the form of particles, for example, granulated or solid particles. The particle is connected or is in direct contact with substantially hydrophobic medium, e.g. a hydrophobic environment described in this description.

Therapeutic agents that can be used in the compositions described in this description, contain any molecule or compound acting as, for example, biological, medical, pharmaceutical or diagnostic products, including the renderer. Therapeutic agents include drugs and other means, including, but not limited to, the funds listed in the U.S. Pharmacopeia and other known pharmacopoeias. A therapeutic agent is included in compositions �of the invention without any chemical modifications. Therapeutic agents include proteins, polypeptides, peptides, polynucleotides, polysaccharides, and small molecule size.

The term "small molecule size" refers to an organic compound of low molecular weight, which can be synthesized or obtained from natural sources, and usually having a molecular weight less than 2000 Da, 1000 Da or less, or even less than 600 Da, for example, less than or about 550 Da or less, or about 500 Da or less, or about 400 Da, or from about 400 Da to about 2000 Da, or from about 400 Da to about 1700 Yes. Examples of molecules of small size are ergotamine (molecular weight = 582 Yes), fondaparinux (molecular weight = 1727 Yes), leuprolide (molecular weight = 1209 Yes), vancomycin (molecular weight = 1449 Yes), gentamicin (molecular weight = 478 Yes) and doxorubicin (molecular weight=544).

The term "polynucleotide" refers to any molecule composed of DNA nucleotides, RNA nucleotides or a combination of both types, which contains two or more bases guanidine, cytosine, thymidine, adenine, uracil or inosine, etc. the Polynucleotide may include natural nucleotides, chemically modified nucleotides and synthetic nucleotides, or their chemical analogues, and may be single-stranded or double-stranded. This term in�includes "oligonucleotides" and includes "nucleic acids".

The term "small interfering RNAS" (siRNAs) understand the RNA molecule (ribonucleotide), which reduces or stops (prevents) the expression of a gene/mRNA of its endogenous or cellular company. The term includes "RNA interference" (RNC) and "double-stranded RNA" (ds),

The term "polypeptide" is understood molecule, consisting of covalently bound amino acids; the term also includes peptides, polypeptides, proteins and peptidomimetics. Peptidomimetic is a compound containing non-peptide structural elements that are able to mimic the biological activity(s) of a natural parent peptide. Some of the classical peptide characteristics such as enzymatic cleavage of peptide bonds, generally lacking in peptidomimetic.

The term "amino acid" refers to a molecule that consists of any one of 20 naturally occurring amino acids, amino acids that have been chemically modified or synthetic amino acids.

The term "polysaccharide" is understood a linear or branched polymer composed of covalently linked monosaccharides, glucose is the most common monosaccharide and usually has at least eight monosaccharide units in the polysaccharide and, as a rule, much more. Polysaccharides have the General formula Cx(H O)ywhere x is usually a large number between 200 and 2500. Considering that the repeating units in the polymer backbone are often the monosaccharides with six carbon atoms, the General formula can be represented as (C6H10O5)nwhere 40≤n≤3000, i.e., usually between 40 and 3000 monosaccharide units in the polysaccharide.

"Glycosaminoglycans" is a polysaccharide that contains amino compounds of sugar.

Examples of anionic therapeutic agents include polynucleotides of different origin, including those derived from human, virus, animal, eukaryotic or prokaryotic, plant or synthetic origin, etc., including systems for therapeutic gene delivery. The polynucleotide of interest can be of various sizes, from, for example, a simple residual nucleotides to the fragment of the gene or the entire gene. This may be a viral gene or plasmid. Examples of polynucleotides that serve as therapeutic agents include specific DNA sequences (e.g., coding genes), specific RNA sequences (e.g., RNA aptamers, antisense RNA, small interfering RNA (siRNAs) or specific inhibitors of RNA (RNC)) poly CPG, or poly I:From synthetic polymers of polynucleotides.

Alternatively, a therapeutic agent can be b�lcom, for example, an enzyme, a hormone, incretin, a proteoglycan, a ribozyme, a cytokine, a peptide, an apolipoprotein, a growth factor, a bioactive molecule, antigen or antibody, or their Framatom(s), etc., the Peptide can be a peptide of the small size, for example, from 2 to 40 amino acids, examples include antagonists of the fibrinogen receptor (peptides containing RGD, which are tetrapeptide with an average molecular weight of about 600). Examples of peptides are somatostatin and its analogs such as octreotide and lanreotide (Somatuline), which are cyclic octapeptide, and pasireotide (SOM-230), which is a cyclic Hexapeptide (Weckbecker et al, 2002, Endocrinology 143(10) 4123-4130; Schmid, 2007, Molecular and Cellular Endocrinology 286, 69-74). Other examples of peptides include glatiramer acetate (Copaxone®), which is a tetrapeptide, terlipressin, consisting of 12 amino acids, which is a peptide analogue (agonist), lysine vasopressin (ADH), and ecstatic, a peptide comprising as amino acids, which is an incretin-mimetic agent, and other analogues of glucagon-like peptide-1 (GLP-1). Byetta® is a trading name of ecstatica (Eli Lilly and Company/Amylin Pharmaceuticals, Inc). Other peptides include dalargin, which is a Hexapeptide, and kyotorphin, which is a dipeptide. The peptides include peptides hormone, to�which are peptides, consisting of approximately 12 amino acids or less; see, for example, the peptides disclosed in U.S. patents Nos. 4411890 (Momany) and 4839344 (Bowers et al.).

Examples of other peptides that can be used in the practice of this invention are disclosed in U.S. patent No. 4589881 (30 or more amino acid residues) in Pierschbacher et al.; U.S. patent No. 4544500 (20-30 residues) in Bittle et al.; and EP 0204480 (>34 residues) Dimarchi et al. and teriparatide. In some embodiments, therapeutic agent may include polysaccharides, such as glycosaminoglycans. Examples of glycosaminoglycans include heparin, heparin derivatives, heparan sulfate, chondroitin sulfate, dermatan sulfate and hyaluronic acid. Examples of heparin derivatives include, but are not limited to, low molecular weight heparins, such as enoxaparin, dalteparin and Tinzaparin. Therapeutic means of a heparin-like effect is fondaparinux.

Other examples of therapeutic agents include, but are not limited to, hormones such as insulin, erythropoietin (EPO), glucagon-like peptide 1 (GLP-1), melanocyte stimulating hormone (alpha-MSH), parathyroid hormone (PTH), teriparatide, growth hormone (GH), leuprolide, leuprolide acetate, factor VIII, releasing factor growth hormone (GHRH), peptide YY amino acids 3-36 (PYY(3_36)), calcitonin, somatotropin, somatostatin, somatomedin, interleukins, such as interle�kin-2 (IL-2), alpha-1-antitrypsin, colony stimulating factor granulocyte/monocyte (GM-CSF), colony stimulating factor granulocyte (G-CSF), T20, testosterone, interferon, such as interferon-alpha (IFN-α), IFN-β and IFN-γ, luteinizing hormone (LH), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG), enkephalin, dalargin, kyotorphin, basic fibroblast growth factor (bFGF), hirudin, hirulog, releasing factor leteinturier hormone (LHRH), analogue releasing factor gonadotropin (GnRH), natriuretic peptide from the brain (BNP), an activator of tissue plasminogen (TPA), oxytocin, and their analogues and combinations.

Other examples of therapeutic agents include, but are not limited to, analgesics, anti-migraines, anticoagulants, antiemetics, cardiovascular, antihypertensive and vasodilators, sedatives, narcotic antagonists, chelating means, antidiuretic agent and an antitumor agent.

Remedies for migraine include, but are not limited to, naratriptan, naproxen, almotriptan, butalbital, frovatriptan, sumatriptan, rizatriptan, acetaminophen, isometheptene, butorphanol, dichloralphenazone, ergot alkaloids such as dihydroergotamine and ergotamine, NSAIDs (NSPs), such as Ketoprofen and Ketorolac, El�ripton, butorphanol, topiramate, zolmitriptan, caffeine, aspirin, and codeine, as well as their analogs and combinations.

Anticoagulants include, but are not limited to, heparin, hirudin, low molecular weight heparins, and their analogues, as well as fondaparinux. Antiemetics include, but are not limited to, scopolamine, ondansetron, domperidone, metoclopramide, and their analogues. Cardiovascular, antihypertensive and vasodilators include, but are not limited to, diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-Mononitrate, organic nitrates, nitroglycerin and their analogues. Sedatives include, but are not limited to, benzodiazepines, phenothiazines and their analogues. Narcotic antagonists include, but are not limited to, naltrexone, naloxone, and their analogues, a Chelating means include, but are not limited to, deferoxamine and its analogues. Antidiuretic agent include, but are not limited to, desmopressin, vasopressin and their analogues (agonists), such as terlipressin; trade name terlipressin is Glypressin®. Antitumor agents include, but are not limited to, 5-fluorouracil, bleomycin, vincristine, procarbazine, temozolamide, 6-thioguanine, hydroxyurea, cytarabine, cyclophosphamide, doxorubicin, Vinca alkaloid, epirubicin, etoposide, ifosfamide, carboplatin, and other protivoop�the core drugs based on platinum, as carboplatin [Platin®], tetraploid, oxaliplatin, paraplatin and transplatin), vinblastine, vinorelbine, chlorambucil, busulfan, chlormethine, mitomycin, dacarbazine, thiotepa, daunorubicin, idarubicin, mitoxantrone, spiramycin A1, dactinomycin, plicamycin, carmustine, lomustine (CCNU), tautomycin, streptozocin, melphalan, dactinomycin, procarbazine, dexamethasone, prednisolone, 2-chlorodeoxyadenosine, cytarabine, docetaxel, fludarabine, gemcitabine, Herceptin, hydroxyurea, irinotecan, methotrexate, Rituxan, semustine, tomudex and topotecan, Taxol and Taxol-like compounds, and their analogues and combinations.

Additional examples of therapeutic agents include, but are not limited to, coagulation factors and neurotrophic factors, anti-TNF antibodies and fragments of the TNF receptors.

Therapeutic agents include pharmaceutically active agents selected from the group consisting of vitamin B12, bisphosphonate (eg, pamidronate, denetria, alendronate, etidronate, tiludronate, risedronate, zoledronic acid, clodronate sodium or ibandronova acid), Taxol, caspofungin or aminoglycoside antibiotics, Additional therapeutic agents include toxin or protivopolojnoe means, such as an antibiotic (e.g., vancomycin), antiviral, protivogribkovye� or antiparasitic agent. Therapeutic agent itself may be directly active or can be activated by the composition in situ to a certain substance or environmental conditions.

In some embodiments, the composition may contain many therapeutic agents (combination of drugs). For example, the composition may contain factor VIII and factor of Villebranda (vWF), GLP-1 and PYY, IFN-α and nucleotide analogues (i.e., ribavirin), and alendronate or insulin, and GLP-1.

In some embodiments, the composition may contain a small molecule size and the peptide or protein. Examples of combinations include the combination of IFN-α and nucleotide analogues (i.e., ribavirin) for the treatment of hepatitis C, teriparatide and alendronate for the treatment of bone disorders, a combination of medications GH plus for HIV therapy (i.e., HAART) for the simultaneous treatment of viral infection and lipodystrophy that accompanies HIV or side effects for AIDS wasting. The combination of two molecules of small size can be applied when one of them usually has insufficient absorption or biodiscovery, even if the second usually has an effective absorption or bioavailability, such as some antibiotics (for example, the combination of vancomycin and aminoglycosides, such as gentamicin). Examples of combinations for the treatment and prevention of metabolic disorders such as diabetes and air�tion, also include the combination of insulin and Metformin, insulin and rosiglitazone, GLP-1 (or accented) and Metformin, GLP-1 (or accented) and rosiglitazone.

The symptoms and conditions that can be treated with the use of fondaparinuksa formulated as described herein, include deep vein thrombosis, prosthetic hip or knee joint, as well as bedridden patients.

In some embodiments, the compositions described herein, the composition includes a combination of protein or peptide molecules of small size, any of which has or does not have strong absorption or bioavailability. For example, the composition may contain at least one therapeutic agent, which can generally be characterized as having a low level of absorption or bioavailability. The composition can also be applied for the introduction of therapeutic agents, which are absorbed in the stomach and/or intestine, but cause irritation of the stomach and/or intestine and, therefore, hard to bear. In this situation, the advantage for the subject can be that the bioavailability of therapeutic agents will be increased or that more therapeutic agent is absorbed directly into the bloodstream; if you enter fewer treatment�whom funds obviously, there will be less chance of irritation of the stomach and/or intestines. Thus, the compositions of the invention provide for the maintenance of two or more therapeutic agents.

In General, the composition may contain from about 0.01% to about 50% by weight of a therapeutic agent, for example, approximately 0,01, 0,02 0,05, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50% by weight. The maximum amount contained in the composition is usually in the range of approximately 6%-33% by weight therapeutic agent. In some embodiments, the compositions described herein, the solid form, containing therapeutic agent, also contains a stabilizer (e.g., a stabilizer of protein structure). The stabilizers of protein structure are compounds that stabilize protein structure in aqueous or non-aqueous conditions, or can reduce or prevent aggregation of a therapeutic agent, for example, during the drying process, such as lyophilization, or during another stage of processing. Stabilizers patterns can be polyanionic molecules, such as phytic acid, polyvalent ions such as Ca, Zn or Mg, sugars such as the disaccharide (e.g., trehalose, maltose), or oligo-or polysaccharides, such as dextrin or dextran, or a sugar alcohol, such as m�of Nitol, or an amino acid such as glycine, or poly-molecules such as spermine, or surfactants, such as tween 80 or Slano 40, or plutonia acid. Uncharged polymers, such as cellulose and polyvinyl alcohol, are also suitable stabilizers.

Salt of fatty acids with medium chain length

The compositions described herein, include a salt of fatty acid with an average chain length or its derivative in solid form. For example, a salt of fatty acid with an average chain length in the form of particles, such as solid particle. In some embodiments, the particle may be described as granular particle. At least in some embodiments, the solid form typically can be the result of the drying process by spraying or evaporation. In preferred embodiments, the salt of a fatty acid with an average chain length is in the same particle, and a therapeutic agent. For example, a therapeutic agent and a salt of fatty acid with an average chain length can be obtained together by preliminary preparation of a solution such as an aqueous solution containing as a therapeutic agent and a salt of fatty acids with medium chain length, and joint lyophilization of the solution to ensure a solid form or a particle that contains both therapeutic use�algebraic means, and salt of fatty acids with medium chain length (and other ingredients). As described above, the resulting solid particles are linked to a hydrophobic environment. For example, the solid particles can be suspended or immersed in a hydrophobic environment.

In various embodiments, the compositions described herein, a salt of fatty acid with an average chain length can be in the same particle or other particle than AFI. It was found that the bioavailability of the compounds cargo below if fatty acid with an average chain length is in the other particle than therapeutic agent, i.e., there is increased bioavailability, provided that the salt of fatty acids with medium chain length and the compound of cargo were dried together after dissolution in a hydrophilic fraction. It is believed that if a salt of fatty acids with medium chain length and the compound dry cargo together after dissolution in a hydrophilic fraction, they are in the same particle powder of the final product,

Salts of fatty acids with medium chain length include salts having a carbon chain length of from 6 to 14 carbon atoms. Examples of salts of fatty acids are hexanoic sodium, heptanoate sodium, octanoate sodium (also called sodium caprylate), nonanoate sodium, sodium decanoate, sodium undecanoate, dodecanoate sodium, tridecanoate sodium and tetradecane�at sodium. In some embodiments, a salt of fatty acids with medium-chain contains a cation selected from the group consisting of potassium, lithium, ammonium and other monovalent cations, for example, salt of fatty acids with medium chain length selected from octanoate lithium or octanoate potassium or octanoate arginine or other monovalent salts of fatty acids with medium chain length. The inventors found that increasing the quantity of salts of fatty acids with medium chain length increases the bioavailability of the resulting composition. In particular, the increase in the number of salts of fatty acids with medium chain length, in particular, octanoate sodium above 10%, in the range of 12% to 15%, increases the bioavailability of therapeutic agents in the pharmaceutical compositions described in this specification.

In General, the amount of salt of a fatty acid with an average chain length in the compositions described herein, can be from 10% to 50% by weight of the bulk pharmaceutical composition. For example, a salt of fatty acid with an average chain length may be present in amounts of about 10% -50%, preferably about 11% -40%, most preferably about 11% -28% by weight, for example, approximately 12%-13%, 13%-14%, 14%-15%, 15%-16%, 16%-17%, 17%-18%, 18%-19%, 19%-20%, 20%-21%, 21%-22%, 22%-23%, 23%-24%, 24%-25%, 25%-26%, 26%-27% or 27%-28% by weight of the bulk pharmaceutical industry�tion of the composition. In other embodiments, the salt of a fatty acid with an average chain length may be present in amounts of at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%at least about 25%, at least about 26%, at least about 27% or at least about 28% by weight of the bulk pharmaceutical composition. In specific embodiments, the salt of fatty acids with medium chain length (sodium, potassium, lithium or ammonium salt or a mixture thereof) is approximately 12%-21% by weight of the bulk pharmaceutical composition, preferably 11%-18% or approximately 11%-17% or 12%-16% or 12%-15% or 13%-16% or 13%-15% or 14%-16%, or 14% -15% or 15%-16%, or more preferably 15% or 16%. In specific embodiments, the salt of fatty acids with medium chain length (with a carbon chain length of from 6 to 14 carbon atoms, in particular 8, 9 or 10 carbon atoms) is approximately 12%-21% by weight of the bulk pharmaceutical composition, preferably�individual 11%-18%, approximately 11%-17% or 12%-16% or 12%-15% or 13%-16% or 13%-15% or 14%-16%, or 14% -15% or 15%-16%, or more preferably 15% or 16%. In specific embodiments, the salt of fatty acids with medium chain length (for example, salts of octanoic acid, a salt subernova acids, salts geraniol acid) is approximately 12%-21% by weight of the bulk pharmaceutical composition, preferably 11%-18%, approximately 11%-17% or 12%-16% or 12%-15% or 13%-16% or 13%-15% or 14%-16%, or 14% -15% or 15%-16%, or more preferably 15% or 16%. In some embodiments, the salt of a fatty acid with an average chain length present in the solid powder in an amount of from 50% to 90%, preferably in an amount of from 70% to 80%,

One of the variants of the invention includes a composition comprising a suspension which consists essentially of the admixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of a therapeutic agent and at least one salt of fatty acids with medium chain length, and where the salt of a fatty acid with an average chain length is the sodium salt. Salt can be a salt of another cation, e.g., lithium, potassium or ammonium, preferably ammonium salt.

The polymer forming the matrix

In some embodiments, a composition according to the invention comprises a suspension, which contains a mixture of a hydrophobic medium and a solid fo�mu, where the solid form contains a therapeutically effective amount of a therapeutic agent, at least one salt of fatty acids with medium chain length and the polymer forming the matrix, and where the polymer forming the matrix is present in the composition in an amount of 3% or more by mass. In some embodiments, the composition comprises a suspension which consists essentially of the admixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of a therapeutic agent, at least one salt of fatty acids with medium chain length and the polymer forming the matrix, and where the polymer forming the matrix is present in the composition in an amount of 3% or more by mass. In specific embodiments, the polymer forming the matrix is dextran or polyvinylpyrrolidone (PVP). In specific embodiments, the polyvinylpyrrolidone is present in the composition in an amount of from about 2% to about 20% by weight, preferably in an amount of from about 3% to about 18% by weight, more preferably in an amount of from about 5% to about 15% by weight, most preferably in amount of about 10% by weight. In some specific embodiments, the polyvinylpyrrolidone is PVP-12 and/or has a molecular weight of approximately 3000. Other primaryprimary matrix have the same effect in the compositions according to the invention; such polymers forming the matrix contain ionic polysaccharides (e.g., alginic acid and alginates) or neutral polysaccharides (e.g., dextran and HPMC), polyacrylic acid and poly (methacrylic acid, and high molecular weight organic alcohols (e.g., polyvinyl alcohol).

Protease inhibitors

Generally accepted in the region regarding the delivery of proteins, polypeptides and peptides, protease inhibitors are usually added to the composition to prevent the collapse of the API. However, it is not necessary to add protease inhibitors in the compositions of the present invention. The compositions according to the invention confer resistance to a therapeutic agent relative to the collapse of proteases during the period of activity patterns, i.e., the composition of the invention are a suppressive environment for the activity of the enzyme. In addition, the inventors conducted an experiment in which the protease inhibitor Aprotinin was added to the composition, and it had no positive effect on the activity. Similar experiment was carried out where a protease inhibitor ε-aminocaproic acid was added to the composition, and it also had a positive effect on the activity. Thus, in some embodiments, a pharmaceutical composition described herein, in substantially does not contain an inhibitor of p�of ateasy.

Hydrophilic fraction

In embodiments of the invention described above compounds, including therapeutic agent and a salt of fatty acids with medium chain length, dissolved in an aqueous medium, and then dried to obtain powder. The drying process can be performed, for example, by lyophilization or by granulation. The resulting powder is called "hydrophilic fraction. In the hydrophilic fraction of the water typically is present in amounts less than 6%.

The lyophilization can be performed, as shown in the examples of this specification and in ways known in this field, for example, as described in Lyophilization: Introduction and Basic Principles, Thomas Jennings, published by Interpharm/CRC Press Ltd (1999, 2002). Valium can be optimally grind (for example, up to 150 microns) or grind in a mortar. In the industrial production of the extract is preferably pulverized before mixing the hydrophilic fraction and the hydrophobic medium to achieve the reproducibility of the parties.

Granulation can be performed, as shown in the examples of this specification, and in ways known in this field, for example, as described in Granulation, Salman et al, eds, Elsevier (2006) and in Handbook of Pharmaceutical Granulation Technology, 2nd edition, Dilip M. Parikh, ed., (2005).

Various connecting means can be used in the granulation process, such as cellulose (including microcrystalline cellulose), lactose (e.g. lactose monohydrate�), dextrose, starch and mannitol, and other linking tools, described in the previous two references.

The hydrophobic environment

Fat: As described above, in the compositions according to the invention described in this description, a therapeutic agent and a salt of fatty acids with medium chain length are in direct contact or connected to a hydrophobic environment. For example, one or both components can be coated, suspended, immersed or otherwise linked to a hydrophobic environment. Suitable hydrophobic environment may contain, for example, aliphatic, cyclic or aromatic molecules. Examples of suitable aliphatic hydrophobic medium include, but are not limited to, mineral oil, monoglycerides of fatty acids, diglycerides, triglycerides, ethers and esters, and combinations thereof. Examples of suitable fatty acids are octanoic acid, cekanova acid and dodekanisa acid, and fatty acids C7 and C9 and dibasic acids such as sabotinova acid and subernova acid and their derivatives. Examples of triglycerides include, but are not limited to, triglycerides of long chain triglycerides with medium-chain triglycerides with a short chain. For example, a triglyceride with a long chain can be castor oil, or coconut oil, or olive oil, TRIG�iceream with a short chain can be glyceryltrinitrate, and a triglyceride with an average chain length can be glyceryltrinitrate. Monoglycerides are considered surfactants and is described below. Examples of esters include utilizabilitate and butyl acetate. Examples of suitable cyclic hydrophobic medium include, but are not limited to, terpenoids, cholesterol, derivatives of cholesterol (for example, cholesterol sulfate and cholesterol esters of fatty acids. A non-limiting example, an aromatic hydrophobic environment includes benzyl benzoate.

In some embodiments, the compositions described herein, it is desirable that the hydrophobic environment contained a variety of hydrophobic molecules. In some embodiments, the compositions described herein, the hydrophobic medium also contains one or more surfactants (see below).

In some embodiments, the compositions described herein, the hydrophobic medium also includes one or more adhesive polymers, such as cellulose, ethylcellulose, hydroxypropylmethyl cellulose (HPMC) or poly(acrylate) derived HPMC® R (Carbopol® 934P, SR). Such adhesive polymers can contribute to the solidity of the composition and/or contribute to the binding to the surface of the mucosa.

Surface-active substances (surfactants)

The compositions of the present invention, description:�nye in this description, may also contain a surfactant. For example, a surfactant can be a component of a hydrophobic environment, as described above, and/or a surfactant may be one component of the solid shape, as described above, for example, a solid form or a particle that contains a therapeutic agent.

Suitable surfactants include ionic and nonionic surfactants. Examples of the ionic surfactant is lecithin (phosphatidylcholine), bile salts and detergents. Examples of nonionic surfactants include monoglycerides, cremophor, a simple ester of polyethylene glycol and fatty alcohol ester of sorbitol and fatty acids, ether polyoxyethylene sorbitan and fatty acids, Solutol HS 15, poloxamer or a combination of both. Examples of monoglycerides are glycerylmonostearate (also called glycerylmonostearate), glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate and glycerylmonostearate.Examples of esters of sorbitol and fatty acids include sorbitan monolaurate, sorbitan monooleate and sorbitan monopalmitate (span 40), or a combination. Examples of esters of polyoxyethylenesorbitan and fatty acids include polyoxyethylenesorbitan monooleate (tween 80), �nostartmenupinnedlist, polyoxyethylenesorbitan monopalmitate or a combination of both. Commercial preparations of monoglycerides that have been used, also contain different quantities of diglycerides and triglycerides.

The compositions described herein, containing a surfactant, usually contain less than 12% by mass of the total amount of surface-active substances (for example, less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, or less than 1%). In some embodiments of the invention, the total amount of all surfactants is approximately 6%.

How to create drug and drugs have been created

Also included in the invention the methods of obtaining the drugs described in this description. Thus, one embodiment of the invention is a method for producing a pharmaceutical preparation that includes the preparation of water-soluble preparation containing a therapeutically effective amount of at least one therapeutic agent and a salt of fatty acids with medium chain length (as described above), drying of water-soluble drug to obtain a solid powder, and suspending the solid powder in a hydrophobic medium, to produce a suspension containing in solid form therapeutic agent and a fatty acid salt with an average length of C�PI and obtaining a pharmaceutical preparation in which the pharmaceutical preparation contains 10% or more by weight of salts of fatty acids with medium chain length.

One option is the process of obtaining a medicinal product, which comprises providing a solid powder therapeutically effective amount of at least one therapeutic agent, and a solid powder containing a salt of fatty acids with medium chain length, and suspending the solid powders in a hydrophobic medium to obtain a suspension containing in solid form therapeutic agent and a salt of fatty acids with medium chain length, thereby producing a drug, where the drug contains 10% or more by weight of salts of fatty acids with medium chain length.

In one embodiment of the processes and products described in this description, the water-soluble product is an aqueous solution. In some embodiments, drying the water soluble drug is achieved by lyophilization or by granulation. In the process of granulation binding agent may be added to the water-soluble drug before drying. In some embodiments, in the drying step removes sufficient water so that the water content of the drug was lower than 6% by weight, about 5% by weight, about 4% by weight, about 3%, �Colo 2%, or about 1% by weight. In some embodiments of the processes and products described in this description, in the drying step removes the amount of water so that the water content in the solid powder is lower than 6%, or 5%, or 4%, or 3%, or, preferably, lower than 2% by weight. The water content is usually small and the water can be adsorbed from the solid phase during freeze-drying, i.e. water can be saved due to intermolecular bonds. In some embodiments, the water-soluble composition further comprises a stabilizer, for example, methylcellulose, In preferred embodiments of the processes and products described in this description, the hydrophobic medium is castor oil, glyceryltrinitrate, glyceryltrinitrate, or their combination, and it may further contain octanoic acid; in some embodiments the hydrophobic medium comprises an aliphatic, olefinic, cyclic or aromatic compound, mineral oil, paraffin, fatty acid, such as octanoic acid, a monoglyceride, a diglyceride, a triglyceride, an ether or an ester, or a combination of both. In some embodiments of the processes and products described in this description, the triglyceride is a triglyceride of long chain triglyceride with an average chain length, preferably glyceryltrinitrate, or a triglyceride with a short chain, �predpochtitelno glyceryltrinitrate, and triglyceride with a long chain is castor oil or coconut oil or their combination. In some embodiments of the processes and products described in this description, the hydrophobic medium contains castor oil, glyceryltrinitrate, glyceryltrinitrate or a combination or mixture, and can optionally contain octanoic acid. In some embodiments of the processes and products described in this description, the hydrophobic medium contains glyceryltrinitrate or low molecular weight complex ester, for example, utilizabilitate or butyl acetate. In some embodiments of the processes and products described in this description, the main component by weight of the hydrophobic medium is castor oil, and it may further contain glyceryltrinitrate. In some embodiments of the processes and products described in this description, the main component by weight of the hydrophobic medium is glyceryltrinitrate, and it may further contain castor oil.

The main drug is provided as a variant, in which the hydrophobic medium consists mainly of castor oil, glycerylmonostearate and glycerylmonostearate; in the next version of the basic drug is hydrophilic fraction consists mainly of a therapeutic agent, PVP-12 and octanoate sodium.

Specific drug resulted in�stage configuration, in which the hydrophobic medium consists mainly of glyceryltrinitrate, castor oil, glycerylmonostearate, and tween 80, and hydrophilic fraction consists mainly of a therapeutic agent (e.g., octreotide), PVP-12 and octanoate sodium. Other specific drug cited as a variant, in which the hydrophobic environment includes glyceryltrinitrate, castor oil, glycerylmonostearate, and tween 80, and hydrophilic fraction includes a therapeutic agent (e.g., octreotide), PVP-12 and octanoate sodium. In some embodiments, the hydrophobic medium consists mainly of glyceryltrinitrate, and in some embodiments further comprises castor oil and/or glycerylmonostearate.

In some embodiments, the drug comprises a suspension which consists essentially of a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective amount of a therapeutic agent and at least one salt of fatty acids with medium chain length, and in which the salt of a fatty acid with an average chain length present in the preparation in an amount of 10% or more by mass. In some embodiments, the hydrophobic medium consists essentially of castor oil, glycerylmonostearate and glycerylmonostearate; or hydrophobic medium consists mainly of glyceryltrinitrate and glycerylmonostearate;or the hydrophobic medium consists essentially of castor oil, glyceryltrinitrate and glycerylmonostearate. In some embodiments, the hydrophobic medium consists of triglyceride and monoglyceride, and in some particular embodiments, the monoglyceride has the same radicals of the fatty acid, and triglyceride. Some of these options, the triglyceride is glyceryltrinitrate and monoglyceride is glycerylmonostearate. In some embodiments, the salt of a fatty acid with an average chain length in water soluble drug has the same radical of a fatty acid, and monoglyceride with an average chain length or triglyceride with an average chain length, or a combination thereof. Some of these options salt of a fatty acid with an average chain length is sodium caprylate (octanoate sodium) and monoglyceride is glycerylmonostearate and triglyceride is glyceryltrinitrate.

Many of the drugs described in this description, contain a slurry which comprises a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective amount of a therapeutic agent and at least one salt of fatty acids with medium chain length, and in which the salt of a fatty acid with an average chain length present in the preparation in an amount of 10% or more by mass. The solid form can be a particle (for example, consists mainly of particles, or consists of particles). Hour�Itza can be obtained by freeze drying or granulation,

In a specific embodiment, the composition includes mainly the suspension, which contains a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective amount of a therapeutic agent and about 10-20%, preferably 15%, salts of fatty acids with medium chain length, preferably octanoate sodium, and about 5-10%, preferably 10% PVP-12; and where the hydrophobic medium contains about 20-80%, preferably 30-70%, triglyceride, preferably glyceryltrinitrate, or glyceryltrinitrate, or castor oil, or mixtures thereof, about 3-10% surfactants, mostly about 6%, preferably of glycerylmonostearate, and tween 80, and about 1% water; in specific embodiments, therapeutic agent is present in amounts less than 33%, or less than 25%, or less than 10%, or less than 1%, or less than 0.1%. The solid form can be a particle (for example, consists mainly of particles, or consists of particles). The particle can be obtained by lyophilization or by granulation. In a particular embodiment, the solid form can be a particle and can be obtained by lyophilization or by granulation.

In yet another embodiment, the drug includes mainly the suspension, which contains a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective kolichestvennogo funds and about 10-20%, preferably 15%, salts of fatty acids with medium chain length, preferably octanoate sodium, and about 5-10%, preferably 10% PVP-12; and in which the hydrophobic medium contains about 20-80%, preferably 30-70%, of the triglyceride with a medium or short chain length, preferably glyceryltrinitrate or glyceryltrinitrate, about 0-50%, preferably 0-30%, castor oil, about 3-10% surfactants, preferably about 6%, preferably of glycerylmonostearate and tween 80, and about 1% water; in private embodiments, therapeutic agent is present in amounts less than 33%, or less than 25%, or less than 10%, or less than 1%, or less than 0.1%.

In a specific embodiment, the composition includes mainly the suspension, which contains a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective amount of a therapeutic agent and about 15% of octanoate sodium and about 10% PVP-12; and in which the hydrophobic medium contains about 41% of glyceryltrinitrate, about 27% of castor oil, about 4% of glycerylmonostearate, about 2% tween 80, about 1% water, 1% or less of a therapeutic agent when therapeutic agent is octreotide, which makes up about 0,058%.

In another private embodiment, the composition includes mainly the suspension, which contains a mixture of a hydrophobic medium and TV�rdeu form in which the solid form comprises a therapeutically effective amount of a therapeutic agent and about 15% of octanoate sodium, and about 10% PVP-12; Yves which the hydrophobic medium contains about 68% of glyceryltrinitrate, about 4% of glycerylmonostearate, about 2% tween-80, about 15% of octanoate sodium, about 10% PVP-12, about 1% water, less than 1% of therapeutic agent when therapeutic agent is octreotide, constituting approximately 0,058%.

One option is preparation, including the suspension, which contains a mixture of a hydrophobic medium and a solid form in which the solid form comprises a therapeutically effective amount of octreotide and at least one salt of a fatty acid with an average chain length; and in the following embodiment, the salt of a fatty acid with an average chain length present in the preparation in an amount of 10% or more by mass, preferably 15% by mass, and in the following embodiment, the solid form further comprises forming the polymer matrix. In the following embodiment, forming the matrix polymer is dextran or polyvinylpyrrolidone (PVP). In a particular embodiment, forming the matrix polymer is polyvinylpyrrolidone, the polyvinylpyrrolidone is present in the product in amounts of from about 2% to 20% by weight, preferably about 10% by weight. In a specific embodiment, the polyvinylpyrrolidone is�is PVP-12 and/or polyvinylpyrrolidone has a molecular weight of about 3000. In specific embodiments, the hydrophobic medium consists mainly of glyceryltrinitrate and solid form further comprises PVP-12 and octanoate sodium. In more specific embodiments, the hydrophobic medium further comprises castor oil or glycerylmonostearate, or a combination thereof, and a surfactant. In further specific embodiments, the hydrophobic medium contains glyceryltrinitrate, glycerylmonostearate, and polyoxyethylenesorbitan monooleate (tween 80). In the following embodiment, the solid form consists mainly of octreotide, PVP-12 and octanoate sodium. In a specific embodiment, the preparation contains about 41% of glyceryltrinitrate, about 27% of castor oil, about 4% of glycerylmonostearate, about 2% tween-80, about 15% of octanoate sodium, about 10% PVP-12, about 1% water and about 0.058% of octreotide. In another specific embodiment, the preparation contains about 68% of glyceryltrinitrate, about 4% of glycerylmonostearate, about 2% tween-80, about 15% of octanoate sodium, about 10% PVP-12, about 1% water, and about 0,058% of octreotide.

In all of the aforementioned drugs listed the percentages represent the weight ratio, and the solid form can be a particle (for example, consist mainly of particles, or consist of particles). The particle can be obtained by lyophilization or by granulation.

Under normal storage conditions, with therapeutic�adsto in the product of the invention remains stable over a long period of time. Chemical and physical state of the drug resistant. When introduced into the intestine, therapeutic remedy is protected from damage by the environment of the gastrointestinal tract as the drugs are created by oil-based, and therefore in the intestine formed a separate local environment in which a therapeutic agent contained in the oil droplets, which gives stability in vivo.

In some embodiments, is developing the production of the drug, which consists mainly of a therapeutic agent, salts of fatty acids with medium chain length and hydrophobic environment. In embodiments of the invention the solid powder (solid form) consists essentially of a therapeutic agent and salts of fatty acids with medium chain length. Further embodiments of the invention are drugs, produced in the process described in this description. Some medicines therapeutic agent is a protein, polypeptide, peptide, polysaccharide glycosaminoglycans, low-molecular compound or the polynucleotide, and, in private embodiments, therapeutic agent is insulin, growth hormone, parathyroid hormone, teriparatide, interferon-alpha (IFN-α), low molecular weight heparin, leuprolide, fondaparinux, octreotide, ecstatic, terlipressin, vancomycin or gentamicin. Special options �of subramania include dosage form for oral delivery, includes drug in a particular dosage form for oral delivery, which is enteric-coated. Further embodiments of the invention include a capsule containing the drug of the invention, in various embodiments, the capsule is a hard or soft gelatin capsule, and in General, the capsule is enteric-coated. Other embodiments of the invention include a rectal dosage form comprising a drug, in particular, candles, or buccal dosage form. Kit includes instructions and dosage form is also provided.

A therapeutic agent or a salt of fatty acids with medium chain length, or any combination of therapeutic agents and other components, such as protein stabilizers can be prepared by dissolving the mixture (for example, forming an aqueous solution or mixture) that can be lyophilized together, and then suspended in a hydrophobic environment. Other components of the drug can also be further dried or added during the dissolution of solids.

In some embodiments, a therapeutic agent dissolved in the mixture, for example, including one or more additional components, such as a salt of fatty acids with medium chain length, stabilizer and/repairmaster-active agent, and the solvent was removed to obtain a solid powder (solid form), which is suspended in a hydrophobic environment. In some embodiments, a therapeutic agent and/or a salt of fatty acid with an average chain length can be formed in granular particle, which then binds to a hydrophobic environment (for example, suspended in a hydrophobic environment or coated with a hydrophobic environment). In General, the drugs described in this description, contain virtually no "membrane-thinning of funds", such as alcohols with an average chain length, Membrane-thinning means" is defined as the alcohols with an average chain length that have a carbon chain length of from 4 to 15 carbon atoms (for example, including from 5 to 15, 5 to 12, 6, 7, 8, 9, 10 or 11 carbon atoms). For example, membrane-thinning remedy can be linear (for example, saturated or unsaturated), branched (for example, saturated or unsaturated), a cyclic (for example, saturated or unsaturated), or aromatic alcohol. Examples of applicable linear alcohols include, but are not limited to, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol and pentadecanol. Examples of branched alcohols include, but are not limited to, geraniol, farnesol, rodinal, citronellol. Examples of aromati�die alcohols include, not limited to, menthol, terpineol, myrtenol, parallel and ethanol. The applicable examples of aromatic alcohols include, but are not limited to, benzyl alcohol, 4-hydroxycinnamic acid, thymol, styrene glycol, and phenol compounds. Examples of phenolic compounds include, but are not limited to, phenol, m-cresol, and m-chlorocresol.

If desired, the drug may also contain small amounts of nontoxic auxiliary substances such as pH buffering agents, and other substances, such as, for example, sodium acetate and triethanolamine.

In at least one embodiment, a therapeutic agent, such as protein, can be chemically modified to increase its half-life in the bloodstream. For example, therapeutic agent can undergo a process such as tahilramani.

In some embodiments, a method of producing a medicinal product includes the preparation of water-soluble preparation containing a therapeutically effective amount of at least one therapeutic agent and salts of fatty acids with medium chain length, drying the water soluble drug to obtain a solid powder, and dissolving the solid powder in a solution consisting mainly of octanoic acid, thereby producing a drug that is a solution. In some�Tory embodiments, the solid form can be a particle (e.g., consists mainly of particles, or consists of particles), In some embodiments, the particle can be obtained by lyophilization or by granulation. In some embodiments of this process octanoic acid is present in the product in amounts of from about 60% to 90%, or about 70% to 85%, preferably about 78%. In some embodiments of this process fatty acid salt is octanoate sodium; in other embodiments this process, salt of fatty acids with medium chain length present in the preparation in an amount of from 11% to 40% by weight, or in the amount of from about 11% to 28% by weight, or in an amount of about 15% by weight. In some embodiments of this process, the preparation further comprises forming the polymer matrix and in private embodiments of this process form the matrix polymer is dextran or polyvinylpyrrolidone (PVP); in other embodiments of this process, the polyvinylpyrrolidone is present in the product in amounts of from about 2% to 20% by weight, or approximately 5% to 15% by weight, preferably in amounts of about 10% by weight. In some embodiments of this process polyvinylpyrrolidone PVP-12 and/or has a molecular weight of about 3000. The drug may also include surfactants described above. The pharmaceutical products of these processes is f�Xia further embodiments of the invention, for example, a drug containing octanoic acid in an amount of from 60% to 90%, or in an amount of from 70 to about 85%, preferably about 78%; fatty acid salt, preferably octanoate sodium, which is present in the formulation in an amount of from 11% to 40% by weight, or in the amount of from about 11% to 28% by weight, or in an amount of about 15% by weight; forming the matrix polymer, for example, polyvinylpyrrolidone, preferably PVP-12, is present in the preparation in an amount of from 2% to 20% by mass, or preferably in an amount of from 5% to 15% by weight, preferably in amounts of about 10% by weight; and a surfactant, as described above. May also be present small amounts of other hydrophobic components, as described above.

Capsules

Preferred drugs are oral dosage forms of delivery or suppositories. Typical dosage forms include gelatin or vegetable capsules, krakhmalopatochnyi hydroxypropylmethylcellulose ("HPMC") capsules, enteric coated tablets, containing bulk dosage form. Capsules, which can be used to encapsulate the drug of the present invention, known in this field and described, for example, Pharmaceutical Capsules edited by Podczcch and Jones, Pharmaceutical Press (2004) and in Hard gelatin capsules today - and tomrrow, 2nd edition, Steggeman ed published by Capsugel Library (2002).

Additional drugs

The preparations of the invention can be prepared using additional methods known in this field, for example, as described in the following publications: Pharmaceutical Dosage Forms, Vols 1-3, ed. Lieberman, Lachman and Schwartz, published by Marcel Dekker Inc, New York (1989); Water-insoluble Drug Formulation 2nd edition, Liu, editor, published by CRC Press, Taylor & Francis Group (2008); Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems, 2nd edition by Ajay K. Banga (author) is published by CRC Press, Taylor & Francis Group (2006); Protein Formulation and Delivery, 2nd edition, McNally and Hasted eds, published by Informa Healthcare USA Inc (2008); and Advanced Drug Formulation to Optimize Therapeutic Outcomes, Williams et al eds, published by Informa Healthcare USA (2008).

The preparations of the invention can be made using the technology of microparticles, for example, as described in Microparticulate Oral Drug Delivery, Gerbre-Selassie ed., published by Marcel Dekker Inc. (1994) and Dey et a] Multiparticulate Drug Delivery Systems for Controlled Release, Tropical Journal of Pharmaceutical Research, September 2008; 7 (3): 1067-1075.

Methods of treatment

The drugs described in this description, showing effective enteral delivery of unmodified bioactive substances (e.g., therapeutic agent) and thus have many applications. For example, the compounds, described herein, can be applied to the treatment of diabetes.

In particular, insulin for the treatment and prevention of subjects (patients) suffering from type II diabetes (diabetes prevention d�of abeta), and for the treatment of patients suffering from dysglycemia, pre-diabetes, metabolic syndrome, and other diseases that may be imposed in accordance with one or more embodiments of the invention. Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. Metabolic syndrome is a collection of different symptoms: (1) fasting hyperglycemia (insulin resistance, type II diabetes, etc.); (2) reducing the level of cholesterol-HDL; (3) increased levels of triglycerides; (4) high blood pressure; (5) Central obesity; and (6) Pro-inflammatory state.

One of the variants of the invention is a method for the treatment or prophylaxis of a subject suffering from the above conditions, when the amount of insulin sufficient to treat a condition, is a small dose of insulin generated in the preparation of the invention. A small dose of insulin provided less than 300 or less than 200 IU per capsule, for example, 40-200 IU per capsule.

Terlipressin or vasopressin analogues) for the treatment of subjects (patients) suffering from hepato-renal syndrome (PPP), including PPP I and II, extended bleeding esophageal varices, portal hypertension, and other conditions that can watitis� in accordance with one or more embodiments of the invention. Such drugs terlipressin can also be used for primary and secondary prevention of variceal bleeding. The drug of the invention includes a slurry which comprises a mixture of a hydrophobic medium and a solid form, where the solid form comprises a therapeutically effective amount of terlipressin (or other analogues of vasopressin) and at least one salt of fatty acids with medium chain length.

Ecstatic to improve glycemic control in patients with type II diabetes and for treatment of other conditions, such as obesity, and for use in the correction of body weight, may be administered in accordance with one or more embodiments of the invention.

Interferon-alpha for the treatment of subjects with chronic hepatitis C and chronic hepatitis b, and to treat other conditions, including cancer, may be administered in accordance with one or more embodiments of the invention.

Copaxone for the treatment of subjects suffering from multiple sclerosis and to treat other conditions, including inflammatory diseases, may be administered in accordance with one or more embodiments of the invention.

Desmopressin for the treatment of subjects suffering from primary nocturnal enuresis, Central diabetes insipidus (ND) or bleeding disorders (disease Villebranda and gamof�lia) may be administered in accordance with one or more embodiments of the invention. The oral form of desmopressin in the drugs known in this field, has extremely low bioavailability when administered orally.

Octreotide was first synthesized in 1979, and is a oktapeptid that pharmacologically mimics natural somatostatin, although it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. Octreotide or other somatostatin analogs may be administered in accordance with one or more embodiments of the invention for use in treating or preventing diseases or disorders in a subject suffering from diseases such as acromegaly, abnormal motility of the gastrointestinal tract, bouts of flushing associated with carcinoid syndrome, portal hypertension, endocrine tumor (e.g., carcinoid tumor, Vipoma), gastroparesis, diarrhea, pancreatic leak or pancreatic pseudocyst. Diarrhea can occur as a result of radiation therapy or may occur, for example, a subject with a pancreatic tumor, the cells of which secrete vasoactive intestinal polypeptide (Vipoma). In addition, patients who had surgery on the pancreas can suffer from external secretion of the pancreas, and they are vulnerable to the development of pancreatic leakage or pseudocysts, which may be subjected�s treatment octreotide preparations according to the invention. Certain preferred embodiments of the aimed at a method of treatment of a subject having a disease such as acromegaly, abnormal motility of the gastrointestinal tract, bouts of flushing associated with carcinoid syndrome, portal hypertension, endocrine tumor (e.g., carcinoid tumor, Vipoma), gastroparesis, diarrhea, pancreatic leak or pancreatic pseudo-cyst, which comprises administering to a subject the drug of the invention, where therapeutic agent is octreotide in an amount sufficient to cure the disease. Drugs with octreotide according to the invention can also be applied for primary and secondary prophylaxis of variceal bleeding, which can cause portal hypertension; varicose veins may be the stomach or esophagus. Other areas of use of the drug octreotide according to the invention is the treatment of hypovolemic shock (e.g., hemorrhagic) or vasodilator (e.g., septic) origin, hepato-renal syndrome (PPS), cardio-pulmonary resuscitation and anesthesia, artificial arterial hypotension. Other somatostatin analogs can be used in the methods and drugs, in which octreotide is used.

Vancomycin (molecular weight of 1449 Da) is glikopeptidnykh antibiotic that is used for the prevention and Les�routes of infections caused by gram-positive bacteria. The initial indication for the use of vancomycin has been the treatment of methicillin-resistant Staphylococcus aureus (MOSS). Vancomycin never became the first-line therapy for Staphylococcus aureus, one of the reasons that Vancomycin should be administered intravenously. Still in this field of drugs vancomycin must be administered intravenously in systemic therapy, since vancomycin must cross the intestinal mucosa. This large hydrophilic molecules, which do not pass through the gastrointestinal mucosa. The only indication for oral vancomycin therapy is the treatment of pseudomembranous colitis, where it must be used orally for access to the site of infection in the large intestine. Vancomycin for use in treating or preventing infection in a subject can be administered orally to this subject in accordance with one or more embodiments of the invention, Certain preferred embodiments of the invention directed to a method of treating or preventing infection in a subject, which comprises administering to a subject the drug of the invention, where therapeutic agent is vancomycin, in an amount sufficient to treat or prevent infection.

Gentamicin (molecular weight = 478) is amino�cosigner antibiotic, which is used to treat many kinds of bacterial infections, particularly those caused by gram-negative bacteria. When gentamicin was administered in oral form, available in the preparations of the field, he did not have systemic activity. This is due to the fact that it is not absorbed to any appreciable extent from the small intestine.

In addition, the preparations according to the invention can also be applied to the treatment of conditions associated with atherosclerosis, thrombus formation, and embolism such as myocardial infarction and stroke. In particular, the formulations may be applied for delivery of heparin, low molecular weight heparin, or fondaparinuksa through the mucous membrane of the epithelium.

The preparations according to the invention can also be applied to the treatment of hematologic diseases and deficient conditions, such as anemia and hypoxia, which are susceptible to the introduction of hematological growth factors. The preparations of the invention can be applied for delivery of vitamin B12 to a subject with a high biodiscovery in which the mucous epithelium of the subject needs sufficient internal factor. GCSF can also be given in accordance with various embodiments. In addition, the preparations according to the invention can be applied to the treatment of osteoporosis, for example, by enteral wedenig, teriparatide or calcitonin one, two or more times a day.

The human growth hormone (GH) for the treatment of growth hormone deficiency, particularly in children, may be entered in accordance with one or more embodiments. In some preferred embodiments, the drug described in this description, including HGH can be administered to a subject for the treatment and prevention of metabolic and lipid-related diseases, e.g., obesity, abdominal obesity, hyperlipidemia or hypercholesterolemia. For example, the preparation of the invention comprising growth hormone may be administered orally to a subject, thereby treating obesity (e.g., abdominal obesity). In some preferred embodiments, the drug described in this description, which contains a growth hormone, is administered to a subject to treat or prevent lipodystrophy associated with HIV (AIDS wasting), or for the treatment of Prader-Willi syndrome, with impaired growth due to insufficient secretion of growth hormone (e.g., associated with gonadal dysgenesis or Turner syndrome), in violation of the growth of prepubertal children with chronic renal failure and replacement therapy in adults with pronounced growth hormone deficiency. The preparations of the invention comprising growth hormone may be injected PE�orally to a subject to promote the healing of wounds and reducing catabolic reactions in severe burns, sepsis, multiple trauma, severe operations, acute pancreatitis and intestinal fistula. Many other conditions, in addition to deficit of GRS, lead to lower growth, but a positive impact on growth (growth) is often worse than in the treatment of deficiency of GR. Other examples of short stature, which can be treated with drugs according to the invention, comprising growth hormone, are intrauterine growth retardation, and severe idiopathic short stature. Another potential application of the preparations of the invention comprising growth hormone, includes treatment for changes in reverse or prevent the effects of aging in older people, to facilitate for building muscle, and for the treatment of fibromyalgia.

Certain preferred embodiments directed to a method of treating diseases, such as obesity, disorder of lipid metabolism associated with HIV, metabolic disorders, or a lack of growth in a subject, which comprises administering to a subject the drug of the invention in which therapeutic agent (effector) is a growth hormone in an amount sufficient to cure the disease.

Certain preferred embodiments directed to a method of treating bone disease in a subject, which comprises administering to a subject the drug of the invention in which a therapeutic agent is t�of repeated or parathyroid hormone, in an amount sufficient to treat bone diseases.

Certain preferred embodiments directed to a method for the treatment or prevention of coagulation of blood diseases in a subject which comprises administering to a subject the drug of the invention in which therapeutic agent is heparin, a derivative of heparin, or fondaparinux, in an amount sufficient to treat or prevent the clotting of blood diseases.

Leuprolide (GnRH agonist), a drug which was developed in the embodiment of the invention may be used to treat female infertility (for example, a dose once or twice a day), prostate cancer and Alzheimer's disease.

One of the variants of the invention relates to a method of treatment of a subject suffering from a disease or diseases, which comprises administering to a subject the drug of the invention in an amount sufficient to treat the disease. Another variant of the invention relates to the preparation of the invention for use in treating diseases or disorders in a subject. Another variant of the invention relates to the use of therapeutic agents in the manufacture of a medicinal product using the process of the invention for treatment of the disease.

Regimen drug is selected according to a number of factors including type, species, age, weight, gender and �condition of the patient, the severity of the condition being treated; the route of administration, the renal and hepatic function of the patient; and the particular compound or salt after use. A skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or suspend the progress of the disease. Oral dose of the drug of the invention, when used for the indicated effects, can be provided in the form of capsules containing 0,001, 0,0025, 0,005, 0,01, 0,025, 0,05, 0,1, 0,25, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0 or 100, 200, 300, 400, 500, 600, 700, 800 or 1000 mg of therapeutic agent.

The preparations according to the present invention can be administered in a single daily dose, or the total daily dose may be administered in fractional doses of two, three, four, five or six times a day. In some embodiments, the drug is administered in a daily dose of from 0.01 to 5000 mg/day, for example, the introduction of once a day (e.g. morning or at bedtime) or twice or more per day (e.g., morning and before bedtime).

A typical product of the invention is a drug for oral administration on the basis of the API, in the form of enteric coated tablets capsules: each capsule contains AFI co-lyophilized with PVP-12 and octanoate sodium, and suspendirovanie in hydrophobic (lipophilic) medium containing: glyceryltrinitrate, glicerina�aprilat and tween-80; in another typical product of the invention is optionally present castor oil. The preparations described herein, can be administered to a subject, i.e. a person or an animal, for the treatment of the subject a pharmacologically or therapeutically effective amount of a therapeutic agent described in this description. The animal may be a mammal such as a mouse, rat, pig, horse, cow or sheep. Used in this description, the term "pharmacologically or therapeutically effective amount" means that amount of drug or pharmaceutical products (therapeutic agent), which will cause the biological or medical response of a tissue, system, animal or human, is such as requires the researcher or Clinician.

The preparations of the invention allow for the inclusion of a drug in development without any chemical modification of a therapeutic agent. In addition, as shown above, many different therapeutic agents successfully made in the preparations of the invention, including polypeptides, nucleotide, small molecules and even proteins of medium size. In addition, the preparations of the invention provide for a high flexibility with the introduction of a therapeutic agent. Limiting parameters of the concentration-dependent therapeutic agents. Today� day the admissible concentration was not found, but the concentration to 1.5%, mass (polypeptides) and 6%, mass (small molecules) have been achieved and provides a higher concentration of 33%. In conclusion, the preparations of the invention protect the connection cargo from inactivation in the environment of the gastrointestinal tract, associated with, for example, proteolytic degradation and oxidation.

Functions and advantages of these and other options will be more fully understood from the following examples. These examples are for the purpose of illustration and are not intended to define the limits of application of the systems and methods described in this description.

EXAMPLES

Example 1: Preparation

A. Composition of the insulin drug

Table.1A shows an example of a drug in accordance with one or more embodiments. More specifically, this composition is an insulin preparation. Insulin was obtained from Diosynth Biotechnology; octanoate sodium and NaOH from Merck, MgCl2, MC400, span 40, lecithin and castor oil from Spectrum; PVP-12 from BASF; utilizabilitate from Merck/Sigma; glyceryltrinitrate from Acros/Penta and glycerylmonostearate from Abitec Corp.

Table 1A
Ingredient%, mass
Hydrophilic f�action insulin0,417
NaOH0,029
MgCl20,104
PVP-122,083
octanoate sodium3,125
cellulose0,104
Hydrophobic Wednesdaycastor oil52,858
glyceryltrinitrate28,466
utilizabilitate8,195
glycerylmonostearate1,779
lecithinTo 1.893
Span 400,946

B. preparation for the leuprolide: PL. 1B shows an example of a composition for API (active pharmaceutical ingredient) in accordance with one or more embodiments. More specifically, this composition is the drug leuprolide.

Table 1B
Ingredient%, mass
Hydrophilic fractionleuprolide0,072
NaOH0,038
MgCl20,137
PVP-122,740
octanoate sodium12,002
cellulose0,137
water0,605
Hydrophobic WednesdaySpan 401,21
lecithin2,43
utilizabilitate10,52
glycerylmonostearate2,28
glyceryltrinitrate23,74
castor oil44,09

V. Drugs with a reduced number of hydrophobic environment (50% hydrophobic environment)

Table.1B shows an example of a composition for API � accordance with one or more embodiments. More specifically, this composition is a drug for dextran (FD4). FD4 is a dextran-labeled FITZ with 4,4 MB kDa (Sigma, FD4), and dextran is used in all examples unless otherwise stated. This formulation contains coconut oil (Sigma) instead of GTB.

Table 1B
Ingredient%, mass
Hydrophilic fractionDextran0,939
NaOH0,001
MgCl20,235
PVP-124,693
octanoate sodium20,662
cellulose0,235
water1,071
Hydrophobic WednesdaySpan 401,04
lecithin2,08
utilizabilitate9,01
glaze�elmongoreal 1,95
coconut oil20,33
castor oil37,75

The above compositions are used for a wide range of therapeutic agents and have good bioavailability of the compounds cargo on the animal models described below. Note that the total quantity of a therapeutic agent may be changed as needed in any drugs and can be changed in the preparations, for example, NaOH is not always used; coconut oil can be used instead of glyceryltrinitrate; MgCl2not always used (for example, the CHt not in use); all of the ingredients can be substituted as described above in the specification.

Example 2: a Schematic representation of the production of insulin drug

Fig.1 illustrates a method of obtaining a composition in accordance with one or more embodiments. For example, this method can realize the manufacture of the compositions disclosed above in example 1.

Example 3: a Combination of solid particles containing octanoate sodium, and hydrophobic environment is crucial for penetrating activity

Fig.2 presents data related to the level of insulin in savoro�ke after rectal administration to rats. The rats were given anesthesia and injected 100 ál bulk dosage form of the drug containing the dose of insulin 328 µg per rat (9 ME a rat). Blood samples were collected at 0, 3, 6, 10, 15, 25, 30, 40, 60 and 90 min after injection and serum was prepared for determination of human insulin using the immunoassay kit without cross-reactivity between insulin rats and humans.

Data are presented as mean value ± standard deviation, n=5. The left part of Fig.2 refers to the introduction of human insulin with octanoate sodium (Na-C8) or solid hydrophilic fraction, suspended in water (solids in water). The right part of Fig.2 refers to the introduction of a fully insulin of the drug (solid particles in a hydrophobic environment). In table.2 below presents the total AUC values calculated from the curve of the dependence of concentration on time.

Table 2
Trial mixAUC(0-∝)
Na-C85753±3569
Solid particles in the water4083±2569
The insulin composition (solid particles in a hydrophobic environment)280933±78692

Data are mean ± standard deviation

The average value (consisting of AUC values) to insulin after rectal administration of insulin-p/d is approximately 50 times higher than the value after administration without hydrophobic environment. Minimal effects were found in rats when administered with insulin octanoate sodium alone or when administered portion of particulate hydrophilic fractions (as described in example 1) suspended in water. These data indicate synergism between solid octanoate sodium and hydrophobic environment.

Example 4: the Intestinal absorption of insulin after administration of insulin in the gastrointestinal tract of rats

Fig.3 presents data related to the level of serum insulin and glucose levels in the blood after rectal administration of a solution of insulin and an insulin of the drug to rats. The rats were given anesthesia and injected 100 μl of the test drug (insulin in the composition or insulin in PBS) containing the dose of insulin 328 µg per rat (9 ME a rat). Blood samples were collected at 0, 3, 6, 10, 15, 25, 30, 40, 60 and 90 min after injection. The glucose level was determined with a glucose meter and serum was prepared for determination of human insulin using the immunoassay kit without cross-reactivity between insulin rats and humans, the glucose Levels are presented as the percentage ratio of operating system�IOD level measured before injection (time 0). The Data Of Fig.3 presented as mean ± standard deviation, n=5.

The levels of insulin (left part of Fig.3) and glucose (right part of Fig.3) after rectal administration of human insulin, dissolved in PBS (solution of insulin) or included in the drug. Insulin levels dramatically increased in the serum of rats after rectal administration of insulin in the drug. Maximum levels were measured for 6 min after injection and found a gradual decrease until reaching baseline at 90 min after injection. Such an abrupt and significant increase in the level of insulin was accompanied by a significant decrease of glucose level, which reached an average of 20% of baseline level at 30 min after injection. In contrast, rectal administration of insulin in the FBI caused only a very slight decrease of glucose level, which coincides with the observed after treatment of control the FBI separately.

Example 5: the Absorption of insulin after rectal administration of insulin in the composition of the rats

Fig.4 presents data relating to changes in the level of blood glucose and insulin concentrations in blood serum as a result s/C (subcutaneous) injection of a solution of insulin (20 µg / rat) and rectal administration of insulin in the composition (328 µg per rat). Blood samples were collected at 0, 3, 6, 10, 15, 25,30, 40, 60, and 90 min after rectal administration and 0, 15, 30, 45, 60, 90 min, 2, 3, and 4 hours after p/to the introduction. Glucose was immediately determined using a glucometer, and insulin - using the kit for immunoassay. The glucose levels are presented as a percentage of the basic level, measured before injection (time 0). The data in Fig.4 presented as mean ± standard deviation, n=5.

The levels of absorption of insulin in the colon of rats after administration of insulin in the composition is compared with the levels of absorption of insulin after p/to the introduction. The insulin concentration was calculated from the area of the curve of the serum concentration versus time (AUC) and activity in terms of relative bioavailability (HBs) according to the following formula:

HBs=(rectal AUC(0-∝)/p/AUC(0-∝))*(p/dose/rectal dose)

The penetration of insulin into the bloodstream occurs in a narrow window of time, usually for about 10 min being rectal insulin in the drug, increasing the level of insulin in serum is accompanied by a fall in the level of glucose in the blood.

In order to obtain information on the bioavailability of insulin developed in the presence of insulin in the colon, AUC(0-∝)was determined by rectal and s/to the introduction, and the volume of HBs human insulin was 29.4+3,4% with coefficient of variation (KO)=11.4 percent. Rectal wegeneration insulinaemia of the drugs was performed on hundreds of animals. The analysis was developed further and qualified as bioassays to support platform development and testing of series with a linear plot with 10-200 μg per rat, the reproducibility of the 39%, and the intra-laboratory error of 33%.

Insulin drug, as described herein, was tested in five different studies using a total of 25 rats. HBs was to 34.1±12.6 per cent to 28.9 per cent.

Example 6; Absorption of insulin after intraaural of insulin in the drug rats

Target site, oral absorption of the platform of the invention is, as a rule, the small intestine. To check the activity of the insulin composition in the intestine of rats considered two basic conditions: 1. Capsules, enteric coated tablets for rats, and hence, no need to bypass the stomach, to enter directly into the jejunum. 2. Insulin is extensively metabolized in the liver; people 50-80% of endogenous insulin secreted pancreatic β-cells, is isolated in the liver, and therefore cannot be detected in the systemic circulation. The introduction of insulin through the intestinal tract (via an insulin preparation) mimics the endogenous method of using insulin as intestinal blood flow is discharged into the portal vein, which leads directly to the liver. Therefore, to define�ing absorption of insulin, blood samples should be taken from the portal vein (the blood flow in the portal vein, to the liver), as well as from the jugular vein (the large circle circulation after liver).

Specialized model in rats, in which three different cannula surgically implanted in anesthetized rats, was developed: 1. Intestinal cannula - bypassing the stomach, allows the introduction of an insulin preparation, 2. The cannulation of the portal vein - blood to the liver, the definition of insulin which intersects the wall of the digestive tract in blood, and 3. The jugular vein cannula - definition of the General level of insulin. Using this model, we determined the insulin bioavailability of the drug (HBs).

Fig.5 presents data from a representative study on the level of insulin in the circulation in the portal vein and in the circulation of a large circle after intregrating the control of insulin and an insulin of the drug to rats. Rats (8 rats in each group) were anestesiologi, and the small intestine has undergone abdominal surgery. The small intestine containing the intestinal loop was placed on the gauze and kept moist and perfectly intact throughout the study. Temporary cannula inserted into the small intestine, and injected insulin drug, Blood was collected from both portal and jugular vein at the same time points, p�around 4 time points in the rat the mean value ± standard deviation for each time point used to create the dependencies of plasma concentration against time curve. AUC was determined and counted HBs.

The level of insulin in both portal and systemic blood flow increased dramatically after intregrating the introduction of the insulin drug. This, in contrast to the minimal absorption of insulin, found when he entered control insulin. The time interval of absorption was short and insulin levels reached a maximum after 6 min. These parameters are similar to those observed after rectal administration of insulin preparation (see above). Higher levels of insulin found in portal blood flow compared to systemic blood flow, with HBs of 10.1% compared to 5.6%, respectively.

Example 7: Additional compositions containing various compounds cargo

Table 3A describes in detail the components of a series of dextran preparations, prepared as described in the following examples. Sodium salt of capric acid were purchased from Fluka/Sigma, olive oil from Fluka, octane acid from Sigma and petroleum products from Acros.

-
Table 3A
CargoDextran
FormulaAndDDEFGN
Ingredient%, mass%, mass%, mass%, mass%, mass%, mass%, mass%, mass
Hydrophilic fractioncargo0,5450,9390,5650,5460,5650,5650,5650,551
NaOH0,0010,0010,0010,0010,0010,0010,0010,001
MgCl20,136 0,2350,1410,1560,1410,1410,141Was 0.138
PVP-122,7264.6932,8233,1172,8232,8232,8232.754
octanoate sodium12,00120,662--9,0029,0029,00212,125
capret sodium--9,002-----
MS 4000,1360,2350,1410,1560,1410,1410,141Was 0.138
water0,6221,0710,5070,1590.5070,5070,5070,661
Gidrofobnaya WednesdaySpan 401,211,041,251,381,251,251,25-
lecithin2,422,082,502,762,502,502,50-
utilizabilitate10,469,0110,8311,9610,8310,8310,83At 11.23
glycerylmonostearate2,271,95Of 2.352,60 Of 2.35Of 2.35Of 2.35-
glyceryltrinitrate23,6220,3324,4624,2924,4624,4624,4625,35
coconut--------
oil
castor oil43,8637,75For 45.4245,07For 45.42--47,08
Caprylic acid--7,80----
mineral oil-----For 45.42--
olive oil------For 45.42-

Table. 3B describes in detail the components of a series of drugs teriparatide and leuprolide, which was prepared as described in the following examples. Teriparatide has acquired Novetide, and leuprolide purchased from Bambio.

Table 3B
CargoTeriparatideLeuprolide
FormulaI JKL
Ingredient%, mass%, mass%, mass%, mass
Hydrophilic fractioncargoAmount of 0.118Amount of 0.1180,0500,050
NaOH--0,0400,04
MgCl20,1370,1370,1420,15
PVP-122,7402,7402,8382,99
octanoate sodium12,00112,0019,012-
capret sodium---4,48
MS 400 0,1370,1370,1420,15
water0,6050,6050,4890,33
Hydrophobic WednesdaySpan 401,2141,2141,261,32
lecithin2,4282,4282,522,65
utilizabilitate10,51510,51510,8911,46
glycerylmonostearate2,2832,2832,362,49
glyceryltrinitrate23,740-24,59Of 25.87
coconut oil-23,740--
castor oil44,08244,08245,6648,04

Table. 3B describes in detail the components of the preparations of the CHt, which was prepared as described in the following examples. HGH acquired from PLR, Israel (GHP-24).

Table 3B
Cargothe CHt
FormulaOP
Ingredient%, mass%, mass
Hydrophilic fractioncargo0,298To 0.303
NaOH--
MgCl2--
PVP-122,8362,738
octanoate sodium9,006
capret sodium--
MS 4000,1420,137
water0,4920,607
Hydrophobic WednesdaySpan 401,2571,213
lecithin2,5142,427
utilizabilitate10,88510,508
glycerylmonostearate2,3632,281
glyceryltrinitrate24,57523,725
coconut oil--
castor oil45,63344,054

The production process for all of these above formulas mainly occurred as described in Fig.1 and in Example 11.

Example 8: Influence of dose octanoate sodium included in the drug on the activity of the composition�and

The effect of increasing the number of octanoate sodium (Na-C8) in the drug on the activity of the composition was tested using preparations containing dextran (average MB=4,4 kDa, labeled FITZ) as compounds cargo, at different doses of Na-C8 namely, preparations of table.3A (which contain 12% of octanoate sodium by weight) dextran and similar preparations containing different doses of Na-C8: 9%, 6% and 3% respectively.

Checked the activity of these drugs in the small intestine panettiruling rats, they created a model of rats, in which two different cannulas surgically implanted male rats of the Sprague-Dole

1 - Intestinal cannula, bypassing the stomach, allows the direct introduction of the drug into the small intestine.

2 - the jugular vein Cannula allows to determine the systemic levels of the held dextran by injection into the small intestine. The rats were healthy for 4 days before the study and were deprived of food for 18 h prior to the study.

Fig.6 presents data from the study, which identifies the bioavailability of dextran (4.4 kDa), labeled FITZ, panettiruling rats by injection into the small intestine preparations containing different amounts of Na-C8 or dextran labeled FITZ, solubilizing with Na-C8 in physiological solution (control).

The bioavailability of different preparations of dextran and control assessing�whether the introduction of various drugs directly into the small intestine panettiruling rats and by measuring the levels of dextran in the plasma at 3, 6, 10, 25, 60 and 90 min after injection. The levels of dextran plasma after administration of dextran in the product or in physiological solution compared with the levels of dextran plasma after intravenous administration. The values of the system contact AUC (0-90) identified for enteral and intravenous administration and the absolute bioavailability (dBA) calculated by the following formula:

Abd = (GJ AUC(0-90))/(p/AUC(0-90))*(p/dose/dose enteric)

Data are presented as mean value ± standard deviation (n>5; 5 rats per group).

The results show that increasing the number of Na-C8 included in the drug improves the bioavailability of dextran method, dose-response, reaching almost 30% Abd 12%, mass dose. Introduced dextran with Na-C8 in similar doses and suspended in a saline solution (i.e., not the drug), showed lower bioavailability (-6% Abd). Further the results of the dose-response is given, as shown in Example 26.

Example 9: the effect of the ratio of hydrophilic fractions / hydrophobic environment on the activity of the drug

Impact on drug activity change ratio (by mass) between the hydrophilic fraction and the hydrophobic medium was performed using preparations containing dextran (average MB=4,4 kDa, labeled FITZ) as connection cargo (drugs A and b in table.3A). Model NEA�etaziranih rats in vivo described in Example 8, was used to compare the activity of drugs described.

In table.4 presents data bioavailability as a result intraaural injection of drugs containing different ratio of hydrophilic groups to hydrophobic environment.

Table 4
VectorCompositionThe weight ratio between the hydrophilic/hydrophobic environmentModel animalMethod of administrationN% Abd ± standard deviation
DextranAnd1/5,2aenesthesiology ratsjejunal1728,0±6,8
In1/2,61924,8±25

Drugs A and b were injected directly into the small intestine panettiruling rats and the levels of dextran plasma was measured after 3, 6, 10, 25, 60 and 90 min after administration of the composition. The levels of absorption of dextran from thin kick� rats after administration of dextran in the product compared with the levels of absorption of dextran after intravenous administration. Exposure AUC(0-90) was determined for enteral and intravenous administration and the absolute bioavailability (Abd) was calculated by the following formula:

Abd = (GJ AUC(0-90))/(p/AUC(0-90))*(p/dose/dose enteric)

Data are presented as mean value ± standard deviation (n>5; 5 rats per group).

The results show that the changing balance between the hydrophilic fraction and the hydrophobic medium in these drugs with low weight % of a therapeutic agent had no significant effect on the bioavailability of cargo, which is provided when filling in the development of additional drugs.

Example 10: activity of preparations containing various compounds cargo

To verify platform capabilities of the drug, active preparations, containing three different connection cargo (AFI), was tested in three different animal models: introduction jejunal nearestterminal rats, rectal anesthetized rats and jejunal introduction nearestterminal pigs. In table.5 the results are presented of experiments to test the bioavailability of drugs containing different API, in three different animal models described above.

Table 5
APICompositionModel animalMethod of administrationN%DB± standard deviation
ITeriparatideInearestterminal ratjejunal514,0**±10,8
IIInearestterminal pigjejunal515,0**±9,3
IIILaprayKnearestterminaljejunal410,1*±7,5
Drat
in/inthe CHtPanesthetized ratrectal517,9**±3,9
* Absolute database (s) in/in)
** Relative DB (compared to p/K)

A. Absorption of leuprolide after jejunal injection of leuprolide in the drug rats

Table.5-III represents data representative studies related to % Abd leuprolide as a result/in (intravenous) injection of a solution of leuprolide (75 µg/kg) and the jejunal administration of leuprolide in the product (450 mg/kg; drug To that table.3B), nearestterminal rats as described above in Example 8.

Blood samples were taken from jugular vein at 3, 6, 10, 15, 25, 40, 60 and 90 min after jejunal injection and at 3, 10, 25, 40, 90 min, 2, 3.3 and 5 hours after administration, prepared plasma and determined the levels of leuprolide in each sample. The level of leuprolide in the systemic circulation has increased dramatically after the jejunal administration of leuprolide in the product. The level of leuprolide blood reached a maximum at 3 min after injection. The average Abd received after the jejunal administration of leuprolide in the product, calculated as described in the above Examples, and the average and�D was 10.1%. In a control experiment, jejunal introduction of leuprolide in the FBI showed little penetration into the bloodstream.

Similar drug leuprolide containing 12% of octanoate sodium, as described in table.1B, was prepared and tested on the above models and the drug showed bioavailability following:

HBs (compared to p/K) = 21,1%±12,0 (CO=57%).

B. Absorption of teriparatide after JEJUNAL introduction of teriparatide in the drug rats

Table.5-I presents data from representative studies related to comparative parameters teriparatide plasma concentration-time as a result of the p/to the introduction of a solution of teriparatide (85 micrograms per squad) and etonline the introduction of teriparatide (teriparatide) in the product (550 mg/kg; drug I, PL.3B), nearestterminal rats as described above in Example 8. Blood samples were taken from jugular vein at 3, 6, 10, 25, 60 and 90 min after etonline injection and at 3, 10, 30, 60, 90 min, 2, and 3 hours after p/to the introduction, prepared plasma and determined the level of teriparatide in each sample. The level of teriparatide in the systemic circulation has increased dramatically after the jejunal administration of teriparatide in the product. The level of teriparatide peaked at 3 min after injection. Calculated average HBs obtained after jejunal introduction of teriparatide in the product, as described in the above When�erah, and the average Abd was 14.0%. In the control experiment jejunal introduction of teriparatide in saline solution showed no penetration into the bloodstream.

V. Absorption of teriparatide after jejunal introduction of teriparatide in the drug pigs

Table. 5-11 represents the data representative of the research connected with comparative options teriparatide "plasma concentration-time" as a result, the p/to the introduction of a solution of teriparatide (10,65 µg/kg) and jejunal introduction of teriparatide in the drug (100 µg/kg; drug I, table 3B), nearestterminal pigs. Created a model of the pig, in which two different cannulas surgically implanted pig home:

1 - Intestinal cannula, bypassing the stomach, allows the direct introduction of the drug into the small intestine.

2 - the jugular vein Cannula allows to determine the systematic levels led cargo as a result jejunal administration.

Pigs were healthy 7 days before the experiment and were deprived of food for 18-20 h before the experiment.

Blood samples were collected from jugular vein on 0, 3, 6, 10, 15, 25, 40, 60, 90 min, 2, 2.5 and 3 hours after introduction jejunal and 0, 3, 6, 10, 15, 20, 30, 45, 60, 90 min, 2, 2,5, 3, and 4 hours after p/to the introduction, prepared plasma and determined the levels of teriparatide in each sample. The level of teriparatide in the systemic circulation has increased dramatically after Euna�professional introduction teriparatide in the product. The level of teriparatide peaked at 10 min after injection.

The average HBs obtained after jejunal introduction of teriparatide in the product, calculated as described in the above Examples, and it increased 15.0%.

A similar experiment with a pig was performed using dextran (PD4, the drug And in tab.3A) and it was found that the average bioavailability of dextran 20% in pigs compared to the/in the introduction.

G. Absorption of HGH after rectal administration in the CHt the drug to rats

Table.5-IV presents data from representative studies related to comparative parameters CHt plasma concentration-time as a result of the p/to the introduction of CHt solution (81 µg/kg) and rectal administration in the CHt the product (800 mg/kg; drug P, table 3B), anesthetized rats.

Male rats of the Sprague-Dole deprived of food for 18 h before the experiment. Rats were anestesiologi with a solution of ketamine/xylazine. The drug (100 μl per rat) was administered rectally using a catheter 14G-venflon. Blood samples were collected from jugular vein on 3, 6, 10, 15, 40, 60 and 90 min after rectal administration and at 15, 30, 45, 60, 90 min, 2, 3, and 4 h after s/to the introduction, prepared and plasma HGH level was determined in each sample. The level of HGH in the systemic circulation has increased dramatically after rectal administration in the CHt the drug. The level of HGH peaked at 15 min. �rudnyy HBs, obtained after rectal administration in the CHt the drug, was calculated as described in the above Examples, and it was 17.9%. In a separate experiment with HGH is injected into the small intestine, and Abd was lower. In the control experiment rectal administration in the CHt FBI showed penetration into the bloodstream.

Thus, the results presented in table.5 show that significant effects were obtained for all the compounds cargo, tested on all tested animal models. The results show that the drugs described in this description, allow the delivery of a wide variety of macromolecules across the intestinal epithelium in various animal models.

Example 11: a Detailed description of the manufacturing process of the drug teriparatide

Obtaining hydrophilic fractions: To 200 ml of water the following ingredients were slowly added one by one (with 2-3 minutes stirring after each ingredient): 172 mg teriparatide, 200 mg of MgCl2, 4.0 g of PVP-12, drain rate is 17.52 g of octanoate sodium and 10.0 g of 2% aqueous solution of MS-400, made as follows: 1 g of powder-MS-400 add 50 ml of water at a temperature of 60±2°C with stirring. After 5 min stirring, the beaker placed on ice to obtain a clear solution.

After adding a solution of MS-400, and the solution was stirred for another 5 min, and�eat lyophilizer for about 24 hours. This procedure produces about 22 g of hydrophilic fraction.

Obtaining a hydrophobic environment: 2 g of span 40, 4 g of lecithin and 3.8 g of GMOs (glycerolphosphate) was dissolved in 17.3 g of utilizability with stirring, To this solution was added 39,1 g GTB (glyceryltrinitrate) and to 72.6 g of castor oil. This procedure produces about 136-138 g hydrophobic environment.

The production of bulk drug product: mixing the hydrophilic fraction with a hydrophobic environment is performed at a temperature of 20±2°C.

To 15.7 g of hydrophilic fraction was slowly added in of 84.3 g of a hydrophobic medium with stirring at a speed of 600±50 rpm After adding all the hydrophilic fraction, the mixing speed was increased to 2000±200 rpm for 2-10 4-8 min followed by cycles of mixing for 15 min at a speed of 600±50 rpm and 2 min stirring speed 2000±200 Rev/min Further degassing was applied using a vacuum, as follows: 5 min at a pressure of 600 mbar, 5 min at a pressure of 500 mbar and 30-120 min at a pressure of 400 mbar. The resulting suspension was poured into vials of dark glass of 100 ml and stored at 2-8°C. This formula teriparatide marked "I" described in table.3B.

All other medications described herein was made with the help of this method, by modifying the ingredients and their amounts in accordance with item�and, given in the relevant tables (see for example. Example 29). Chart of this method (with insulin as cargo) are shown in Fig 1.

Example 12: effect of oil introduced into the drug, the drug activity

It was tested the influence of oil type, introduced in the technology of preparation of medicines (hydrophilic environment) on the activity of the drug. Medicines containing dextran (average molecular weight = 4,4 kDa, marked FITZ) as cargo and different types of oils in the hydrophobic environment (drugs E, F and G in table.3A) were tested on rats. To test the activity of these drugs in the small intestine panettiruling rats, was used a model in which the male rats of the Sprague-Dole surgically implanted two different catheter:

1 - catheter of the small intestine to gastric bypass and direct injection of medications into the small intestine,

2 - the jugular vein catheter to systematically determine the level of the injected dextran after injection of the drug into the small intestine.

Rats were left to recover for 4 days before the study and were deprived of food for 18 h before the study.

Table.6 represents the data of a study in panettiruling rats, after entering the inside of the small intestine PR�preparations, containing various oils in the hydrophobic environment.

Table 6
Cargo
DrugOilN% absolute
bioavailability ± allowed deviation
DextranECastor oil + GTB1419,8±5,5
FMineral oil + GTB512,2±5,0
GOlive oil + GTB512,0±9,9

Preparations containing various oils, was injected directly into the small intestine panettiruling rats and the levels of dextran in the plasma was measured after 3, 6, 10, 25, 60 and 90 min after drug administration. The levels of absorption of dextran from the small intestine of rats after administration of dextran in the product compared with the levels absorbed after intravenous dextran BB�Denia. Exposure numbers and metrics AUC(0-90) were determined for administration in the small intestine and intravenous administration, the absolute bioavailability was determined in accordance with the following equation:

Absolute bioavailability = (AUC(0-90) for insertion into the small intestine)/(AUC(0-90), intravenous)*(IV dose/dose introduced into the small intestine). Data are presented as the average ± standard deviation (n>5 rats per group),

Similar bioavailability was achieved, with the inclusion of dextran in preparations containing castor or coconut oil. Good bioavailability was also achieved in the small intestine of the rat, when applying teriparatide as cargo, using products I and J; which contain castor oil and GTB, castor oil and coconut oil, respectively.

The results showed that formulations containing different types of oils in the hydrophobic environment are active, ensuring the permeability of the cargo (dextran, teriparatide) carried by the drug. These data demonstrate that all tested oils provided the bioavailability of the cargo. Castor oil and coconut oil are probably the best of the other tested oils.

Example 13: preparation with the use of granulation instead of lyophilization.

The production of hydrophilic fractions: plastics�e packages were added the following ingredients: 1.00 g of PVP-30, 6,70 g octanoate sodium and 13,00 g of lactose monohydrate, the binder substance. After 5 minutes of mixing all the powder was transferred into a mortar and triturated. An aqueous solution of dextran FD4 was prepared in the following way: 0.42 g of dextran was dissolved in 1.2 g of water for injection. Then all the dextran solution was slowly added to the powder while mixing with a slow x trituration in a mortar and pestle; mixing took about 45 min. the Mixture was then transferred to a tablet for lyophilization and dried for 20 hours at a temperature of 50°C. This method yields about 20 g well granulated hydrophilic fraction.

The production of hydrophobic environment: 2 g of span 40 (sorbitan monopalmitate), 4 g of lecithin and 3.8 g of GMOs was dissolved in 17.3 g of isovaleric alcohol with stirring. To this solution was added of 39.1 g of nth and to 72.6 g of castor oil. This method produces about 136-138 g hydrophobic environment.

Manufacture of bulk drug:

Mixing the hydrophilic fraction and the hydrophobic medium was carried out at a temperature of 20±2°C.

19,00 g (29,58% final beclomethasone dipropionate BJP) hydrophilic fraction was slowly added to 45,23 g (70,42% final BJP) hydrophobic environment, while stirring at a speed of 600±50 rpm After adding all of the hydrophobic fraction, the mixing speed was increased to±200 rpm for 2-10 min, followed 4-8 cycles of 15-minute stirring at 60±50 rpm and 2 min stirring speed 2000±200 Rev/min.

Further degassing was applied using a vacuum, as follows: 5 min at a pressure of 600 mbar, 5 min) at a pressure of 500 mbar and 30-120 min at a pressure of 400 mbar. The resulting suspension was poured into vials of dark glass of 100 ml and stored at 2-8°C.

A study on rats: the Above suspension was administered rectally to rats as described in the above examples and the results were as follows: 35% bioavailability, 12.9% of the allowable tolerance. Other party of the suspension prepared by granulation, as described above, were prepared and injected into the small intestine of rats, as described in the above examples and the results were as follows: 21.8% of the bioavailability, a 4.0% allowable deviation. A number of drugs prepared in a similar manner, with the use of granulation and administration of certain medicinal substances, and changing the number of octanoate sodium.

Example 14: the selection capsules

In vitro experiments were conducted separately using 3 types of solutions: a hydrophilic environment, as described in the example above, the only isovaleric alcohol and isovaleric alcohol containing 5% of each of the following surfactants: lecithin, span 40 and glycerylmonostearate. Each of the 3 types of printed capsules, gelatin, starch and HPMC (hydroxypropylmethylcellulose), filled with this solution. Filled capsules were stored further in vitro 29 days when those�ture 22±2°C and relative humidity of 30-50%. Gelatin capsules and the capsules of HPMC showed the best results, namely the absence of deformation of the capsule.

Similar experiments were conducted using the same 3 solutions, gelatin and HPMC capsules. The capsules were filled with a solution, sealed (tied) and stored for 8 days at a temperature of 22±2°C, relative humidity of 30-50%. Both types of capsules demonstrated the stability of the tested solutions, for example, was not of seep and deformation of capsules.

Example 15: effect of various cations in salts of fatty acids with medium chain length

Drugs were prepared with dextran (FD4) like a drug And table.3A except that 12% octanoate sodium (0,722 M) substituted by octanoate lithium, octanoate potassium or octanoate arginine is equal to the molarity (the latter as a model for the ammonium salts). These drugs are given in tab.7A below.

Table 7A
The drug, cargo = dextranIngredientK-octanoate (%, mass)Li-octanoate (%, mass)Arg-octanoate (%, mass)
Hydrophilic fractionAPI0545 0,5460,546
MgCl20,1340,1360,124
PVP-122,6732,7222,475
Octanoate potassium13,6170,000,00
Octanoate lithium0,0010,8260,00
Octanoate arginine0,000,0022,989
MS 4000,1340,1360,124
Water0,6840,6270,919
Hydrophobic WednesdaySpan 401,1851,2061,097
Lecithin2,3692,4122,193
Utilizabilitate10,26Of 10.459,50
Glycerylmonostearate2,2272,2682,062
Glyceryltrinitrate23,1623,5821,44
Castor oil43,0143,7939,82

Each of these drugs were tested on the model of the small intestine of rats described in example 8. Data were obtained and used to calculate bioavailability. The results are presented below in table.7B.

Table 7B
Salts of fatty acids with medium chain length in the tested drugN% bioavailability ± allowed deviation
Octanoate sodium (drug A)1822,2±10,8
Octanoate lithium118,4±3,8
Octanoate potassium 107,9±6,4
Octanoate arginine1217,5±7,4

The drug, which is used in the above experiment, was of a different party than the one used in example 8, and therefore the results of bioavailability submitted to the drug And do not differ from those listed in the table.4.

The above results show that when replacing 12% of octanoate sodium drug octanoate lithium or octanoate potassium equivalent to molarity, the drug still had the bioavailability, but on a smaller level. Drug with octanoate arginine showed activity similar to the drug, with 12% octanoate sodium.

Example 16: effect of addition of alcohols with a chain of medium length (geraniol and octanol) to the hydrophobic environment

Products containing geraniol (BASF) and octanol (Spectrum /LL) were prepared as described above, using the ingredients shown below in table.8. Dodecanoate sodium was purchased from Spectrum/Acros.

The drug Q - low % salts of fatty acids with medium chain length: the preparation of dextran (FD4) was prepared substantially as described in example 11, containing a total of 2.9% of salts of fatty acids with medium chain length (octanoate sodium 1,042% + dodecanoate sodium 1,869%), and also with the content� of geraniol and octanol in a hydrophobic environment, as shown below in table.8.

The drug is R - more than 10% salts of fatty acids with medium chain length: the preparation of dextran prepared, substantially as described for the preparation A, except that geraniol and octanol were added to a hydrophobic environment, as shown in table.8.

Table 8
The drug, cargo IngredientDextran Q (%, mass)Dextran R (%, mass)
Hydrophilic fractionAPI0,5450,456
NaOH0,0290,000
MgCl20,1040,114
PVP-122,0832,282
Octanoate sodium1,04210,046
Dodecanoate sodium1,869-
MS 4000,104 0,114
Water0,2310,521
Hydrophobic WednesdayGeraniol9,148Of 8.39
Octanol8,6277,92
Span 401,0410,96
Lecithin2,081Of 1.91
Utilizabilitate9,0128,27
Glycerylmonostearate1,9561,80
Glyceryltrinitrate21,82520,03
Castor oil40,53237,20

The drug is Q (low % salts of fatty acids of medium chain length EXDC) was tested for intra-intestinal rat model described above and was calculated bioavailability: the absolute bioavailability = 4,4%, the allowable deviation = 3,8 (n=12). Preparation of R (greater than 10% salt EXDC) was tested for intra-intestinal rat model, op�above toboggan, was intended bioavailability; the absolute bioavailability = 22,7%, the allowable deviation = 1,6 (n=6).

The bioavailability of these drugs did not differ significantly from similar preparations described in the example above, which did not contain geraniol.

Example 17: preparation for gentamicin and for RNA

Drugs for gentamicin and for RNA, were prepared substantially as described in Example 11, with the bulk ingredients of a medicinal product, as described in table.9, Gentamicin was purchased from Applichem and RNA was submitted to the sodium salt polyinosinic-polycytidylic acid (Sigma).

Table 9A

The drug, AFI IngredientGentamicin (%wt)RNA (%wt)
Hydrophilic fractionAPI6,0000,100
NaOH0,670-
MgCl20,1270,137
PVP-12 2,5452,741
Octanoate sodium12,02612,001
MS 4000,1270,137
WaterIndexes of 0.8600,605
Hydrophobic WednesdaySpan 401,1191,214
Lecithin2,2382,429
Utilizabilitate9,6910,52
Glycerine monooleate2,1032,283
Glyceryltrinitrate21,8823,74
Castor oil40,6244,09

Drug gentamicin was tested on the model of the small intestine of rats and rectal rat model as described above (e.g., Example 4 and 5). Gentamicin were analyzed using immunoassay (ELISA). The results are presented below in table.9V; % bioavailability was calculated and compared with the/in the introduction�amount of force. Drugs demonstrated the ability to ensure the bioavailability of gentamicin.

Table 9B
CargoDrugROAN% bioavailability ± allowed deviation
Gentamicinas in table.9Asmall bowel612,9±4,5
as in table.9Arectal550,1±5,8

Similarly, the RNA product from the table.9A is tested on the model of the small intestine of rats and rectal rat model as described above. The PKK is analyzed and it is assumed that the drug provides bioavailability RNA.

Example 18: effect on the activity of the drug surfactant in a hydrophilic environment

Influence on the activity of the drug extracted surface-active substances from hydrophilic environment was tested using preparations containing dextran (average molecular weight = of 4.4 kDa FITC-labelled) as cargo (drugs A and N in table.3A).

<> Table.10 represents the data of a study on panettiruling rats after administration inside the small intestine drugs with or without a surfactant (such as Slano 40, lecithin, glycerin of monooleate) in a hydrophobic environment.

Table 10
CargoDrugSurfactants in a hydrophobic environmentN% absolute bioavailability ± allowed deviation
DextranAnd+1728,0±6,8
N-411,1±8,2

Drugs with or without surfactants in a hydrophobic environment were injected directly into the small intestine panettiruling rats and measured the levels of dextran in the plasma at 3, 6, 10, 25, 60 and 90 min after drug administration. The level of absorption of dextran in the small intestine of rats after administration of dextran in the product compared with the level of dextran absorbed after intravenous administration.

Determined exposure value, metrics, AUC(0-90), for insertion in a thin quiche�nick and intravenous and determined the absolute bioavailability according to the following equation:

absolute bioavailability = (AUC(0-90) for insertion into the small intestine)/(IV AUC (0-90))*(IV dose/dose introduction in the small intestine)

Data are presented as the mean absolute bioavailability ± allowed deviation

Smaller biodiscovery was achieved by inclusion of dextran in the preparation, not containing surfactants in a hydrophobic environment (preparation H), in comparison with a preparation containing a surfactant in a hydrophobic environment (the drug And). The results demonstrate that extraction of the hydrophobic environment of surfactants adversely affect the activity of the drug.

Example 19: effect on the activity of the drug extraction of fatty acids with medium chain length from the hydrophilic fraction

Impact on drug activity extraction of fatty acids with medium chain length (EXDC) from the hydrophilic fraction was tested using preparations containing dextran (average molecular weight = 4,4 kDa, FITC labeled) as cargo.

Table.11 presents the survey data on panettiruling rats after administration of drugs in the small intestine with or without octanoate of sodium in the hydrophilic fraction (drugs A and D in table.3A, respectively).

Cargo
Table 11
DrugEXDC in hydrophilic fractionN% absolute bioavailability + allowable deviation
DextranAnd+1728,0±6,8
D-50,6±1,0

The preparations described above, was injected directly into the small intestine panettiruling rats and at 3, 6, 10, 25, 60 and 90 min after the drug has measured the level of dextran in the plasma. The level of absorption of dextran in the small intestine of rats after administration of dextran in the mixture compared with the level of dextran absorbed after intravenous administration.

Determined exposure value, metrics, AUC (0-90), for insertion into the small intestine and for intravenous administration and the absolute bioavailability was determined according to the following equation:

absolute bioavailability = (AUC(0-90) for insertion into the small intestine)/(IV AUC(0-90))*(IV dose/dose introduction in the small intestine)

Data are presented as the mean absolute bioavailability ± allowed deviation.

Minor Prony�the novena dextran was achieved, when you turn on the dextran in the preparation of the lack of fatty acids with medium chain length at the hydrophilic fraction ((substance D, % absolute bioavailability = 0,6±1,0) in comparison with a preparation containing 12% of octanoate sodium in a weight ratio of the hydrophilic fraction (drug A, % absolute bioavailability = 28,0±6,8).

The results demonstrate that the drug without fatty acids with medium chain length at the hydrophilic fraction is not active.

A similar experiment was performed using octreotide as cargo in superior drug (see below). rBA was 0.11% (coefficient of variation = 158%)

Example 20: effect on the activity of the drug to simplification of the

Impact on drug activity simplify the composition was tested using a preparation containing dextran (average molecular weight = 4,4 kDa, FITC labeled) or octreotide (Novetide) as cargo. The main drug, as described in the example above (for example drugs, marked A, I and P) was simplified by the fact that they have not added MgCl2and 400 MS to a hydrophilic environment and not adding span 40, lecithin and isovaleric alcohol to hydrophobic environment. This leads to an increase in the number of glycerol monooleate (surfactants) and glyceryltrinitrate added to a hydrophobic environment. Such drugs are presented below in table.12A. These simplified compositions of n� show visible deposition, although the particles are visible with the microscope, that is, they are stable suspensions.

Table 12A
The drug, AFI IngredientDextran simplified (%, mass)Octreotide simplified (%, mass)
Hydrophilic fractionAPI0,5450,058
NaOH0,0010,000
MgCl20,0000,000
PVP-122,7352,750
Octanoate sodium12,00012,019
MS 4000,000,000
Water0,611By 0.593
Hydrophobic WednesdaySpan 400,000,000
�eciton 0,000,000
Utilizabilitate0,000,000
Glycerylmonostearate5,915,947
Glyceryltrinitrate34,1934,385
Castor oil44,0044,248

The manufacturing process of the above-mentioned simplified drugs substantially the same as described in Fig.1 and in Example 11 for the essential drugs. The main drug octreotide is presented below in table.12V.

Table 12B
Cargo Drug IngredientOctreotide main M (%, mass)
The hydrophilic fraction (HFP)Cargo0,058
NaOH0,000
MgCl20,137
PVP-122,742
Octanoate sodium12,003
MS 4000,137
Water0,603
Hydrophobic fraction (LPP)Span 401,215
Lecithin2,430
Utilizabilitate10,522
Glycerylmonostearate2,284
Glyceryltrinitrate23,756
Castor oil44,113

Table.13 represents the data of a study on panettiruling rats after administration inside the small intestine of two different preparations of dextran - drug And from table.3A and simplified drug are presented in table.12A

Table 13
CargoDrugNAUC (0-60 min)/dose/kg of body weight ± allowed deviation
DextranAnd (OS�IOD) 2867062±27368
Simplified1263897±24210

The above results show that similar AUC values were achieved, with the inclusion of dextran in the preparation containing basic drug (drug A) in comparison with the simplified preparation.

Table.14 below presents the survey data on panettiruling rats after administration in the small intestine of two different preparations of octreotide is the primary drug are shown in table.12V, simplified preparation is shown in table.12A. Detected the levels of absorption of octreotide in the small intestine of rats after administration of octreotide with the main drug and simplified drug.

Determine the values of the system contact, metrics AUC(0-25).

2,3±0,8
Table 14
CargoDrugNAUC (0-25 min)/dose/kg of body weight ± allowed deviation
OctreotideMain132,8±1,4
Simplified13

Presented in table.14 the results show that the AUC values were slightly less than for the inclusion of octreotide in simplified drug, in comparison with the full drug.

Example 21: effect on the activity of the drug substitution castor oil octanoic acid

Impact on drug activity replacement of castor oil (and glyceryltrinitrate and utilizability) octanoic acid (Aldritch) was tested using a preparation containing dextran as cargo. This was done to maintain the C8 fragment in the product, i.e. it was assumed that the presence of C8 acid in a hydrophobic environment in addition to S8 of salt in the hydrophilic fraction can be favorable.

Effect of addition of ricinoleic acid (Spectrum) was also tested with the manufacture of the drug dextran containing octanoic acid/ricinoleic acid. Ricinolein acid was chosen as the main component of triglyceride in castor oil is formed from ricinoleic acid. Three drugs dextran were prepared as shown below in table.15A. The main drug of dextran was prepared mainly as described in the example above. Dextran octane of the drug was prepared mainly as described in the example above, but castor oil, glycerides�Tirat and utilizabilitate were substituted octanoic acid. This drug is visually represented the solution, but the true tests of solubility was carried out. Apparently, octanoic acid in high concentration (about 78% of the drug) solid dissolves hydrophilic fraction, with PVP and octanoate sodium dissolved in octanoic acid at high concentration. Dextran preparation of ricinoleic/octanoic acid was prepared mainly as described in the example above, but castor oil, glyceryltrinitrate and utilizabilitate replaced with a mixture of octane and ricinoleic acids. The drug was introduced a suspension, like most drugs of the invention.

Table 15A
The drug, AFI IngredientThe main dextran (%, mass)Dextran octanoic acid (%, mass)Dextran ricinoleate and/octanoic acid (%, mass)
Hydrophilic fractionAPI0,5450,5450,545
NaOH0,0010,0010,001
MgCl20,1360,1360,136
PVP-122,7262,7262,726
Octanoate sodium12,00112,00212,002
MS 4000,1360,1360,136
Water0,6220,6220,622
Hydrophobic WednesdaySpan 401,2081,2071,207
Lecithin2,4162,4142,414
Utilizabilitate10,460,000,00
Glycerine monooleate2,2712,2722,272
Glyceryltrinitrate23,620,00 0,00
Castor oil43,860,000,00
Octanoic acid0,00077,9423,38
Ricinolein acid0,0000,0046,76
Ethyl octanoate0,0000,007,80

The drugs described above in table.15A was injected directly into the small intestine panettiruling rats, and the levels of dextran in the plasma was measured after administration of the drug. Exposure number, the AUC parameters were determined for different drugs. These results are presented below in table.15V.

Table 15B
CargoDrugNAUC (0-60)/dose/kg of body weight ± allowed deviation
DextranMain1272385±37827
Octane�Vaya acid 11180824±32778
Ricinolein/Octanoic acid11113204±33057

The results are shown in table.15V above, demonstrate that the absorption of dextran significantly increased (more than doubled) in the preparation containing octanoic acid. In addition, the appearance of the charts was changed, showing a slower but more prolonged secretion. This can be an advantage, since it provides a more long-term effect of the API in the body. Indicators of ricinoleic/octane dextran showed less activity than the drug octane acid, but were still improved compared to the main drug.

As octanoic acid and preparations of ricinoleic acid/octanoic acid showed high activity, similar preparations were made with ecstatica as cargo. Three-drug ecstatica were produced, as shown below in table.16A. Basic drug ecstatica was made mainly as described in the examples above. Drug ecstatica/octanoic acid were prepared mainly as described above, but with the substitution in them of castor oil, glyceryltrinitrate and utilizability octanoic acid. This drug containing b�than 78% octanoic acid, visually represented the solution, such as the preparation of dextran, as described above, Preparations of ecstatica ricinoleic/octanoic acid were prepared mainly as described above, but with the substitution in them of castor oil, glyceryltrinitrate and utilizability octane and ricinoleic acids.

Ricinolein acid
Table 16A
The AFI formula IngredientAccented base (%, mass)Ecstatic Octanoic acid (%, mass)Ecstatic Ricinolein n/octanoic acid (%, mass)
Hydrophilic fractionAPI0,0550,0550,055
NaOH0,0000,0000,000
MgCl20,1370,1370,137
PVP-122,7422,7422,742
Octanoate sodium 12,00312,00312,003
MS 4000,1370,1370,137
Water0,6030,6030,603
Hydrophobic WednesdaySpan 401,2131,2141,214
Lecithin2,4342,4292,429
Utilizabilitate10,5220,0000,000
Glycerylmonostearate2,2832,2852,285
Glyceryltrinitrate23,7590,0000,000
Castor oil44,1120,0000,000
Octanoic acid0,00078,39547,035
0,0000,00023,518
Ethyl octanoate0,0000.0007,842

The drugs described in table.16A above, was injected directly into the small intestine nearestterminal rats and after administration of the drug was measured the levels of ecstatica in the plasma. Defined system contact, AUC parameters for different drugs. These results are shown below in table.16B.

Table 16B
CargoDrugNAUC(0-90) ± allowed deviation% bioavailability ± allowed deviation
EcstaticMain101961±17918,8±8,2
Octanoic acid11612±350 [AUC(0-180) ± allowed deviation]3,1±1,8
Ricinolein/octanoic acid 9476±3212,2±1,5

The results presented above in table.16 To demonstrate that the drug ecstatica containing octanoic acid, showed the bioavailability, but the absorption of ecstatica was reduced compared with the baseline drug. The appearance of the charts was changed, showing a slower, but longer release, as in the case of the preparation of dextran octanoic acid described above; this prolonged pharmacokinetic profile may be favorable. Note that in the case of drug octanoic acid, AUC 0-180 min was used for calculations of bioavailability due to prolonged pharmacokinetic profile. Drug ecstatic ricinoleic/octanoic acid has a lower bioavailability than the drug octanoic acid.

Example 22: a dose-dependent response to octanoic acid

A. Octreotide drugs: impact on drug activity change in the number of octanoic acid was tested using preparations containing octreotide, as cargo. Four of the drug octreotide were prepared using 0%, 5%, 10% or 15% octanoic acid, as shown below in table 17... Drugs are the basic preparations of octreotide, mostly cooked as described above, in which the octane number of sour�s varies, as described, and quantity. Other ingredients in a hydrophobic environment (utilizabilitate and glyceryltrinitrate) was correspondingly reduced (In these drugs hydrophilic fraction has been simplified with the exception of MgCl2and 400 MS)

Table 17
The drug, AFI IngredientOctreotide 0% octane (%, mass)Octreotide 5% octane (%, mass)Octreotide 10% octane (%, mass)Octreotide 15% octane (%, mass)
Hydrophilic fractionAPI0,0580,0570,0570,057
PVP-122,7502,7502,7502,750
Octanoate sodium12,01912,03412,03412,034
WaterBy 0.5930,5940,5940,594
Hydrophobic WednesdaySpan 401,2171,2191,2191,219
Lecithin2,4412,4372,4372,437
Utilizabilitate10,554000
Octanoic acid05,05310,55315,021
Glycerylmonostearate2,2902,2912,2912,291
Glyceryltrinitrate23,83229,32523,82519,357
Castor oil44,24644,24144,24144,241

V. Drug ecstatica: impact on drug activity change in the number of octanoic acid was tested� with the use of the drug, containing ecstatic as cargo. 5 specimens of ecstatica were prepared with the use of 0%, 10%, 15%, 20% or 35% octanoic acid, as shown below in table.18. Drugs which is the basic form of ecstatica, prepared substantially as described above, where the number of octanoic acid ranges, as described, and a number of other ingredients in a hydrophobic environment (utilizabilitate and glyceryltrinitrate) was correspondingly reduced.

2,742
Table 18
The drug, AFI IngredientEcstatic 0% octane (%, mass)Ecstatic 10% octane (%, mass)Ecstatic 15% octane (%, mass)Ecstatic 20% octane (%, mass)
Hydrophilic fractionAPI0,0550,0550,0550,055
MgCl20,1370,1370,1370,137
PVP-122,7422,7422,742
Octanoate sodium12,00312,00312,00312,003
MS 4000,1370,1370,1370,137
Water0,6030,6030,6030,603
Hydrophobic WednesdaySpan 401,2131,2131,2131,213
Lecithin2,4342,4342,4342,434
Utilizabilitate10,522000
Octanoic acid010,52215,08120,085
Glycerylmonostearate2,2832,283 2,2832,283
Glyceryltrinitrate23,75923,75919,20114,197
Castor oil44,11244,11244,11244,112

The drugs described above in table.17 and 18, were directly injected into the small intestine nearestterminal rats, and plasma levels of octreotide and ecstatica was measured after administration of the composition. Exposure number, the AUC parameters were determined for different drugs. These results are shown below in table.19.

Table 19
CargoFormulaNAUC (0-60)/dose/kg of body weight ± allowed deviation
OctreotideBasic142,8±1,0
Basic 5% octanoic acid122,7±1,2
Base 10% octanoic acid1 3,2±1,2
Base 15% octanoic acid124,5±2,3
AccentedBasic103,9±3,8
Basic, 10% octanoic acid154,6±2,8
Basic, 15% octanoic acid63,0±1,8
Basic, 20% octanoic acid52,2±0,5
Base, 35% octanoic acid61,9±0,7

The results presented above in table.19 demonstrate that the drug octreotide shows increased activity compared to the main drug, if you increase the octane number of acid up to 15% (the maximum tested number). In addition, the results shown in table.19 demonstrate that the drug ecstatica shows increased activity in comparison with the basic formula, when the number of octanoic acid to 15%,with higher levels of octanoic acid activity decreased..

A. the Sodium salt sabatinovka acid (disodium salt octadecanoic acid): it was tested the influence on the activity of the drug substitution octanoate sodium sebacinales sodium (disodium 10 salt) in the preparation of dextran. Sebacate sodium was prepared in situ from sabatinovka acid (Aldrich) and sodium hydroxide. Produced by the drug described in table.20 below. The drug was mainly cooked, as described above, but 12% octanoate sodium was replaced by sebacinales sodium, with the same molar concentration of octanoate sodium, i.e., it was used an equimolar amount of sebacina sodium (namely, 0,72 M).

Table 20
The drug, AFI IngredientDextran Na-sebacate (%, mass)
Hydrophilic fractionAPI0,545
NaOH0,000
MgCl20,129
PVP-122,589
Sebacate sodium16,190
MS 4000,129
Water0,783
Hydrophobic WednesdaySpan 401,147
Lecithin2,295
Utilizabilitate9,94
Glycerylmonostearate2,157
Glyceryltrinitrate22,44
Castor oil41,66

The drug described above in table.20, was injected directly into the small intestine is not anesthetized rats, after administration of the drug was measured by the dextran levels in plasma. Exposure value, the AUC parameters were determined for the drug and compared with similar preparations made with octanoate sodium. These results are shown below in table.21.

Table 21
CargoDrugNAUC (0-60)/dose/kg of body weight ± allowed deviation
DextranWith Na-octanoate 1272385±37827
With Na-sebacinales918691±11887

The results shown in table.21 demonstrate that the drug dextran containing sodium sebacate, showed activity, but the absorption of dextran in comparison with a preparation containing an equimolar amount of octanoate sodium was reduced.

V. Monolatry suberate or denetria subert: octreotide-containing drugs were prepared with substitution of 12% of octanoate of equimolar amounts of sodium (0,72 M) monolatry of suberate or denetria of suberate, which are salts of C8. These sodium salts were prepared in situ from subernova acid (Tokyo Chemical Industry Co.) and sodium hydroxide.

Table 22A
The drug, AFI IngredientOctreotide of moonacre suberate (0,72 M) (%, mass)Octreotide, denetria suberate (0,72 M) (%, mass)
Hydrophilic fractionAPI0,0580,059
PVP-122,6502,620
Monolatry subert15,0870
Denetria subert015,996
Water0,7120,747
Hydrophobic WednesdaySpan 401,1731,159
Lecithin2,3522,325
Utilizabilitate10,16910,055
Glycerylmonostearate2,2062,181
Glyceryltrinitrate22,96222,704
Castor oil42,63242,152

The drugs described above in table.22, are introduced directly into the small intestine nearestterminal rats, and the levels of octreotide in plasma are measured after administration of the drug. Exposure value, the AUC parameters are defined for drugs, and compared with a similar drug made with octanoate sodium.

S. Salt sour geranium�s.

Two octreotide-containing drug were prepared as described above, in which 12% of octanoate sodium was replaced the 18% sodium salt of geranium acid (0.95 M) and 14.6% (0,77 M) sodium salt geranium acid, which is 3,7-dimethyl-2,6-octadienal acid (obtained from SAFC). Made the preparations described in table.22V below.

Table 22B
The drug, AFI IngredientOctreotide Na Gernat A (%, mass)Octreotide Na Gernat (%, mass)
Hydrophilic fractionAPI0,0570,057
NaOH00,543
PVP 1210,0069,833
Gernat sodium18,05314,625
Water1,1831,084
Hydrophobic WednesdayTween 802,0011,970
Glycerylmonostearate4,0013,923
Glyceryltrinitrate63,23565,927
Castor oil0,0000

The drugs described above in table.22V, was injected directly into the small intestine panettiruling rats, and the levels of octreotide in plasma was measured after administration of the drug. Exposure number, the AUC parameters were determined for preparations and compared with similar preparations made with octanoate sodium. The results are presented in table.22C below and demonstrate that the drug 18% geranate sodium had the same activity as the drug, with 12% of octanoate sodium, and drug, with 14.6% geranate sodium had increased activity.

Table 22C
CargoDrugNA AUC (0-60)/dose/kg of body weight ± allowed deviation
OctreotideGernat sodium And94,48±1,79
GE�Anat sodium 96,33±2,1
Improved94,38+1,66

Example 24: effect of polyvinylpyrrolidone on the activity of the drug

Influence on the activity of the drug replacing PVP-12 mannitol (Sigma) was tested using preparations containing ecstatic as cargo. It was clear that PVP-12 is a stabilizer and could be replaced in the product by another stabilizer such as mannitol is a Drug that is presented in the table.23 below, was prepared This drug is a basic drug ecstatica, mostly cooked as described above, but it is PVP-12 replaced by mannitol.

Table 23
The drug, AFI IngredientEcstatic mannitol (%, mass)
Hydrophilic fractionAPI0,055
MgCl20,137
Mannitol2,742
Octanoate sodium12,003
MS 4000,137
Water0,603
Hydrophobic WednesdaySpan 401,213
Lecithin2,434
Utilizabilitate10,522
Glycerylmonostearate2,283
Glyceryltrinitrate23,759
Castor oil44,112

The drug described above in table.23, were injected directly into the small intestine panettiruling rats, and the levels of octreotide in plasma was measured after administration of the drug. Exposure number, the AUC parameters were determined for preparations and compared with the main drug. These results are presented below in table.24

Table 24
CargoDrugNAUC (0-60)/dose/kg of body weight ± allowed deviation
Ecstatic103,9±3,8
Mannitol is PVP-1261,6±1,7

The results shown above in table.24, demonstrate the surprising and unexpected result that the activity of the drug ecstatica without PVP-12 significantly decreased in comparison with the main drug. It was decided therefore to investigate the effect of PVP on the bioavailability.

Influence on the activity of the drug changes the molecular weight of PVP was tested using preparations containing ecstatic as cargo. 3 drug ecstatica were prepared using PVP-12, PVP-17 or PVP-25 (all obtained from BASF). All products: PVP-12, PVP 17 and PVP-25 polymers are polyvinylpyrrolidone; average molecular weight of approximately 2500-3000, 10000 and 30000 respectively. Drugs are the main drugs of ecstatica, mostly cooked as described above, where PVP varies as described and in which the hydrophilic fraction has been simplified by neglect of MgCl2and 400 MS.

Table 25

The drug, AFI IngredientEcstatic PVP 12/17/25 (%, mass)
Hydrophilic fractionAPI0,022
PVP 12/17/252,752
Octanoate sodium12,005
Water0,602
Hydrophobic WednesdaySpan 401,218
Lecithin2,442
Utilizabilitate10,561
Glycerylmonostearate2,291
Glyceryltrinitrate23,846
Castor oil44,272

Three of the drug described above in table.25, was injected directly into the small intestine is not anesthetized rats, and the levels of ecstatica in the plasma was measured after administration of the drug. For drugs was determined exposure value, the AUC parameters. The results are presented below in table.26.

Table 26
CargoDrugNAUC (0-60)/dose/kg of body weight ± allowed deviation
EcstaticPVP-12118,0±7,7
PVP-1763,4±2,9
PVP-2552,6±2,3

The results presented above in table.26, show that the drugs ecstatica containing PVP-12 exhibit much greater activity than the drugs ecstatica containing PVP-17 and PVP-25. Thus, only the influence of PVP-12 was investigated further and it was decided to conduct a study of the dose-dependent response, with the use of PVP-12. The effect of increasing the amount of PVP-12 in the drug on the activity of the drug was tested using preparations containing octreotide, as a mixture of cargo and different doses of PVP-12, as shown in table.27 below. Tested GTWP-12 dose was 2,75% (standard dose, which is used in the preparations above) and 5.0%, and 7.5% and 10.0% PVP-12; hydrophilic fraction has been simplified by neglect of MgCl2and 400 MS. Preparation containing 10% PVP was semisolid, �.e.was a visible semi-liquid slurry.

Table 27
The drug, AFI IngredientOctreotide PVP 2,75% (%, mass)Octreotide PVP 5,0% (%, mass)Octreotide PVP 7,5 % (%, mass)Octreotide PVP 10,0% (%, mass)
Hydrophilic fractionAPI0,0580,0570,0570,057
PVP-122,7505,0137,51410,046
Octanoate sodium12,01912,03112,03712,018
WaterBy 0.5930,6840,7840,885
Hydrophobic WednesdaySpan 401,2171,1831,1451,108
Lecithin 2,4412,3732,2972,222
Utilizabilitate10,55410,2599,9349,608
Glycerylmonostearate2,2902,2262,1552,084
Glyceryltrinitrate23,83223,16622,43121,694
Castor oil44,24643,00941,64540,278

The drugs described above in table.27, was injected directly into the small intestine nearestterminal rats, and the levels of octreotide in plasma was measured after administration of the drug. For four different preparations was determined exposure value, the AUC parameters. The results are presented below in table.28A.

Table 28A
CargoDrugN AUC (0-60)/dose/kg of body weight ± allowed deviation
Octreotide2,75% PVP-12142,8±1,0
5,0% PVP-12123,7±1,6
A 7.5% PVP-12124,2±1,5
Of 10.0% PVP-12114,7±1,4

The results shown above in table 28A, demonstrate that the absorption of octreotide dramatically increased when the drug increases the amount of PVP. Preparation containing 10% PVP-12, absorbed octreotide 1.7 times more than the drug containing 2,75% PVP-12. Improved preparation of octreotide, which was 10% PVP-12, but there was no octanoate sodium, almost did not show activity rBA was 0.11% (CV=158%) n=5

Apparently, salt of fatty acids with medium chain length acts as a permeable amplifier (via a relief or increased permeability and/or absorption of therapeutic agent), and that PVP serves to increase the influence of permeable amplifier in a synergistic manner, as one PVP actually has no effect see also example 31.

Further experimental� was conducted to investigate the possibility of substitution of 10% PVP-12 dextran with preservation of activity of the drug Dextran produced by Fluka, the average molecular weight of approximately 6000. Drugs were prepared mainly as described above, PVP and dextran varied, as described, the hydrophilic fraction has been simplified with the exception of MgCl2and 400 MS and the number of octanoate sodium was increased to 15%, see also example 16

Table 28B
The drug, AFI IngredientOctreotide 10% PVP (%, mass)Octreotide 10% Dextran; not PVP (%, mass)Octreotide 5% Dextran; not PVP (%, mass)
Hydrophilic fractionAPI0,0580,0580,058
PVP-1210,0110,00,0
Dextran0,010,0115,011
Octanoate sodium15,00815,00815,015
Water 1,0031,0030,803
Hydrophobic WednesdayTween 802,0272,0272,169
Glyceryl monocaprylin4,0364,0364,319
Glyceryltrinitrate40,71440,71443,574
Castor oil27,14327,14329,049

Three of the drug described above in table.28B, was injected directly into the small intestine is not anesthetized rats, and the levels of octreotide in plasma was measured after administration of the drug. For preparations was determined exposure value, the AUC parameters. The results are presented below in table.28C.

Table 28C
CargoDrugNAUC (0-25)/dose/kg of body weight ± allowed deviation
Octreotide 10% Dextran94,4±1,7
10% Dextran; not PVP53,3±1,6
5% Dextran; not PVP93,2±1,5

The results presented in table.28C demonstrate that the absorption of octreotide decreased when PVP in the product was replaced by dextran, but the activity was still significant. Preparation containing 10% dextran absorbed about 75% of the drug containing 10% PVP, and the preparation containing 5% dextran, absorbed about 73% of the drug octreotide containing 10% PVP.

Example 25: a comparative study of C8, C9, and C10 salts of fatty acid chains of medium length, namely octanoate sodium, nonanoate sodium and sodium decanoate

Influence on the activity of the drug substitution octanoate other sodium salts of fatty acids sodium with a chain of medium length was tested using preparations containing octreotide as cargo.

Were cooked 3 of the drug octreotide, as shown below in table.29. All major drugs was mainly cooked as described above, where the hydrophilic fraction has been simplified with the exception of MgCl2and 400 MS and in which the salt of a fatty acid with a chain of medium length is equimolar to�iCustom of octanoate sodium, nonanoate sodium or sodium decanoate.

Table 29
The drug, AFI IngredientOctreotide NaC8 12% (0,72 M) (%, mass)Octreotide NaC9 13% (0,72 M) (%, mass)Octreotide NaCIO 14% (0,72 M) (%, mass)
API0,0580,0570,058
PVP-122,7502,7182,685
Octanoate sodium12,01900
Nonanoate sodium013,0230
The sodium decanoate0014,019
WaterBy 0.5930,6320,670
Hydrophobic WednesdaySpan 401,217 1,2031,188
Lecithin2,4412,4122,383
Utilizabilitate10,55410,42810,303
Glycerylmonostearate2,2902,262Was 2,235
Glyceryltrinitrate23,83223,54723,265
Castor oil44,24643,71843,194

The drugs described above in table.29, was injected directly into the small intestine nearestterminal rats, and the levels of octreotide in plasma was measured after administration of the drug. For drugs was determined exposure value, the AUC parameters. The results are presented below in table.30.

Table 30
CargoDrugNAUC (0-25)/dose/kg of body weight ± allowed deviation
Octreotide
Octanoate sodium NaC892,1±0,8
Nonanoate sodium NaC9102,5±0,4
Decanoate sodium NaC10101,7±0,4

The results presented above in table.30 demonstrates that the substitution of octanoate sodium drug nonanoate sodium or sodium decanoate remained the same activity. Based on statistical analyses, there is no difference in activity between all three drugs.

Example 26: dose-dependent effect of octanoate sodium

Dose-dependent effect of octanoate sodium, with 12%, 15% and 18% had been tested through the preparation of drugs shown in table.31. All major drugs are prepared mainly as described above, in which the hydrophilic fraction has been simplified with the exception of MgCl2and 400 MS and cargo was octreotide. In addition, the corrected viscosity of the drug, i.e., equal or similar viscosity was maintained for all three drugs; what has been achieved by varying the amount of castor oil and glyceryltrinitrate.

Table�CA 31
The drug, AFI IngredientOctreotide NaC8 12% (%wt)Octreotide NaC8 15% (%wt)Octreotide NaC8 18% (%wt)
The hydrophilic fraction (simplified)API0,0580,0580,058
PVP-122,7502,652Sector (2.554
Octanoate sodium12,01915,04018,016
WaterBy 0.5930,7100,825
Hydrophobic WednesdaySpan 401,2171,1731,130
Lecithin2,4412,3532,267
Utilizabilitate10,55410,1759,802
Glycerylmonostearate 2,2902,2072,126
Glyceryltrinitrate23,83232,81641,090
Castor oil44,24632,81622,132

The drugs described above in table.31, was injected directly into the small intestine is not anesthetized rats, and the levels of octreotide in plasma was measured after administration of the drug. For preparations was determined exposure value, the AUC parameters. The results are presented below in table.32.

Table 32
CargoDrugNAUC (0-60)/dose/kg of body weight ± allowed deviation
OctreotideNaC8 12%142,8±1,0
NaC8 15%124,1±1,9
NaC8 18%123,6±1,1

The results presented above in table.32 exhibit h�about increasing the number of octanoate sodium from 12% to 15%, occurs and the increase in activity, but further increase in the number of octanoate sodium to 18% does not lead to further increase in activity, more than that achieved at 15%. Thus, the number of octanoate sodium about 15% is preferred.

Example 27: the influence of changes in hydrophilic/lipophilic balance of surfactants in the product

Table. 33 below describes the various preparations of octreotide. The first column, the drug(a) is the main drug made mostly as described above, in which the hydrophilic fraction has been simplified with the exception of MgCl2and 400 MS, and cargo represented by octreotide. Surfactant - span 40, lecithin and glycerine monooleate, and when calculating the HLB of approximately 5-6. In other preparations (preparations b, C and d) HLB has changed how the display (up to 3.5; 6.7 and 14) substitution of span 40 and lecithin different amounts of tween 80 and by varying the number of glycerylmonostearate.

Table 33
The drug, AFI IngredientOctreotide HLB 5-6 [a] (%, mass)Octreotide HLB of 3.5 [b] (%, mass)Octreotide HLB of 6.7 [c] (%, mass)Octreotide HLB 14 d] (%, mass)
Hydrophilic fractionAPI0,0580,0570,0570,057
PVP-122,7502,7482,7482,748
Octanoate sodium12,01912,02712,02712,027
WaterBy 0.5930,5940,5940,594
Hydrophobic WednesdaySpan 401,217000
Lecithin2,441000
Utilizabilitate10,55410,54710,54610,547
Tween 8000,502 2,0035,500
Glycerine monooleate2,2905,5004,0020,502
Glyceryltrinitrate23,83223,81123,81123,811
Castor oil44,24644,21544,21544,215

The drugs described above in table.33, was injected directly into the small intestine nearestterminal rats, and the levels of octreotide in plasma was measured after administration of the drug. For drugs was determined exposure value, the AUC parameters. The results are presented below in table.34.

Table 34
CargoDrugNAUC (0-25)/dose/kg of body weight ± allowed deviation
HLB 5-6 [a]92,1±0,8
HLB 3,5 - [b]12 3,3±0,9
HLB of 6.7 [s]113,8±0,9
HLB 14 - [d]103,7±0,9

The results are shown in table.34 demonstrate that all 3 new drug that replaces span 40 and lecithin on tween 80 [b, c, and d] had the best activity what is the drug [and] even if HLB in [b] below, and [with] was slightly higher and [d] was much higher than the HLB of the surfactant in (a). In addition, activity of all new drugs [(b, C, and d] were statistically very similar. Thus, only HLB of all surfactants, apparently, does not affect the activity, but it is possible that the properties of the surfactants play an important role. In particular, the replacement of span 40 and lecithin on tween 80 is favorable for activity of these preparations of octreotide.

Example 28: Preparation of octreotide with different ratios of glyceryltrinitrate to castor oil

Based on the accumulated results, described above, which include the results of the ETA-12 dose-dependent effect and the results for surfactants among others, a series of preparations of octreotide were prepared using a 10% PVP-12 and 15% of octanoate sodium and varying relations of glyceryltrinitrate to�strovolou oil. In addition, glycerylmonostearate and glyceryltrinitrate replaced (if used) glycerylmonostearate and glyceryltrinitrate (both purchased from Abitec). It is necessary to preserve C8 motive in the composition. Thus, the hydrophilic fraction contains salt of C8 acid (octanoate) and the hydrophobic medium contains monoglycerides and triglycerides, including the same C8 acid. The inventors believe that the use of C8 compounds in the hydrophilic fraction and the hydrophobic medium may contribute to bioavailability. The number of tween 80 and glycerylmonostearate also varied in the drug. The drugs were prepared as shown in table.35A below. Drugs I, II, V and VI were semi (undoubtedly, suspensions) and preparations III and IV were conventional liquid suspensions.

Table 35A
The drug, AFI ingredientOctreotide I (%, mass)Octreotide II (%, mass)Octreotide III%, mass)Octreotide IV(%, mass)Octreotide V (%, massOctreotide VI (%, mass)
Hydrophilic fractionAPI 0,0580,0580,0580,0580,0580,058
PVP-1210,01110,01110,01110,01110,01110,011
Octanoate sodium15,00815,00815,00815,00815,00815,008
Water1,0031,0031,0031,0031,0031,003
Hydrophobic WednesdayTween 802,0272,0272,0272,0276,0636,062
Glycerol monocaprylin4,0364,0364,0364,0360 0
Literitica-
Pilat
40,71413,57161,07167,85740,7140
Castor oil27,14354,2866,7860,00027,14367,857

The drugs described above in table.35A, were injected directly into the small intestine is not anesthetized rats, and the levels of octreotide in plasma was measured after administration of the drug. For compositions were determined exposure AUC value. The results are presented below in table.35B.

Table 35B
CargoDrugNAUC (0-25)/dose/kg of body weight ± allowed deviation
OctreotideThe drug I (glyceryltrinitrate/castor oil 6:4)94,4±1,7
Preparation II (glyceryltrinitrate/castor oil 2:8) 83,0±1,7
Preparation III (glyceryltrinitrate/castor oil 9:1)93,1±0,5
Drug IV (glyceryltrinitrate/castor oil, 10:0)74,1±2,1
The V drug - without glycerylmonostearate (glyceryltrinitrate/castor oil, 6:4)61,6±1,0
Preparation VI - without71,1±0,6
glycerylmonostearate and glyceryltrinitrate (glyceryltrinitrate/castor oil, 0:10)

The results presented above in table.35B show that the drugs I and IV have the greatest activity. Since castor oil is not available in part IV, it is shown that castor oil is not essential for activity.

Probably a high ratio glyceryltrinitrate: castor oil, for example, 6:4 is preferred from the viewpoint of activity. In addition, as the composition of V (which has low activity) has the same ratio glyceryltrinitrate/Casteau�new oil, that and composition I, this implies that additional glycerylmonostearate (or monoglyceride) is preferred from the viewpoint of activity. In addition, a composition was prepared similar to the preparation of the I table.36, but octanoate sodium expelled. This structure is not actually active, HBs=0,1%. Bulk drug product drug IV (improved, without castor oil) was ground using a 150 micron sieve, and, further, the particle size was determined with the use of laser diffraction Malvern. Preliminary results indicate that 90% (V / V) of particles had a size less than 130 microns, and 50% (V / V) of the particles were less than 45 microns. Preliminary experiments with the use of such compositions to the drug I, but with a variation of increasing amounts of octreotide, all showed similar biological activity, i.e. it was approximately independent linear exposition of the load API. A preliminary experiment using a similar drug to the IV drug under the higher load of octreotide - 1.5% (in weight ratio) also gave similar biological activity.

Similar improved composition for the above preparation I prepared using PD4 as cargo, instead of octreotide, and were compared with the basic composition. These drugs are given in tab.36A no�E.

Table 36A
The AFI drug ingredientFD4 core (without Mg, MS) (%, mass)FD4 improved (%, mass)
Hydrophilic fractionAPI0,5450,545
NaOH0,0010
PVP-122,73410,012
Octanoate sodium12,03615,009
water0,6131,023
Hydrophobic WednesdayTween 800These patients is 2.013
Glycerylmonostearate04,008
Glyceryltrinitrate040,434
Span 401,210
Lecithin2,420
Utilizabilitate10,490
Glycerylmonostearate2,280
Glyceryltrinitrate23,690
Castor oil43,9826,956

The drugs described above in table.36A, were injected directly into the small intestine is not anesthetized rats, and FD4 levels in plasma were measured after administration of the drug. For compositions were determined exposure AUC value. The results are presented below in table.36V.

Table 36V
CargoDrugNAUC (0-90)/dose/kg of body weight ± allowed deviation
DF4 (dextran)Main667448±16977
Improved695374±47490

the Results presented above in table.36V, demonstrate that the improved composition has significantly greater activity than the basic structure.

Example 29: a Detailed process of producing for breeding (improvement) of the drug octreotide

The drug octreotide in Example 28 (table.6, first column) was mainly cooked as described in the Examples above. Following is a detailed description of the process to obtain this drug.

Obtaining hydrophilic fractions: To 150 ml of water was slowly added and mixed the following ingredients: is 24.05 g of octanoate sodium, 16,04 g of PVP-12 and 92,4 g 10 mg/ml aqueous solution of octreotide. The resulting solution liofilizirovanny.

Obtaining a hydrophilic environment:

3.25 g tween 80, 6,47 g glycerylmonostearate, 65,25 g glyceryltrinitrate and of 43.50 g of castor oil were mixed together.

Receive bulk drug product:

To 26.08 g of hydrophilic fraction was slowly added to 73,92 g hydrophobic environment at 20±2°C with stirring. After all of the hydrophilic fraction, the mixing speed was increased. Then applied the vacuum degassing and the resulting suspension was stored at 2-8°C. To allow dissolution of large quantities of octreotide, have developed the following method:

1. The amount of water the hydrophilic fraction of the drug was the same as the calculated final volume neras�savannaha medicinal product.

2. PVP-12 was dissolved in half the quantity above water.

3. Octanoate sodium was dissolved in the second half of the amount of water.

4. Octreotide was dissolved in PVP-12 solution (from section 2).

5. A solution of octanoate sodium was added to a solution of octreotide and PVP-12.

At this stage fell a little aftertaste, but it was dissolved after stirring.

Example 30: Experiments on pigs using capsules

To test the activity of the compositions according to the invention, when administered capsules, was established animal model that allowed them to enter the capsule to the hogs (domestic swine). In order to bypass the stomach and allow easy introduction of capsules in the small intestine of a pig, is well proven model in dogs ("Nipple Valve model"; Wilsson-Rahmberg & O. Jonsson, Laboratory Animals (1997), 31, 231-240) adapted to the industrial pig.

Cooked two of the drug octreotide, are shown below in table.37. The drug octreotide (x) were prepared directly as described above for the primary drug, in which the hydrophilic fraction has been simplified with the exception of MgCl2and MS. The drug octreotide (y) was prepared directly as described above for improved drug octreotide. The preparations were placed in gelatin capsules (Capsugel), the main drug (x) of 0.42 ml per capsule and superior product (I) of 0.44 ml per capsule, which leads to 5 mg net keeped�I octreotide in both types of filled capsules.

Capsules were coated with enteric coating, i.e. they were not covered.

Table 37
The drug is AFI, ingredientOctreotide (x) main (%, mass)Octreotide () improved (%, mass)
Hydrophilic fractionAPI1,3571,277
PVP-122,71710,011
Octanoate sodium12,01115,008
Water0,6431,052
Hydrophobic WednesdayTween 8001,992
Glycerylmonostearate03,967
Glyceryltrinitrate040,016
Castor oil43,56226,677/td>
Span 401,1980
Lecithin2,4030
Utilizabilitate10,3910
Glycerylmonostearate2,2540
Glyceryltrinitrate23,4630

The drugs described in table.37 above, were injected directly into the small intestine is not anesthetized pigs using bypass gastric bypass described above, and levels of octreotide in plasma was measured after administration of the drug. For compositions were determined the values of the system contact the AUC. The percentage of BA was calculated by comparison with the system contact of octreotide after subcutaneous injection. The results are presented below in table.8.

Table 38
CargoDrugNAUC (0-240) ± allowed deviation% BA ± allowed deviation
Octreotide Octreotide (x)4896±3052,1±0,7
Octreotide ()42574±8896,2±2,1

The results presented in table.36 In the above, show that in a model pig has a biological activity for encapsulated formulations, for both base and improved formulations. Biological activity enhanced drug octreotide was approximately 3 times higher than the level of biological activity of the main drug.

The results obtained for bioavailability to be underestimated, because the sampling time is not enough for what would be the level of octreotide returned to baseline (0 ng/ml). This was associated with a longer waiting time exposure in pigs in comparison with that previously measured in rats. The shape of the graph changed compared with the results obtained from rats, indicating a longer time to achieve the maximum level of the peak and extended period of time in which octreotide is constantly present in the blood. This can be useful, since it allows octreotide long-acting in the body. Thus, the actual bioavailability in pigs should be in�more than the resulting number.

Based on the results obtained from the rats, the level of bioavailability of octreotide in pigs, introduced in aqueous solution, extrapolated to a value of about 0.1%. This level of bioavailability below the level of sensitivity of bioassays, which are used for pigs.

Example 31: results of a dose-dependent effect for PVP in the superior composition

In addition to PVP results in Example 24, investigated the effect on the activity of increasing the amount of PVP-12 in the superior part. Improved preparations made primarily as described above, contained octreotide as cargo, and different doses of PVP-12, as presented in table.39 below. Tested PVP with 12 doses of 7.5%, 10% and 15% PVP-12. Products containing 10% and 15% PVP were semi-fluid, that is, they were, undoubtedly, semi-liquid suspensions, and the drug containing 7.5% PVP was a viscous suspension.

Table 39
The AFI drug ingredientOctreotide PVP 7,5% (%, mass)Octreotide PVP 10,0% (%, mass)Octreotide PVP 15,0% (%, mass)
Hydrophilic fractionAPI 0,0580,0580,058
PVP-127,50610,01115,009
Octanoate sodium15,01215,00815,009
Water0,9031,0031,203
Hydrophobic WednesdayTWEEN 802,0982,0271,884
Glycerylmonostearate4,1784,0363,752
Glyceryltrinitrate42,14740,71437,851
Castor oil28,09827,14322,234

The drugs described above in table.39, were injected directly into the small intestine is not anesthetized rats and the levels of octreotide in plasma was measured after administration of the drug. For the three compositions were determined exposure AUC value. Et� the results are presented below in table.40.

Table 40
CargoDrugN(0-25)/dose/kg of body weight ± allowed deviation
OctreotideA 7.5% PVP-1272,9±2,2
Of 10.0% PVP-1294,4±1,7
15% PVP-12102,1±1,2

The results presented in table.40 demonstrate that the absorption of octreotide was greatest when the PVP in the composition was 10% and increase to 15% leads to a significant decrease in the activity. This confirms the choice of 15% in PVP improved the formula.

Example 32: Activity API in the composition compared to the API, introduced along with the composition

Three different basic composition of three different compounds cargo prepared (dextran, gentamicin and ecstatic), mainly as described above (in which the basic structure is the primary hydrophilic non-simplified fraction). Each of the three drugs were administered directly into the small intestine is not anesthetized rats, the level of cargo in the plasma of the ISM�rali after drug administration. Exposure AUC values were determined for compounds. In addition, a similar composition was prepared with unusual cargo connection (simulator of the drug). Separately, the simulator of the drug were injected with dextran, gentamicin and ecstatica in aqueous solution and determined exposure AUC value. Joint injection was performed using the introduction of cargo in an aqueous solution immediately after the introduction of the simulator of the drug through a catheter in the small intestine (gastric bypass anastomosis). For each connection, the exposure after administration of is composed of cargo compared with exposure after injection is not entered in the drug cargo (collateral).

The comparison results are presented below in table.41. The results show that the highest activity (bioavailability) is achieved when the cargo in all three cases is made in comparison with have not been the drug (concomitant) cargo, and that ecstatic showed a significant increase in activity due to the drug.

Note that the dextran and gentamicin connections insensitive to cleavage by the protease, whereas ecstatic, being a peptide, is subject to degradation by intestinal enzymes. A significant difference in activity between the dosage form is composed of ecstatica in comparison with not entered in the drug may be associated with a protective effect of pre�Arata from degradation.

Table 41
AFI/cargoIntroduced to the drug in relation to not put into the preparation (ratio of activity)
Dextran1,7
Gentamicin1,5
Ecstatic4,4

Example 33: Evaluation of intestinal hyperprolinemia

A. Size limitations: Technology and drugs described above are intended to enhance the permeability of the intestine, allowing specific delivery of proteins, peptides and other impervious substances through this barrier in a different way,

To a certain extent non-specific penetration of intestinal content may be the result of side effects of this amplification of the specific permeability. The size of molecules that could not specifically to penetrate through the intestine, was evaluated with the use of marker molecules of different size. To evaluate the limit of the size of the molecules is increased permeability of the gastrointestinal tract, chose five different. FITZ-labeled dekstranov with different molecular weight as molecular markers for the test increased permeability of the intestine; CPE�average molecular weight of 5 kinds of dextran 4,4, 10, 20, 40 and 70 kDa, equivalent to a radius of 14, 23, 33, 45, and 60 A, respectively. These different size markers were injected directly into the small intestine is not anesthetized rats through implanted in the intestine, the catheter, and showed practically no primary permeability of the intestine, when testing one by one. Each of these markers were injected directly into the small intestine is not anesthetized rats with 300 ml of the drug, and the level of permeability was evaluated by testing the level of dextran in the blood,

The dextran levels in plasma were measured before dosing and on 3, 6, 10, 25, 60, 90 min after drug administration. Determined exposure AUC(0-90)the results shown in Fig.7. Data are presented as mean value ± allowed deviation, n≥4. The results show that tested the lowest molecular marker (dextran with an average molecular weight of 4.4 kDa), penetrates through the intestinal tract when it is administered together with a compound that increases molecular size, degree of penetration decreases: molecular marker 10 kDa permeates less and marker 20 kDa even less. Molecular marker 40 kDa gives the minimum permeability then, as a molecular marker 70 kDa shows no permeability at all (primary permeability). These results indicate that 40-70 kDa is considered as the limit for amplification of nonspecific permeability of the preparations according to the invention. Thus, the introduction of a large amount of the drug (300 ml) in the intestine of rats resulted in increased permeability across the intestinal barrier, and this enhanced permeability bounded by the size of the molecule, has a size limit of 40-70 kDa and minimum permeability at 40 kDa,

Published values of the dangerous size of the molecules (molecular weight and radius) that may potentially be present in the intestine, shown below in table.42.

Table 42
Molecular mass (kDa)Radius (A)
Macromolecules>414 or more
Lipopolysaccharides>100short - 100, length - 1000
Toxins enterobacteria70-900-
Viruses-600-1000
Bacteria-10000 or more

Table.42 shows that the amount of potentially dangerous molecules, the presence�appropriate in the intestine, more size limit enhanced penetration of test compounds, as shown above. Thus, these results suggest that the tested drugs will not facilitate the penetration threat of molecules through the intestinal barrier and these drugs can therefore be considered as safe. Other formulations of the invention give similar results.

V. Re-introduction of the drug: to explore the influence of repeated administration of the drug on the intestinal permeability, improved the drug octreotide (12% octanoate sodium castor oil) was injected to rats consistently for 14 days with the use of in vivo models described above (rats implanted with two in the small intestine catheters). 1, 7 and 14 day of administration, the marker dextran permeability (FITZ-dextran with a molecular weight of 4.4 kDa; FD4) was injected 60 min after drug administration. This was done to assess the permeability of the intestine by the ability to penetrate FD4 from the intestine into the blood. Not found a significant difference in the impact of FD4 for the following 14 days repeated administration of the drug. These results suggest that the increased permeability of the intestine as a result of the recurring period of the introduction of no, and increased permeability of the intestine retains a reversible process during this period.

The results suggest that drugs do not cause damage to the tissue of the intestine, but act through a specific opening of the intestinal barrier, showing the effect of the gain constant.

Example 34: Assessment of hyperprolinemia bowel: dynamics and reversibility

In addition to studied in the Examples above, the study was planned to determine the dynamics of the increased permeability of the bowel preparations according to the invention and the reversibility of this process, using dextran as a marker of permeability.

To determine the time interval to increase the intensity of permeability, has developed the rat model in vivo in the small intestine which were implanted with one or two of the catheter. FTIC-labeled dextran (average molecular weight of 4.4 kDa, FD4) that actually has basal intestinal penetration, served as a molecular marker in the test for intestinal permeability. Was a planned experiment in which dextran marker was administered together with the composition (through a catheter implanted in the small intestine), or with different time intervals between drug administration (via separate secondary catheter implanted in the small intestine). Intestinal permeability was calculated by testing PD4 permeability in the blood. Rats were administered the basic structure together with dextran marker, or the main structure and then dextran marker with RA�personal time intervals (10, 30 and 60 min). Blood samples were analyzed for the concentration of dextran before the introduction and 3, 6, 10, 25, 60, and 90 min after injection of dextran. The results are presented in Fig.8. Data are presented as mean value ± allowed deviation, n≥5.

Fig.8 demonstrates that dextran marker penetrates the gut in the highest degree, when the introduction was carried out with the composition. The interval of 10 min between drug administration and the introduction of dextran marker results in a significant reduction in the amount of penetration of the marker, and increase the interval, and results in an exponential decrease in the penetration of the marker.

These results show that with some degree of increase of nonspecific permeability of the drug is limited to a short period of time after administration of the drug. Intestinal permeability decreases sharply with time, and for 60 min after drug administration was observed penetration of the drug. Thus, the introduction of the drug in the intestine of the rats was the result of increased permeability of the intestinal barrier in a very short period of time. Other drugs according to the invention gave similar results.

Example 35: the Oral administration of octreotide monkeys

For the purpose of testing the pharmacokinetics of octreotide after oral administration to monkeys of the drug octreotide�, five Javanese makaka prescribed oral administration of capsules containing the improved composition of octreotide in castor oil (like a drug I from the table.35, but with higher content of octreotide). Capsules that were used were gelatin capsules, covered 6.7% of Acryl-EZE® enteric-coated size 1; this shell prevents the destruction of the capsule in the stomach and allows you to open the capsule in the small intestine of animals. Used dose of octreotide was 5 mg per capsule.

Monkeys were not fed the night before administration of capsules. After oral administration, blood samples were collected via 9.75 hours, was extracted from plasma and analyzed for the content of octreotide method of liquid chromatography with tandem mass spectrometry (LC/MS/MS method), see Fig.9. Similar experiments were carried out with improved composition without castor oil/GTC (similar to the drug from table IV.35, but with more significant content APIs) and got similar results. Such experiments are also conducted with several different enteric-coated membranes and obtained similar results. To compare the pharmacokinetics of octreotide after the introduction of improved drug octreotide, pharmacokinetics introduced injection of octreotide, acetate solution of octreotide (0.1 mg per monkey) were injected subcutaneously two monkeys�am from the aforementioned group, which act as a reference. Blood samples were collected for 4 h, were separated from plasma and analyzed on the content of octreotide LC/MS/MS method. The pharmacokinetics of octreotide was compared after oral administration and subcutaneous injection of a solution of octreotide (see Fig.9 and 10). Results oral administration of the drug show the absorption for several hours. The shape of the graph changed in comparison with subcutaneous administration, showing a slower, but longer release of octreotide in the blood. This may be advantageous, since it allows to penetrate the octreotide in the blood over a long period, potentially extending the interval of activity.

The approved dose for injections of octreotide acetate in humans is 0.1 mg per patient. The above results in monkeys suggest that an improved composition containing about 10 mg of octreotide per dose, will produce a therapeutic effect on humans.

Example 36: Data stability

Basic and improved composition of octreotide according to the invention was kept at 4°C and at 25°C and were periodically tested for the content of octreotide. Both drugs were found to be stable.

Example 37: Preparation containing vancomycin, interferon alpha and terlipressin

A. Vancomycin: PL. 43 below describes the improved composition of vancomycin, soda�containing 10% PVP and 15% of octanoate of sodium in the hydrophilic fraction, and containing glyceryltrinitrate, as the main component of the hydrophobic environment. Vancomycin was purchased from Gold Biotechnology.

Table 43
The drug is AFI, ingredientVancomycin (%, mass)
Hydrophilic fractionAPI6,267
NaOH0,082
PVP-1210,005
Octanoate sodium15,016
Water1,216
Hydrophobic WednesdayTween 802,004
Glycerylmonostearate4,008
Glyceryltrinitrate61,400
Castor oil0,000

In previous experiments, the preparations, are described below in table.43, were injected directly into the small intestine panettiruling rats, and measured the levels of vancomycin in plasma after administration of prepar�TA. Exposure AUC values were determined for compounds. The results showed that the Abd is about 15% (compared with IV, n=6). When vancomycin in saline was injected into the small intestine is not anesthetized rats, the bioavailability was not found.

Interferon-alpha: PL. 44 below describes the improved drug interferon-alpha containing 10% PVP and 15% of octanoate of sodium in the hydrophilic fraction and containing glyceryltrinitrate as the main component of the hydrophobic environment. Interferon-alpha is supplied in buffer (Intas Biopharmaceuticals) and the ingredients of the buffer of interferon-alpha in the part marked with asterisk (*).

Table 44
The drug is AFI, ingredientInterferon-alpha (%, mass)
Hydrophilic fractionAPI0,050
*Na2HPO40,032
*NaH2PO40,030
*Polysorbate (tween 80)0,002
*Denetria EDTA0,002
PVP-12 10,026
Octanoate sodium14,997
Water1,006
Hydrophobic WednesdayTween 802,005
Glycerylmonostearate4,005
Glyceryltrinitrate67,84
Castor oil0

The drugs described above in table.44, were injected directly into the small intestine panettiruling rats. Measured the levels of interferon-alpha in plasma after drug administration.

C. Terlipressin: PL. 45 above describes terlipressin primary drug and terlipressin improved drug containing 10% PVP and 15% of octanoate of sodium in the hydrophilic fraction, and containing glyceryltrinitrate as the basic structure in a hydrophobic environment.

Terlipressin acquired from Bambio. The main structure was mainly cooked as described above, and improved composition prepared primarily also as described above.

Table 45
The drug is AFI, ingredient Terlipressin primary (%, mass)Terlipressin improved (%, mass)
Hydrophilic WednesdayAPI0,2350,235
MgCl20,1370,000
PVP-122,73610,004
Octanoate sodium12,00415,015
MS0,1370,000
Water0,6101,010
Hydrophilic fractionSpan1,2110,000
Lecithin2,4280,000
Utilizabilitate10,5000,000
Glycerylmonostearate2,2780,000
Glyceryltrinitrate23,708 0,000
Castor oil44,0160,000
Tween 800,0002,002
Glycerylmonostearate0,0004,004
Glyceryltrinitrate0,00067,731

The drugs described above in table.45, were injected directly into the small intestine is not anesthetized rats. Measured levels terlipressin in plasma after administration of the composition.

Example 38: Inhibition of growth hormone by octreotide in vivo

One of the best described effects of octreotide is the inhibition of release of growth hormone. For the purpose of testing the efficiency of inhibition of growth hormone composition of octreotide according to the invention, the model used rats, where the level of endogenous rat growth hormone (GSR) controlled after the administration of octreotide in the small intestine of the model is not anesthetized rats (described above).

The introduction of the basic drug octreotide (containing 12% of octanoate sodium) in the small intestine of rats showed a decrease in the level rGH to 87.4% in comparison with injection of saline control. The results showed that octreotide formulations, op�toboggan in this description, ensures the delivery of octreotide in its active form from the intestinal cavity into the blood stream.

Example 39: Toxicological studies

28 - Day Toxicological study of the control of the drug (only the fillers, not cargo) was carried out on Wistar rats. Animals in the test group were injected daily rectal maximum permissible dose (100 μl per animal per day) for 28 consecutive days. The test group was compared with two control groups: not subjected to the group (untreated) and one group was injected with saline solution (n=15/group).

General clinical study was done twice daily, and detailed clinical investigations were carried out on a weekly basis. Body weight and food consumption were measured weekly. Clinical pathology and macropathology studied 1 day after the last treatment. Histological studies were performed on the rectum, the colon, the liver and kidneys, and toxic effects reported. It was histopathological examinations of the digestive tract without local or General results, clinical results, not related to drugs, without changes in hematological and chemical blood parameters that are not associated with macroscopic results from autopsy and mortality.

In conclusion, this experiment showed that there were no toxic�spine during daily rectal dosing in rats for 28 consecutive days.

Having thus described several aspects of at least one of the options, it is clear that various changes, modifications and improvements will be easily carried out by specialists in this field. Accordingly, such changes, modifications and improvements are part of this disclosure and are within the scope of the invention. Accordingly, the foregoing description and figures are presented only as examples, and the scope of the invention may be determined from the appropriate design of the attached claims and their equivalents.

1. Pharmaceutical composition comprising a suspension which comprises a mixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of octreotide and at least one salt of fatty acids with medium-chain having a chain length of from 6 to 14 carbon atoms, and the polymer forming the matrix is selected from dextran and polyvinylpyrrolidone (PVP), and a salt of fatty acids with medium chain length present in the composition in an amount of 10% by mass or more.

2. Pharmaceutical composition according to claim 1 in which the salt of a fatty acid with an average chain length has a chain length of 8, 9 or 10 carbon atoms.

3. Pharmaceutical composition according to claim 1, wherein the solid form comprises a particle and/or powder.

4. Pharmaceutical.�ia according to claim 3, where the particle is obtained by lyophilization or by granulation.

5. Pharmaceutical composition according to claim 1, where the water content in the composition is less than 6% by mass.

6. The pharmaceutical composition according p.. 5, where the water content in the composition is less than 2% by mass.

7. Pharmaceutical composition according to claim 1, where the water content in the solid form is less than 6% by mass.

8. Pharmaceutical composition according to claim 7, where the water content in solid form less than 2% by mass.

9. Pharmaceutical composition according to claim 1, wherein the salt of a fatty acid with an average chain length represents hexanoate sodium, heptanoate sodium, octanoate sodium, nonanoate sodium, sodium decanoate, sodium undecanoate, dodecanoate sodium, tridecanoate sodium or tetradecanoate sodium, or the corresponding potassium, lithium or ammonium salt, or a combination thereof.

10. Pharmaceutical composition according to claim 1, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 11% to 40% by mass.

11. Pharmaceutical composition according to claim 10, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 12% to 18% by mass.

12. Pharmaceutical composition according to claim 1, wherein the salt of a fatty acid with an average chain length present in solid form in an amount of from 50% to 90% by mass.

13. Pharmaceutical composition according to claim 12, wherein the fatty acid salt with� medium-chain is present in solid form in an amount of from 70% to 80% by mass.

14. Pharmaceutical composition according to claim 1, wherein the polyvinylpyrrolidone is present in the composition in an amount of from 2% to 20% by mass.

15. Pharmaceutical composition according to claim 14, where the polyvinylpyrrolidone is present in the composition in an amount of from 5% to 15% by mass.

16. Pharmaceutical composition according to claim 14, where the polyvinylpyrrolidone is present in the composition in an amount of 10% by mass.

17. Pharmaceutical composition according to any one of claims. 14-16, where the molecular weight of polyvinylpyrrolidone is 3000.

18. Pharmaceutical composition according to claim 1, wherein the hydrophobic medium contains castor oil or glyceryltrinitrate, or glyceryltrinitrate, or a combination thereof.

19. Pharmaceutical composition according to claim 1, where the main component by weight of the hydrophobic medium is glyceryltrinitrate or where the hydrophobic medium consists essentially of glyceryltrinitrate.

20. Pharmaceutical composition according to claim 1, wherein the hydrophobic medium contains an aliphatic, olefinic, cyclic or aromatic compound, or where the hydrophobic medium contains mineral oil, paraffin, fatty acid.

21. Pharmaceutical composition according to claim 20, wherein the fatty acid is selected from the group consisting of octanoic acid, a monoglyceride, diglyceride, triglyceride, simple or complex ether, or a combination thereof.

22. Pharmaceutical composition pop. 21, where the hydrophobic environment includes triglyceride, where the triglyceride is a triglyceride with a long chain, with a chain of medium length or short chain or mixtures thereof.

23. Pharmaceutical composition according to claim 1, wherein the hydrophobic environment further comprises ionogenic surface-active substance (surfactant) or nonionic surface-active agent.

24. Pharmaceutical composition according to claim 23, where the surfactant is a lecithin or a bile acid salt, or detergent, or where the surfactant is a monoglyceride, cremophor, a simple ether of fatty alcohol and of polyethylene glycol, the ether of sorbitol and fatty acids, polyoxyethylene ester of sorbitol and fatty acids, Solutol HS15 (polyoxyethylene ester of 12-hydroxystearic acid), or poloxamer, or a combination thereof.

25. Pharmaceutical composition according to claim 24, where the monoglyceride is glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, or glycerylmonostearate, or glycerylmonostearate, or a combination thereof.

26. Pharmaceutical composition according to claim 24, where the ester of sorbitol and fatty acids includes sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate, or a combination thereof.

27. Pharmaceutical composition according to claim 24, where polyoxyethylene ester of sorbitol and fatty to�slots contains polyoxyethylenesorbitan monooleate (tween 80), polyoxyethylenesorbitan monostearate or polyoxyethylenesorbitan monopalmitate, or a combination thereof.

28. Pharmaceutical composition according to claim 19, where the hydrophobic environment further comprises castor oil and/or glycerylmonostearate.

29. Pharmaceutical composition according to claim 1, wherein the solid form comprises 10-20% salts of fatty acids with medium chain length.

30. Pharmaceutical composition according to claim 29, where the solid form includes 15% salts of fatty acids with medium chain length.

31. Pharmaceutical composition according to 30, wherein the salt of a fatty acid is octanoic sodium.

32. Pharmaceutical composition according to claim 29, where the solid form comprises 5-10% PVP-12.

33. Pharmaceutical composition according to claim 32, where the solid form comprises 10% PVP-12.

34. Pharmaceutical composition according to claim 29, where the hydrophobic environment includes 20-80% triglyceride, or castor oil, or mixtures thereof, 3-10% surfactant and 1% water.

35. Pharmaceutical composition according to claim 34, where the hydrophobic environment includes 30-70% triglyceride, or castor oil, or mixtures thereof, 3-10% surfactant and 1% water.

36. Pharmaceutical composition according to claim 34, where the triglyceride is glyceryltrinitrate or glyceryltrinitrate.

37. Pharmaceutical composition according to claim 34, where the surfactant is a 6% glycerylmonostearate and tween 80.

38. Pharmaceutical composition according to any one of claims. 29-37, where OK�reached is present in an amount of less than 33%.

39. Pharmaceutical composition according to claim 38, where octreotide is present in an amount of less than 25%.

40. Pharmaceutical composition according to claim 38, where octreotide is present in an amount of less than 10%.

41. Pharmaceutical composition according to claim 38, where octreotide is present in an amount of less than 1%.

42. Pharmaceutical composition according to claim 38, where octreotide is present in amounts less than 0.1%.

43. Pharmaceutical composition comprising a suspension which comprises a mixture of a hydrophobic medium and a solid form, where the solid form contains a therapeutically effective amount of octreotide and at least one salt of fatty acids with medium-chain having a chain length of from 6 to 14 carbon atoms, wherein the salt of a fatty acid with an average chain length present in the composition in an amount of 10 mass% or more and the polymer forming the matrix is selected from dextran and polyvinylpyrrolidone (PVP), wherein the polymer forming the matrix, is present in the composition in an amount of 3% by mass or more.

44. Pharmaceutical composition according to claim 43, in which the salt of a fatty acid with an average chain length has a chain length of 8, 9 or 10 carbon atoms.

45. Pharmaceutical composition according to claim 43, where the solid form comprises a particle and/or powder.

46. Pharmaceutical composition according to claim 43, where the particle is obtained by lyophilization or by granulation.

47. Pharmaceutical�viteska composition according to claim 43, where the water content in the composition is less than 6% by mass.

48. Pharmaceutical composition according to claim 43, where the water content in the composition is less than 2% by mass.

49. Pharmaceutical composition according to claim 43, where the water content in the solid form is less than 6% by mass.

50. Pharmaceutical composition according to claim 43, where the water content in solid form less than 2% by mass.

51. Pharmaceutical composition according to claim 43, wherein the salt of a fatty acid with an average chain length represents hexanoate sodium, heptanoate sodium, octanoate sodium, nonanoate sodium, sodium decanoate, sodium undecanoate, dodecanoate sodium, tridecanoate sodium or tetradecanoate sodium, or the corresponding potassium, lithium or ammonium salt, or a combination thereof.

52. Pharmaceutical composition according to claim 43, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 11% to 40% by mass.

53. Pharmaceutical composition according to claim 43, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 12% to 18% by mass.

54. Pharmaceutical composition according to claim 43, wherein the salt of a fatty acid with an average chain length present in solid form in an amount of from 50% to 90% by mass.

55. Pharmaceutical composition according to claim 54, wherein the salt of a fatty acid with an average chain length present in solid form in an amount of from 70% to 80% by mass.

56. Pharm�pharmaceutical composition according to claim 55, where the polyvinylpyrrolidone is present in the composition in an amount of from 2% to 20% by mass.

57. Pharmaceutical composition according to claim 56, where the polyvinylpyrrolidone is present in the composition in an amount of from 5% to 15% by mass.

58. Pharmaceutical composition according to claim 56, where the polyvinylpyrrolidone is present in the composition in an amount of 10% by mass.

59. Pharmaceutical composition according to claim 56, where the molecular weight of polyvinylpyrrolidone is 3000.

60. Pharmaceutical composition according to claim 43, where the hydrophobic medium contains castor oil or glyceryltrinitrate, or glyceryltrinitrate, or a combination thereof.

61. Pharmaceutical composition according to claim 43, where the main component by weight of the hydrophobic medium is glyceryltrinitrate or where the hydrophobic medium consists essentially of glyceryltrinitrate.

62. Pharmaceutical composition according to claim 43, where the hydrophobic medium contains an aliphatic, olefinic, cyclic or aromatic compound, or where the hydrophobic medium contains mineral oil, paraffin, fatty acid.

63. Pharmaceutical composition according to claim 62, where the fatty acid is selected from the group consisting of octanoic acid, a monoglyceride, diglyceride, triglyceride, simple or complex ether, or a combination thereof.

64. Pharmaceutical composition according to claim 63, where the hydrophobic environment includes triglyceride, �de triglyceride is a triglyceride of long chain with a chain of medium length or short chain or mixtures thereof.

65. Pharmaceutical composition according to claim 43, where the hydrophobic environment further comprises ionogenic surface-active substance (surfactant) or nonionic surface-active agent.

66. Pharmaceutical composition according to claim 65, where the surfactant is a lecithin or a bile acid salt, or detergent, or where the surfactant is a monoglyceride, cremophor, a simple ether of fatty alcohol and of polyethylene glycol, the ether of sorbitol and fatty acids, polyoxyethylene ester of sorbitol and fatty acids, Solutol HS15 (polyoxyethylene ester of 12-hydroxystearic acid), or poloxamer, or a combination thereof.

67. Pharmaceutical composition according to claim 66, where the monoglyceride is glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate or glycerylmonostearate, or glycerylmonostearate, or a combination thereof.

68. Pharmaceutical composition according to claim 66, where the ester of sorbitol and fatty acids includes sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate, or a combination thereof.

69. Pharmaceutical composition according to claim 66, where polyoxyethylene ester of sorbitol and fatty acids contains polyoxyethylenesorbitan monooleate (tween 80), polyoxyethylenesorbitan monostearate or polyoxy�transorbital monopalmitate, or a combination of both.

70. Pharmaceutical composition according to claim 61, where the hydrophobic environment further comprises castor oil and/or glycerylmonostearate.

71. Pharmaceutical composition according to claim 43, where the solid form comprises 10-20% salts of fatty acids with medium chain length.

72. Pharmaceutical composition according to claim 71, where the solid form includes 15% salts of fatty acids with medium chain length.

73. Pharmaceutical composition according to claim 71, wherein the salt of a fatty acid is octanoic sodium.

74. Pharmaceutical composition according to claim 71, where the solid form comprises 5-10% PVP-12.

75. Pharmaceutical composition according to claim 74, where the solid form comprises 10% PVP-12.

76. Pharmaceutical composition according to claim 71, where the hydrophobic environment includes 20-80% or triglyceride of castor oil, or mixtures thereof, 3-10% surfactant and 1% water.

77. Pharmaceutical composition according to claim 76, where the hydrophobic environment includes 30-70% or triglyceride of castor oil, or mixtures thereof, 3-10% surfactant and 1% water.

78. Pharmaceutical composition according to claim 76, where the triglyceride is glyceryltrinitrate or glyceryltrinitrate.

79. Pharmaceutical composition according to claim 75, where the surfactant is a 6% glycerylmonostearate and tween 80.

80. Pharmaceutical composition according to any one of claims. 71-79, where octreotide is present in an amount of less than 33%.

81. Pharmaceutical composition according to �. 80, where octreotide is present in an amount of less than 25%.

82. Pharmaceutical composition according to claim 80, where octreotide is present in an amount of less than 10%.

83. Pharmaceutical composition according to claim 80, where octreotide is present in an amount of less than 1%.

84. Pharmaceutical composition according to claim 80, where octreotide is present in amounts less than 0.1%.

85. Capsule containing a composition according to any one of claims. 1-42, intended for oral administration.

86. Capsule according to claim 85, where the capsule is a hard gelatin or soft gelatin capsule.

87. Capsule according to claim 86 or 87, where the capsule is enteric-coated.

88. Capsule containing a composition according to any one of claims. 43-84, intended for oral administration.

89. Capsule according to claim 88, where the capsule is a hard gelatin or soft gelatin capsule.

90. Capsule according to claim 88 or 89, where the capsule is enteric-coated.

91. A method of obtaining a pharmaceutical composition according to claims. 1-42, which comprises preparing a solid powder therapeutically effective amount of octreotide and solid powder comprises a salt of fatty acids with medium-chain having a chain length of from 6 to 14 carbon atoms, and suspending the solid powder in a hydrophobic medium, comprising forming the matrix polymer is selected from dextran or n�of livinginbarcelona (PVP), to obtain a suspension containing in solid form therapeutic agent and a salt of fatty acids with medium chain length, thus obtaining a pharmaceutical composition containing a salt of a fatty acid with an average chain length in an amount of 10% by mass or more.

92. A method according to claim 91, in which the salt of a fatty acid with an average chain length has a chain length of 8, 9 or 10 carbon atoms.

93. A method according to claim 91, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 11% to 40% by mass.

94. A method according to claim 91, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 12% to 18%.

95. A method according to claim 91, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 50% to 90%.

96. A method of obtaining a pharmaceutical composition according to claims. 43-84, which comprises preparing a solid powder therapeutically effective amount of octreotide and solid powder comprises a salt of fatty acids with medium-chain having a chain length of from 6 to 14 carbon atoms, and suspending the solid powder in a hydrophobic medium, comprising forming the matrix polymer is selected from dextran, or polyvinylpyrrolidone (PVP) to produce a suspension containing in solid form therapeutic agent and a salt of fatty acids with medium chain length, thus make the structure�thus obtaining a pharmaceutical composition, containing a salt of a fatty acid with an average chain length in an amount of 10% by mass or more.

97. A method according to claim 96, in which the salt of a fatty acid with an average chain length has a chain length of 8, 9 or 10 carbon atoms.

98. A method according to claim 96, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 11% to 40% by mass.

99. A method according to claim 98, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 12% to 18%.

100. A method according to claim 96, wherein the salt of a fatty acid with an average chain length is present in the composition in an amount of from 50% to 90%.



 

Same patents:

FIELD: medicine.

SUBSTANCE: medication based on tripeptide Ac-Ala-Phe-Lys-Pip·AcOH or its pharmaceutically acceptable salts is applied. The claimed medication can be made in the form of a solution, gel, plate or sponge.

EFFECT: application of the said medication makes it possible to considerably reduce the volume of haemorrhage and reduce the time of bleeding stopping due to high anti-plasmin activity of the tripeptide Ac-Ala-Phe-Lys-Pip·AcOH with the absence of side effects.

2 cl, 8 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: wound canal is packed with a preparation of recovered oxygenated cellulose. Thereafter in an entrance wound, the preparation is exposed to 2 cycles of cryotherapy with liquid nitrogen at a temperature of minus 196°C for 1-2 minutes until an ice crust is formed on the wound surface.

EFFECT: method provides excluding the possibility of bleeding and bile flowing from an inner surface of stab wounds, reducing a risk of recurrent bleedings, formation of liver haematomas postoperatively.

3 dwg, 2 tbl, 2 ex

Haemostatic agent // 2545991

FIELD: medicine.

SUBSTANCE: invention relates to medicine and veterinary and is intended for the acceleration of stopping bleeding in case of injury to blood vessels in traumas and wounds. A haemostatic agent contains 3-20 wt % of a polysaccharide, where the polysaccharide is represented by chitosan and/or starch, 0.1-2 wt % of calcium chloride and a 0.5-5% water solution of succinic or hydrochloric acid - the remaining part.

EFFECT: accelerating the initiation of the thrombus-forming process and enhancement of the regenerative ability of tissues in the area of wounds of different aetiology.

1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable salts specified in a group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylaminte salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzylethylene diamine salt, methyl glucamine salt, tromethamine salt, quaternary tetramethylammonium salt, quaternary tetraethylammonium salt and choline salt, bicyclosubstituted azopyrazole derivatives of general formula

.

The invention also refers to a method for preparing them, a pharmaceutical composition containing them, and using them as a therapeutic agent, particularly as thrombopoietin (TPO) mimetics, using them as TPO agonists. In general formula (I), Het is specified in a group consisting of phenyl, furanyl and thienyl; each R1, R2, R3 andR4 are independently specified in a group consisting of hydrogen and alkyl; n is equal to 0, 1 or 2.

EFFECT: improving the pharmokinetic properties of the compound of formula (I) ensured by better solubility.

19 cl, 1 tbl, 25 ex

FIELD: biotechnology.

SUBSTANCE: bispecific antibody is proposed, that binds to both the blood coagulation factor IX/activated blood coagulation factor IX and with the blood coagulation factor X, and functionally replaces the function of blood coagulation factor VIII. The nucleic acid is considered, encoding the antibody of the invention, a vector, a cell and a method of producing the antibody, and also a pharmaceutical composition and a kit for use in the method of preventing and/or treating bleeding or diseases associated with or caused by bleeding.

EFFECT: invention may find further application in the treatment of diseases associated with impaired blood clotting.

16 cl, 2 ex, 6 dwg

FIELD: chemistry.

SUBSTANCE: claimed is bispecific antibody, which is bound with both blood coagulation factor IX/activated blood coagulation factor IX and with blood coagulation factor X and functionally replaced function of blood coagulation factor VIII. Described are nucleic acid, coding antibody by invention, vector, cell and method of obtaining antibody, as well as pharmaceutical composition and set for application in method of prevention and/or treatment of bleeding or diseases, associated with or induced by bleeding.

EFFECT: invention can be applied in therapy of diseases, associated with blood coagulation disorders.

16 cl, 2 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: antiproteolytic preparation Ambene in a dose of 50-250 mg is introduced intravenously by the stream infusion for at least three days every 3-4 hours in a combination with heparin. Heparin is introduced subcutaneously is a dose of 250 units 4 times a day.

EFFECT: effective treatment of endogenous intoxication syndrome caused by proteolysis by blocking fibrinolysis and enhancing the detoxifying and anti-inflammatory action of Ambene.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: what is described is a biodegradable haemostatic therapeutic agent for control of bleeding, which provides co-immobilising ε-aminocapronic acid 50 mg, lysozyme 5 mg in distilled water 6.5 l for 3 hours at room temperature for dialdehyde cellulose 1 g at a degree of oxidation 12%. The material is pressed out and dried to residual moisture no more than 10% in the air in darkness. After having dried, the material is milled in a fine mill to particles having a size of 20 to 50 mcm. A rate of control of bleeding is 102 seconds. A time of total resorption is 10 days.

EFFECT: agent provides a high degree of hydrolytic destruction and a good haemostatic activity.

4 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention represents a biodegradable haemostatic therapeutic agent for bleeding. Using the prepared haemostatic agent according to the declared method provides a rate of control of bleeding making 45±2 seconds.

EFFECT: higher rate of control of bleeding.

4 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: agent further contains aluminium and/or magnesium oxides and satisfies the formula: CaO·(SiO2)m·(M)n·(H2O)k, where M is Al2O3 and/or MgO; m=0.5-3.0; n=0.01-0.05; k=0.2-1.2.

EFFECT: shorter time for onset of hemostasis and low exothermic effect during interaction with blood.

2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and concerns methods of treating growth hormone or insulin-like growth factor 1 deficiency in a patient involving administering an immunogenic amount of a vaccine containing a chimeric somatostatin-14 based polypeptide bound to inactivated chloramphenicol acetyltransferase (CAT), and an adjuvant; the vaccine for treating the patient having growth hormone or insulin-like growth factor 1 deficiency; a method of treating obesity in the patient involving administering the immunogenic amount of the vaccine.

EFFECT: group of inventions provide the immunogenicity for somatostatin and higher release of endogenously produced growth hormone and/or insulin-like growth factor 1.

22 cl, 8 ex, 6 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: suspension containing 300 thousand endometrial stem cells recovered from woman's menstrual blood is introduced experimentally into a pseudopregnant rat's uterine wall. That is followed by subcutaneous administration of progesterone 2 mg per gram of animal's weight.

EFFECT: method provides stimulating the endometrial decidua formation thereby modelling a control of a decidual reaction by stem cell transplantation.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns a pharmaceutical composition for treating hGH deficiency in the form of a solid oral dosage form which contains human growth hormone (hGH) and N(5-chlorsalicyloyl)-8-aminocaprylic acid (5-CNAC); a method of treating hGH deficiency which involves administering the above pharmaceutical composition into the patient.

EFFECT: group of inventions provides rapid absorption of hGH and good acceptability.

10 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology, particularly to obtaining a modified growth hormone, and can be used in medicine. By recombination, a polypeptide is obtained, which has antagonistic effect on the growth hormone receptor.

EFFECT: invention enables to obtain a polypeptide which is effective when treating conditions caused by excess growth hormone in the body of the patient.

11 cl, 19 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention provides using a prepared compound of a ghrelin splicing version for preparing an effective drug preparation activating body weight and food intake gain and/or stimulating growth hormone release, as well as for treating or preventing cachexia, lipodystrophy and muscle atrophy.

EFFECT: higher clinical effectiveness.

6 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to peptidyl analogues of ghrelin having greater stability which are active with respect to the GHS receptor, having the formula given below: (R2)-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-Rl, where values of A1-A28, R1 and R2 are given in the description, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing an effective amount of said compound, as well as therapeutic and non-therapeutic applications thereof.

EFFECT: high stability.

22 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods for synthesis of nonapeptide ethylamide, having strong LH-RH/FSH-RH activity, of formula pGlu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·2AcOH (I), and intermediate compounds for synthesis thereof. The nonapeptide ethylamide is obtained via condensation of a C-terminal tetrapeptide of formula H-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (II) with a dipeptide of formula: X-Ser-Tyr-OH (IV), where X is a protective group. The obtained N-substituted hexapeptide ethylamide of formula X-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5·HCl (III) is treated with an unblocking agent to remove the N-protective group, and then condensed with a tripeptide of formula pGlu-His-Trp-OH·HCl (V) and the end product is purified through chromatography and extracted in form of a monoacetate salt.

EFFECT: high output.

4 cl, 1 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention refers to the field of pharmaceutical chemistry, and more precisely to a new way of buserelin production with the formula: pGlu-His-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5·2AcOH (I) consisting in the fact that the synthesis is performed by means of condensing of C-ended protected dipeptide with the formula: X-pGlu-His-OH (IIa), where X is a protective group, with N-ended protected heptapeptide with the formula: H-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5 (III) and obtained N-protected nonapeptide ethylamide with the formula: X-pGlu-His-Trp-Ser-Tyr-D-Ser(Bu1)-Leu-Arg-Pro-NH-C2H5 (IV) that is treated with an unblocking agent in order to remove the N-protective group, and the end product is extracted with the help of chromatography.

EFFECT: way of buserelin production.

4 cl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to obstetrics, and concerns treating placental insufficiency in trimester II-III of pregnancy. For this purpose, conventional therapy is complemented with oxygen therapy and foetal sex determination. Those pregnant women with a predicted female foetuses require therapeutic inhalations with mixed gas containing oxygen - 40%, atmospheric air - the rest at air flow 5-6 litres per minute, length of a session 30 min once a day, the therapeutic course 10 procedures, while those pregnant women carrying female foetuses require therapeutic inhalations with mixed gas containing oxygen - 60%, atmospheric air - the rest at air flow 5-6 litres per minute, length of a session 45 min once a day, the therapeutic course 15 procedures.

EFFECT: method provides effective treatment of placental insufficiency with reduced side effects ensured by dosed oxygen therapy shown by foetus sex determination test.

2 ex

Ghrelin analogues // 2427587

FIELD: medicine.

SUBSTANCE: invention relates to peptide analogues of formulae (I) and (II): (R2R3)- A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21A22-A23-A24-A25-A26-A27-A28-R1 in which A1-A28 and R2-R3 are defined in the description for each of the formulae (I) and (II), pharmaceutically acceptable salts thereof and pharmaceutical compositions containing an effective amount of formula (I) compounds and which can be used in the method of suppressing growth hormone secretion and a method of screening a compound which is capable of binding with the GHS receptor.

EFFECT: high efficiency of using the composition.

31 cl, 5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention represents an agent for accelerating wound healing and tissue regeneration, containing oxymethyluracil, loratadine, sodium alginate, glycerol, a stabilising agent, a preserving agent and distilled water; the ingredients of the agent are taken in certain proportions, wt %.

EFFECT: accelerating wound healing and tissue regeneration, as well as possesses the pronounced immunomodulatory, anti-inflammatory, anti-allergic, anti-pruritic, anti-edematous and wound-healing action.

2 cl, 3 ex, 1 tbl

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