Matrix carrier compositions, methods and uses

FIELD: chemistry.

SUBSTANCE: invention relates to a matrix carrier composition for use in a pharmaceutical delivery system for oral administration, which is a suspension consisting of particles of a material in a continuous oil phase. The material consisting of particles comprises a first solid phase comprising silicon dioxide nanoparticles having hydrophobic surface, with particle size of 5-1000 nm, and a second solid phase comprising a biopolymer having hydrophilic and hydrophobic parts, said biopolymer containing polysaccharide. Said continuous oil phase is associated with the first and second solid phases, and the weight of the biopolymer is double that of the silicon dioxide nanoparticles. The invention also relates to a method of producing a matrix carrier composition, which includes mixing a first solid phase comprising silicon dioxide nanoparticles with oil, activating a second solid phase containing polysaccharide, wherein activation includes grinding, vacuum treatment, chemical treatment or ultrasonic treatment, adding said activated second solid phase to the oil and mixing the oil containing the first solid phase and oil containing the activated second solid phase.

EFFECT: improved efficiency and bioavailability of a medicinal agent encapsulated in a matrix carrier.

13 cl, 3 dwg, 1 tbl, 8 ex

 

The SCOPE of the INVENTION

This invention relates to compositions of matrix media, methods for their preparation and their applications, for example, in pharmaceutical delivery systems.

The LEVEL of TECHNOLOGY

It is believed that oral delivery is a convenient and widely recognized way of administering drugs. Achieving good oral bioavailability for drugs is the cornerstone for effective oral therapy. The effective carrier for drugs with low bioavailability, makes it possible for effective oral administration with improved efficacy of the medicinal product and can be used for new drugs and old drugs, which historically have not been available for oral administration.

The term bioavailability in relation to oral administration of drugs refers to the fraction of drug that reaches the systemic blood flow after oral administration taking into account both absorption and metabolism of this drug. Bioavailability can be influenced by/dependent on several factors, some of which relate to the gastrointestinal (GI) tract and some are related to the metabolism of the drug before wheeden who eat in the systemic circulation. These factors include, for example, factors such as the gastro-intestinal tract (GI), GI pH and composition of enzymes, including protease, lipase, nuclease, and the like, the particle size (active drug), physico-chemical interaction with the contents of the intestine, the metabolism of the drug by enzymes and electrolytes in the gastrointestinal tract, metabolism during the presystemic clearance of drugs (e.g., metabolism of the drug in the liver), chemical characteristics of a drug (for example, low solubility in lipids, the acidity of this drug funds) etc.

As for protein drugs, two main factors limit their use of the oral route of administration. One factor is the rapid degradation of these protein drugs, which is in the GI-tract by intestinal enzymes in the mucosal tissues, which cover the body cavity. Another factor that limits the oral administration of protein drugs is that most protein drugs are relatively large molecules and, therefore, cannot easily cross the intestinal epithelium. As a result, the bioavailability of oral Leka entered the public funds on the basis of proteins is usually very low. Thus, the most common method of administration of protein drugs is a parenteral method, which has several disadvantages, such as, for example, the inconvenience for patients and higher cost of administering drugs. Thus, there is an unmet medical need for effective neprestrelne the method of administration of protein drugs, which will provide protection against biological degradation, improved pharmacokinetics and reduced toxicity. Although they were developed complex aparentally, such as intranasal or inhalation systems, oral administration is preferred, having the great advantage of facilities for the increased patients ' adherence and regimen. It was suggested different strategies for oral administration of protein drugs, such as, for example, the strategy described in the following publications: US 7090868, US 7195780, US 7316818, WO 06/062544, US 6071535, US 5874105, US 6551576, US 6808720, US 7083572, US 2007/0184076, WO 06/097793, WO 05/094785, WO 03/066859 and EP 0491114B1.

In addition, since the bioavailability may be low and non-protein drugs, there is also a need in the development of drug delivery, which can protect the drug from the environment and the point is this drug to the site or the target organ, avoiding unwanted side effects while reducing the dose and toxicity, to improve the effectiveness of this medication and to improve the bioavailability of the drug.

The INVENTION

The following options and their aspects are described and illustrated together with the systems, tools and methods that should be considered as exemplary and illustrative, not limiting the scope of invention.

According to several variants of implementation, provided the composition of the matrix carrier for use in a pharmaceutical composition with a pharmaceutical agent. This matrix contains intermolecular Association of at least one first solid phase, preferably nanoparticles with the size of 5-1000 nm, having a hydrophobic surface; a second solid phase, preferably a biopolymer (such as, for example, polysaccharide)having both hydrophilic and hydrophobic parts; and a continuous phase of oil associated with all of these ingredients of this matrix.

In addition, the provided methods for making compositions of matrix carriers and methods of using compositions of matrix media.

According to some variants of implementation, provided the composition of the matrix of media suitable for delivering pharmaceutical AG the NTA, containing consisting of particles of a material containing pharmacologically inert nanoparticles in non-covalent Association with a biopolymer and a pharmaceutical agent, where this consists of particles of material associated with a continuous phase of oil. According to additional options of implementation, further provided methods of preparing compositions of matrix media, pharmaceutical compositions containing it, and uses therapeutic methods. In some embodiments, implementation, this delivery is oral delivery. In some embodiments, implementation, this delivery is parenteral. In some embodiments, implementation, this delivery is local.

According to some variants of implementation, provided a pharmaceutical composition comprising containing oil, consisting of particles of the material, where it is composed of particles of material contains a biopolymer in non-covalent Association with nanoparticles of silica having a hydrophobic surface; and a pharmaceutical agent, ecovalence associated with these nanoparticles of silicon dioxide and this biopolymer. According to some variants of the implementation is provided a method of manufacturing a pharmaceutical composition that includes mixing the nanoparticles with the biopolymer, whereby e is and the nanoparticles form a non-covalent Association with a biopolymer; the mixing of the pharmaceutical agent with butter and mixing the nanoparticles and biopolymer with oil, where the pharmaceutical agent forms a non-covalent Association with these nanoparticles and this biopolymer and where these inert nanoparticles, this biopolymer and this pharmaceutical agent associated with this oil.

According to additional options of implementation, this pharmaceutical composition is anhydrous.

According to additional options of implementation, the matrix composition of the medium preferably contains no water.

According to additional options of implementation, the matrix composition of the medium preferably contains no additional surfactant.

In some embodiments, implementation, these inert nanoparticles include nanoparticles of silicon dioxide, where at least 80% of the silica is a hydrophobic silica.

According to additional options of implementation, essentially anhydrous pharmaceutical composition of the matrix medium may include molecules and/or particles having hydrophilic properties. Non-limiting examples are hydrophilic silica, water-soluble vitamins, etc.

According to additional options of implementation, these nanoparticles include SEB the nanoparticles of silicon dioxide, and the size of the majority of these nanoparticles of silicon dioxide may be equal to the 1-1000 nanometers. According to additional options of implementation, the biopolymer can include a polysaccharide, a sugar and/or oligosaccharide. This polysaccharide can include branched and/or unbranched and/or cyclic polysaccharides, where these polysaccharides may include, but are not limited to, such polysaccharide, nutrioso, beta-cyclodextrin, xylitol, mannitol, cellulose, amylopectin, glucan, starch, glycogen and glycosaminoglycans (GAG), mucopolysaccharides or their derivatives. According to additional options of implementation, this pharmaceutical composition used branched biopolymer.

According to additional options of implementation, this pharmaceutical composition may further include a structural protein selected from the group consisting of, but not limited to, for example, elastin, collagen, keratin and fibrinogen. This pharmaceutical composition may further include an amino acid selected from the group consisting of arginine, lysine, glutamic acid, aspartic acid and histidine. According to other variants of implementation, this pharmaceutical composition may further include an antioxidant.

According to another variant the days before implementation, this pharmaceutical composition may further include one or more amplifiers and/or targeting agents.

According to some variants of implementation, this pharmaceutical composition may include more than one pharmaceutical agent and/or a nutritional agent.

According to additional options for implementation, a method of manufacturing this matrix composition provides education complex, which includes non-covalent connection between the hydrophobic surface of the nanoparticles (the"First solid phase"), biopolymers (the"Second solid phase") and/or molecules of the oil and the hydrophobic surface of the pharmaceutical agent.

According to additional options of implementation, the method of manufacturing of this matrix leads to the formation of the complex, which includes additional non-covalent connection between the hydrophilic surface of a pharmaceutical agent, a biopolymer (the"Second solid phase") and the polar groups of these oils.

According to additional options of implementation, the composition of the matrix medium may optionally include a hydrophilic nanoparticles and one or more additional amplifiers and/or targeting agents.

According to some variants of implementation, the volume ratio between the volume PE the howl of the solid phase and the volume of the second solid phase may be desired with respect to optimization of the protective properties of this matrix media. This is the volume ratio can be determined in accordance with the speed of sound (C) each solid phase. In some embodiments, implementation, this volume ratio can be determined in accordance with equation 1: V1×c1≤V2×c2 (equation 1);

where

V1 denotes the volume of the first solid phase;

C1 denotes the speed of sound in the first solid phase;

V2 denotes the volume of the second solid phase; and

c2 denotes the speed of sound in the second solid phase.

According to some variants of implementation, methods of preparation of the matrix carrier include at least some of the following stages:

surface activation of the second phase of the matrix carrier additional grinding, vacuum processing, chemical or ultrasonic cleaning or grinding; mixing one or more biopolymers with liquid oils under vacuum or in an inert atmosphere; the introduction of nanoparticles in oil and additional vacuum treatment to remove air from the surface of these nanoparticles, the introduction of one or more pharmaceutical agents in a pure oil with hydrophobic nanoparticles or oil biopolymer nanoparticles or without nanoparticles dioxide cremene, depending on the physical properties (such as, for example, hydrophobicity, susceptibility to mechanical stress) Pharma is eticeskaja agent; homogenization of this system taking into account the sensitivity of the active pharmaceutical agent to mechanical stress. Homogenization can be performed in an inert atmosphere with controlled temperature, speed and time. This homogenization or this mixing can reduce the viscosity of these ingredients and stimulate their packaging. In some embodiments, the implementation, the order of these stages may depend on the equipment used and/or on the properties of the pharmaceutical agent.

According to some variants of implementation, provided the composition of the matrix carrier for use in the pharmaceutical system additives, and this composition contains intermolecular Association of at least: a first solid phase containing nanoparticles having a hydrophobic surface, where the size of these nanoparticles is in the range of about 5-1000 nm; a second solid phase containing the biopolymer having a hydrophilic and a hydrophobic portion; and a continuous phase containing the oil associated with the specified first and the second solid phases.

According to some variants of implementation, the first density of the solid phase is greater than 1.4 g/cm3. In some embodiments, implementation, these nanoparticles are surface modified that is they way it is hydrophobic. These nanoparticles can be practically insoluble in water. These nanoparticles may include nanoparticles of silicon dioxide. These nanoparticles can include nanoparticles colloidal silicon dioxide. These nanoparticles may include nanoparticles of zinc oxide. These nanoparticles may include carbon nanoparticles. These nanoparticles may include nanoparticles of titanium oxide. In some embodiments, implementation, these nanoparticles can include a mixture of nanoparticles selected from silicon dioxide, zinc oxide, titanium oxide and carbon.

According to other variants of implementation, this biopolymer can be linear in structure, cyclic structure and/or branched in structure. This biopolymer can include saccharide. This biopolymer can include a polysaccharide. This polysaccharide may include starch, dextrin, cellulose, chitin, alpha-glucan, beta-glucan, amylopectin, glycogen, chitosan, cyclodextrin, mucopolysaccharide or their derivatives, or a combination. In some embodiments, implementation, this biopolymer includes a structural protein. This structural protein may include structural protein of high molecular weight. This structural protein can include a fibrous protein. This structure is RNA protein can include scleroprotein. This structural protein may include elastin, collagen, keratin, fibrinogen, or any combination thereof.

According to other variants of implementation, this oil may include one or more natural-occurring oils. This oil may include non-polar oil having the polar regions. In some embodiments, implementation, this oil is selected from the group consisting of sesame oil, olive oil, Flaxseed oil, evening primrose oil, silicone oil, and oil of sea-buckthorn, palm oil, or any combination thereof. In some embodiments, implementation, this oil can be selected from the group consisting of sunflower oil, corn oil, soybean oil, jojoba oil, bone marrow oil, grapeseed oil, oil of nutmeg, apricot oil, oil, Australian nut, palm oil, almond oil, castor oil, etc. or any combination thereof. In some embodiments, implementation, this oil may include lanolin. In some embodiments, implementation, this oil comprises a synthetic oil. In some embodiments, implementation, this oil may include one or more natural-occurring oils, one or more synthetic oils, or a combination of both. In some embodiments, implementation, this oil mod is et to include fatty alcohol. This oil can be 2-octyldodecanol. This oil may be selected from fatty acid ester and phenylsilane. This oil may be selected from fenitrothion, diphenylmethane and polymethylphenylsiloxane. In some embodiments, implementation, oil is at least one wax. In some embodiments, implementation, this oil may include sea buckthorn oil, jojoba oil, olive oil, or combinations thereof. In some embodiments, implementation, this oil can include olive oil, Flaxseed oil, sea buckthorn oil, sesame oil, palm oil, or combinations thereof. In some embodiments, the implementation of this oil may include jojoba oil, sea buckthorn oil, sesame oil, olive oil or a combination of both. In some embodiments, implementation, this oil may include wax, jojoba oil, sea buckthorn oil, sesame oil, olive oil, or combinations thereof. In some embodiments, implementation, this oil may include linseed oil, sea buckthorn oil, olive oil, palm oil, or combinations thereof.

According to other variants of implementation, this composition may further include at least one antioxidant. This antioxidant may include beta-carotene.

According to other variants of implementation, this to the position may optionally include an amino acid selected from the group consisting of arginine, lysine, glutamic acid, aspartic acid and histidine and combinations and derivatives.

According to additional options of implementation, the volume ratio between the first solid phase and a second solid phase is determined in accordance with equation 1:

V1×c1≤V2×c2 (equation 1);

where

V1 denotes the volume of the first solid phase;

C1 denotes the speed of sound in the first solid phase;

V2 denotes the volume of the second solid phase; and

c2 denotes the speed of sound in the second solid phase.

According to some variations, the composition may further include at least one active pharmaceutical agent. This composition may further include an amplifier. This composition may further comprise a targeting agent. This composition may optionally include one nutritional agent.

According to some variants of implementation, this composition may be adapted for oral administration.

According to additional options of implementation, this composition may be adapted for parenteral administration.

Under additional options, provided the method of manufacturing the composition of the matrix carrier for use in pharmaceutical compositions that provide for: )is their first solid phase with butter, where this is the first solid phase contains nanoparticles having a hydrophobic structure and a particle size of about 5-1000 nm; activating a second solid phase, where the second solid phase contains a biopolymer having a hydrophilic and a hydrophobic part; adding this activated second solid phase in the oil; and mixing the oil containing a first solid phase, and the oil containing the activated second solid phase.

In some embodiments, implementation, activating includes grinding, vacuum processing, chemical treatment, ultrasonic treatment, or any combination thereof.

In some embodiments, the implementation of one or several steps of this method can be performed in vacuum or in an inert atmosphere.

In some embodiments, implementation, this method may additionally include the homogenization of the mixture of oils containing first solid phase, and the oil containing the activated second solid phase.

In some embodiments, implementation, this method may additionally include the maturation of the composition of the matrix carrier for about 1-72 hours. This maturation can be performed at a temperature in the range of about 1 to 25.

In addition to the exemplary aspects and variants described here, additional considerations and options will acheve is generated with reference to the figures and in the study of the following detailed description.

BRIEF DESCRIPTION of DRAWINGS

Exemplary embodiments of the implementation are illustrated in the drawings. Dimensions of components and features depicted in these drawings, usually chosen for convenience and clarity of presentation and are not necessarily shown for comparison. It is assumed that described here implement and drawings should be considered more illustrative and not restrictive. These drawings are listed below.

Figure 1 - LC/MS-chromatogram of samples of Insulin in the composition of the matrix carrier in accordance with some of the options for implementation.

Figures 2A-B - graphs depicting levels of glucose (mg/DL) and insulin levels over time (hours) in the blood of rats with different insulin preparations.

DETAILED DESCRIPTION

According to some variants of implementation, provided the composition of the matrix carrier for use in the pharmaceutical composition/pharmaceutical delivery system with the pharmaceutical agent. This matrix contains intermolecular Association of at least: a first solid phase, which preferably includes nanoparticles with size in the range of 5-1000 nm, having a hydrophobic surface; a second solid phase, preferably a biopolymer having both hydrophilic and hydrophobic ends; and a continuous phase of oil, and zolirovanija with these components of this composition.

According to some variants of implementation, this second solid phase consists of a biopolymer, which can be linear, branched, cyclic or any combination thereof.

In some embodiments, the implementation of this pharmaceutical agent may include pharmaceutical drug (substance intended for use in medical treatment, therapy, prevention and/or diagnosis-related health conditions). In some embodiments, the implementation of this pharmaceutical agent is a nutrient agent (drug, intended to Supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids or amino acids that may be missing or may not be consumed in sufficient quantities in the diet of the subject). In some embodiments, the implementation of this pharmaceutical agent is a cosmetic agent (agent used for the treatment, prevention-related cosmetic conditions).

In some embodiments, implementation, composition of matrix carrier for use in the delivery system are suitable for oral administration. In some embodiments, the implementation of these compositions of matrix carriers for use in the delivery system are appropriate for parenteralnogo introduction.

In the context of this description, it is assumed that the following words and phrases usually have the following meaning, except to the extent that the context in which they are used indicates otherwise.

In this context, the terms "non-covalent interactions", "non-covalent bond" and "non-covalent forces" may be used interchangeably and refer to the interaction, also called Association, the first substance and the second substance, which does not form a covalent bond between the two substances. Non-limiting, representative interactions are van der Waals interaction, the formation of hydrogen bond and electrostatic interaction (also called formation of ionic bonds).

In this context, the terms "treating" and "treatment" in respect of a disease or condition related to the use of stages for obtaining beneficial or desired results, including, but not limited to, mitigate, or eliminate one or more symptoms of a disease or condition, reduction of the extent of the disease or condition, preventing the disease or condition, delay or slowing of disease progression, the elimination, reduction or stabilization of the disease or condition of partial or complete re is the mission, prolonged survival and other favorable results known in this field.

In this context, the term "pharmaceutical agent" refers to any substance, molecule, etc. that may have an effect on one or more health-related and/or food and/or cosmetic conditions. In some embodiments, the implementation, the pharmaceutical agent may include a pharmaceutical drug or a combination of pharmaceutical drugs. The term "pharmaceutical drug" (interchangeably referred to here as the "drug"refers to a substance that may be suitable for use in medical treatment, treatment, prevention and/or diagnosis of health-related condition (such as, for example, disease). The term "pharmaceutical drug" is intended to include substances having a pharmacological, and/or pharmaceutical and/or biological activity. In some embodiments, the implementation of this pharmaceutical agent may include nutritional (dietary) an agent or combination of nourishing agents. The term "nutritional agent" refers to a substance used as an additive to the diet and provide nutrients, such as vitamins is s, minerals, fiber, fatty acids or amino acids that may be missing or may not be consumed in sufficient quantities in the diet. In some embodiments, the implementation of this pharmaceutical agent may include a cosmetic agent or a combination of cosmetic agents. The term cosmetic agent refers to a substance used for the treatment and/or prevention-related cosmetic conditions. In some embodiments, the implementation of this pharmaceutical agent may include a substance used for the treatment and/or prevention-related cosmetic conditions. In some embodiments, the implementation of this pharmaceutical agent may include any combination of pharmaceutical medicines, nutritional (dietary) agent and/or cosmetic agent.

In this context, the terms "pharmaceutical composition", "delivery system" and "pharmaceutical delivery system" may be used interchangeably. These terms refer to any applicable system type additives/pharmaceutical compositions, which can be used with matrix media of this specification to deliver the pharmaceutical agent (as defined here).

In this context, the term "intimate mixture" refers to a physical mixture of at IU the e two components, which are in close physical contact with each other. For example, one component may cover another component or one component may be attached directly to the outer surface of the particles containing the other component. Alternatively, the material of one component may be mixed or intertwined with another component.

In this context, the term "efficiency (effectiveness)") refers to the dose of the pharmaceutical agent required to obtain a specific effect of a given intensity in comparison with a reference standard. Efficiency is comparative, not absolute expression of the activity of the agent. The effectiveness of the drug depends on various factors, such as one or more factors of bioavailability, targeting lifetime in the circulation of body fluids and efficiency.

In this context, "ADME" is an acronym in pharmacokinetics and pharmacology for Absorption, Distribution, Metabolism and Excretion input pharmaceutical drugs and describes the placement of pharmaceutical drugs (compounds) in the body. All four criteria ADME may affect the levels of drugs and kinetics of drug exposure to the tissues and, therefore, can influence namasterest and pharmacological activity of this compound as a drug. Absorption can determine the bioavailability of the compounds, whereas the half-life of drug is determined by its distribution, metabolism and removal from the body through excretion.

In this context, the term "bioavailability" refers to the fraction of the administered dose of intact drug that reaches the systemic circulation. Bioavailability is largely determined by the properties of a particular dosage form and not the physico-chemical properties of the pharmaceutical agent, which determine the capacity of absorption. By definition, when the drug is administered intravenously (IV), its bioavailability is 100%. When administered orally, its bioavailability is usually reduced.

Age, gender, physical activity, genetic phenotype, stress disorders (such as, for example, syndromes of achlorhydria and malabsorption), previous GI surgery (e.g., surgery, medicine, developing methods of prevention and treatment of obesity), and the like, may also affect the bioavailability of the drug. Chemical reactions, which reduce the absorption can reduce bioavailability. Such reactions include, for example, the formation of the complex (for example, between tetracycline and ions of polyvalent metals), hydrolysis of acid gastric juice or pediatricain the mi enzymes (for example, the hydrolysis of penicillin and chloramphenicolpurchase), conjugation in the intestinal wall (for example, sulphonylurea of isoproterenol), the absorbance relative to other medicines (eg, digoxin relative to cholestyramine and metabolism luminaries microflora).

In this context, the term "half-life" refers to the duration of drug action, i.e. the period of time required for halving the concentration or amount of drug in the body. The molecule drugs, which leaves the plasma, may have one or more lives. For example, this molecule drugs can be eliminated from the body by kidneys or liver. Removal of drug from plasma known as clearance and distribution of the drug in various tissues of the body is known as a volume distribution. Both of these pharmacokinetic parameters associated with determining the half-life of the drug.

The term "branched" includes in this context as biopolymers, which are natural branched, and biopolymers, are designed in such a way as to be branched at least one physical processing, such as thermal or ultrasonic treatment. The term "razvetvlennye the" include biopolymers, in which Deputy Monomeric subunit of the polymer replaced by another covalently linked chain of this biopolymer. In some embodiments, implementation, this branched biopolymer is sewn. In some embodiments, implementation, this branched biopolymer is not stitched.

In this context, the term "saccharide" refers to any simple carbohydrates, including simple sugars, derivatives of monosaccharides, analogs of monosaccharides and sugar, including sugar, which form individual units in the polysaccharide. In this context, the term "monosaccharide" refers to polyhydroxyvalerate (aldose) or polyhydroxyether (ketosis) and their polisaharidnyi derivatives and analogues. In this context, the term "polysaccharide" refers to polymers formed from approximately 500 to 100000 and more sharidny of links associated with each other hemiacetals or glycosidic bonds. This polysaccharide can be either straight chain or branched once or multiple branching, where each branch may have additional secondary branches, and these monosaccharides can be a standard D - or L-cyclic sugars in the forms of pyranose (6-membered ring) or furanose (5-membered ring), such as D-fructose and D-galactose, respectively, or they can be derived is Ilichevsky sugars, for example, amino sugars such as D-glucosamine, deoxysaccharides, such as D-fucose or L-rhamnose, Sharafutdinov, such as D-ribose-5-phosphate, sharokina, such as D-galacturonic acid, or multiderivative sugars, such as N-acetyl-D-glucosamine, N-acetylneuraminic acid (sialic acid), or N-sulfate-D-glucosamine. In the allocation of natural conditions drugs polysaccharides contain molecules that are heterogeneous in molecular weight. Non-limiting examples of polysaccharides include, among other compounds, galactomannans and derivatives of galactomannans; galactooligosaccharide, and derivatives of galactooligosaccharide, and galactooligosaccharide, and derivatives of galactooligosaccharide.

In this context, the term "beta-glucan" refers to polysaccharides, which contain D-glucopyranosyl units which are linked together by (1→3) or (1→4) beta-links. Beta-glucans are found in nature in many grain cereals, such as oats and barley. The molecular mass of molecules of beta-glucan, found in grains, equal to, e.g., 200-2000 kDa.

In this context, the term "dextrin" refers to low molecular weight carbohydrates produced by the hydrolysis of starch. In some embodiments, implementation, this term refers to a linear polymer of α-(1,4)-linked D-gluco is s, starting with α-(1,6)-linkages, or mixtures thereof. Dextrins are widely available commercially and can be obtained inter alia by cleavage of branched amylopectin or glycogen α-amylase. Non-limiting examples of dextrin is maltodextrin. But there are many types of dextrin, and these various types can be used in other variants of the implementation.

In this context, the term "fibrillar polymer" refers to a polymer in the form of a network of discrete filamentary sections. In this context, the term "fiber" and "dietary fiber" refers to compounds including, but not limited to, nevereverever residue polysaccharides of plant cell and lignin, all of which are resistant to hydrolysis by digestive enzymes of man. Non-limiting examples of kletchatki are members selected from the guar resin, pectin, fructo-oligosaccharides and their derivatives. Small amounts of other not digested compounds such as phytates, tannins, saponins and cutin may be included in dietary fiber, as these connections are neperevershenymy and associated with polysaccharides dietary fiber.

In this context, the term "silica" refers to silicon dioxide. Silicon dioxide is widely recognized as a safe food additive (Thirteenth report of the Joint FAO/WHO Expert Committee on Food Additives, FAO Nutrition Meetings Report Series; from the Joint FAO/WHO Expert Committee on Food Additives meeting in Rome, May 27 - June 4, 1969).

In this context, the term "silicate" refers to a compound containing silicon and oxygen, for example, tetrahedral units SiO4. In other embodiments, implementation, this term refers to a compound containing the anion, in which at least one of the Central silicon atom is surrounded by electronegative ligands. Non-limiting, representative examples of silicates are fluorosilicate preparation, sodium silicate (Na2SiO3), aluminosilicates and magnesium silicates.

In this context, the term "wax" means a lipophilic compound that is solid at room temperature (25ºC), having a melting point of ≥ 30 º C, which may be equal to 120 ºC.

In some embodiments, implementation, this invention provides a matrix composition of media, which includes pharmacologically inert nanoparticles in non-covalent Association with a biopolymer and a lipid containing non-polar and polar communication with the pharmaceutical agent, where these inert nanoparticles include nanoparticles of silicon dioxide, and where the diameter of these nanoparticles is between the 1-1000 nanometers, and where the biopolymer includes a combination of branched and unbranched biopolymer, and where this lipid on which includes a mixture of synthetic and/or natural saturated and unsaturated fatty acids, associated with the nanoparticles, biopolymer or carbohydrate and include a pharmaceutical agent, and, in some cases, the amplifier and/or targeting agent. Each possibility represents a separate variant implementation of the invention.

In some embodiments, implementation, this invention provides a matrix composition of media containing pharmacologically inert nanoparticles in non-covalent Association with a biopolymer, where these inert nanoparticles include nanoparticles of silicon dioxide, and where the diameter of these nanoparticles is between the 1-1000 nanometers, and this complex nanoparticle-biopolymer associated with oil, and where the diameter of the nanoparticles of the composition of the matrix carrier is located between the 100-500 nanometers (nm). In some preferred embodiments, the implementation, the diameter of the particles of this composition matrix of the carrier is between 100-50000 nm. In another embodiment, the oil phase of the composition of the matrix carrier contains a lot of oils. Each possibility represents a separate variant implementation of the invention.

In another embodiment, the composition of the matrix carrier is held together by non-covalent forces. In another embodiment, without the desire to associate in any theory or any IU what Anisman actions the authors believe that non-covalent forces between the components of this matrix compositions allow the matrix composition to samsobeats when mixing these components together as described here. In another embodiment, this matrix carrier includes two solid phases containing at least two solid pharmacologically inert material (nanoparticles and biopolymers) with different properties. In another embodiment, these non-covalent forces make these nanoparticles and biopolymer to form a mixture. In another embodiment, this matrix composition detects ordered, fractal structure. Each possibility represents a separate variant of the present invention. Structure and composition of this matrix carrier may allow the application of this matrix media in various ways, for example by oral administration, by parenteral methods, local methods, etc.

In another embodiment, without the desire to associate in any theory or any mechanism of action, the authors believe that the energy of non-covalent bonds between the pharmaceutical agent and a matrix carrier may be less than about 10 kcal per mole (e.g., in the range of approximately 1-5 kcal per mole). This value is higher, che is the energy of thermal fluctuations in 37º (approximately of 0.615 kcal per mol), which is sufficient to preserve or protect the pharmaceutical agent in the gastrointestinal tract. This energy is relatively close, for example, the bond energy between insulin and its receptor. This may provide a possible control of the pharmacokinetics and pharmacodynamics pharmaceutical agent. In some embodiments, implementation, this matrix media can provide protection from biodegradation of pharmaceutical agent in 37º in the stomach (acidic solution of pepsin and other enzymes) and the small intestine (neutral solution pancreatic enzymes, salts of bile acids and so on) for more than 8 hours.

In some embodiments, implementation, this matrix carrier may release pharmaceutical agents as a consequence of synthetic surfactants (such as TWEEN 20, TWEEN 80, and the like) or natural surfactants in biological fluids (such as blood, lymph, interstitial fluid, and the like).

In another embodiment, the complex nanoparticle-biopolymer dispersed in the oil phase of this matrix composition. In another embodiment, this oil phase impregnated complex nanoparticle-biopolymer this matrix composition. As described herein, the invention provides a computer the positions, in which the nanoparticles and biopolymer to form a matrix which is impregnated and completely surrounded by an oil phase. Each possibility represents a separate variant implementation of the invention.

The oil which has consisting of particles of material associated with it, means consisting of particles of the material which is in contact with the oil. For example, "associated with" may include embedded, dispersed, dipped, suspended, etc. in this oil. This composition generally does not need to be homogeneous with respect to the distribution containing particles of material. Rather, this consisting of particles of material capable of being sealed, dispersed, dipped, suspended, etc. in the oil with stirring. This consists of particles of the material should not be completely homogeneous and rather characterized by the content of its ingredients, is described here, and its contact with the oil of the present invention. Compositions in which this consisting of particles of the material is agglomerated, are within the scope of this invention.

The composition of the matrix carrier

In accordance with some of the options for implementation, provided the composition of the matrix carrier for use in the pharmaceutical composition for injection containing Marmolejo the popular Association of at least one biopolymer, nanoparticles and at least one oil. The introduction may include a variety of routes of administration, such as, for example, but not limited to oral administration, parenteral administration, local injection, etc.

This intermolecular Association can be carried out spontaneously, and may lead to the formation of stable structures. The progress of this Association process and properties of the obtained product can depend on the nature of these components and/or the conditions under which this Association.

According to some variants of implementation, the volume ratio between the first solid phase and the volume of the second solid phase may be in the desired ratio to optimize the protective properties of this matrix media.

The ratio of the first hard phase and the second volume of the solid phase can be determined in accordance with the speed of sound (C) each of the solid phase as follows:

The speed of sound (c) in this material is a function of its density: c=√C/ρ;

where c is the speed of sound, C is the stiffness coefficient; ρ - density

Thus, the volume ratio between the first and second solid phases can be calculated in accordance with the following equation (equation 1):

V1×c1≤V2×c2 (Equation 1);

where V1 is the volume of the first solid phase; c1 is the speed of sound in the first solid phase; V2 - volume of the second solid phase is s; c2 is the speed of sound in the second solid phase.

In some embodiments, implementation, this intermolecular Association maintains a network of non-covalent interactions between the at least one biopolymer nanoparticles, and at least one oil. That is, these components may be held together non-covalent forces. In some embodiments, implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that non-covalent forces are able to get these components to samsobeats when mixing these components together. In some embodiments, implementation, again without the desire to associate in any theory or any mechanism of action, the authors believe that these non-covalent forces make these nanoparticles and biopolymer to form a close mixture. In some embodiments, implementation, again without the desire to associate in any theory or any mechanism of action, the authors believe that this Association leads to an orderly, fractal structure.

In some embodiments, implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that the compositions described herein matrix media can be turned into the digestive system in relation to particles smaller in size but similar is the structure with the original composition, which are absorbed like a drop of fat and like chylomicrons reach the bloodstream with exposure to presystemic metabolism or without exposure to presystemic metabolism in the liver.

In some embodiments, implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that the energy of non-covalent bonds between the pharmaceutical agent and a matrix carrier may be less than about 10 kcal per mole (e.g., in the range of approximately 1-5 kcal per mole). This value is higher than the energy of thermal fluctuations in 37º (approximately of 0.615 kcal per mol), which is sufficient to preserve or protect the pharmaceutical agent in the gastrointestinal tract. This energy is relatively close, for example, the bond energy between insulin and its receptor. This may provide a possible control of the pharmacokinetics and pharmacodynamics pharmaceutical agent. In some embodiments, implementation, this matrix media can provide protection from biodegradation of pharmaceutical agent in 37º in the stomach (acidic solution of pepsin and other enzymes) and the small intestine (neutral solution pancreatic enzymes, salts of bile acids and so on) for more than 2 hours. In some embodiments, implementation, matrix media provide the provides protection for more than 4 hours, more than 6 hours more than 8 hours more than 12 hours more than 16 hours. In some embodiments, implementation, this matrix carrier can release and keep active pharmaceutical agent after processing of surface-active substances, which may cause disassembly of this complex matrix associated through non-covalent bonds (as demonstrated advanced in example 7).

According to some variants of implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that the compositions described herein matrix media can ensure the protection of the pharmaceutical agent from the external environment. In some embodiments, the implementation described here, the composition of matrix carriers may allow oral delivery of a pharmaceutical agent. In some embodiments, the implementation described here, the composition of matrix carriers can modulate the pharmacokinetics and/or pharmacodynamics pharmaceutical agents, administered through oral and/or parenteral compared with other routes of administration and/or other pharmaceutical compositions and ready-made forms.

In some embodiments, implementation, this intermolecular Association maintains a network of non-covalent interactions at the ore one biopolymer, nanoparticles and at least one oil, where optionally one or more covalent bonds between at least one biopolymer and nanoparticles, and/or at least between one biopolymer and at least one oil and/or between at least one oil and nanoparticles. For example, in some embodiments, the implementation of at least part of at least some of the nanoparticles or, more specifically, nanoparticles of silicon dioxide, covalently linked to a biopolymer according to methods known to a skilled in this area specialists.

In some embodiments, implementation, biopolymer and/or nanoparticles dispersed in at least one oil. In some embodiments, implementation, biopolymer and/or nanoparticles suspended in at least one oil. In some embodiments, implementation, biopolymer and/or nanoparticles embedded in at least one oil. In some embodiments, the implementation of at least one oil integrirovanno the biopolymer and/or nanoparticles. In some embodiments, implementation, these associated nanoparticles and biopolymer to form a matrix which is impregnated and surrounded by at least one oil. In some embodiments, the implementation of these nanoparticles and biopolymer associated in any way Myung is our least one oil.

In some embodiments, implementation, provided a pharmaceutical composition matrix media with the pharmaceutical agent, where this matrix contains intermolecular Association of at least:

1) the first solid phase, preferably nanoparticles with size in the range of 5-1000 nm, having a hydrophobic surface;

2) a second solid phase, preferably a biopolymer having both hydrophilic and hydrophobic parts;

3) a continuous phase of oil associated with the components of the pharmaceutical compositions of matrix media.

According to some variants of implementation, this composition matrix media should not necessarily be homogeneous, but rather can be characterized by the content of its ingredients described here.

According to some variants of implementation, this composition matrix media is a suspension. In some embodiments, implementation, this composition matrix carrier is an emulsion. In some embodiments, implementation, this matrix media forms in water emulsion of water in which the nonpolar phase is a suspension.

In some embodiments, implementation, this composition matrix media is agglomerated.

In some embodiments, exercise, weight of at least one biopolymer can is to be at least equal to the weight of the nanoparticles. In some embodiments, exercise, weight of at least one biopolymer may be greater than the mass of the nanoparticles. In some embodiments, exercise, weight of at least one biopolymer may be at least two times greater than the mass of the nanoparticles. In some embodiments, exercise, weight of at least one biopolymer can be five times greater than the mass of the nanoparticles. In some embodiments, exercise, weight of at least one biopolymer may be at least ten times greater than the mass of the nanoparticles. In some embodiments, the implementation of the mass of the at least one biopolymer may be at least 100 times greater than the mass of the nanoparticles.

In some embodiments, the implementation of this matrix media contains intermolecular Association of at least one biopolymer nanoparticles of silicon dioxide and at least one oil.

In some embodiments, implementation, this matrix media contains intermolecular Association of at least one biopolymer containing polysaccharide nanoparticles and at least one oil.

In some embodiments, implementation, this matrix media contains intermolecular Association of at least one biopolymer containing branched polysaccharide nanoparticles dioxide, PU glue, which I and at least one oil.

In some embodiments, implementation, this matrix media contains intermolecular Association of at least one biopolymer containing branched polysaccharide nanoparticles and at least one oil.

In some embodiments, implementation, this composition matrix media does not consist of silicon nanoparticles having a hydrophobic surface, polysaccharide and at least one oil.

In some embodiments, implementation, when the composition of the matrix of media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, dietary fiber, silicon nanoparticles, sea buckthorn and sesame oil. In some embodiments, implementation, when the composition of the matrix of media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, polysaccharides, rice, nanoparticles of silicon dioxide, sea buckthorn oil and evening primrose oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, dietary fiber, nanoparticles of silicon dioxide, sea buckthorn mA is La, oil of evening primrose and Flaxseed oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, dietary fiber, sea buckthorn oil, nanoparticles of silicon dioxide and sesame oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, sea buckthorn oil, sesame oil, amylopectin, chitin and nanoparticles of silicon dioxide. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, polysaccharides, rice, nanoparticles of silicon dioxide, sea buckthorn and sesame oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, dietary fiber, sea buckthorn oil, nanoparticles of silicon dioxide and sesame oil. In some embodiments done what I when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, polysaccharides, rice, nanoparticles of silicon dioxide, sea buckthorn oil and evening primrose oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration of insulin, the matrix composition of the medium does not contain in its composition of olive oil, sea buckthorn oil, sesame oil, amylopectin, chitin and nanoparticles of silicon dioxide.

In some embodiments, implementation, when this composition matrix media should be used for oral administration of erythropoietin, the matrix composition of the medium does not contain in its composition of olive oil, polysaccharides, rice, nanoparticles of silicon dioxide, sea buckthorn oil and linseed oil.

In some embodiments, implementation, when this composition matrix media should be used for oral administration of growth hormone, this composition matrix media does not contain in its structure of amylopectin from maize, nanoparticles of silicon dioxide, olive oil, sea buckthorn oil and sesame oil.

In some embodiments, implementation, when this composition matrix media due shall be used for oral administration of Copaxone, this composition matrix media does not contain in its composition of jojoba oil, olive oil, alpha-glucan, beta-glucan, amylopectin, nanoparticles of silicon dioxide, sea buckthorn and sesame oil.

In some embodiments, implementation, when this composition matrix media should be used for oral administration of Copaxone, the matrix composition of the medium does not contain in its composition of sea-buckthorn oil, olive oil, beta-glucan, amylopectin, nanoparticles of silicon dioxide and beeswax.

In some embodiments, implementation, when this composition matrix media should be used for oral administration And is a mimetic peptide of Apolipoprotein, this composition matrix media does not contain in its composition of sea-buckthorn oil, olive oil, beta-glucan, chitin, amylopectin, nanoparticles of silicon dioxide and beeswax.

In some embodiments, implementation, when this composition matrix media should be used for oral administration Rituxan, this composition matrix media does not contain in its composition of sea-buckthorn oil, olive oil, chitin, amylopectin, nanoparticles of silicon dioxide and beeswax.

In some embodiments, implementation, when the matrix composition of the medium should be used on the I peroral introduction of Gnkazy, this composition matrix media does not contain in its composition of jojoba oil, sea buckthorn oil, polysaccharides, rice, nanoparticles of silicon dioxide, olive oil and sesame oil. In some embodiments, implementation, when this composition matrix media should be used for oral administration Gnkazy, this composition matrix media does not contain in its composition of jojoba oil, sea buckthorn oil, dietary fiber, nanoparticles of silicon dioxide, olive oil and sesame oil.

In some embodiments, implementation, when this composition matrix media should be used for oral administration RNase, this composition matrix media does not contain in its composition of polysaccharides rice, nanoparticles of silicon dioxide, flax oil, sea buckthorn oil, olive oil, sesame oil, L-glutamic acid, glycine, L-lysine and L-arginine.

In some embodiments, implementation, when the pharmaceutical agent is a protein or peptide having therapeutic activity, this pharmaceutical composition does not contain in its composition of nanoparticles of silicon dioxide having a hydrophobic surface, polysaccharide and at least one oil.

In some embodiments, the implementation of this pharmaceutical agent is a protein or peptide having therapeu the practical activity.

The first hard phase Nanoparticles

The nanoparticles will usually have a surface capable of forming intermolecular Association of at least one biopolymer with butter. In some embodiments, implementation, these nanoparticles have a hydrophobic surface. The reference to "hydrophobic" surface, in some embodiments, implementation, indicates that at least 40% of the surface of the nanoparticles is hydrophobic (e.g., at least 50%, 50-60%, 60-70%, or 70-100%)and the remainder of this surface is negitiable.

In some embodiments, implementation, these nanoparticles are surface modified in such a way that it is hydrophobic, and, in some embodiments, the implementation of at least 40% of the surface of the nanoparticles is hydrophobic (e.g., at least 50%, 50-60%, 60-70%, or 70-100%)and the remainder of this surface is negitiable. In some embodiments, implementation, these nanoparticles modified by coating the surface of the hydrocarbon. In some embodiments, implementation, this coating causes the exposure (exposure) nanoparticles of hydrocarbon molecules on their surface. In some embodiments, implementation, these hydrocarbon moiety selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentile and from antila. In some embodiments, implementation, this coating causes the exposure (exposure) nanoparticles of methyl groups on their surface.

In some embodiments, implementation, these nanoparticles are nanoparticles of silicon dioxide, the use of which is known in this field, as described, for example, in U.S. Patents 6322765 and 6698247.

In some embodiments, implementation, these inert nanoparticles include nanoparticles of silicon dioxide, where at least 80% of the silica is a hydrophobic silica. In some embodiments, implementation, these inert nanoparticles include nanoparticles of silicon dioxide, where at least 95% of the silica is a hydrophobic silica.

In some embodiments, the implementation, the first density of the solid phase can be greater than 1.2 g/cm3. In some embodiments, the implementation, the first density of the solid phase may be greater than 1.3 g/cm3. In some embodiments, the implementation, the first density of the solid phase may be greater than 1.4 g/cm3. In some embodiments, the implementation, the first density of the solid phase may be greater than 1.5 g/cm3.

The ways of imparting hydrophobic surface of the nanoparticles is well known in this field, and are described here. In some embodiments, the implementation of the population, the surface of the nanoparticles, for example, when the nanoparticle contains colloidal silicon dioxide, may be chemically modified to reduce the number of silanolate groups. For example, silanolate group can be substituted with hydrophobic groups by obtaining a hydrophobic silica. These hydrophobic groups can be: trimethylsiloxy that receive, for example, the processing of colloidal silicon dioxide in the presence of hexamethyldisilazane. The thus treated silica known as "similat silicon dioxide in accordance with the CTFA (6th edition, 1995). They are sold, for example, under the names "Aerosil R812®" by the company Degussa, and "CAB-OSIL TS-530®" by the company Cabot; dimethylsiloxy or polydimethylsiloxane groups that receive, for example, the processing of colloidal silicon dioxide in the presence of polydimethylsiloxane or clear. The thus treated silica known as "dimethylsilane silicon dioxide in accordance with the CTFA (6th edition, 1995). They are sold, for example, under the names "Aerosil R972®", "Aerosil R974®" by the company Degussa, and "CAB-O-SIL TS-610®and CAB-O-SIL TS-720®"by the company Cabot.

Other ways to impart hydrophobic surface of the nanoparticles is well known in this field and are described in various documents, such as: Chung et al. (Considered are hydrophobic modification of silica nanoparticle y using aerosol spray reactor. Colloids and Surfaces A: Physicochem. Eng. Aspects 236 (2004) 73-79); Fu X, et al. (Physicochem. Eng. Aspects 179: 65, 2001); Krysztafkiewicz A, et al. (Colloids Surf. A: Physicochem. Eng. Aspects 173:73, 2000); Jean J and Yang S, J (Am. Ceram. Soc. 83(8): 1928, 2000); Zhang J and Gao L. (Ceram. Int. 27: 143, 2001); US Patent applications: US 2007/0172426, US 2006/0053971, US 2007/0098990.

In some embodiments, implementation, these nanoparticles are practically insoluble in water. The term "practically insoluble" refers to a substance with a solubility of less than 100 parts per million (weight/weight) (ppm). In some embodiments, implementation, this term refers to a solubility of less than 200 ppm, In some embodiments, implementation, this term refers to a solubility of less than 80 ppm, In some embodiments, implementation, this term refers to a solubility of less than 60 ppm, In some embodiments, implementation, this term refers to a solubility of less than 50 ppm, In some embodiments, implementation, this term refers to a solubility of less than 40 ppm, In some embodiments, implementation, this term refers to a solubility of less than 30 ppm, In some embodiments, implementation, this term refers to the solubility less than 20 ppm, In some embodiments, implementation, this term refers to a solubility of less than 15 ppm, In some embodiments, implementation, this term refers to a solubility of less than 10 ppm

In some of the s variants of implementation, these nanoparticles are pharmacologically inert. In some embodiments, implementation, these nanoparticles consist of substances that are generally regarded as safe (GRAS). In some embodiments, implementation, these nanoparticles are non-toxic. In some embodiments, implementation, these nanoparticles are non-teratogenic. In some embodiments, implementation, these nanoparticles are biologically inert.

In some embodiments, implementation, these nanoparticles include nanoparticles of silicon dioxide. In some embodiments, implementation, these nanoparticles include nanoparticles of colloidal silicon dioxide.

The term "nanoparticles of silicon dioxide" refers, for example, the nanoparticles are selected from silica, silicates and combinations thereof.

Nanoparticles of silica are commercially available, for example, in the form of pure 99.99%, finely ground silica. Qualified in this field specialists will be clear that can be used to lower purity silicon dioxide.

In some embodiments, implementation, these nanoparticles are the only type. In some embodiments, implementation, these nanoparticles are multiple types of nanoparticles. In some embodiments, implementation, these nanoparticles are a mixture of nanoparticles on the silicon oxide and other types of nanoparticles. In some embodiments, implementation, essentially all of these nanoparticles are nanoparticles of silicon dioxide.

In some embodiments, implementation, these nanoparticles contain nanoparticles of zinc oxide.

In some embodiments, implementation, these nanoparticles contain carbon nanoparticles.

In some embodiments, implementation, these nanoparticles contain nanoparticles of titanium oxide.

In some embodiments, implementation, these nanoparticles include nanoparticles, other than the nanoparticles of silicon dioxide, but with a stiffness similar to the stiffness of the nanoparticles of silicon dioxide.

In some embodiments, implementation, these nanoparticles contain a mixture of nanoparticles selected from silicon dioxide, zinc oxide, titanium oxide and carbon.

In some embodiments, implementation, these nanoparticles contain silver nanoparticles and/or compounded nanoparticles of silver.

In some embodiments, implementation, these nanoparticles include nanoparticles of gold and/or compounded gold nanoparticles.

In some embodiments, implementation, these nanoparticles include nanoparticles of platinum and/or compounded nanoparticles of platinum.

In some embodiments, implementation, these nanoparticles contain a mixture of nanoparticles of gold, platinum and silver, and any combination or compound.

In some the variants of implementation, the average diameter of these nanoparticles is equal to the 1-800 nanometers (nm). In some embodiments, implementation, this average diameter equal 2-400 nm. In some embodiments, implementation, this average diameter equal 2-300 nm. In some embodiments, implementation, this average diameter of 3-200 nm. In some embodiments, implementation, this average diameter of the nanoparticles is equal 4-150 nm. In some embodiments, implementation, this average diameter equal 4-100 nm. In some embodiments, implementation, this average diameter of 1-100 nm. In some embodiments, implementation, this average diameter of 5-50 nm. In some embodiments, implementation, this average diameter of 5-40 nm. In some embodiments, implementation, this average diameter of 5-30 nm. In some embodiments, implementation, this average diameter equal 7-40 nm. In some embodiments, implementation, this average diameter equal 6-25 nm. In some embodiments, implementation, this average diameter is equal to 10-11 nm. In some embodiments, implementation, this average diameter of the nanoparticles is equal to 5-600m nm.

In some embodiments, the implementation, the average diameter of approximately 5 nm. In some embodiments, the implementation, the average diameter of approximately 6 nm. In some embodiments, the implementation, the average diameter of approximately 7 nm. In some embodiments, implementation, userdn the config diameter of approximately 8 nm. In some embodiments, the implementation, the average diameter of approximately 9 nm. In some embodiments, the implementation, the average diameter of approximately 10 nm. In some embodiments, the implementation, the average diameter of approximately 12 nm. In some embodiments, the implementation, the average diameter of approximately 14 nm. In some embodiments, the implementation, the average diameter of approximately 16 nm. In some embodiments, the implementation, the average diameter of approximately 18 nm. In some embodiments, the implementation, the average diameter of approximately 20 nm. In some embodiments, the implementation, the average diameter is a different diameter within the range described here.

In some embodiments, implementation, these nanoparticles have a melting point in the range suitable for the compositions described herein matrix media. In some embodiments, implementation, these nanoparticles have a melting temperature (Tm) of more than 600ºC. In some embodiments, implementation, Tm 600-4500º, for example, in some embodiments, implementation, Tm is equal to 800-4500º. In some embodiments, implementation, Tm is equal to any Tm that are described in this range. Tm can be determined using methods well known to determine the tempo of the atur melting point for metals and nanoparticles.

The second solid phase Biopolymer (Biopolymers)

According to some variants of implementation, this second phase of the matrix medium may include one or more biopolymers.

According to some variants of implementation, the biopolymers used in the methods and compositions of the present invention, may include any biopolymer known in this field. For example, the biopolymer can include a linear polymer, branched polymer, unbranched polymer, a cyclic polymer, etc. This biopolymer can be natural occurring, semi-synthetic or synthetic biopolymer. In some embodiments, the implementation of this biopolymer can include a monomer, dimer, oligomer and/or polymer. In some exemplary embodiments, the implementation, the biopolymer includes a sugar (carbohydrate). In some embodiments, implementation, this biopolymer comprises a polysaccharide.

In some embodiments, the implementation, the "Second solid phase" contains both hydrophilic and hydrophobic residues/part/area. In some embodiments, implementation, these hydrophilic and hydrophobic residues interact with the hydrophobic and/or hydrophilic regions of the pharmaceutical agent and/or components of the "Second solid phase" and/or nanoparticles ("First solid is phase").

In some embodiments, implementation, use one biopolymer. In other embodiments, implementation, there is more than one biopolymer. In some embodiments, the implementation of this biopolymer is linear in structure. In some embodiments, implementation, this biopolymer is cyclic in structure. In some embodiments, implementation, this biopolymer is branched in structure.

In some embodiments, the implementation, the "Second solid phase", has a melting temperature (Tm) below 400ºC. In some embodiments, implementation, this Tm below 350º. In some embodiments, implementation, this Tm below 300OC. In some embodiments, implementation, this Tm below 250º. In some embodiments, implementation, this Tm below 200ºC. In some embodiments, implementation, this Tm below 150 º C. In some embodiments, implementation, this Tm is equal to 100-400ºC. In some embodiments, implementation, this Tm is equal to any Tm that are described in this range. Tm can be determined using standard methods known in this field, to analyze the melting temperature of the polymers.

In some embodiments, implementation, this biopolymer is a saccharide. This saccharide is, in some embodiments, implementation of natural-occurring saccharide. In some embodiments, implementation, this saccharide is synthetic is practical a saccharide.

In some embodiments, implementation, this biopolymer contains a polysaccharide. Biopolymers, such as polysaccharides, were known in this area as excipients in oral dosage forms, as described, for example, in U.S. Patent 6667060 and the application for U.S. patent 2004/0115264. This polysaccharide contains, in some embodiments, implementation of natural-occurring polysaccharide. In some embodiments, implementation, this polysaccharide contains synthetic polysaccharide. Non-limiting examples of synthetic polysaccharides can be found in US 6528497 and M. Okada et al. Polymer journal, 15 (11); 821-26 (1983). In some embodiments, implementation, this polysaccharide may be synthetic. In some embodiments, implementation, this biopolymer comprises at least one positively charged polysaccharide. But regardless of whether this is a natural polysaccharide occurring, semi-synthetic or synthetic, it is a biopolymer used here in the sense of the term.

In some embodiments, implementation, this polysaccharide contains a branched polysaccharide. This term is quite understandable qualified in this field specialists and can refer to any number and any branch structure of this polysaccharide. In some embodiments, implementation, this polysaccharide contains nature is the bottom-occurring branched polysaccharide. In some embodiments, implementation, this polysaccharide contains synthetic branched polysaccharide.

In some embodiments, implementation, biopolymer Second solid phase may include an unbranched biopolymer. The term "unbranched biopolymer" refers to a linear or cyclic biopolymers. Non-limiting examples of non-branched biopolymers include, but are not limited to, for example, glucosaminoglycans (GAG) or mucopolysaccharides, which are long unbranched polysaccharides consisting of a repeating disaccharide glycosides link, cyclodextrin, etc.

In some embodiments, implementation, biopolymer Second solid phase can include a carbohydrate selected from nutriose, maltisorb, xylitol, mannitol, polysaccharide rice, starch, dextrin, cellulose, chitin, alpha-glucan, beta-glucan, amylopectin, glycogen, chitosane, glucosaminoglycans (GAG), mucopolysaccharides and their derivatives.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide containing starch. Non-limiting examples of starch are corn starch, rice starch, wheat starch, refined (purum) starch and starch from algae. In some embodiments, implementation, this starch is any other is Oh starch, known in this field.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide containing dextrin. The term "dextrin" in another embodiment, relates to low molecular weight carbohydrates produced by the hydrolysis of starch. In another embodiment, this term refers to a linear polymer of α-(1,4)-linked D-glucose, starting with α-(1,6)-linkages, or mixtures thereof. Dextrins are widely commercially available and can be easily obtained inter alia by cleavage of branched amylopectin or glycogen α-amylase. Non-limiting examples of dextrin is a maltodextrin having the structure shown below. In another embodiment, the dextrin is any other dextrin, known in this area. Each possibility represents a separate variant implementation of the invention.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide containing cellulose. Non-limiting examples of cellulose is α-cellulose. In other embodiments, implementation, this pulp is any other cellulose known in this field.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide containing hit the N. A non-limiting example of chitin has the molecular formula (C8H13NO5)n. In other embodiments, implementation, this chitin is any other chitin, known in this field.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide containing alpha-glucan. Alpha-glucan can be linear or branched polymers of glucose with alpha 1-2, alpha 1-3, alpha 1-4 and/or alpha 1-6 glycosidic linkages. For example, alpha-glucan, such as alpha-amylase derived from plants are unbranched linear polymers of glucose with alpha 1-4 glycosidic bonds, and alpha-glucan, such as amylopectin derived from plants, are glucose polymers with alpha 1-4 glycosidic bonds in the skeleton and alpha 1-6 linkages at the branching points. In other embodiments, implementation, alpha-glucan is any alpha-glucan, known in this field.

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide, which is beta-glucan. "Beta-glucan" is called polysaccharides, which contain D-glucopyranosyl units which are linked together by (1→3) or (1→4) beta-links. Beta-glucan found in nature in many grains of cereals, such as oats and barley, and mushrooms (edible mushrooms), and, as intended is moved in clinical studies and in animal studies, they increase some aspects of the immune system. In addition, studies suggest that the polysaccharides of edible mushrooms may also be able to enhance the function of dendritic cells. The molecular mass of molecules of beta-glucans, found in cereals, usually equal 200-2000 kDa. Non-limiting examples of beta-glucan is Lentinan, which is isolated from the mushroom Shi(and)take. In another embodiment, this beta-glucan is any other beta-glucan, known in this area. Each possibility represents a separate variant of implementation of the present invention. Additional example beta-glucan is 346210 β-Glucan isolated from Saccharomyces cerevisiae (Calbiochem production, 9008-22-4 Ref. in the catalog Merck chemicals).

In some embodiments, implementation, biopolymer Second solid phase can include a polysaccharide, which is glycosaminoglycanes (GAG) or mucopolysaccharides, which are long unbranched polysaccharides consisting of a repeating disaccharide glycosides elementary level. This is a recurring elementary link may include hexose (Castiglioni sugar) or hexuronic acid associated with hexosamines (Castiglioni sugar containing nitrogen). Some of the GAG chain can be covalently linked to a protein with the formation of proteoglycans; the exception is the GAG is hyaluronan, which uniquely synthesized without the protein core and "stretched" by the enzymes from the cell surface into the extracellular space. Some examples of uses of fractions in nature include heparin as an anticoagulant, hyaluronan as a component in a lubricating substance synovial fluid in the joints of the body and chondroitin, which can be found in the connective tissues, cartilage and tendons. Members of the family of glycosaminoglycans vary in type elementary level, hexosamine, hexose or hexuronic acid that they contain (e.g., glucuronic acid, iduronovoy acid, galactose, galactosamine, glucosamine). They also vary in the geometry of the glycosidic bonds. Sample GAG include GAG, but not limited to: 385908 hyaluronic acid, sodium salt, Streptococcus sp., Natural mucopolysaccharide high viscosity with alternating β1,3-glucuronid and β1,4-glucosaminidase links. The primary glycosaminoglycan in liquids connective tissue, freeze-Dried powder (CAS 9067-32-7, Calbiochem), polysaccharides edible mushrooms (pharmaceutical grade), such as, for example, lichen, Cordyceps, etc.

In some embodiments, implementation, this at least one nanoparticle ("First solid phase") and this at least od the n biopolymer ("Second solid phase"), which intermolecular associated, are composed of particles of material.

In some embodiments, implementation, this "Second solid phase" may include a biopolymer containing fibrillar biopolymer, such as dietary fiber. Biopolymers can be either natural fibrillar or made fibrillar using physical and chemical treatments. In some embodiments, implementation, dietary fiber contains soluble fiber. In some embodiments, implementation, dietary fiber contains a linear soluble fiber.

In some embodiments, implementation, this "Second solid phase" may include a biopolymer containing mucopolysaccharide (such as, for example, certified medical mucopolysaccharides edible mushrooms Aloha Medicinals Inc).

In some embodiments, implementation, this "Second solid phase" may include a biopolymer containing structural protein.

In some embodiments, implementation, this "Second solid phase" may include a biopolymer, which can contain one or many types of biopolymers. In some embodiments, implementation, this biopolymer contains two or more types of biopolymers. In some embodiments, implementation, this biopolymer contains three or more types of bio is polimerov. In some embodiments, implementation, this biopolymer contains four or more types of biopolymers. In some embodiments, implementation, this biopolymer contains more than four types of biopolymers.

In some embodiments, implementation, this "Second solid phase" may include a biopolymer containing a branched biopolymer, and/or a linear biopolymer, and/or cyclic biopolymer. In some embodiments, implementation, this "Second solid phase" includes a biopolymer, which contains a branched carbohydrate and linear carbohydrate and/or cyclic carbohydrate. In some embodiments, implementation, this "Second solid phase" includes a biopolymer, which contains a branched carbohydrate and linear carbohydrate and/or cyclic carbohydrate and/or any combination of them. Each possibility represents a separate variant implementation of the invention.

In some embodiments, implementation, this "Second solid phase" may include a biopolymer containing a branched biopolymer and cyclic biopolymer. In some embodiments, implementation, this biopolymer contains branched polysaccharide and a cyclic polysaccharide. In some embodiments, implementation, this cyclic polysaccharide contains cyclodextrin. In some embodiments, the implementation, the cyclodextrin is selected from α-cycle is dextrin, β-cyclodextrin, γ-cyclodextrin and derivatives thereof. A non-limiting example of such combination is the polysaccharide starch-based, such as, but not limited to: amylopectin and/or nutrioso, and/or a cyclodextrin, such as, for example, beta-Cyclodextrin.

In some embodiments, implementation, biopolymer "Second solid phase" contains a branched biopolymer and macromolecular structural protein. In some embodiments, implementation, this biopolymer contains branched polysaccharide of high molecular structural protein.

In some embodiments, implementation, biopolymer "Second solid phase" contains a linear biopolymer and cyclic biopolymer. In some embodiments, the implementation of this biopolymer contains linear and cyclic polysaccharide polysaccharide. In some embodiments, implementation, this linear polysaccharide selected from cellulose, chitin, glucans and cellulose.

In some embodiments, implementation, biopolymer "Second solid phase" contains a branched biopolymer, cyclic and linear biopolymer biopolymer. In some embodiments, implementation, biopolymer "Second solid phase" contains a branched polysaccharide, a cyclic polysaccharide, and a linear polysaccharide. In some embodiments, implementation, this cyclic polysaccharide contains cyclogest is in. In some embodiments, implementation, this linear polysaccharide selected from chitin, glucans, cellulose, maltisorb and pulp.

In some embodiments, implementation, biopolymer "Second solid phase" contains a branched biopolymer, cyclical and structural biopolymer protein. In some embodiments, implementation, biopolymer "Second solid phase" contains a branched polysaccharide, a cyclic polysaccharide, and a structural protein. In some embodiments, implementation, this branched polysaccharide contains amylopectin. In some embodiments, implementation, this cyclic polysaccharide is a cyclodextrin, for example α-Cyclodextrin. In some embodiments, the implementation of this structural protein is selected from melanin and keratin, and in some embodiments, the implementation of this keratin is a neutral-basic (keratin 1-8) or acid (keratin 9-20) forms.

In some embodiments, implementation, biopolymer "Second solid phase" contains a branched biopolymer, structural protein and insoluble fiber. In some embodiments, implementation, biopolymer "Second solid phase" contains a branched polysaccharide, a structural protein and insoluble fiber. In some embodiments, implementation, this branched polysaccharide is amylopectin. In some embodiments, the OS is enforced, this structural protein is keratin.

In some embodiments, implementation, biopolymer "Second solid phase" contains a branched biopolymer, a linear biopolymer and insoluble fiber. In some embodiments, implementation, biopolymer "Second solid phase" contains a branched polysaccharide, a linear polysaccharide and insoluble fiber. In some embodiments, implementation, this branched polysaccharide is amylopectin. In some embodiments, implementation, this linear polysaccharide is chitin.

In some embodiments, implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that the use of the selected biopolymer "Second solid phase" (or any combination of biopolymers) can provide added value to the matrix composition of the medium, which may be dictated by the internal properties of this biopolymer. For example, the biopolymer can be used to target this composition matrix media to plot the target and/or to facilitate access this matrix media to a desired location. For example, mannitol, which, as you know, crosses the blood-brain barrier (BBB)may be used in this matrix compositions to promote this media preseka the AI of this barrier. For example, the biopolymer may be inherent profitable activity, which may increase or enhance the beneficial activity of this reagent in the media. For example, it is known that beta-glucans such as Lentinan, has an advantageous effect on the immune system.

According to some variants of implementation, the biopolymer of the "Second solid phase" may be a structural protein. In this context, "structural protein” called a protein that may be a biopolymer and is included for the structure, which he attaches consisting of particles of material. In some embodiments, implementation, this term refers to a protein, which can be a biopolymer, which gives the structure of the cell, the cell membrane or extracellular membrane in vivo. In some embodiments, the implementation of this structural protein is devoid of therapeutic, pharmacological, pharmaceutical and/or biological activity, whereas in other embodiments, the implementation of this structural protein has an additional therapeutic activity. In the variants of implementation, in which this structural protein has therapeutic activity of the pharmaceutical agent, in some embodiments, the implementation is other than this structural protein.

In some embodiments, the implementation of this structural protein contains both hydrophilic and hydrophobia residues. In some embodiments, implementation, these residues interact with the hydrophobic and/or hydrophilic regions, respectively, of the pharmaceutical agent, and/or biopolymer "Second solid phase", and/or nanoparticles "First solid phase".

In some embodiments, the implementation of this structural protein contains high molecular weight (MW) of the structural protein. In some embodiments, implementation, average MW (molecular weight) of this structural protein is equal to at least 100 kilodaltons (kDa). In some embodiments, implementation, this average MW equal to at least 150 kDa. In some embodiments, implementation, this average MW equal to at least 200 kDa. In some embodiments, implementation, this average MW equal to at least 300 kDa. In some embodiments, implementation, this average MW equal to at least 400 kDa. In some embodiments, implementation, this average MW equal to at least 500 kDa. In some embodiments, implementation, this average MW equal to at least 600 kDa. In some embodiments, implementation, this average MW equal to at least 800 kDa. In some embodiments, implementation, this average MW equal to at least 1000 kDa. In some embodiments, implementation, this average MW is in the range of 100-1000 kDa. In some embodiments, implementation, this average MW is in the range of 150-1000 kDa. In some variant of the x implementation this average MW is in the range of 200 to 1,000 kDa. In some embodiments, implementation, this average MW is in the range 100-800 kDa. In some embodiments, implementation, this average MW is in the range of 100 to 600 kDa.

In some embodiments, the implementation of this structural protein has a Tm below 400ºC. Tm can be determined using standard methods known in the field for analysis of the melting temperature of proteins.

In some embodiments, the implementation of this structural protein contains fibrillar protein. In some embodiments, the implementation of this structural protein contains scleroprotein. In some embodiments, the implementation of this structural protein is selected from elastin, collagen, keratin and fibrinogen. In some embodiments, the implementation of this structural protein is any other fibrillar protein or scleroproteins known in this field.

In some embodiments, the implementation of this structural protein contains elastin. Non-limiting examples elastin proteins are described, for example, in GenBank Accession numbers NP_031951, NP_786966 and AAC98394. In some embodiments, implementation, this elastin is any other elastin known in this field.

In some embodiments, the implementation of this structural protein contains collagen. Non-limiting examples of collagen proteins include is in itself proteins, encrypted COL3A1 gene symbols, COL14A1, COL11A2, COL5A2, COL11A1, COL5A1, COL4A6, COL4A5, COL4A4, COL4A3, COL4A2, COL1A2, COL5A3, COL18A1, COL12A1, COL19A1, COL24A1, COL4A1 and COL2A1. In some embodiments, implementation, this collagen is any other collagen known in this field.

In some embodiments, the implementation of this structural protein contains keratin. Non-limiting examples of keratin proteins include keratin 18, keratin 14, keratin 3 and keratin 86 (GenBank Accession numbers P05783, P02533, P12035, O respectively). In some embodiments, implementation, this keratin is any other keratin, known in this field.

In some embodiments, the implementation of this structural protein contains fibrinogen. Fibrinogen is a glycoprotein consisting of three parts polypeptides: two alpha, two beta and two gamma chains. Non-limiting examples of alpha, beta and gamma chains of fibrinogen are described, inter alia, in GenBank Accession numbers P02671, P02675 and P02679. In some embodiments, the implementation, the fibrinogen is any other fibrinogen, known in this field.

Oil

This oil may consist of either one type or many types of oils. In some embodiments, implementation, this oil contains a lot of oils. In some embodiments, the implementation described here, the composition of the matrix carrier contains three or more oils. Some in the ways of implementation, described here, the composition of the matrix carrier contains four or more oils. In some embodiments, the implementation described here, the composition of the matrix carrier contains more than four oils.

In some embodiments, the implementation of at least one oil is a liquid. In some embodiments, the implementation of at least one oil selected from solid and liquid oils. In some embodiments, the implementation of at least one oil selected from solid oils.

According to some variants of implementation, this component has a melting temperature (Tm) of at least 5ºC. In some embodiments, implementation, this oil contains a component having a relatively high melting temperature. In some embodiments, the implementation of this component with high Tm is liquid at room temperature. In some embodiments, implementation, this oil is a component with a high Tm. In some embodiments, the implementation of this component with high Tm included in addition to another oil. One non-limiting example of an oil with a high Tm is jojoba oil. In some embodiments, implementation, oil with a high Tm is any other oil with a high melting point, known in this area. In some embodiments, implementation, this oil with high Tm is used as the basis of the ERN part of this oil. Tm can be determined using standard methods known in this field, to analyze the melting temperature of proteins.

In some embodiments, implementation, this oil contains at least one lipid. In some embodiments, implementation, this oil contains at least one natural-occurring lipid.

In some embodiments, implementation, this oil contains one or several natural occurring oils. In some embodiments, implementation, this oil contains one or more oils selected from natural vegetable oils and their synthetic analogues.

In some embodiments, the implementation is mostly non-polar oil may include polar fraction/portion/region.

In some embodiments, implementation, this oil contains sesame oil. In some embodiments, implementation, this oil contains olive oil. In some embodiments, implementation, this oil contains linseed oil. In some embodiments, implementation, this oil contains evening primrose oil.

In some embodiments, implementation, this oil contains oil of sea-buckthorn. In some embodiments, implementation, this oil is selected from sesame oil, olive oil, linseed oil, palm oil, jojoba oil, silicone oil, and oil of sea-buckthorn. Some of the options that implementation this oil is selected from sunflower oil, corn oil, soybean oil, jojoba oil, bone marrow oil, grapeseed oil, oil of nutmeg, apricot oil, oil of Australian walnut, paimogo oil, almond oil, castor oil, etc. or any combination thereof.

In some embodiments, implementation, this oil can be an oil of animal origin, such as lanolin.

In some embodiments, implementation, this oil contains synthetic oil, such as silicone oil with a molecular weight that provides optimum viscosity.

In some embodiments, implementation, this oil contains at least one natural-occurring oil and at least one synthetic oil.

In some embodiments, implementation, this oil contains unsaturated and saturated oils in a ratio that provides optimum viscosity.

In some embodiments, implementation, this oil contains fatty alcohol. In some embodiments, implementation, this oil contains 2-octyldodecanol. In some embodiments, implementation, this oil may be selected from fatty acid ester and phenylsilane. In some embodiments, implementation, this oil can be selected from fenitrothion, diphenylmethane and polymethylphenylsiloxane.

In some Islands Ianto implementation this oil component contains a component capable of stimulating the secretion of bile salts or bile acids ingestion by the subject. In some embodiments, implementation, stimulating bile component is oil. In some embodiments, implementation, this component contains olive oil or extract. In some embodiments, implementation, this component is any other stimulating salts of bile acids/bile acid-soluble lipid substance known in this field. In some embodiments, implementation, this oil is stimulating salts of bile acids/bile acid substance. In some embodiments, implementation, this is a stimulating salt of the bile acid/bile acid substance is a substance separate from the oil.

In some embodiments, the implementation, the oil may contain at least one antioxidant. For example, oil of sea-buckthorn (sea buckthorn oil) contains beta-carotene. In some embodiments, the implement may be used any other oil, enriched with at least one antioxidant. In some embodiments, the implement may be used any other oil, enriched with at least one vitamin. Non-limiting examples are vitamin a, Vitamin E, beta-carotene, Vitamin D, or the combination.

In some embodiments, implementation, this oil can be other suitable oil, known in the field.

In some embodiments, implementation, this composition matrix media contains additional oil component. This additional oil component may contain additional oil or mixture of oils. In some embodiments, implementation, oil additional oil component is olive oil. In some embodiments, implementation, this oil is a suitable oil, is known in this field.

In some embodiments, implementation, this additional oil component further comprises an antioxidant.

In some embodiments, implementation, this additional oil or mixture of oils may have a higher viscosity than the first added oil or mixture of oils.

In some embodiments, implementation, this composition matrix of the medium additionally contains a third oil or mixture of oils, along with the above additional oil component. In some embodiments, implementation, this third oil component contains an antioxidant.

In some embodiments, implementation, this third oil component contains sesame oil. In some embodiments, implementation, this third oil component is other is to them a suitable oil, known in this field.

In some embodiments, implementation, this is the third oil or mixture of oils may have a higher viscosity than more oil or more butter-oil mixture. In some embodiments, implementation, this third component is a suitable oil, is known in this field.

In some embodiments, implementation, this is the third butter, oil or mixture of oils may have a higher viscosity than additional oil or mixture of oils. Non-limiting examples for the third oil is palm oil.

In some embodiments, the implementation is at least one oil is one wax. In some embodiments, implementation, this wax is a substance having the following properties: (a) is plastic (malleable) at normal ambient temperature; (b) has a melting point above approximately 45 º C (113ºF); (c) has a low viscosity at the melting relative to conventional plastics; (d) insoluble in water and (e) is hydrophobic. In some embodiments, implementation, this wax is a natural wax, for example, beeswax, wax, obtained from plant material, or a synthetic wax obtained by esterification fatty acids and alcohols with long chain. Other suitable waxes include oxidized paraffins, such as arafin.

The use of a composition of matrix media

Described here is the composition of matrix carriers can be combined with one or more pharmaceutical agents, as described below, to obtain the pharmaceutical composition/delivery system suitable for injection. The introduction may include any type of introduction, such as, for example, oral administration, parenteral administration, local injection, etc.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions leads to enhanced effectiveness (efficiency) of the pharmaceutical agent in comparison with oral introduction one of the pharmaceutical agent. In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions results at least comparable to, if not enhanced, the efficiency of the pharmaceutical agent in comparison with neuroretinal the introduction of this pharmaceutical agent. In some embodiments, implementation, oral administration described herein, the pharmaceutical composition provides increased efficiency, for example, prolongation of time half-life of the pharmaceutical agent in the blood, improve the targeting ability of the pharmaceutical agent and/or reducing side effects of farmacevticheskaja, in comparison with the input separately medicine.

In some embodiments, the implementation, the relative efficacy of the pharmaceutical agent when ingested in the form of the parts described herein, the pharmaceutical compositions is at least 20% higher than the relative efficacy of the pharmaceutical agent when orally administered separately; alternatively, at least 50% higher; alternatively, at least 2 times higher; alternatively, at least 3 times higher; alternatively, at least 4 times higher; alternatively, at least 5 times higher; alternatively, at least 10 times higher; alternatively, more than 10 times higher.

In some embodiments, implementation, ADME profile of the pharmaceutical agent when ingested in the form of the parts described herein, the pharmaceutical compositions modified in comparison with the ADME profile of the pharmaceutical agent when orally administered separately.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions leads to increased oral bioavailability of the pharmaceutical agent in comparison with orally administered pharmaceutical agent separately. In some embodiments done what I the relative oral bioavailability of the pharmaceutical agent when introduced as part of the here described pharmaceutical compositions is at least 10% higher than the relative efficacy of the pharmaceutical agent when orally administered separately; alternatively, at least 20% higher; alternatively, at least 50% higher; alternatively, at least 60% higher; alternatively, at least 70% higher; alternatively, at least 80% higher. In some embodiments, the implementation, the relative oral bioavailability of the pharmaceutical agent when introduced as part of the here described pharmaceutical compositions is at least two times higher than the relative oral bioavailability of the pharmaceutical agent when orally administered separately; alternatively, at least three times higher; alternatively, at least four times higher; alternatively, at least five times higher; alternatively, at least ten times higher.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions can lead to improved targeting and/or improved specificnostima pharmaceutical agent in comparison with oral introduction one active ingredient. Such targeting and specificity in some embodiments, the implementation can be further improved by applying one or more of the amplifiers discussed here, as part of the here described pharmaceutical compositions.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions leads to increased time half-life in the circulation of plasma or lymph pharmaceutical agent in comparison with the individual by oral administration. It should be clear that the ability to increase the half-life of the pharmaceutical agent with the use described herein, the pharmaceutical compositions may be independent from the oral bioavailability of the pharmaceutical agent. Described herein a pharmaceutical composition, when administered orally, can be used loosely for longer half-life, as well as highly available oral medications. In some embodiments, the implementation, the half-life of the pharmaceutical agent described herein, pharmaceutical compositions, when administered orally, is at least 10% higher than the half-life of the pharmaceutical agent when introduced separately; alternatively, at least 20% higher; alternatively, at least 3% higher; alternatively, at least 40% higher; alternatively, at least 50% higher; alternatively, at least 60% higher; alternatively, at least 70% higher; alternatively, at least 80% higher; alternatively, at least 90% higher; alternatively, at least 2 times higher; alternatively, at least 3 times higher.

In some embodiments, implementation, oral administration described herein, the pharmaceutical composition may lead to a more controlled time half-life of the pharmaceutical agent in the blood flow and lymph flow in comparison with the introduction of the pharmaceutical agent by injection or inhalation.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may not lead to high initial peak concentration after administration in comparison with high initial peak concentration after the introduction, which is found when using injectable or inhalation of drugs of the same pharmaceutical agent. This high concentration may cause side effects, such as immune response and inflammation, like a bruise.

In some embodiments, implementation, oral administration is described ZV is camping pharmaceutical composition can lead to slower release profile of the active reagent from the blood compared with orally administered active ingredient separately.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may result in reduced side effects or allergic reactions, even by oral administration of daily doses of a higher order, in comparison with oral administration of the pharmaceutical agent separately. This reduction may be seen in the number of patients reporting side effects or allergic reactions, or severity of side effects or allergic reactions.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may lead to treatment of diseases and conditions that otherwise could not be treatable by the same pharmaceutical agent when orally administered separately. In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may lead to improved treatment of diseases and conditions than under the separate introduction of the pharmaceutical agent in any other way than oral method, such as intravenous or inhalation administration.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may lead to the use of a lower dose (the number is TBA) the pharmaceutical agent to achieve a certain effect in comparison with the dose (amount) of a pharmaceutical agent, required to achieve the same effect when orally administered separately or when introduced separately in another way than oral method.

In some embodiments, implementation, oral administration described herein, the pharmaceutical compositions may lead to different biodistribution (i.e. distribution in various tissues and organs) in comparison with the biodistribution of the pharmaceutical agent when orally administered separately or with the introduction of separately injecting method.

Provided a pharmaceutical composition comprising intermolecular Association of at least one pharmaceutical agent, at least one biopolymer nanoparticles and at least one oil.

In some embodiments, implementation, this pharmaceutical composition is anhydrous. In some embodiments, implementation, this composition is preferably free of water and surfactants.

In some embodiments, implementation, this pharmaceutical composition is prepared in a form suitable for oral delivery using conventional methods known in this field. In some embodiments, implementation, this form is selected from the capsules (including soft gel capsules, hard gelatin capsules, tablets (including with pokr is ment tablets pressed pellets), liquid form (including solutions and suspensions), the jelly form, liquid form, covered with jelly or solid phase, pastes and the like, or combinations thereof. In some embodiments, implementation, this pharmaceutical composition can be prepared in the form of small droplets or microdroplets, impregnated in soluble biocompatible porous nutrient material similar to agar, fruit jellies, flakes, etc. or any biocompatible gel is water-based.

In some embodiments, implementation, can be used for parenteral administration described herein, the pharmaceutical compositions. This parenteral administration may be used in patients with any gastrointestinal problem, difficulty swallowing, or in accordance with the preference of the patient and the doctor. Parenteral administration of the pharmaceutical agent described herein, the pharmaceutical compositions may lead to different pharmacodynamic profile and/or profile of pharmakinetic in comparison with parenteral administration of these pharmaceutical agents without matrix of the carrier of this invention.

The pharmaceutical agent

In some embodiments, the implementation described here, the composition of the matrix of the carrier can be combined with one or more pharmaceutical the agents. In some embodiments, the implementation, one or more pharmaceutical agents covalently linked to one or more components of this composition matrix media.

In some embodiments, the implementation of this pharmaceutical agent contains one or more compounds with poor oral bioavailability. In some embodiments, the implementation of this pharmaceutical agent is poorly absorbed or not absorbed at all from the gastrointestinal tract or bowel. In some embodiments, the implementation of this pharmaceutical agent has low solubility in water and/or a slow rate of dissolution.

In some embodiments, the implementation of this pharmaceutical agent is a pharmaceutical agent that has a short half-life (t½) in plasma. In some embodiments, the implementation of this pharmaceutical agent is a drug with a half-life in plasma, shorter than 10 hours; alternatively, a drug with a half-life in plasma, shorter than 8 hours; alternatively, a drug with a half-life in plasma, shorter than six hours; alternatively, a drug with a half-life in plasma, shorter than four hours; alternatively, a drug with time pologize the plasma, shorter than three hours; alternatively, a drug with a half-life in plasma, shorter than two hours.

In some embodiments, implementation, these one or more pharmaceutical agents are slightly soluble in water and are crystalline, semi-crystalline, amorphous, or a combination of such conditions.

In some embodiments, the implementation of this pharmaceutical agent is branched in structure.

In some embodiments, the implementation of this pharmaceutical agent is essentially hydrophobic.

In some embodiments, the implementation of this pharmaceutical agent is essentially hydrophilic.

In some embodiments, implementation, these one or more pharmaceutical agents are water-soluble.

In some embodiments, implementation, this pharmaceutical composition comprises more than one pharmaceutical agent.

In some embodiments, the implementation of this pharmaceutical agent may include nutritional agent, or a combination of nourishing agents. The term "pharmaceutical drug" is intended to include substances having a pharmacological, and/or pharmaceutical and/or biological activity.

Additional components

According to some VA is yantam implementation this composition of the matrix medium may additionally include one or more additional components that can be used to enhance the effect achieved by applying this composition matrix media, and provide additional value to this matrix. In embodiments in which one or more additional components are the amplifier, as discussed below, this amplifier can be associated with the composition of the matrix media. For example, this additional components (optional components) may have a structural effect, favorable therapeutic effect (which may be synergistic against active reagent of this matrix), the target action, to allow better control of the pharmacokinetics of these compositions and the like, or any combination of them. These additional components may include any type of natural-occurring molecules, synthetic molecules, or combinations thereof. For example, the composition can be used in a variety of amino acids (such as, for example, but not limited to, arginine, histamine, aspartate, glutamate and the like), as the amplifier targeting. For example, molecules isolated from natural sources, can be used to provide additional therapeutic goals the surface active agent in the matrix. For example, these additional components may include extracts from various natural sources. Natural sources can include edible mushrooms, such as, for example, medicinal mushrooms, mushrooms Cordiceps (genus ascomycete fungi, plants, animals, etc. Sample molecules isolated from fungi, may include such components, but are not limited to, such as polysaccharides, such as, for example, beta-glucan, which stimulate the natural branch of the immune system, it was shown that beta-glucan can stimulate macrophages, NK-cells, T-cells and production of cytokines of the immune system; antioxidants, such as, for example, but not limited to, eritadenine, lovastatin, etc.; molecules with antihormone activity; vitamin D2; molecules with antiviral, antibacterial and/or antifungal properties; molecules with anticancer activity, such as, for example, polysaccharide compounds, isolated from Grifola frondosa (Grifola curly) (mushroom-RAM). Molecules isolated from plants, may include such molecules, but are not limited to, as polyphenols, which are characterized by the presence of more than one phenolic link or element structure in the molecule. Polyphenols are usually divided into hydrolyzable tannins (esters of Gallic acid glitch the system and other sugar) and containing, such as lignins, flavonoids, and condensed tannins, and may have antioxidant activity. In some embodiments, implementation, this additional component may include a selected molecule, selected fraction or extract molecules Cordiceps. In some embodiments, implementation, this additional component may include any type of glucagon-like peptide (GLP)such as GLP-1, GLP-2, or their equivalents. Glucagon-like peptide derived from the transcription product of the gene of proglucagon. The main source of GLP in the body is the intestinal L-cell, which secretes GLP as a hormone of the gastrointestinal tract (gastrointestinal hormone). Secretion of GLP-1 depends on the presence of nutrients in the lumen of the small intestine. The physiological role of GLP include: increasing the secretion of insulin from the pancreas-dependent glucose; decreases the secretion of glucagon from the pancreas; increases beta cell mass and gene expression of insulin; inhibition of gastric secretion and gastric emptying; reduction of food intake; increased insulin sensitivity. In some embodiments, implementation and without the desire to associate in any theory or any mechanism of action, the authors believe that GLP in this matrix provides structural effect through stabil the organization structure of this matrix. In addition, GLP provides additional beneficial effect (for example, when used in the composition of the matrix of media, which includes insulin as a protein reagent) by providing additional means of control of blood sugar levels and prevent ulcers. In addition, the use of GLP in the composition of the matrix medium may facilitate the targeting of matrix media.

In some embodiments, implementation, this composition matrix of the carrier and/or the pharmaceutical composition additionally contains at least one antioxidant. In some embodiments, implementation, this at least one antioxidant may include, but are not limited to, vitamin E, superoxide dismutase (SOD), catalase, glutathione peroxidase, N-acetylcysteine, Vitamin a, Vitamin D, Vitamin C, omega-3 and beta-carotene.

In some embodiments, implementation, essentially anhydrous pharmaceutical composition of the matrix medium may include molecules and/or particles having hydrophilic properties. Non-limiting examples are hydrophilic silica, water-soluble vitamins, etc.

In some embodiments, implementation, this composition matrix of the carrier and/or pharmaceutical composition further comprises at least one surface-act the main ingredient of the pharmaceutical category. Surfactants are well known in this field and are described, inter alia, in the Handbook of Pharmaceutical Excipients (eds. Raymond C Rowe, Paul J Sheskey and Sian C Owen, copyright Pharmaceutical Press, 2005). In some embodiments, the implementation, at least one surfactant is any other surface-active substance known in this field. Amplificatory and emulsifiers, each of which is an example of a surface-active substances is well known in this field and are described, inter alia, in the Handbook of Pharmaceutical Excipients (ibid). Non-limiting examples of emulsification and emulsifiers are eumulgin, Eumulgin B1 PH, Eumulgin B2 PH, hydrogenated castor oil, cetosteatil alcohol and cetyl alcohol. In some embodiments, implementation, emulsifier or emulsifier is any other emulsifier or emulsifier known in this field.

In some embodiments, implementation, this composition matrix of the carrier and/or pharmaceutical composition further comprises at least one stabilizer pharmaceutical grade. Stabilizers are well known in this field and are described, inter alia, in the Handbook of Pharmaceutical Excipients (ibid). In some embodiments, implementation, this at least one stabilizer is any other stabilizer known in this field.

According to n which which options implementation this composition matrix of the carrier and/or pharmaceutical composition may further include an amplifier and/or the target component.

The term "power" refers to any substance that directly or indirectly enhances the pharmacological effectiveness of the pharmaceutical agent. Non-limiting examples of enhancers include, but are not limited to: omega-3, beta-carotene, bioflavonoid, Biotin, antioxidant, amino acid, SOD, catalase, salts, trace elements, etc. or any combination of them. For example, it is known that beta-glucans such as Lentinan, has a beneficial effect on the immune system and can be used as an amplifier.

The term "target component" refers to any substance that can improve the targeting and/or biodistribution of the pharmaceutical agent to the desired spatial location. This target component may include any target agent that is known in this field, which can be used for targeting of the pharmaceutical agent to the desired spatial location. For example, this target component may include, but are not limited to, components such as specific antibodies, specific polysaccharides; positive and/or is a negative charged amino acids and/or polysaccharides; small molecules, which have an increased affinity in relation to specific receptors on the cell membrane and/or organelle tumor; short peptides; receptor antagonist and the like, or any combination of them. In some embodiments, the implementation of this target receptor selected from positively charged amino acids such as lysine, arginine, histidine, aspartate and glutamate. In some embodiments, implementation, this amp is the sugar alcohols. In some embodiments, the implementation of this target component is selected from mannitol and xylitol. Non-limiting examples of targeting agents include, but are not limited to: mannitol (which may improve penetration through the blood-brain barrier), amino acids, antibodies, and the like, or any combination of them.

In some embodiments, implementation of the amplifiers targeting can be used metals, metalloprotein, electrolytes, or any combination thereof, to assist in the targeting of these pharmaceutical agents to the desired spatial location based on the local environment in this location. These amplifiers targeting can be added at different stages depending on their properties and the desired action. This local environment may include, but are not limited to, such p is the parameters, as a local acidity, local temperature, the local concentration of the pharmaceutical agent, the potential distribution in the membrane, or any combination of them.

In some embodiments, implementation, this amplifier is selected from: bioflavonoids, heat shock proteins, minerals, etc.

According to some variants of implementation, this pharmaceutical composition may include more than one pharmaceutical agent, one or more amplifiers and/or targeting components, or a combination of both. Each possibility represents a separate variant implementation of the invention.

In some embodiments, implementation, this composition matrix of the carrier and/or pharmaceutical composition may further comprise at least one amplifier therapeutic activity of the pharmaceutical agent. In some embodiments, implementation, this composition matrix of the carrier and/or pharmaceutical composition may further comprise at least one cofactor.

In some embodiments, the implementation, as qualified in this area specialists, the amplifier can detect therapeutic activity. That is, in some embodiments, the implementation, the amplifier can perform a dual function, namely as the pharmaceutical is ski agent independently and as agent, which enhances the activity of another pharmaceutical agent.

In some embodiments, implementation, this composition matrix of the carrier and/or pharmaceutical composition further comprises at least one amino acid selected from arginine, lysine, aspartate, glutamate, and histidine. In some embodiments, implementation, analogues and modified versions of arginine, lysine, aspartate, glutamate and histidine included in the term "arginine, lysine, aspartate, glutamate, and histidine respectively. In some embodiments, implementation, this at least one amino acid stimulates the interaction of the pharmaceutical agent with the cell-target.

In some embodiments, the implementation of at least one excipient provides the desired taste of this pharmaceutical composition. In some embodiments, implementation, this at least one excipient affect the consistency of the medicinal product and the final dosage form, such as a gel (gelatin) capsule, hard gelatin capsule, tablet or soft gel.

Non-limiting examples of excipients include:

Protivovspenivayushchie agents (Dimethicone, simethicone);

Antimicrobial preservatives (benzalkonium chloride, chloride benzelconia, butylparaben, chloride of cetylpyridinium, chlorbutanol, chlorocresol, cresol, tilaran, methylparaben, sodium methylparaben, phenol, phenethyl alcohol, PHENYLMERCURIC, PHENYLMERCURIC, potassium benzoate, potassium sorbate, propylparaben, sodium propylparaben, sodium benzoate, dehydroacetic sodium, sodium propionate, sorbic acid, thimerosal, thymol);

Hepatoblastoma agents (edetate disodium, ethylenediaminetetraacetic acid and its salts, adamovo acid);

Agents for coating (sodium-carboxymethyl cellulose, acetate cellulose, acetate-phthalate cellulose, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate-phthalate, shellac, sucrose, titanium dioxide, Carnauba wax, microcrystalline wax, Zein);

Coloring (caramel, red, yellow, black, or mixtures thereof, an oxide of trivalent iron);

Complexing agents (ethylenediaminetetraacetic acid and its salts (EDTA), adamovo acid, ethanolamide hentaimovi acid, sulfate oksihinolina);

Desiccant (calcium chloride, calcium sulfate, silicon dioxide);

Emulsifying and/or solubilizing agents (Arabian gum, cholesterol, diethanolamine (Supplement), glycerylmonostearate, lanolin alcohols, lecithin, mono - and diglycerides, monoethanol the amine (additive), oleic acid (additive), alerby alcohol (stabilizer), poloxamer, polyoxyethylene-50 stearate, polyoxyl-35-castor oil, polyoxyl-40-hydrogenated castor oil, polyoxyl-10-alerby simple ether, polyoxyl-20-cetosteatil simple ether, polyoxyl-40-stearate, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, monolaurate sorbitan, monooleate sorbitan, monopalmitate sorbitan, monostearate sorbitan, stearic acid, trolamine, emulsifying wax);

Flavors and fragrances (anethole, benzaldehyde, ethylvanillin, menthol, methyl salicylate, MSG, oil, orange flower, pepper mint, peppermint oil, spirit of peppermint, pink (essential) oil, stronger rose water, thymol, tinctures townscape balsam, vanilla, vanilla tincture, vanillin);

Moisturizers (glycerin, hexyleneglycol, propylene glycol, sorbitol);

Polymers (e.g. cellulose acetate, alkylaryl, hydroxyethylcellulose, acrylic polymers and copolymers);

Suspendresume and/or increasing the viscosity agents (Arabian gum, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, the bentonite in the form of magma, carbomer 934p, carboxymethylcellulose calcium, carboxin is etilzelluloza sodium, the of carboxymethylcellulose sodium 12, carrageenan, microcrystalline cellulose and carboxymethylcellulose sodium, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, magnesium silicate-aluminum, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragakant, xanthan gum);

Sweetening agents (aspartame, dextrine, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol solution sorbitol, sucrose, compressible sugar, confectionery sugar, syrup); or any combination of them.

It is assumed that this list is not an exclusive list, but is merely representative of classes of excipients and types of excipients that may be used is described here, the oral pharmaceutical compositions.

Methods of preparing compositions of matrix carriers

According to some variants of implementation, provided the methods of preparation described herein, the composition of the matrix media. In some embodiments, implementation method, intended to illustrate the disclosure of the invention, but without limiting its scope, contains at least n is which of the following stages:

1. Activating a surface of the second solid phase matrix media additional grinding, vacuum processing, chemical or ultrasonic cleaning or grinding.

2. Mixing of biopolymers with liquid oils in vacuum or in an inert atmosphere.

3. The introduction of nanoparticles in oil and optional vacuum to remove air from the surface of the nanoparticles.

4. Introduction pharmaceutical agent (pharmaceutical agents) in net oil with hydrophobic nanoparticles or oil with biopolymers, with silicon dioxide or without silicon dioxide, depending on the physical properties (such as hydrophobicity) of the pharmaceutical agent.

5. Mixing and homogenization of this system may take into account the sensitivity of this pharmaceutical agent to mechanical stress. This process can be performed in an inert atmosphere with temperature control, speed and time. This homogenization can reduce the viscosity and to stimulate the package.

"Maturation" of the composition matrix of the carrier can be achieved by maintaining under controlled temperature (for example, in the range of about 1-37º) within 1-72 hours with an inert atmosphere or without an inert atmosphere.

According to some variants of implementation, the order of the stages of cooking can aviati on the specific equipment used and the properties of the pharmaceutical agent and can be changed accordingly.

In other embodiments, implementation method, designed to illustrate this description, but not limiting of its scope, provides:

mixing at least one oil of nanoparticles and at least one biopolymer, whereby is formed intermolecular Association that at least one biopolymer, these nanoparticles and at least one oil.

In some embodiments, the implementation, a method of manufacturing the composition of the matrix of media designed to illustrate this description, however, without limiting its scope, provides:

a) combining the nanoparticles with at least one biopolymer; and

b) mixing the combination of at least one oil,

whereby is formed intermolecular Association of at least one biopolymer nanoparticles and at least one oil.

In some embodiments of the exercise, this mix can include dry mixing. In variants, including dry mixing, combining the nanoparticles with at least one biopolymer additionally includes the stage of confirmation that this combination properly homogenized. In some embodiments, implementation, use any of the following three tests, and for determining the appropriate homogenization enough, the EU and a positive result was obtained in any of these three tests, even in the case when one or more of the other tests may not detect a positive result: (a) this mixture has the appearance of a homogeneous mixture; (b) the volume of the mixture is less than the sum of these two components; and (c) this mixture is not absorbed when placed on the surface of stagnant water. If this combination does not satisfy any of these three criteria, in some embodiments, the implementation of this method further includes adding additional nanoparticles or hydrophobic agent to the mixture. These stages repeat until this combination will not satisfy at least one of the above criteria.

In some embodiments, the implementation, a method of manufacturing the composition of the matrix of media designed to illustrate this description, but without limiting its scope, provides stage:

a) combining the nanoparticles, at least one biopolymer and at least one structural protein; and

b) mixing the combination, at least one lubricant whereby is formed intermolecular Association of at least one biopolymer nanoparticles, at least one structural protein and at least one oil.

Provided the methods of manufacture described herein, the pharmaceutical compositions.

In some embodiments, the implementation of the Oia, a method of manufacturing these pharmaceutical compositions involves stages:

(a) providing the composition of the matrix carrier;

(b) mixing at least one pharmaceutical agent is at least one oil; and

(c) combining the composition of matrix media with a mixture of the pharmaceutical agent is at least one oil.

In some embodiments, implementation, production, these pharmaceutical compositions involves stages:

(a) mixing the nanoparticles with at least one biopolymer;

(b) mixing at least one pharmaceutical agent is at least one oil; and

(c) combining the mixture of nanoparticles and at least one biopolymer with a mixture of the pharmaceutical agent is at least one oil.

In some embodiments, implementation, production, these pharmaceutical compositions involves stages:

(a) mixing at least one biopolymer, at least one oil;

(b) mixing the nanoparticles with at least one oil;

(C) combining the mixture of nanoparticles and at least one biopolymer with a mixture of the pharmaceutical agent is at least one oil.

In some embodiments, implementation, methods of preparation described here pharmaceutically what songs include:

the manufacture of pharmaceutical compositions in a form suitable for oral delivery.

Qualified in this field specialist is known that the order of mixing and the order of addition of the individual components can be modified to meet any specific requirements.

In some embodiments, the implementation, the manufacturing process can be used an inert gas, such as, for example, N2or CO2to prevent oxidation of at least one oil (or one or more other components during the manufacturing process. This manufacturing process can be carried out in a closed reactor having an inner rotor. In this reactor can be added N2and/or CO2.

In some embodiments, implementation, use the mixer with a high cutting force. In some embodiments, implementation, use other means to generate a homogeneous product, defined above, of the nanoparticles and at least one biopolymer.

In some embodiments, implementation, this method additionally provides for the suspension of the composition of the matrix carrier in at least one oil until you obtain a homogeneous distribution determined above, this solid phase, using technologies such as ozonation (arlift) or fluidized bed. The oil used in the preparation of this suspension may be the same oil or oil that is different from at least one of the oils used in the manufacture of the composition of the matrix medium.

Technology ozonation (airlift) includes the introduction of gas bubbles into the liquid composition. A stream of bubbles effectively mixes the liquid and/or suspension and may facilitate the interaction and/or adsorption of particles. Specifically, the surface of the bubbles adsorb various particles and generates a shock wave during the destruction of the bubbles. This "boiling layer" gas form flying droplets and/or particles in the ascending stream of gas above the liquid surface. Droplets can be created by the spray from the ultrasonic transducer. This fluidized bed improves the interaction of these particles and liquid droplets (oil) due to increased frequency and energy of collisions.

In some embodiments, implementation, this biopolymer can be subjected to dry grinding/grinding before use. In some embodiments, the implementation can be achieved particle size of the biopolymer (for example, to improve homogeneity, for example, less than 10 μm, by means of homogenization of the biopolymer of at least one oil before adding the nanoparticles. In some embodiments, is sushestvennee, can be used vacuum means for removing moisture and air from a mixture of biopolymer and/or lyophilized pharmaceutical agent (in oil or without oil).

In some embodiments, implementation, to improve absorption, biopolymer and the surface of the nanoparticles release from microbubble air and small droplets of water. This can be achieved by vacuum drying and removing gas and/or drying transmission desiccant (such as, for example, gases such as N2, CO2He or other inert gases) through the mixture. Removing gas may also be performed by centrifugation and/or deep vacuum.

In some embodiments, the implementation, a method of manufacturing the composition of the matrix carrier is provided for stage add more oil after adding at least one oil. The term "extra oil" includes oil or mixture of oils, as described herein elsewhere. In some embodiments, implementation, this additional oil, or a mixture of oil has a higher viscosity than the first added oil or for the first time added a mixture of oils. In some embodiments, implementation, without the desire to associate in any theory or any mechanism of action, the authors believe that the use of oil or mixture of oils of higher viscosity n is this stage may promote the formation of ordered structures in this composition.

In some embodiments, the implementation, a method of manufacturing the composition of the matrix carrier is provided for adding a third stage of oil or oil mixture after adding the above-described at least one oil.

In some embodiments, the implementation is at least one oil comprises at least one wax. In some embodiments, implementation, this at least one wax is heated. In some embodiments, implementation, this at least one wax pulverizer (sprayed). In some embodiments, implementation, these heating and/or spraying performed before mixing with other components. In some embodiments, implementation, this at least one wax is still hot when you start mixing with other components. In some embodiments, implementation, these heating and/or spraying performed before mixing, and during mixing with these other components.

In some embodiments, the implementation, the wax may be additionally used as an additional stabilizing the rheological component. The wax does not have a hydrophilic surface and has an internal energy, which is lower than the internal energy of polysaccharides and silicon dioxide. Low internal energy of the wax is associated with a low melting point is Oska. A high melting point can deactivate/denaturing pharmaceutical agent during the process of making this composition. To this end, the eutectic mixture with a lower melting point between them can be prepared prior to mixing of the wax with additional wax or oil having a high thermostability. The application of this eutectic mixture of wax and oil mixture with a pharmaceutical agent, with gentle stirring (for example, at about 2000-2500 rpm) allows the cooling of the eutectic mixture, and, therefore, are formed of solid and liquid dispersed phase. This process may optionally allow the formation of small droplets of solid wax. Without the desire to associate in any theory or any mechanism of action, the authors believe that the formation of such small solid fat droplets, these droplets, after the introduction will not be digested by lipases and can move in the faeces, and therefore effective against penetration of this anticancer reagent will increase relative to the liquid composition without the wax and additional liquid phase. The choice of the type of wax with the desired specific melting point and its final concentration, and the method of its introduction allow you to adjust the dispersion and stability and design is stencil of the final composition.

This oil or mixture of oils used for each pharmaceutical agent may be the same or different.

In some embodiments, implementation, two or more different pharmaceutical agents may be combined in a single mixture of nanoparticles associated with the biopolymer, and then mixed with oil components.

In some embodiments, implementation, two or more pharmaceutical agents may be separately combined with nanoparticles associated with the biopolymer, and then these separate mixture may be further mixed together with these oil components.

In some embodiments, the implementation stage of mixing the pharmaceutical agent is at least one oil includes a stage direct dissolution of the pharmaceutical agent is at least one oil. In some embodiments, the implementation, the solution of the pharmaceutical agent in a solvent such as water, is mixed with at least one oil, and then the solvent is removed. In some embodiments, the implementation, the solution of the pharmaceutical agent may be dried before adding to oil.

In some embodiments, the implementation of this pharmaceutical agent forms a suspension when mixed with at least one oil. In some embodiments, the wasp is estline, this pharmaceutical agent is dissolved in at least one oil.

In some embodiments, the implementation of this pharmaceutical agent is mixed with at least one oil in the presence of alcohol.

In some embodiments, the implementation of this pharmaceutical agent is mixed with at least one oil in the presence of the presence of polyethylene glycol. In some embodiments, the implementation, the polyethylene glycol has a molecular weight in the range 200-8000 Dalton.

In some embodiments, the implementation of this pharmaceutical agent is mixed with at least one oil in the presence of perfluorocarbons. In some embodiments, implementation, this perfluorocarbons is liquid at room temperature.

In some embodiments, the implementation of this pharmaceutical agent is mixed with at least one oil with anhydrous conditions. In some embodiments, implementation, moisture is present. In some embodiments, implementation, an aqueous solution of the pharmaceutical agent is mixed with at least one oil.

In some embodiments, the implementation of this pharmaceutical agent can be dissolved in oil and remains there for 10-48 hours or more before manufacture of the drug.

In some embodiments, the implement, the combination of multiple pharmaceutical agents is s may be made in the form of a single substance. In some embodiments, implementation, manufacture consisting of material particles, each containing a pharmaceutical agent, perform separately, and in the last stage of these separate consisting of particles of materials are put together without additional mixing. Can be used several technologies to prevent comparative adsorption of these pharmaceutical agents on this solid phase, and the chemical interaction between them: each of these pharmaceutical agents are prepared in the form of jelly (jelly) (non-cryogenic preparation) or with any bioavailable induration; these drugs pharmaceutical agent can be prepared in the form of a mixture of small droplets or particles of almost solid materials (at room temperature) and/or suspension in a liquid lipid phase solid or semi-solid balls and/or pieces with pharmaceutical agents.

In some embodiments, the implementation, a method of manufacturing a pharmaceutical agent comprising the Association of these pharmaceutical agents with the biopolymer and/or nanoparticle, can be performed, for example, through the "Sandwich”technology ("sandwich"technology ensures the formation of a multilayer structure that consists of sequentially adsorbed components. Thus, this process provides serial is inuu spatial and temporal adsorption with the desired properties). Exposure can occur within 30 minutes to 72 hours, depending on the specific pharmaceutical agent and requirements therapy (which may affect FC and FD). Can be further mixed with other ingredients, for example, can be used for pre-adsorption 0-100% nanoparticles or biopolymers in accordance with the required FC and FD. Activity adsorption of nanoparticles and/or biopolymers can be achieved by pretreatment in a homogenizer and/or ultrasound. For some pharmaceutical agents can be used, colloidal metals, such as Zn, Cu, Fe, etc. as constituting the element structure. To ensure these colloidal metals in the finished form can be used a controlled electrolysis with the additional lyophilization or vacuum drying.

Provided the products described herein manufacturing methods.

According to additional options for implementation, and as shown in example 7, for the extraction of pharmaceutical agent from the composition matrix media solution should be used in the extraction procedure. The application of such procedures extraction indicates that the pharmaceutical agent is retained in the matrix medium in complex non-covalent forces, and the investigator is about, the use of an organic solvent and a surfactant is necessary for the extraction of the specified agent from the matrix.

Although the above has been discussed a number of exemplary aspects and options, qualified in this field specialists will be known some modifications, permutations, additions, and their subcombination. Thus, it is assumed that the following appended claims and the formula entered next, should be interpreted as including all such modifications, permutations, additions and subcombination as within their actual entities and volume.

In this description and the attached claims each of the words "include", "includes" and "have" and their shape is not necessarily limited to members of the list with which these words can be associated.

EXAMPLES

The following examples are intended to illustrate this description of the invention, but without limiting its scope.

Example 1: Manufacture of pharmaceutical compositions of matrix media - common Protocol No. 1

The following process can be used for the manufacture of pharmaceutical compositions, as described herein.

Stage 1. Add the pharmaceutical agent is at least one oil. Optional keep in the refrigerator for 12 to 72 hours./p>

Stage 2. Mix and/or homogentisate biopolymer and silicon dioxide in oil.

Stage 3. Can be used a vacuum to remove adsorbed gases.

Stage 4. Continue mixing.

Stage 5. Add amplifiers, continue mixing.

Stage 6. Packing finished stage 5.

Example 2: Production of pharmaceutical compositions of matrix media - common Protocol No. 2

The following process can be used for the manufacture of pharmaceutical compositions, as described herein.

Stage 1. Optional dry grinding of one or more biopolymers together (extra dry mixing).

Stage 2. Introduction parts of a mixture of biopolymers in the oil, mixing; the introduction of part of the silicon dioxide, mixing and continue adding one by one until you enter the entire silicon dioxide and all biopolymers.

Stage 3. Vacuum mixing for removal of gases.

Stage 4. Adding a pharmaceutical agent blending.

Stage 5. Optional add amplifiers, additional components, mixing.

Stage 6. Packing finished stage 5.

Example 3: Production of pharmaceutical compositions of matrix media - common Protocol No. 3

The following process can be used for the manufacture of pharmaceutical compositions, is described here.

Stage 1. The introduction of hydrophobic nanoparticles of silicon dioxide and polysaccharides (or mixture of polysaccharides) in the lipid or mixture of lipids (oils), for example, using technologies such as ozonation inert gases or fluidized bed and a strong mixing using a mixer or homogenizer with high power shift, until it is homogeneous distributed suspension oil-based.

Stage 2. Adding a pharmaceutical agent in the slurry, based on the lipid/oil phase 1; it is important to control the temperature, the intensity of mixing and oxidation properties of the gas phase reactor, in which perform the mixing.

Stage 3. Mixing the suspension of oil-based stage 2, until it is homogeneous distributed suspension oil.

Stage 4. Add target and/or reinforcing component, such as arginine, vitamins or coenzymes for homogeneous distributed suspension of oil-based with stage 3 and careful mixing with the inert mixer materials in an inert atmosphere.

Stage 5. Adding, mixing, additional oils, such as palm oil and/or wax for physical stabilization of this form.

Stage 6. Packing finished stage 5.

Example 4: Production of pharmaceutical compositions of matrix media - General Protocol # :

The following process can be used for the manufacture of pharmaceutical compositions, as described herein.

Stage 1. Dry mixing the hydrophobic nanoparticles of silicon dioxide or a mixture of polysaccharides in the reactor with a sealing liquid or gas (sealing with controlled leakage of the working environment provides protection to the media, valves and the environment from contamination by aerosols and nanoparticles). Dry mixing may be performed by a mixer with protected blades or gas using fluidized bed technology.

Stage 2. The introduction of a pharmaceutical agent in a lipid, oil or mixture of oils.

Stage 3. Careful mixing of the suspension based on the lipid phase 2 and powder of nanoparticles of silicon oxide and polysaccharide stage 1, has not yet achieved a homogeneous distribution of the solid phase.

Stage 4. Add target and/or reinforcing component, such as arginine, vitamins or coenzymes for homogeneous distributed suspension of oil-based stage 3 and careful mixing with the inert mixer materials in an inert atmosphere.

Stage 5. Adding, mixing, additional oils, such as palm oil and/or wax for physical stabilization of this form.

Stage 6. Packing finished stage 5.

Example 5: Production pharmacist the political composition of matrix media General Protocol No. 4

The following process can be used for the manufacture of pharmaceutical compositions, as described herein.

1. Activation of the second solid phase matrix carrier additional grinding, vacuum processing, chemical or ultrasonic cleaning or grinding.

2. Mixing the activated biopolymer (such as polysaccharides) with liquid oils under vacuum or in an inert atmosphere.

3. The introduction of nanoparticles in oil and additional processing to remove air from the surface of the particles.

4. Introduction pharmaceutical agent (pharmaceutical agents) in net oil with hydrophobic nanoparticles or oil with biopolymers with silicon dioxide or without silicon dioxide, depending on the hydrophobicity of the pharmaceutical agent.

5. Mixing and homogenization of this system takes into account the sensitivity of these pharmaceutical agents to mechanical stress. This process is provided by an inert atmosphere with temperature control, speed and processing time.

6. This homogenization makes possible the introduction of this material for more energy, which can reduce the viscosity of these materials and to enhance their packaging.

7. The maturation of this material can be achieved by maintaining at a controlled temperature (in the range is 1-25ºC) for 1-72 hours. This maturation can increase the viscosity and the binding energy of the matrix carrier with the pharmaceutical agent.

Example 6: Analysis and comparison of insulin matrix carrier or without matrix-media

Stability analysis LC/MS samples of insulin was performed to assess the stability of insulin in the product matrix of the carrier, or without the drug matrix media at different time points (0, 2 weeks, 1 month and 3 months) during storage at 4-5ºC. The crude bulk material of insulin without the drug matrix media were stored in glass vials. Insulin drug matrix media, the composition of which is described in more detail in example 7, was encapsulated in gelatin capsules (Capsugel, size 00). For analysis VGH and LC/MS these samples were subjected to similar extraction procedure, as described in more detail in example 7 below.

Figure 1, panel A, shows the LC/MS of the crude material of insulin (i.e. insulin, not in matrix media) after 3 months of storage at 4-5ºC. Fig. 1, panel B, shows the LC/MS of insulin extracted from the drug matrix media, after 3 months of storage at 4-5ºC.

Comparison of the spectra of LC/MS panels a and b of Fig. 1 shows that these two spectra are similar. These results suggest that the drug matrix media does not reduce the camera is lnost pharmaceutical agent and that the connections between these pharmaceutical agent (insulin) and the matrix carrier are not covalent.

Example 7: Extraction of pharmaceutical agent from the matrix carrier

To demonstrate that this pharmaceutical agent forms a complex with this matrix carrier, protecting it from the external environment, tested two oral drug sensitive pharmaceutical agent such as proteins. These testing pharmaceutical agents were Tnkase and insulin.

The composition of the drug dnaase (Packed in a capsule):

50 gTnkase
25 gSilicon dioxide
80 gJojoba oil
80 gSea buckthorn oil
60 gOlive oil
90 gPalm oil
75 gThe amylopectin
25 gBeta-cyclodextrin

A member of the drug insulin (Packed in a capsule):

2 gInsulin
30 gSilica R972
50 gBeta-cyclodextrin
200 gNutrioso
50 gMaltisorb
260 gOlive oil
260 gPalm oil
200 gSea buckthorn oil

Ways

Each capsule drug Gnkazy was treated with 20 ml of water at 35 º C for ~1 hour. Took the first test. Added 5 ml of hexane and the mixture is gently mixed and then centrifuged at 3000 rpm for 10 minutes and took the second test. Then the mixture was strongly stirred, and centrifuged, and took the third sample (diluted 5 times). Contents Gnkazy was calculated from the peak area of Gnkazy in the chromatogram compared with the calibration curve. These results are summarized in the table below.

The number of Gnkazy the capsule, calculated using VIH-way
The calculated mass of Gnkazy (mg)
3rd2nd1st3rd2nd1st
to 97.9117,8612,6721460,319570,713890,1capsule 1
106,1521,709,8323265,423781,710767,7capsule 2
101,6119,6411,6422269,821522,212752,8capsule 3
97,5916,69to 8.3421389,118293,59134,4capsule 4
102,3818,5910,9722439,1 12025,6capsule 5
98,8016,0414,7821653,817578,616194,6capsule 6
127,23of 22.4411,6827886,524594,4012797,7capsule 7
101,9418,4211,0622343,320183,1012122,1capsule 8
103,0420,5110,7522584,822471,9011783,9capsule 9
119,3821,9813,6526165,8024084,0014955,4capsule 10
105,6019,3911,54 The average standard deviation
9,852,241,84
was 9.3311,5515,99The relative standard deviation

Additional analysis shows that the addition of 2.5% surfactant (such as TWEEN-20) leads to an additional 8-10% increase in extraction Gnkazy from the composition of the matrix media. Similar results were repeated for insulin as a pharmaceutical agent in the preparation of the composition of the matrix medium.

In addition, the drug is insulin was tested by incubation with a mixture of intestinal enzymes in 37º for various periods of time up to 16 hours. These results did not show degradation of insulin.

Performed additional experiments for dissolution of the drug insulin incubation at 37º in different environments, such as clean water, saline solution, acid solution with pepsin, fetal pig serum and saline with 2.5% Tween-20. The destruction of this matrix media mainly observed in environments that contain synthetic or natural surfactants blood, such as, for example, tween-20 or serum.

Primer: Injection of the composition matrix media containing insulin, in comparison with standard injection of insulin

Used the following insulin:

The drug IStandard drug insulin

Injection solution of insulin in SFR, 50 IU

Recombinant human insulin in lyophilized form was dissolved in phosphate buffer at a concentration of 50 IU/ml

Preparation IIThe composition of matrix media

Composition of matrix media with the drug, insulin, 50 IU

- Ingredients for this preparation is described in example 7 above.

Experimental details

This study consisted of 8 animals (rats) in each group.

Blood samples were taken under anesthesia with halothane gas from the tail of the rat. Glucose levels were measured from each blood sample by glucosemeter FreeStyle, Abbott. After taking blood samples were kept on ice and then centrifuged at 3500 rpm, 4ºC to separate plasma. The level of insulin in the plasma of rats was measured using an ELISA kit for human insulin (Millipore kit (Cat. # EZHI-14K).

After taking the first blood samples of rats were injected with the Drug I (insulin only, 50 IU) or II Drug (the same insulin in the composition of matrix media, 50 IU). Additional blood samples were taken at time intervals after the injection: 3 hours, 6 hours, 9 hours, 12 hours and 24 hours.

The results, illustrated in the figure And, show that the blood glucose levels decreased after the injection II in comparison with standard injection of insulin (Preparation I). In addition, the results illustrated in figure 2B show that the concentration of plasma injected human insulin in rats was measured using the ELISA kit for human insulin (Cat. # EZHI-14K), is still high after 25 hours, if these rats were injected Drug II, in comparison with standard injection drug insulin (Preparation I).

1. The composition of the matrix carrier for use in the pharmaceutical delivery system for oral administration, and this composition is a suspension comprising particles of material in a continuous oil phase, where consisting of particles of material contains:
the first solid phase containing nanoparticles of silica having a hydrophobic surface, where the size of these nanoparticles of silicon dioxide is in the range of about 5-1000 nm; and
the second solid phase containing the biopolymer having a hydrophilic and a hydrophobic part, where the specified biopolymer contains polysaccharide,
moreover, the specified continuous oil phase is associated with the specified first and the second solid phases, and weight of the biopolymer of at least two times greater than the mass of nanoparticles of silicon dioxide.

2. Com is azizia matrix carrier according to claim 1, where the density of the first solid phase is higher than 1.4 g/cm3.

3. The composition of the matrix carrier according to claim 1, where the nano-particles of silicon dioxide have a surface that is modified so that it is hydrophobic.

4. The composition of the matrix carrier according to claim 1, where the biopolymer has a structure selected from a linear structure, a cyclic structure and a branched structure.

5. The composition of the matrix carrier according to claim 1, where the polysaccharide contains starch, dextrin, cellulose, chitin, alpha-glucan, beta-glucan, amylopectin, glycogen, chitosan, cyclodextrin, mucopolysaccharide or their derivatives or combinations.

6. The composition of the matrix carrier according to claim 1, where the oil contains one or several natural occurring oils; one or more synthetic oils, one or more waxes, lanolin, fatty alcohol, preferably 2-octyldodecanol, fatty acid ester or phenylsilane, preferably penultimately, diphenylmethane and polymethylphenylsiloxane or combinations thereof.

7. The composition of the matrix carrier according to claim 1, where this oil is selected from the group consisting of sesame oil, olive oil, Flaxseed oil, evening primrose oil, silicone oil, oil of sea-buckthorn, palm oil, or any combination thereof; or from the group consisting of sunflower mA is La, corn oil, soybean oil, jojoba oil, bone marrow oil, grapeseed oil, oil of nutmeg, apricot oil, oil, Australian nut, palm oil, almond oil, castor oil, etc. or any combination thereof; or from the group consisting of sea buckthorn oil, jojoba oil, olive oil, or combinations thereof; or from the group consisting of olive oil, flax seed oil, sea buckthorn oil, sesame oil, palm oil, or combinations thereof; or from the group consisting of jojoba oil, sea buckthorn oil, sesame oil, olive oil or combinations thereof; or from the group consisting of wax, jojoba oil, sea buckthorn oil, sesame oil, olive oil, or combinations thereof; or from the group consisting of linseed oil, sea buckthorn oil, olive oil, palm oil, or combinations thereof.

8. The composition of the matrix carrier according to claim 1, where the volume ratio between the first solid phase and a second solid phase is determined in accordance with equation 1:
V1×c1≤V2×c2 (equation 1);
where
V1 denotes the volume of the first solid phase;
C1 denotes the speed of sound in the first solid phase;
V2 denotes the volume of the second solid phase; and
C2 denotes the speed of sound in the second solid phase.

9. The composition of the matrix carrier according to claim 1, where the specified composition additionally contains at the ore one antioxidant, where is that at least one antioxidant contains beta-carotene; and/or amino acid selected from the group consisting of arginine, lysine, glutamic acid, aspartic acid and histidine and combinations and derivatives.

10. The composition of the matrix carrier according to claim 1, where the specified composition is anhydrous.

11. The method of obtaining the composition of the matrix carrier according to claim 1, including:
mixing the first solid phase with oil, where the first solid phase contains nanoparticles of silica having a hydrophobic surface and a particle size of about 5-1000 nm;
activating the second solid phase, where the second solid phase contains a biopolymer having a hydrophilic and a hydrophobic part, where the biopolymer contains polysaccharide, and activation involves grinding, vacuum processing, chemical treatment, ultrasonic treatment, or any combination of them;
adding this activated second solid phase in the oil; and
blending oils containing first solid phase, and the oil containing the activated second solid phase.

12. The method according to claim 11, where
one or several stages of this method is performed in a vacuum or in an inert atmosphere, and/or
where this method additionally provides for the homogenization of the mixture of oils containing first solid phase, and the oil is, containing activated second solid phase; and/or
additionally provides for the maturation of the composition of the matrix carrier for about 1-72 hours, where the specified maturation preferably performed at a temperature in the range of about 1-25°C.

13. The method according to claim 11, further providing for the addition of an agent selected from an antioxidant, amino acids or combinations thereof, optionally pre-mixed with oil, and the oil containing the activated second solid phase; (b) oil containing a first solid phase; or (C) of the oil mixture containing the activated second solid phase, and the oil containing the first solid phase.



 

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19 cl, 3 dwg

FIELD: metallurgy.

SUBSTANCE: proposed method comprises mixing of carrier powder with superfine modifying powder in planetary-type mill and compaction of obtained composition. Said superfine modifying powder represents the composition of powders of silicon carbide (SiC) - 50÷70%, silicon nitride (Si3N4) - 20÷30%, sodium hexafluoraluminate (Na3AlF6) - 10÷20% produced by azide process of self-propagating high-temperature synthesis with particle size of 70-100 nm Note here that silicon carbide features β-modification. Said superfine modifying powder carrier represents the copper powder with particle size not over 180 mcm at copper-to-superfine powder ratio of 9:1.

EFFECT: application of modifier of aluminium alloys allows making of dendrites 2,4 time smaller to up the alloy mechanical properties.

1 tbl, 1 dwg

Cutting plate // 2528288

FIELD: process engineering.

SUBSTANCE: invention relates to machine building, particularly, to metal forming. Cutting plate comprises substrate of hard alloy with wearproof ply applied thereon of nanostructured tungsten carbide and niobium carbide with grain size of 20-50 nm at their following ration, wt %: nanostructured tungsten carbide - 90, nanostructured niobium carbide making the rest.

EFFECT: higher wear resistance at hard cutting modes.

1 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: method includes mechanical-activation processing in a planetary ball mill of solid solutions, which contain bismuth and antimony tellurides with an addition of a grinding agent and further sintering of obtained powders. Mechanical-activation processing is carried out successively in two stages: first, with centrifugal acceleration of grinding bodies in the interval from 800 to 1000 m/sec2 for 10-30 min, then with centrifugal acceleration of the grinding bodies in the interval from 20 to 100 m/sec2 for 20-40 min. As the grinding agent used are compounds of a layered structure, selected from the group: MoS2, MoSe, WS2, WSe, BN or graphite. The grinding agent is taken in an amount of 0.1-1.5 wt % of weight of the solid solution of bismuth and antimony tellurides. The obtained thermoelectric material consists of particles of the triple solid solutions of bismuth and antimony tellurides with a size from 5 nm to 100 nm, between which from 1 to 10 nm thick layers of a compound, selected from the group: MoS2, MoSe, WS2, WSe, BN or graphire, are located.

EFFECT: increase of the thermoelectric figure of merit.

2 cl, 3 dwg

FIELD: measurement equipment.

SUBSTANCE: invention relates to gas analysis and may be used to control toxic and explosive gases and in these areas of science and engineering, where analysis of gas media is required. A semiconductor sensitive element according to the invention represents an isolating substrate with previously applied contacts, on which, by application of a film-forming water-alcohol solution SnCl2 with carbon nanotubes they form a layer of nanocomposite of tin dioxide. The sensitive element manufactured in this manner is exposed to drying for 10 minutes at 150°C with subsequent stabilising annealing on air for 30 minutes at temperature of not below 370°C for formation of the nanocrystalline structure.

EFFECT: invention is aimed at increasing value of gas sensitivity and selectivity of a sensor element.

2 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: method includes modification of a carrier, which is represented by amine-containing nanoparticles of silicon dioxide with a size up to 24 nm, by processing the latter with N-hydroxysuccinimide ether of aliphatic azido acid, then obtaining modified nucleosidetriphosphate (pppN) by processing the latter with a mixture of triphenylphosphine/dithiodipyridine with further incubation of the formed active derivative pppN with 3-propinyloxypropylamine and further immobilisation of the modified pppN on the obtained asidomodified nanoparticles for 2-4 hours.

EFFECT: reduction of the method duration and an increased quality of the target product.

3 cl, 4 dwg, 9 ex

FIELD: ammunition.

SUBSTANCE: gun barrel cleaning device comprises flat rag shaped to isosceles triangle with centre and three vertices, cut-outs made along every edge of triangular rag. When rag is fitted in the barrel with the help of wire brush, the position of every vertex is defined by wire brush to fold excess rag material towards every side and making, in fact, identical folds while every cut-out makes the place to fit rag material in folds. Rag can be made with the help of bunch to minimise the wastes or rule them out.

EFFECT: uniform barrel cleaning.

18 cl, 1 tbl, 6 dwg

FIELD: metallurgy.

SUBSTANCE: nano-sized surface coating is produced by metal article surface processing by doping alloy in fine power form. Surface is irradiated with focused heat beam of high-energy quantum generator by displacing laser beam at spacing of 25 mcm and at power sufficient for point fusion of said alloy consisting of nano-composite systems. Doping alloy ply is fused in processed article. Then part surface is cooled by compressed airflow at 20°C and 8 kPa for crystallisation of doping alloy on metal surface for provision of extra adhesion between doing alloy and cooled surface without change in surface structure and with formation of alloying ply with nitride and/or carbide matrix of nano-composite structure. Note here that laser radiation power is defined by equation P=1*10-2*V*C*T/L, where P is laser radiation power, W, 1*10-2 - mathematical constant, V is beam displacement speed, mm/s, C is doping alloy capacity, J/K, T is alloy melting point, K, L - doping alloy depth, mm.

EFFECT: higher quality of surface coating, higher heat, corrosion and erosion resistance.

3 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a polymer electrochromic device which is capable of varying light absorption in a controlled manner when voltage is applied. The polymer electrochromic device includes at least two electrodes and an electrochromic composition. The electrochemical composition contains a cathode component(s) and an anode component(s), at least one of which is an electrochromic component, and an electrolyte. The electrochromic component is a dispersion of nanoparticles of an insoluble electrochromic polymer in an organic solvent.

EFFECT: invention ensures easy production of the device by using a more readily available insoluble electrochromic polymer compared to insoluble electrochromic polymers currently used.

4 cl, 4 dwg, 6 ex

FIELD: nanotechnology.

SUBSTANCE: use: of new products nanoelectronics for a closed cycle of production. The essence of the invention consists in that in nanotechnology complex based on ion and probe technologies, comprising a distribution chamber with pumping means, in which there is a central robot-distributor with the ability of axial rotation, comprising a grip of substrate carriers, at that the distribution chamber comprises flanges by means of which it is connected to the loading chamber and the module of ion implantation, the grip of substrate carriers has the ability of interaction with the loading chamber and the module of ion implantation, the measuring module is integrated, comprising a scanning probe microscope and a module of ion beams with a system of gas injectors, and they are connected to the flanges of the distribution chamber and have an ability to interact with the grip of substrate carriers. The technical result: providing an ability to vary the technological routes and enhance the functional capabilities of the distribution chamber and have an ability to interact with the grip of substrate carriers.

EFFECT: implementation extends the functional capabilities of the nanotechnology complex.

5 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the chemical industry and can be used to produce composites which are used in photocatalytic processes as catalysts of oligomerisation of olefins and polymerisation of ethylene. The composite material based on silica gel is obtained by precipitation of silicon dioxide from sodium silicate in the presence of titanium dioxide or copper oxide by bubbling of carbon dioxide through the thickness of the suspension at the atmospheric pressure to form the composite material with the type "core (silicon dioxide)/shell (metal oxide)". The method can be used both in the laboratory and in industrial conditions.

EFFECT: invention enables to simplify the process of obtaining a composite, as the need for complex instrumental execution of the process is eliminated, connected with the use of high pressure of carbon dioxide in obtaining the silica gel, as well as environmental safety of the technology, which is connected to the lack of carbon dioxide emissions, achieved by its repeated use.

3 dwg, 2 ex

FIELD: electricity.

SUBSTANCE: method involves application of a fluoropolymer layer onto a metal electrode, application of a discrete layer consisting of isolated nano-sized aggregates out of titan-containing nanostructures onto the fluoropolymer surface, and further electreting in positive corona discharge. Prior to the application of titan-containing nanostructures the fluoropolymer surface is treated by plasma of high-frequency capacitive discharge in the atmosphere of saturated water vapour. The usage of this technical solution enables increase of positive charge surface density in fluoropolymers by at least 1.45 times and increase charge temporal and thermal stability.

EFFECT: increase of magnitude and stability of positive charge surface density in film fluoropolymers.

2 dwg, 5 ex

FIELD: process engineering.

SUBSTANCE: proposed coat for solar hearing is applied metal substrate, in particular, thin aluminium sheet. Said coat represents sol-gel-type coat based on metal oxide sol. Wherein pigment particles are thoroughly mixed with sol with subsequent application of mixed sol lacquer on said substrate. Then, said mix is air dried at 180-600°C it increased temperature to get sol-gel coat. Said coat represents sol-gel-type metal oxide sol-based coat with particles of pigments of manganese black ferrite (Mn3Cu2FeO8) to be thoroughly mixed with sol prior to application on substrate.

EFFECT: sufficient solar power absorption, thermal emissivity, thermal stability and durability.

14 cl, 3 dwg, 2 tbl

FIELD: physics.

SUBSTANCE: invention relates to organic electronics and specifically to organic photovoltaic devices (solar panels and photodetectors) using organic fluorine-containing compounds as modifying additives. The invention relates to an organic photovoltaic device with a bulk heterojunction, comprising series-arranged substrate, hole-collecting electrode, hole-transporting layer, photoactive layer consisting of a mixture of an n-type semiconductor material, a p-type semiconductor material and an organic fluorine-containing compound, an electron-transporting layer, an electron-collecting electrode and a substrate. The photoactive layer further contains a fluorine-containing modifier F1-F8 in concentration of 0.000000001-40 wt %. The invention also relates to a method of making a photovoltaic device, where a fluorine-containing modifier is added to a solution of semiconductor components, from which photoactive films are formed. The invention also relates to use of fluorine-containing modifiers F1-F8 to enhance performance of organic solar panels with a bulk heterojunction.

EFFECT: developing novel nano-structure modifying additives for polymer-fullerene systems capable of enhancing performance of photovoltaic devices.

3 cl, 14 dwg, 8 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: method includes modification of a carrier, which is represented by amine-containing nanoparticles of silicon dioxide with a size up to 24 nm, by processing the latter with N-hydroxysuccinimide ether of aliphatic azido acid, then obtaining modified nucleosidetriphosphate (pppN) by processing the latter with a mixture of triphenylphosphine/dithiodipyridine with further incubation of the formed active derivative pppN with 3-propinyloxypropylamine and further immobilisation of the modified pppN on the obtained asidomodified nanoparticles for 2-4 hours.

EFFECT: reduction of the method duration and an increased quality of the target product.

3 cl, 4 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: nanoparticles of carbonyl iron, as such used are magnetite particles with size from 5.0 to 10.0 nanometers, covered with surface-active substance, as such used is oleic acid, are introduced into kerosene. After that, kerosene with nanoparticles of carbonyl iron is sprayed through sprayer in 20-30 mcm drops into chamber with three-phase electric winding, creating spiral rotating magnetic field. Glass powder, which is caught by kerosene drops rotating in magnetic field, is supplied into the same chamber by compressed air. After that, it is supplied into first zone of low intensity of microwave oven, where particles of carbonyl iron are heated to 700-800°C, and as a result kerosene is decomposed and nanoparticles of carbonyl iron precipitate on the surface of glass powder particles. As particles of glass powder with nanoparticles of carbonyl iron continue moving, temperature of nanoparticles increases to 1300-1350°C. Glass melts and under action of molecular forces moves throughout the entire volume and forms microballs, which later are cooled, nanoparticles of carbonyl iron are restored and attracted to poles of permanent magnet.

EFFECT: improving efficiency and safety.

1 dwg

FIELD: food industry.

SUBSTANCE: invention relates to the technology for natural thickeners production and may be used in food industry. The method for production of green pea shell pectin envisages soaking preliminarily milled green pea shells in water. Then the produced mixture is filtered; press cake extracted with 45-55°C water during 25-35 minutes is separated, the ratio of press cake to water being 1:6. The produced extract is cooled and filtered with the press cake separation; after water extraction the press cake is subjected to acid- thermal hydrolysis with a tartaric acid solution with subsequent separation of a pectin-containing hydrolysate. The hydrolysate is subjected to staged molecular-mass separation by way of nanofiltration with polymer nanofilters usage in two stages. At the first stage the hydrolysate is passed through a filter with retention threshold within the range of 1 kDa with dividing into a low-molecular (less than 1 kDa) and a high-molecular (more than 1 kDa) fractions. The low-molecular fraction is discharged while the high molecular one, at the second stage, is passed through a filter with retention threshold within the range of 50 kDa; the produced fractions are divided in two high-molecular fractions - more than 50 kDa and 1 - 50 kDa; the latter fraction is concentrated by way of reverse osmosis with polymer membrane usage till dry substances content in the concentrate is equal to 4-5 %. Then the fraction is dried to produce pectin.

EFFECT: proposed method for pectin production allows to reduce pectin losses and enhance the product yield and quality.

3 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: claimed is composite ion-exchange membrane, characterised by higher mobility of nitrate-anions and higher constant of ion exchange with respect to nitrate-anion. Membrane contains ion-exchange polymer matrix, which is volume- or gradient- modified with cerium oxide nanoparticles.

EFFECT: efficient application of obtained membrane in processes of purification of various solutions, including liquid food products, from nitrate-anions.

3 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely to a stable pharmaceutical composition of nanostructured telmisartan for treating hypertension, containing nanostructured telmisartan having an average particle size less than approximately 600 nm, and at least one stabilising agent specified in a group of sodium dodecyl sulphate and polyvinyl pyrrolidone, wherein the composition in prepared in a continuous flow reactor, preferentially in a microfluidics continuous flow reactor, as well as to a method for preparing the composition and using it.

EFFECT: invention provides better physical-chemical characteristics and pharmacokinetics of the active principle.

11 cl, 9 ex, 3 tbl, 14 dwg

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