Compositions and methods of delivery of pharmacological agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the delivery of a pharmaceutical agent to a focus of a disease. The composition contains a water-insoluble pharmaceutical agent which is paclitaxel, a pharmaceutically acceptable carrier which is albumin, preferentially human serum albumin. The relation (wt/wt) of albumin to paclitaxel makes 9:1. The pharmaceutical composition contains nanoparticles containing paclitaxel and albumin wherein the nanoparticles have a size of less than 200 nm.

EFFECT: administering the pharmaceutical composition according to the invention provides enhanced characteristics of the delivery of paclitaxel to the site of the disease and reduced adverse side effects.

24 cl, 5 tbl, 51 ex

 

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority based on provisional application for the grant of U.S. patent No. 60/432317, filed December 9, 2002, provisional application for the grant of a US patent application (attorney docket No. 225519), filed December 3, 2003, provisional application for a patent (attorney docket No. 225549), filed December 4, 2003, and provisional application for the grant of a US patent application (attorney docket No. 225585), filed December 5, 2003.

The technical FIELD TO WHICH the INVENTION RELATES.

This invention relates to pharmaceutical compositions containing pharmaceutically active agents for parenteral or other internal use, which, if have the effect of reducing some unwanted side effects when compared with available drugs similar drug.

The LEVEL of TECHNOLOGY

It is well known that many drugs (substances) means for parenteral use, especially drugs, intravenous, cause unwanted side effects such as irritation of the veins, phlebitis, burning and pain during injection, venous thrombosis, hemorrhage, and others associated with the introduction, side effects. Many of these drugs insoluble in the ode, and thus, they are produced using solubilizing agents, surface-active agents, solvents and/or emulsifiers, which are irritating, allergenic or toxic in the introduction of their patients (see, for example, Briggs et al.,Anesthesis37, 1099 (1982) and Waugh et al.,Am. J. Hosp. Pharmacists, 48, 1520 (1991)). Often unrelated drugs presented in the product, causing pain and irritation at their introduction. For example, 50% of patients who had received when introduced through a peripheral vein ifosfamide and vinorelbine as initial chemotherapy common non-small cell lung carcinoma, observed phlebitis (see, for example, Vallejo et al.,Am. J. Clin. Oncol., 19 (6), 584-8 (1996)). In addition, it was shown that vancomycin may cause such side effects as phlebitis (see, for example, Lopes Rocha et al.,Braz. J. Infect. Dis., 6 (4), 196-200 (2002)). The use of cisplatin, gemcitabine and SU5416 in patients with solid tumors has led to the emergence of adverse reactions, such as deep vein thrombosis and phlebitis (see, for example, Kuenen et al.,J. Clin. Oncol.,20 (6), 1657-67 (2002)). In addition, propofol, an anaesthetic agent, can cause pain on injection, burning and irritation of the veins, especially in the introduction as a stable lecithin fat emulsion (see, for example, Tan et al.,Anathesia, 53, 468-76, (1998)). Other Lek is stennie means, which are side effects associated with their introduction, include, for example, Taxol (paclitaxel) (see, for example, the leaflet in the package Taxol for intravenous use), cordarone (amiodarone hydrochloride) (see, for example, the leaflet in the package cordarone intravenous use), thyroid hormone T3 or liotironin (commercially available as triostat), thiotepa, bleomycin and diagnostic radiopaque means.

Another problem associated with the industrial production of drugs for injection, particularly water-insoluble drugs is to ensure sterility. Sterile pharmaceutical emulsions/dispersions can be done with the full sterilization of all components prior to production, followed by absolutely aseptic technique at all stages of industrial production. However, such methods are time consuming and expensive. In addition, the oxidation of drugs under influence of air during the industrial production or storage may cause, for example, to lower the pH, the degradation of drugs and discoloration, thereby, disrupting the stability of the medicinal product and/or reducing the shelf life.

In order to overcome the problems associated with related to the introduction of medicinal PR the drug side effects, tried to make alternative medicines. Compared to propofol, for example, ways to reduce pain caused by the introduction of propofol include increased fat content in the solvent (for example, long-chain triglycerides (LCT)), pre-medical preparation, pre-treatment non-steroidal drugs, local anesthetics, opiates, adding lidocaine, adding cyclodextrin and microfiltration (see, for example, Mayer et al.,Anaesthesist, 45(11), 1082-4 (1996), Davies, et al.Anaesthesia, 57, 557-61 (2002), Doenicke et al.,Anaesth. Play mode display., 82, 472-4 (1996), Larsen et al.,Anaesthesist, 50, 842-5 (2001), Lilley et al.,Anaesthesia, 51, 815-8 (1996), Bielen et al.,Anaesth. Play mode display., 82(5), 920-4 (1996) and Knibbe et al.,Br. J. Clin. Pharmacol., 47 (6), 653-60 (1999)). These compositions, however, cause other side effects (e.g. cardiovascular complications) or cause violations of the stability of emulsions with propofol.

In order to overcome the problem of bacterial contamination were developed preparations of propofol with antibacterial agents such as the analog of EDTA (e.g., edetate), pentetate or containing sulfite agents, or prepared at lower pH values (see, for example, U.S. patents№№ 5714520, 5731355, 5731356, 6028108, 6100302, 6147122, 6177477, 6399087, 6469069 and a preliminary application for the grant of a patent # WO 99/39696). Although edetate and the Penta is tat are chelators of metal ions, they, however, have the opportunity to be dangerous, removing important metal ions from the body system. Furthermore, the addition of sulfites in the formulations of drugs is the cause of the possible side effects in children and in people in the General population, who are allergic to sulfur.

Thus, there remains a need for a composition and method that reduce or remove the adverse effects associated with parenteral introduction or the introduction ofin vivoof medicines. There is also a need in the creation of a pharmaceutical composition, which is sterile and methods of preparation of such compositions. Additionally, there is a need for the creation of a pharmaceutical composition and method that reduce or eliminate oxidation of pharmaceuticals to prevent violations of the stability of the medicinal product.

This invention relates to such compositions and methods. There are other advantages of the invention and additional features of the invention will be apparent from the present description.

DISCLOSURE of INVENTIONS

The invention relates to various implementations of pharmaceutical compositions. One, some or all of the properties of different options can be found in different assests the deposits and yet they are within the scope of the attached claims.

The invention relates to a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises a protein, such as albumin, more preferably, the albumin human serum, in an amount effective to reduce one or more side effects with the introduction of the pharmaceutical composition to a person, and in which the pharmaceutically acceptable carrier contains deferoxamine in an amount effective to inhibit the growth of microorganisms in pharmaceutical compositions. The invention also relates to a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises a protein, such as albumin, in an amount effective to reduce one or more side effects with the introduction of the pharmaceutical composition to a person, and in which the pharmaceutically acceptable carrier comprises deferoxamine in the amount effective for inhibiting oxidation in pharmaceutical compositions.

The invention relates to a method of reducing one or more side effects associated with the introduction of the pharmaceutical composition to the individual, including (a) introduction to the human a pharmaceutical composition comprising a pharmaceutical is th agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises albumin and deferoxamine. The invention relates to methods of inhibiting the growth of microorganisms or inhibiting oxidation, or inhibiting the growth of microorganisms and oxidation in the pharmaceutical composition. These methods include preparation of a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit the growth of microorganisms, or in the amount effective for inhibiting oxidation in pharmaceutical compositions.

The invention also relates to a method of increasing transport of a pharmaceutical agent to a disease site, which includes an introduction to the human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises albumin, and in which the ratio of albumin and pharmaceutical agent in the pharmaceutical composition is about 18:1 or less. Further, the invention relates to a method of increasing the binding of the pharmaceutical agent cellin vitroorin vivowhere the method comprises applying to said cellsin vitroorin vivopharmaceutical compo is icii, containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises albumin, and in which the ratio of albumin and pharmaceutical agent in the pharmaceutical composition is about 18:1 or less.

The invention also relates to a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises albumin in an amount effective to increase the transport of drugs to the hearth disease in humans, and in which the ratio of albumin and pharmaceutical agent is about 18:1 or less.

The invention also relates to a method of increasing transport of the pharmaceutical agent to the cellin vitroorin vivoby mergingthe specified agent with the protein, where this protein binds to a specific receptor on the cell surface of the specified cells, where the specified binding combination of protein and a pharmaceutical agent with a specified receptor causes the transport, and where the ratio of protein and a pharmaceutical agent is about 18:1 or less.

The IMPLEMENTATION of the INVENTION

The invention relates to pharmaceutical compositions containing pharmaceutical is a Gent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises a protein, such as albumin, preferably albumin human serum, in an amount effective to reduce one or more side effects with the introduction of the pharmaceutical composition to a person, and in which the pharmaceutically acceptable carrier comprises deferoxamine in an amount effective to inhibit the growth of microorganisms in pharmaceutical compositions. The invention also relates to a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier comprises a protein, such as albumin, in an amount effective to reduce one or more side effects with the introduction of the pharmaceutical composition to a person, and in which the pharmaceutically acceptable carrier comprises deferoxamine in the amount effective for inhibiting oxidation in pharmaceutical compositions.

Any suitable pharmaceutical agent can be used in pharmaceutical compositions according to the invention. Suitable pharmaceutical agents include, as non-limiting examples of anti-cancer agents or anti-cancer agents, agents acting on the microtubules, immunosuppressive agents, anaesthetics, hormones, agents to use the Oia in cardiovascular disorders, antiarrhythmic agent, antibiotics, antifungal agents, antihypertensive agents, anti-asthma drugs, analgesics, anti-inflammatory agents, antiaritmicheskie agents and vasoactive agents. The invention is also applicable to many other classes of drugs. More specifically, suitable pharmaceutical agents include, as non-limiting examples, taxanes (e.g., Taxol®(paclitaxel) and TaxotereTM(docetaxel)), epothilone, computacin, colchicine, amiodarone, thyroid hormones, vasoactive peptides (e.g., vasoactive putting peptide), amphotericin b, corticosteroids, propofol, melatonin, cyclosporine, rapamycin (sirolimus), tacrolimus, mycophenolate acid, ifosfamide, vinorelbine, vancomycin, gemcitabine, SU5416, thiotepa, bleomycin, diagnostic radiopaque agents and their derivatives. Other medicines which are used in the composition according to the invention are described, for example, in U.S. patent No. 5916596 and simultaneously pending application for U.S. patent No. 09/446783. Preferably, the pharmaceutical agent is propofol, paclitaxel or docetaxel. More preferably, the pharmaceutical agent is propofol or paclitaxel. Most preferably, the pharmaceutical agent is provided which allows propofol.

Taxol®(paclitaxel) (Bristol-Myers Squibb) is active against carcinomas of the ovary, breast, lung, esophageal and head and neck. However, it was shown that Taxol induces toxicity associated with its introduction, as well as significant acute and cumulative toxicity such as myelosuppression, atropunicea fever, anaphylactic reactions and peripheral neuropathy. Because paclitaxel is poorly soluble in water, typically using cremophor as solvent, requiring large amounts of infusions and special pipes and filters. Cremophor is associated with side effects that can be severe, including anaphylaxis and other allergic reactions that may require pre-treatment with corticosteroids, antihistamines and H2-blockers (see, for example, Gelderblom et al.,Eur. J. Of Cancer, 37, 1590-1598, (2001)). TaxotereTM(docetaxel) is used in the treatment of resistant anthracycline breast cancer, but also, as was previously described, causes side effects in the form of allergies and swelling, which can be severe. Epothilone (and its derivatives) are also typically injected with cremophor, and, as has been shown, it causes severe neutropenia, allergies and neuropathy.

Propofol (2,6-diisopropylphenol) is a hydrophobic water-insoluble oil, the cat who PoE is widely used as an intravenous anesthetic, in order to induce and maintain General anesthesia and sedative effects in humans and animals. Propofol typically injected directly into the bloodstream, and it passes through the blood-brain barrier. Pharmaceutical compositions containing propofol must be sufficiently soluble to pass through this barrier and provide a dampening effect on the relevant mechanisms of the brain. The maximum solubility of propofol in water is 1.0±0.02 mm at a temperature of 22.5°C (see, for example, Tonner et al.,Anesthesiology, 77, 926-931 (1992)). As such, propofol mainly prepared as emulsions containing solubilizing agents, surface-active products, solvents, or as an emulsion of the type oil-in-water (see, for example, U.S. patent No. 6150423, 6326406 and 6362234). The compositions of the present invention include, in addition to the active pharmaceutical agent, pharmaceutical carriers or excipients. The choice of media is not necessarily decisive, and in the song you can use any of the media known in the field. The choice of the carrier is preferably partially determined by the specific area in which you want to enter the pharmaceutical composition, and a particular method used to administer the pharmaceutical composition. Preferably, pharmaceutically priemel the range of the carrier includes proteins. You can use any suitable protein. Examples of suitable proteins include, as non-limiting examples of albumin, immunoglobulins, including IgA, lipoproteins, apolipoprotein B, beta-2-macroglobulin, thyroglobulin, and the like. Most preferably pharmaceutically acceptable carrier contains albumin, most preferably albumin human serum. Proteins, including albumin, suitable for the invention may be of natural origin or obtained synthetically.

Albumin human serum (HSA) is a soluble globular protein Mr65K and consists of 585 amino acids. HSA is present in large quantities in the plasma and is 70-80% of the colloid osmotic pressure of human plasma. Amino acid sequence of HSA contains a total of 17 disulfide bridges and one free thiol (Cys 34) and one tryptophan (Trp 214). The use of intravenous solutions HSA prescribed for the prevention and treatment of hypovolemic shock (see, for example, Tullis,JAMA, 237, 355 to 360 above, 460-463, (1977) and Houser et al.,Surgery, Gynecology and Obstetrics, 150, 811-816 (1980)) and in conjunction with exchange transfusion for treatment of neonatal hyperbilirubinemia (see, for example, Finlayson,Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).

Albumin human serum (HSA) contains many hidrovo the different binding sites (a total of eight for fatty acids, endogenous ligand HSA) and binds a diverse range of medicines, especially neutral and negatively charged hydrophobic compounds (Goodman et al.,The Pharmacological Basis of Therapeutics, 9thed, McGraw-Hill, New York (1996)). The presence of two high affinity binding sites suggested in subdomains IIA and IIIA of HSA, which are very elongated hydrophobic pockets with charged residues lysine and arginine on the surface, which act as connection points of the polar structural elements of the ligand (see, for example, Fehske et al.,Biochem.Pharmcol., 30, 687-92 (1981), Vorum,Dan.Med.Bull., 46, 379-99 (1999), Kragh-Hansen,Dan.Med.Bull., 1441, 131-40 (1990), Curry et al.,Nat. Struct. Biol., 5, 827-35 (1998), Sugio et al.,Protein. Eng, 12, 439-46 (1999), He et al.,Nature, 358, 209-15 (1992) and Carter et al.,Adv. Protein. Chem., 45, 153-203 (1994)). Paclitaxel and propofol been shown to be associated with HSA (see, for example, Paal et al.,Eur. J. Biochem., 268 (7), 2187-91 (2001), Purcell et al.,Biochim. Biophys. Acta, 1478 (1), 61-8 (2000), Altmayer et al.,Arzneimittelforschung, 45, 1053-6 (1995) and Garrido et al.,Rev. Esp. Anestestiol. Reanim., 41, 308-12 (1994)). Additionally, it was shown that docetaxel binds to human plasma protein (see, for example, Urien et al., Invest. New Drugs, 14 (2), 147-51 (1996)). Thus, while not wishing to bound to any particular theory, I believe that the inclusion of proteins, such as albumin, in the pharmaceutical compositions according to the invention leads to a reduction FOB is cnyh effects associated with the introduction of the pharmaceutical composition, which is due, at least in part, the binding of albumin human serum with any drug, present in the composition in a free form.

The amount of albumin included in the pharmaceutical compositions of the present invention, will vary depending on the active pharmaceutical agent, fillers, application method and the place of the planned introduction. It is desirable that the amount of albumin that is included in the composition was a quantity effective to reduce one or more side effects of the active pharmaceutical agent due to the introduction of the pharmaceutical composition according to the invention of man. Typically, the pharmaceutical composition is prepared in liquid form, and then added to a solution of albumin. Preferably, the pharmaceutical composition is in liquid form contains from about 0.1 to about 25 wt.% (for example, about 0.5 wt.%, approximately 5 wt.%, approximately 10 wt.%, approximately 15 wt.% or about 20 wt.%) albumin. Most preferably, the pharmaceutical composition is in liquid form contains from about 0.5 to about 5 wt.% albumin. The pharmaceutical composition can be degidratiruth, for example,liabilitities, when spray drying, drying in a fluidized bed, wet granulation and other appropriate methods known in this field. When the composition is prepared in solid form, such as wet granulation, drying in a fluidized bed and other methods known to experts in this field, the albumin is preferably used with an active pharmaceutical agent and other excipients, if present, as a solution. The HSA solution preferably contains from about 0.1 to about 25 wt.% (approximately 0.5 wt.%, approximately 5 wt.%, approximately 10 wt.%, approximately 15 wt.% or about 20 wt.%) albumin.

In addition to albumin compositions of the present invention preferably contain deferoxamine. Deferoxamine is a natural product isolated fromStreptomyces pilousand he is able to form complexes with iron. Deferoxamine mesilate injection according to the requirements of USP, for example, approved by Management under the control over products and medicines (USA) as chelat forming agent for iron, and it is available for intramuscular, subcutaneous and intravenous administration. Deferoxamine mesilate, according to the requirements of USP, is a powder from white to almost white. It is freely soluble in water, and its molecular weight is leaves 656,79. Chemical name nelfinavir deferoxamine is nanomeasurement (g) N-[5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamido]pentyl]-3-[[5-((N-hydroxyacetamido)pentyl]carbarnoyl]propionohydroxamic acid, and its structural formula represents a C25H48N6O8.CH3SO3H. As described in the examples, deferoxamine or its analogues, derivatives or salts (for example, salts of nelfinavir inhibit the growth of microorganisms and inhibit oxidation in the pharmaceutical composition. It was also shown that deferoxamine is associated with phenolic compounds (see, for example, Juven et al.,J.Appl.Bacteriol., 76 (6), 626-31 (1994)). Paclitaxel, docetaxel, propofol and the like, are either connection, similar to the phenolic or contain phenol or phenyl substituents. So, I think that deferoxamine can contact the drug in free form or to reduce its amount in the pharmaceutical composition according to the invention, thus, also reducing or weakening the irritation or soreness at injection.

The number of deferoxamine and its preferred salt, i.e. salt nelfinavir deferoxamine, which is included in the composition depends on the active pharmaceutical agent and other fillers. It is desirable that the composition of the number of deferoxamine, with the Lee and its analogues were a number, effective to inhibit the growth of microorganisms and/or inhibiting oxidation. As described above, the pharmaceutical composition is prepared typically in liquid form, and deferoxamine, its salts and its analogues add then in the solution. Preferably, the pharmaceutical composition is in liquid form contains from about 0.0001 to about 0.5 wt.% (for example, about 0.005 wt.%, approximately 0.1 or approximately 0.25 wt.%) deferoxamine, its salts or its analogues. More preferably, the composition is in liquid form contains a similar number of preferred salts deferoxamine, nelfinavir deferoxamine. Most preferably, the pharmaceutical composition is in liquid form contains about 0.1 wt.% nelfinavir deferoxamine. When the composition is prepared in solid form, as described above, such as wet granulation, drying in a fluidized bed and by other methods known to experts in this field, deferoxamine mesilate preferably used with an active pharmaceutical agent and other excipients, if present, as a solution. The solution nelfinavir deferoxamine preferably contains from about 0.0001 to about 0.5 wt.% (for example, about 0.005 wt.%, approximately 0.1 or approximately 0.25 wt.%) deferoxamine.

In accordance with the image what emeniem, the pharmaceutical composition may contain other agents, excipients or stabilizers, in order to improve the properties of the composition. For example, to improve stability by increasing the negative Zeta-potential of nanoparticles or nanocable, you can add certain negatively charged components. Such negatively charged components include as non-limiting examples of bile salts bile acids consisting of glycocholic acid, holeva acid, chenodesoxycholic acid, human beings need it to acid, glockengiesserwall acid, taurochenodeoxycholate acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid and others; phospholipids including phospholipids-based lecithin (egg yolk), which include the following phosphatidylcholine: palmitoyloleoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine, stearoylbenzoylmethane, stearoylethanolamine, stearoylbenzoylmethane and dipalmitoylphosphatidylcholine. Other phospholipids include L-α-dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), phosphatidylcholine hydrogenomonas soybean (HSPC), D-α-phosphatidylcholine-β-acetyl-γ-O-hexadecyl, L-α-phosphatidylcholine-β-acetyl-γ-O-hexadecyl, DL-α - phosphatidylcholine-β-acetyl-γ-hexadecyl, L-α-phosphatidylcholine-β-acetyl-γ-O-octadecyl, L-α-phosphatidylcholine-β-arachidonoyl-γ-O-hexadecyl, L-α-phosphatidylcholine-β-acetyl-γ-O-(octets-9-CIS-enyl), D-α-phosphatidylcholine-β-arachidonoyl-γ-O-Palmitoyl, 3-sn-phosphatidylcholine-2-arachidonoyl-1 stearoyl, L-α-phosphatidylcholine-β-arachidonoyl-γ-stearoyl, L-α-phosphatidylglycerol, L-α-phosphatidylglycerol, L-α-phosphatidylcholine-β-(CIS-8,11,14-eicosatrienoic)-γ-O-hexadecyl, L-α-phosphatidylcholine-β-oleoyl-γ-myristoyl, L-α-phosphatidylcholine-β-(pyrene-1-yl)decanoyl-γ-Palmitoyl, 3-sn-phosphatidyl-N,N-dimethylethanolamine-1,2-dipalmitoyl, L-α-phosphatidylethanolamine, 3-sn-phosphatidylethanolamine-1,2-Dilauroyl, 3-sn-phosphatidylethanolamine-1,2-dimyristoyl, 3-sn-phosphatidylethanolamine-1,2-diolein, 3-sn-phosphatidylethanolamine-1,2-dipalmitoyl, L-α-phosphatidylethanolamine, L-α-phosphatidylethanolamine-N-dansyl, L-α-phosphatidylethanolamine-N,N-dimethyl, L-α-dimyristoylphosphatidylcholine (sodium salt) (DMPG), dipalmitoylphosphatidylcholine (sodium salt) (DPPG), distearoylphosphatidylglycerol (sodium salt) (DSPG), N-(carbonyl-methoxypolyethyleneglycol)-1,2,-distearoyl-sn-glycero-3-phosphoethanolamine sodium (MPEG-cells of the dspe), sodium salt of didecanoyl-L-α-phosphatidic acid, sodium salt of digitalcamera-L-α-phosphatidic acid, sodium salt of 1,2-dimyristoyl-3-sn-phosphatidic acid, sodium salt of dioctanoyl-L-is-phosphatidic acid, the sodium salt of dioleoyl-L-α-phosphatidic acid, sodium salt of dipalmitoyl-L-α-phosphatidic acid, sodium salt of dimyristoyl-L-α-phosphatidyl-DL-glycerol sodium salt dioleoyl-L-α-phosphatidyl-DL-glycerol, ammonium salt dipalmitoyl-L-α-phosphatidyl-DL-glycerol, ammonium salt distearoyl-L-α-phosphatidyl-DL-glycerol, ammonium salt of L-α-phosphatidyl-DL-glycerol-β-oleoyl-γ-Palmitoyl, ammonium salt L-α-phosphatidylinositol, sodium salt of L-α-phosphatidylinositol, sodium salt of L-α-phosphatidyl-L-serendipol, sodium salt of L-α-phosphatidyl-L-serine and dipalmitoyl. Negatively charged surfactants emulsifiers are also suitable as additives are, for example, cholesterolfed sodium and the like.

The pharmaceutical agent (e.g., propofol) can be used individually or dissolved in immiscible in water solvent. You can use a wide range of immiscible in water solvents, such as soybean, safflower, cottonseed, corn, sunflower, peanut, castor or olive oil. The preferred oil is a vegetable oil, from which soybean oil is the most preferred. Soybean oil can be used in the composition in the range from 1 to 10 wt.% Preferably, soybean oil is present in the pharmaceutical composition in the share of the ve approximately 3 wt.%

The pharmaceutical composition according to the invention can be stabilized pharmaceutically acceptable surfactant. Used herein, the term "surface active agent" refers to surface-active group (s) of amphiphilic molecules. Surface-active products can be anionic, cationogenic, nonionic and zwitterionic. Any surface-active agent can be included in the pharmaceutical compositions according to the invention. Suitable surface-active products include nonionic surface-active products, such as phosphatides, polyoxyethylene esters of sorbitol and succinate of tocopherolacetate. Preferred surface-active means are egg lecithin, tween 80 and vitamin E-td-α-tocopherylacetate-1000 succinate (TPGS). For products containing soybean oil, egg lecithin is preferred is not more than 1.2 wt.% for preparation containing 3% soybean oil, preferably to 1.1 wt.% of the composition. For containing no soybean oil preparations, tween 80 or vitamin E-TPGS are the preferred surface-active agents. Typical suitable from 0.1 to 1.5 wt.% tween 80, or from 0.5 to 4 wt.% vitamin E-TPGS. Preferably use a 1.5 wt.% tween 80 or 1 wt.% vitamin E-TPGS. Examples of other suitably the surface-active agents described, for example, Becher,Emulsions: Theory and Practice, Robert E. Krieger Publishing, Malabar, Fla. (1965).

There is a wide variety of suitable preparations of pharmaceutical compositions according to the invention (see, for example, U.S. patent No. 5916596). The following drugs and methods are merely illustrative and in no way limiting. Preparations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in solvents such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more fillers from lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, solvents, buffer funds, moisturizing agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Forms of drug candies may contain the active ingredient in a flavor, usually sacharose acacia or tragakant, as well as tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia, emulsions, gels and the like containing, in addition to the active ingredient such fillers which are known in this field.

Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which contain antioxidants, buffers, antimicrobial additives and solutions that bring drugs to isotonic condition with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspendresume agents, solubilization, thickeners, stabilizers and preservatives. Drugs can be presented in the form of standard-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in dried by sublimation (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water for injection immediately before use. Prepared for immediate acceptance solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the previously described type. Injectable drugs are preferred.

Drugs suitable for aerosol use, who will win the pharmaceutical composition according to the invention, include aqueous and non-aqueous isotonic sterile solutions, which can contain antioxidants, buffers, antimicrobial additives and solutions, and aqueous and non-aqueous sterile suspensions that can include suspendresume agents, solubilization, thickeners, stabilizers and preservatives by themselves or in combination with other suitable components, which can be prepared in aerosol medications that will be administered by inhalation. Aerosol preparations can be placed into pressurized acceptable propellants such as DICHLORODIFLUOROMETHANE, propane, nitrogen and the like. They also can be prepared as pharmaceutical drugs for drugs not under pressure, such as a nebulizer or atomizer.

Other suitable drugs, for example, suppositories can be obtained using various bases, such as emulsifying bases or water-soluble bases. Drugs that are suitable for vaginal administration, you can provide as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in this area are appropriate.

In a preferred implementation of the invention the pharmaceutical composition g is tovat so, so she had pH in the range from 4.5 to 9.0, and more preferably a pH of from 5.0 to 8.0. The pharmaceutical composition can also be prepared so that it was isotonic with blood by adding a suitable modifier toychest, such as glycerin. In addition, pharmaceutically acceptable carrier preferably also contains desterrado pyrogens water or water for injection according to the requirements of the USP. Preferably, the pharmaceutical composition according to the invention is prepared as a sterile aqueous preparation, nanoparticles, emulsions of the type oil-in-water or emulsion type water in oil.

For pharmaceutical compositions containing propofol, according to the invention the emulsion of the type oil-in-water prepared by dissolving propofol in only one water-immiscible solvent and preparing the aqueous phase, containing albumin, deferoxamine, surface-active agent and other water soluble components, and mixing the oil and aqueous phase. The primary emulsion is homogenized at high pressure at a pressure of from 10000 to 25000 psi and subjected to recirculation within 5 to 20 cycles before the formation of a perfect emulsion. The preferred pressure ranges from 15000 to 20000 psi and more preferably 10000 psi. The primary emulsion can be recycled within from 7 to 15 cycles and preferably it recircula the Ute in 15 cycles. Alternatively, you can use a separate pass through the homogenizer.

Preferably, the pharmaceutical composition according to the invention may contain particles or droplets of a size less than approximately 200 nanometers (nm). For example, in the case of paclitaxel, docetaxel, rapamycin, cyclosporine, propofol and others, the average size of the data dispersion is less than 200 nm.

Further, the invention relates to a method of reducing one or more side effects associated with the introduction of the pharmaceutical composition to the human. The method comprises the administration to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier contains albumin and deferoxamine. The descriptions of pharmaceutical compositions, the pharmaceutical agent and a pharmaceutically acceptable carrier and components described above in connection with the pharmaceutical composition according to the invention is also applicable to those same aspects of the method according to the invention.

The dose of the pharmaceutical composition according to the invention, the input man, in the context of the present invention will vary for certain pharmaceutical compositions, method of administration and the specific treatment site. The dose should be sufficient to cause the desired response, so the th as a therapeutic or prophylactic response against a particular disease, or when a pharmaceutical agent is an anesthetic agent, such as propofol, anesthetic response in the desired time interval.

Despite the fact that you can use in the context of the invention, any suitable route of administration of the pharmaceutical composition to a human, preferably, the pharmaceutical composition is administered by means of intravenous administration, intraarterial administration, intra-lungs injection, oral administration, inhalation, intravesical injection, intramuscular, intratracheal injection, subcutaneous injection, intraocular injection, intrathecal injection or percutaneous administration. For example, the pharmaceutical composition according to the invention can be activated by inhalation for the treatment of pathological conditions of the respiratory tract. There are minimal side effects associated with inhalation pharmaceutical composition according to the invention, since albumin is a natural component of the mucosa and secretions of the respiratory tract. The composition according to the invention can be used to treat respiratory conditions such as pulmonary fibrosis, obliterative bronchiolitis, lung cancer, bronchoalveolar carcinoma, and the like.

The method according to the invention results in reducing one or more side effects associated the with the introduction of the pharmaceutical composition to the human. Such side effects include myelosuppression, neurotoxicity, hypersensitivity, inflammation, irritation of veins, phlebitis, pain, skin irritation, and combinations thereof. These side steps, however, are illustrative only, and other side effects, or a combination of side effects associated with various pharmaceutical agents can be reduced or avoided using new compositions and methods of the present invention.

Further, the invention relates to a method of inhibiting the growth of microorganisms in pharmaceutical compositions. "Growth inhibition of microorganisms" means either the complete removal of microorganisms from pharmaceutical compositions, or reducing the number or the rate of growth of microorganisms in pharmaceutical compositions. The method comprises the preparation of a pharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier contains deferoxamine, its salts, its analogues, and combinations thereof in amounts effective to inhibit the growth of microorganisms in pharmaceutical compositions. Additionally, the invention relates to a method of inhibiting oxidation in the pharmaceutical composition. This method covers the preparation of pharmaceutical companies who stand, containing a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier contains deferoxamine, its salts, its analogues, and combinations thereof in an amount effective for inhibiting oxidation in the pharmaceutical composition. The descriptions of pharmaceutical compositions, the pharmaceutical agent and a pharmaceutically acceptable carrier and components described above in connection with the pharmaceutical composition according to the invention is also applicable to those same aspects of the method according to the invention.

The number of deferoxamine or preferred salt, salt deferoxamine mesilate, included in the composition will depend on the active pharmaceutical agent and other fillers. It is desirable that the number of deferoxamine, its salts and their analogues in the song was a number, effective to inhibit the growth of microorganisms and/or inhibiting oxidation. As described above, typically, the pharmaceutical composition is prepared in liquid form, and deferoxamine, its salts and analogues were then added into the solution.

Preferably, the pharmaceutical composition is in liquid form contains from about 0.0001 to about 0.5 wt.% (for example, about 0.005 wt.%, approximately 0.1 or approximately 0.25 wt.%) deferoxamine, its salts or their analogue of the century More preferably, the composition is in liquid form contains a similar number of preferred salts deferoxamine, nelfinavir deferoxamine. Most preferably the pharmaceutical composition is in liquid form contains from about 0.5 wt.% nelfinavir deferoxamine. When the composition is prepared in solid form, as described above, such as by wet granulation, drying in a fluidized bed and other methods known to experts in this field, deferoxamine mesilate preferably used with an active pharmaceutical agent and other excipients, if present, as a solution. The solution nelfinavir deferoxamine preferably contains from about 0.0001 to about 0.5 wt.% (for example, about 0.005 wt.%, approximately 0.1 or approximately 0.25 wt.%) deferoxamine.

The invention also relates to a method of increasing transport of a pharmaceutical agent to a disease site, where the method comprises the administration to a human a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutically acceptable carrier contains albumin and in which the ratio of albumin and pharmaceutical agent in the pharmaceutical composition is about 18:1 or less. Further, the invention relates to STRs is also increasing the binding of a pharmaceutical agent to cells in vitroorin vivoin which method comprises introducing into the specified cellin vitroorin vivopharmaceutical composition containing a pharmaceutical agent and a pharmaceutically acceptable carrier, where the pharmaceutically acceptable carrier contains albumin and in which the ratio of albumin and pharmaceutical agent in the pharmaceutical composition is about 18:1 or less. The descriptions of pharmaceutical compositions, pharmaceutical agent, a pharmaceutically acceptable carrier, techniques and components described above in connection with the pharmaceutical composition according to the invention is also applicable to those same aspects of the methods of transport and binding.

In the method for enhancing transport of a pharmaceutical agent to a disease site or increase the binding of the pharmaceutical agent with the cell pharmaceutically acceptable carrier comprises albumin, most preferably albumin human serum. Not adhering to any particular theory, I believe that the ratio of protein, such as albumin human serum and pharmaceutical agent in the pharmaceutical composition affects the ability of the pharmaceutical agent to bind and transfer pharmaceutical agent into the cell. In this respect, a higher ratio of protein and pharmaceutical agents is a, primarily attributable to a weak cell binding and migration pharmaceutical agent, which may be the result of competition for receptors on the cell surface. The ratio of protein, such as albumin and active pharmaceutical agent should be such that a significant amount of pharmaceutical agent contacted them or transferred them into the cell. Illustrative ranges for drugs drugs and protein are protein ratio and medicines (wt./wt.) from 0.01:1 to about 100:1. More preferably, the ratio is in the range from 0.02:1 to about 40:1. Despite the fact that the ratio of protein and a pharmaceutical agent should be optimized for various combinations of protein and a pharmaceutical agent, in General, the ratio of protein, such as albumin and pharmaceutical agent is about 18:1 or less (e.g., about 15:1, about 10:1, about 5:1 or about 3:1). More preferably, the ratio is about 0.2:1 to about 12:1. Most preferably, the ratio is from about 1:1 to about 9:1. Preferably, the drug, mainly, does not contain cremophor and, most preferably, does not contain cremophor EL (BASF). Cremophor EL®is a non-ionic emulsifying agent, which is a simple polyester castor oil and ethylene oxide. As described above, cremophor typically used as a solvent for paclitaxel, and it is associated with side effects that can be dangerous (see, for example, Gelderblom et al.,above).

The pharmaceutical agent can be any suitable described herein, the pharmaceutical agent (e.g., propofol, paclitaxel or docetaxel). Additionally, the pharmaceutical agent may be a nucleic acid sequence, most preferably, the DNA sequence. In this regard, the pharmaceutical composition according to the invention can be used to transport genes into the cell by receptor-mediated kaueranga/vesicular transport. In order to transfer DNA sequences, such as genes and other genetic material, including as non-limiting examples of a plasmid or cDNA in a cell (e.g., an endothelial cell or a tumor cell), it is possible to obtain pharmaceutical compositions containing albumin in combination with genetic material. Because tumor cells and other cells in the seat of the disease are increased capture of proteins, genetic material etc is doctitle gets these types of cells and can be introduced into the genetic material of cells for successful therapeutic effect. The use of proteins such as albumin human serum, serves as non-viral vectors for delivery of genetic material without the risk of virus-related diseases or side effects. For example, it is possible to prepare pharmaceutical composition comprising a nucleic acid sequence encoding β-galactosidase or green fluorescent protein (GFP) and albumin, and its contact with endothelial cells derived from umbilical veins person or microvessels of human lungs in order to facilitate introduction of the nucleic acid sequence in endothelial cells. The occurrence of nucleic acid sequence can be determined by methods known in this field, such as, for example, fluorescence or staining.

In the method according to the invention for increasing the transport of the pharmaceutical agent to the seat of the disease, the disease may be any suitable disease or condition. Preferably, the disease is a cancer, cardiovascular disease or arthritis.

In the method according to the invention to increase the binding of the pharmaceutical agent cellin vitroorin vivo, the pharmaceutical composition is injected into the cellin vitroorin vivo. Preferably, the cell is pre which accounted for a cell of the animal. More preferably, the cell is a mammalian cell, and most preferably, the cell is a human cell. The pharmaceutical composition is administered preferably in a cagein vivo. The cell can be any suitable cell, which is a necessary target for the introduction of the pharmaceutical composition. For example, the cell may be located in the tissues either derived from the tissues of the digestive system, including the esophagus, stomach, small intestine, large intestine, rectum, anus, liver, gall bladder and pancreas. The cell may also be in the tissues either derived from the tissues of the respiratory system, including, for example, larynx, lungs and bronchi. The cell can be in tissues or occur from tissue, for example, cervix, uterus, ovary, vagina, prostate, testicles and penis, which constitute the male and female reproductive system, and urinary bladder, kidney, renal pelvis and ureter, which make up the urinary system. The cell can be in the tissues either derived from the tissues of the cardiovascular system, including, for example, endothelial cells and cardiac muscle cells. The cell may also be in the tissues either derived from the tissues of the lymphatic system (e.g., lymph cells), nervous system (e.g. the R, neurons or glial cells) and endocrine system (e.g., cells of the thyroid gland). Preferably, the cell located in the tissues either derived from the tissues of the cardiovascular system. Most preferably, the cell is an endothelial cell. In the context of the method according to the invention to increase the transport and binding of the pharmaceutical agent with a cell, a pharmaceutical composition is preferably in contact with more than one cell.

In another aspect of the invention the method according to the invention to increase the transport and increase the binding of the pharmaceutical agent with the cell can be used to treat tumor cells. Tumor cells show increased capture of proteins, such as albumin and transferrin, in comparison with normal cells. Because tumor cells are growing with great speed, they require additional sources of nutrients compared with normal cells. Studies of tumors with the pharmaceutical composition according to the invention, containing paclitaxel and albumin human serum showed increased capture of albumin to paclitaxel in the tumor. It was found that this seizure is the result of the previously uncertain phenomena transport of albumin with medicine through receptor glycoprotein 60 ("gp60"), the cat is which are specific for albumin.

Thus, according to another aspect of the present invention specific for albumin gp60 receptor and other receptors, transport proteins, which are presented on tumor cells, can be used as targets for suppression of tumor growth. Blocking the gp60 receptor using antibodies against the gp60 receptor or large compounds or small molecules that bind to, block or inactivate gp60 and other receptors, transport proteins on tumor cells or tumor endothelial cells may block the transport of proteins to the cells and thereby reduce their rate of growth and induce cell death. Blocking this mechanism, therefore, leads to the treatment of the individual (for example, a person with cancer or another disease. Determination of blocking/binding a specific protein receptor is carried out by means of screening any number of compounds against selected gp60 or other receptors, such as gp16 or gp30, or using whole cell preparations. Additionally you can also use for this purpose a suitable animal model, such as, for example, a mouse containing a "knock-out" mutations of the genes encoding gp60 or caveolin is the essential component-1 or other proteins that are specific to vehicles. Thus, the method of identifying compounds that block the display or link gp60, gp16, gp30 or other protein receptors are within the scope of this invention.

Additionally, compounds that block or bind the gp60 receptor or other receptors, can be used to treat some diseases, including cancer. In relation to the treatment of cancer, blocking or binding compound can be used as a single agent or in combination with other standard means for chemotherapy or chemotherapy. For example, it is useful to treat cancer conventional chemotherapy or pharmaceutical compositions of albumin with the medicinal product according to the invention (which show high accumulation in tumors)involving the use of compounds that block the transport of proteins to tumor cell. Blocking compounds can be entered before or in conjunction with other chemotherapeutic or anti-cancer agents. Therefore, any compounds that block or bind the gp60 receptor or other receptors are within the scope of the present invention.

The composition of the albumin with the medicinal product according to the invention, such as, for example, albumin to paclitaxel, albumin with docetaxel, albumin with epothilones, albumin with camptothecin or albumin with rapamycin and other, used in the treatment of diseases. I believe that such drug to the position effective due to increased receptor-mediated transport of the composition of the protein drug to the desired site, for example, tumors. Not wishing to bound to any particular theory, the transport of the composition of the protein with drug using receptor-mediated transport, leading to a therapeutic effect is believed to be the transport mechanism, for example, compositions of albumin to paclitaxel in the tumor, as well as the transport of albumin to paclitaxel and albumin with rapamycin through the lungs. Transport is affected by the presence of gp60, gp16, or gp30 in these tissues. Accordingly, medicines and composition of proteins and drugs, whose transport to the hearth diseases such as inflammation (e.g. arthritis) or tumors associated with gp60 receptors, gp16 or gp30 and that result in therapeutic effect, considered as compositions of the present invention.

In accordance with another aspect of the present invention, endothelial cells can work together to cultivate cells with a specific function. Incubation of endothelial cells with other cell types, such as insularity, hepatocytes, neuroendocrine cells, and others, considers necessary transport components, such as proteins and other useful components, such cells. Endothelial cells provide the data transport components to cultivated types of cells to morovati conditions in vivothat is in those cases where these types of cells normally would be in close proximity to endothelial cells and was dependent on endothelial cells in relation to transport nutrients, growth factors, hormonal signals, etc. that are necessary for their proper functioning. Previously it was impossible adequately to cultivate such a variety of cell types and get their physiological functioning in those cases when there was no endothelial cells. The presence of endothelial cells in culture with the desired cell type allows differentiation and proper functioning of insulation, hepatocytes or neuroendocrine tissuein vitroorex vivo. Thus, it was found that a collaborative culture of endothelial cells with insularity result in getting insulation with improved physiological properties, for example, the ability to secrete insulin compared with insularity, cultured in the absence of endothelial cells. Such fabrics can then useex vivoor to transplant in vivo for the treatment of diseases caused by the loss of the corresponding cellular functions (e.g., diabetes, in the case of insulation, impaired liver function in case of hepatocytes and neuroendocrine disorders or mo is olivana in the case of neuroendocrine cells). Cells derived from other tissues and organs (as described above), you can cultivate together with endothelial cells to provide the same effect. In addition a collaborative culture can be used to introduce genetic material into desired cell types. The presence of albumin in such cultures, as found, is very beneficial.

The following examples further illustrate the invention but, of course, they should not be construed as in any way limiting its scope.

EXAMPLE 1

This example demonstrates the preparation of a pharmaceutical composition comprising albumin and paclitaxel. The preparation of compositions of paclitaxel with albumin described in U.S. patent No. 5439686 and 5916596, which are fully incorporated here by reference. In particular, 30 mg of paclitaxel was dissolved in 3.0 ml of methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (2 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system is the bore in the rotary evaporator, and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes. The resulting dispersion was translucent, and the typical average diameter of the obtained particles of paclitaxel were in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot could easily restore to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization.

It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting. When compared with the toxicity of paclitaxel dissolved in drugs with cremophor, the pharmaceutical composition according to the invention containing albumin, showed significantly lower toxicity.

EXAMPLE 2

This example demonstrates the preparation of pharmaceutical compositions containing amiodarone and albumin. 30 mg of amiodarone was dissolved in 3.0 ml of methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (1 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to get Pervy the ing the emulsion, and then lifted into a high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a rotary evaporator and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles of amiodarone was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization.

It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting. When compared with the toxicity of amiodarone dissolved in drugs with twin, the pharmaceutical composition according to the invention c albumin showed a significantly lower toxicity.

EXAMPLE 3

This example demonstrates the preparation of pharmaceutical compositions containing the compositions of liothyronine and albumin. Liotironin (or a suitable salt) was dissolved is water-alcohol solution or an alkaline solution in a concentration of 0.5-50 mg/ml Alcohol (or alkaline) solution was added to a solution of albumin (0.1 to 25%) and mixed them. Stirring was carried out on a mixer with low shear effort or ultrasonic installation or homogenizer, high shear forces. At low concentrations of liothyronine (5-1000 μg/ml) was obtained transparent solution. As increased concentration, have a stable suspension milky-white color. These solutions or suspensions were filtered through a sterilizing filter. Organic solvents were removed by evaporation or other suitable method.

EXAMPLE 4

This example demonstrates the preparation of a pharmaceutical composition comprising rapamycin and an albumin. 30 mg of rapamycin was dissolved in 2 ml system chloroform/ethanol. The solution was added to 27.0 ml solution of albumin human serum (3 wt./vol.%). The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20 to 30 minutes of Receiving the Naya dispersion was transparent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting.

EXAMPLE 5

This example demonstrates the preparation of pharmaceutical compositions containing epothilone In and albumin. 30 mg epothilone was dissolved In 2 ml system chloroform/ethanol. The solution was added to 27.0 ml solution of albumin human serum (3 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 min Paucisnabilis was transparent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are not limiting. When compared with the toxicity epothilone In dissolved in drugs with cremophor, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 6

This example demonstrates the preparation of pharmaceutical compositions containing dimer colchicine and albumin. 30 mg of the dimer colchicine was dissolved in 2 ml system chloroform/ethanol. The solution was then added to 27.0 ml solution of albumin human serum (3 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion,of at least within 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are not limiting. When compared with the toxicity of the dimer colchicine dissolved in twin, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 7

This example demonstrates the preparation of a pharmaceutical composition containing docetaxel and albumin. 30 mg of docetaxel was dissolved in 2 ml system chloroform/ethanol. The solution was then added to 27.0 ml solution of albumin human serum (3 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order for the returns of the primary emulsion, and then it was transferred into the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are not limiting. When compared with the toxicity of docetaxel dissolved in the system twin/ethanol, which is the standard solvent for the drug, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 8

This example demonstrates the preparation of a pharmaceutical composition containing docetaxel and albumin. 150 mg of docetaxel was dissolved in 1 ml system etelaat the/butyl acetate and 0.5 ml of oil, for example, soybean oil or oil with vitamin E. Used different ratios of solvents and oils, and song data are also considered part of this invention. Also optional was added a small amount of negatively charged component, for example benzoic acid (0,001%-0,5%). The solution was then added to 27.0 ml solution of albumin human serum (5 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantity is the ratio of the medicinal product, solvents, proteins used in this example are not limiting. When compared with the toxicity of docetaxel dissolved in the system twin/ethanol, which is the standard solvent for the drug, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 9

This example demonstrates the preparation of pharmaceutical compositions containing Texan IDN5390 and albumin. 150 mg IDN5390 was dissolved in 1 ml system ethyl acetate/butyl acetate and 0.5 ml of oil, such as soybean oil or oil with vitamin E. Used different ratios of solvents and oils, and song data are also considered as part of this invention. Also optional was added a small amount of negatively charged component, for example benzoic acid (0,001%-0,5%). The solution was then added to 27.0 ml solution of albumin human serum (5 wt./vol.%). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting si is theme carried in Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes The resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are not limiting. When compared with the toxicity IDN5390 dissolved in twin, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 10

This example demonstrates the preparation of pharmaceutical compositions containing Texan IDN5109 and albumin. 150 mg IDN5109 was dissolved in 2 ml system chloroform/ethanol. Used different ratios of solvents and oils, and song data are also considered as part of this invention. Also optional was added a small amount of negatively charged component, for example benzoic acid (0,001%-0,5%). The solution was then added to 27.0 ml solution of albumin human serum (5 wt./vol.%). If necessary, was added deferoxamine. In order to get the ü primary emulsion, the mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.), and then it was transferred into the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents and proteins used in this example are not limiting. When compared with the toxicity IDN5109 dissolved in twin, the pharmaceutical composition comprising albumin, showed significantly lower toxicity.

EXAMPLE 11

This example demonstrates the preparation of a pharmaceutical composition containing 10-hydroxycamptothecin (10 NS) and albumin. 30 mg of 10 NA was dissolved in 2 ml of DMF system/stands the chloride/soybean oil. The solution was then added to 27.0 ml solution of albumin human serum (3 wt./vol.%). In order to obtain a primary emulsion, the mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) and then it was transferred into the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting.

EXAMPLE 12

This example demonstrates the preparation of a pharmaceutical composition containing cyclosporin and albumin. 30 mg of cyclosporine was dissolved in 3.0 ml of methylene chloride. The solution is then added to the to of 27.0 ml solution of albumin human serum (1 wt./vol.%). The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting system was transferred into a Rotavap and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes the resulting dispersion was translucent, and the typical average diameter of the obtained particles was in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization.

EXAMPLE 13

This example demonstrates the preparation of pharmaceutical compositions containing oil and which includes cyclosporine and albumin. 30 mg of cyclosporine was dissolved in 3.0 ml of a suitable oil (sesame oil containing 10% orange oil). The solution was then added to 27.0 ml solution of albumin human serum (1 wt./vol.%). The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain the primary the second emulsion, and then lifted into a high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least, for 5 cycles. The resulting dispersion contained typical average particle diameter in the range 50-220 nm (Z-average, Malvern Zetasizer). The variance directly used or liofilizirovanny within 48 hours, optionally adding a suitable cryoprotector. The resulting clot was easily restored to the original dispersion by adding sterile water or saline. It should be understood that the number, types, and quantitative relationships of drugs, solvents and proteins used in this example are in no way limiting.

EXAMPLE 14

This example demonstrates the preparation of a pharmaceutical composition comprising amphotericin and albumin. 30 mg of amphotericin b was dissolved in 3.0 ml system methylpyrrolidinone/methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (1 wt./vol.%). The mixture is homogenized for 5 minutes at low rpm (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred it into a high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion, at least in t the value of 5 cycles. The resulting system was transferred into a rotary evaporator and quickly solvent was removed at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes. The resulting dispersion was translucent, and the typical average diameter of the obtained particles amphotericin b ranged between 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours. The resulting clot could easily be restored to its original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. It should be understood that the number, types, and quantitative relationships of drugs, solvents and proteins used in this example are in no way limiting. The addition of other components, such as lipids, bile salts, etc. also resulted in the receipt of appropriate drugs.

EXAMPLE 15

This example demonstrates preclinical pharmacokinetics and pharmacodynamics pharmaceutical composition comprising albumin and paclitaxel.

Several preclinical pharmacokinetic studies were conducted in mice and rats in order to evaluate the possible advantages of the pharmaceutical compositions of albumin to paclitaxel above pharmaceutical compositions with cremophor-paclitaxel (Taxol is). These studies showed: (1) that the pharmacokinetics of albumin to paclitaxel in rats were linear, whereas the pharmacokinetics of Taxol had a non-linear relative to dose, (2) a pharmaceutical composition comprising albumin and paclitaxel, showed lower values of AUC and Cmaxplasma, indicating a more rapid distribution of the compositions of albumin to paclitaxel in tissues compared with Taxol (emphasis similarly), (3) a pharmaceutical composition comprising albumin and paclitaxel showed a lower value of Cmaxthat may explain the low toxicity associated with maximum levels in the blood relative to Taxol, (4) the half-life shown pharmaceutical compositions containing albumin and paclitaxel was approximately 2 times higher in rats and 4 times higher in mice with tumors relative to Taxol and (5) the metabolism of paclitaxel in the pharmaceutical compositions containing albumin and paclitaxel, was slower than in the pharmaceutical compositions of Taxol. 24 hours after injection in rats 44% of the total radioactivity was still associated with paclitaxel in the case of pharmaceutical compositions containing albumin and paclitaxel, compared to only 22% in the case of Taxol. The main effect of the above pharmacodynamics, i.e. uvelichenie what about the intracellular capture, prolonged time half-life and slow metabolism, is shown in the case of pharmaceutical compositions containing albumin and paclitaxel leads to higher 1.7 times the value of the AUC of the tumor, the higher 1.2 times the value of the Cmaxtumors and longer 1.7 times the time half-life in the tumor than in the case of Taxol in mice with tumor.

EXAMPLE 16

This example illustrates the reduced side effects and reduced toxicity associated with pharmaceutical compositions containing paclitaxel and albumin.

Due to the unique nature of the pharmaceutical compositions containing paclitaxel and albumin in the absence of cremophor, the toxicity of pharmaceutical compositions containing paclitaxel and albumin significantly lower than Taxol. In preclinical studies in mice and rats the study of the acute toxicity of a single dose showed that the dose LD50approximately 59 times more pharmaceutical compositions containing paclitaxel and albumin than for Taxol. In the toxicity study with multiple doses in mice dose LD50was approximately 10 times more to pharmaceutical compositions containing paclitaxel and albumin than for Taxol. The study determined the degree mielosupression in rats, which legilimancy compositions containing paclitaxel and albumin, and Taxol. The results showed that at equal doses of a pharmaceutical composition comprising paclitaxel and albumin, leading to a much lesser mielosupression in rats than Taxol. In a study of acute toxicity in rats was observed necrosis of the cerebral cortex or severe neurotoxicity in animals receiving Taxol at a dose of 9 mg/kg, but these effects were absent in animals receiving pharmaceutical composition comprising paclitaxel and albumin at a dose up to 120 mg/kg Thus, the presence of albumin to pharmaceutical compositions containing paclitaxel, leads to a significant reduction of side effects and toxicity compared with conventional compositions containing paclitaxel.

EXAMPLE 17

The data demonstrates the clinical effects of a pharmaceutical composition comprising paclitaxel and albumin, people.

Clinical studies of more than 500 sick people to date provide evidence that supports the fact of reducing the toxicity and side effects pharmaceutical composition comprising paclitaxel and albumin (albumin to paclitaxel"), in comparison with compositions containing cremophor and paclitaxel (Taxol). In a study of 19 patients at stage I, the maximum permissible dose of albumin with pacl what Taxila, he was given every 3 weeks, was 300 mg/m2. It is much higher than conventionally administered dose of cremophor with paclitaxel, which is 175 mg/m2, which is given once every 3 weeks. Hematologic toxicity in these patients was average without allergies, weak and without neuropathy associated with the introduction of drug side effects such as venous irritation, etc.

In another study, 27 patients at stage I, the maximum permissible dose of albumin to paclitaxel, which was given on a weekly schedule, was 125-150 mg/m2. It is much higher than conventionally administered dose of cremophor with paclitaxel, which is 80 mg/m2if it is given on a weekly schedule. Hematologic toxicity in these patients was weak without allergies, weak and without neuropathy associated with the introduction of drug side effects such as venous irritation, etc.

In two studies in phase II of albumin to paclitaxel given either 175 or 300 mg/m2every 3 weeks 43 and 63 patients, respectively, hematologic toxicity was low, only 7% and 24% of patients ANC < 500/mm3at doses of 175 mg/m2and 300 mg/m2, respectively. Severe neuropathy occurred in 0% and 14% of patients with dosiro the Ah 175 mg/m 2and 300 mg/m2, respectively. No cases of severe allergies and no cases associated with the introduction of drug side effects such as venous irritation, pain during injection, etc. these side effects were significantly lower than those studied patients with Taxol.

In the testing stage III, which compares the composition of albumin to paclitaxel, ABI-007 and Taxol (which contains cremophor with paclitaxel), the dose of ABI-007 was significantly higher (260 mg/m2versus 175 mg/m2Taxol), indicating that he better move. Composition of albumin to paclitaxel also exhibit significantly reduced neutropenia compared with cremophor-paclitaxel.

EXAMPLE 18

This example demonstrates improved preclinical efficacy of using a pharmaceutical composition comprising paclitaxel and albumin.

The study of the cytotoxicity ofin vitrocomparing the effect of albumin to paclitaxel and Taxol on cervical squamous cell carcinoma A431, showed approximately 4-fold increase in cytotoxic activity of albumin to paclitaxel with values IC500,0038 and a 0.012 µg/ml for albumin to paclitaxel and Taxol, respectively.

Five different models of tumor xenografts man in Nude, we is it (related to breast MX-1, easy NCI-H522, ovarian SK-OV-3, prostate PC-3 and the colon HT-29) MTD or equally toxic dose of ABI-007 was above 1.5-3.4 times than for Taxol and led to statistically significant improvement in slowing tumor growth (p<0,05) in all tumors except lung tumor (p=0,15).

In models of breast cancer MX-1 one hundred percent (100%) of the animals treated with albumin to paclitaxel, has survived for 103 days compared to 20-40% of survivors in the groups that were treated with the same doses of Taxol.

EXAMPLE 19

This example demonstrates improved clinical effectiveness of using a pharmaceutical composition comprising albumin and paclitaxel, administered intraarterially.

Research phase I/II intraarterial administration of a pharmaceutical composition comprising albumin and paclitaxel, as described herein, patients registered head and neck cancer (N=31) and cancer of the anal canal (N=12). Increasing the dose of 120 -300 mg/m2introduced more than 30 minutes percutaneous intra-arterial infusion of 3-4 weeks. Patients with head and neck cancer showed the degree of response is equal to 76% (N=29), whereas patients with cancer of the anal canal showed the degree of response is 64% (N=11).

EXAMPLE 20

This example illustrates the preparation of a pharmaceutical composition containing 3% oil and includes propofol and albumin./p>

The emulsion of the type oil-in-water containing 1% (by weight) of propofol, was prepared as follows. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). An oil phase was prepared by dissolving egg lecithin (0.4 wt.%) and propofol (1 wt.%) in soybean oil (3 wt.%) at approximately 50°C-60°C, and which to dissolve. The oil phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recirculation within 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen. The obtained pharmaceutical composition contained the following main ranges of components (wt.%): propofol 0.5 to 5%; albumin human serum 0.5 to 3%; soybean oil 0,5-3,0%; egg lecithin 0,12-1,2%; glycerin of 2.25%; water for injection q.s. to 100; pH 5-8. Optional added suitable chelators, such as deferoxamine (0,001-0,1%).

EXAMPLE 21

This example illustrates the preparation of a pharmaceutical composition containing 5% oil and comprising propofol and albumin.

The emulsion of the type oil-in-water containing 1% (by weight) proof the La, received the following way. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). An oil phase was prepared by dissolving egg lecithin (0.8 wt.%) and propofol (1 wt.%) in soybean oil (5 wt.%) at approximately 50°C-60°C, and which to dissolve. The oil phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recirculation within 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen. The obtained pharmaceutical composition contained the following main ranges of components (wt.%): propofol 0.5 to 5%; albumin human serum 0.5 to 3%; soybean oil 0.5 to 10.0%; egg lecithin 0,12-1,2%; glycerin of 2.25%; water for injection q.s. to 100; pH 5-8. Optional added suitable chelators, such as deferoxamine (0,001-0,1%).

EXAMPLE 22

This example illustrates the preparation of a pharmaceutical composition that includes propofol and albumin and does not contain oil.

Using a method similar to the method described in example 18 was prepared compositions with propofol containing al is boomin and tween 80. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%), albumin human serum (0.5%), tween 80 (1.5 wt.%) and deferoxamine mesilate (0.1 wt.%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Propofol (1 wt.%) was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recirculation within 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen. The obtained pharmaceutical composition contained the following main ranges of components (wt.%): propofol 0.5 to 5; albumin human serum 0.5 to 3%; tween 80 0.1 to 1.5%; deferoxamine mesilate of 0.0001 to 0.1%; glycerin of 2.25%; water for injection q.s. to 100; pH 5-8.

EXAMPLE 23

This example illustrates the preparation of a pharmaceutical composition comprising propofol, albumin and vitamin E-TPGS, which does not contain oil.

Using a method similar to the method described in example 19 was prepared compositions with propofol containing albumin and vitamin E-TPGS. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%), albumin human serum (0.5%), vitamin E-TPGS (1 wt.%) and deferoxamine mesilate (0.1 wt.%) in water for injection, and USB Stivali to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Propofol (1 wt.%) was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recirculation within 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen. The obtained pharmaceutical composition contained the following main ranges of components (wt.%): 0.5 to 5 propofol; 0.5 to 3% albumin human serum; 0.5 to 4.0% vitamin E-TPGS; not necessarily of 0.0001-0.1% nelfinavir deferoxamine; of 2.25% glycerin; water for injection q.s. to 100; pH 5-8.

EXAMPLE 24

This example illustrates the preparation of pharmaceutical compositions containing propofol, albumin, vitamin E-TPGS and 1% oil.

The emulsion containing 1% (by weight) of propofol was prepared in the following way. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Surface-active agent, for example, vitamin E-TPGS (0,5%) was added to the aqueous phase. The oil phase consisted of propofol (1 wt.%) and 1% soybean oil. The oil phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes in ECENA 5 minutes The primary emulsion is homogenized at high pressure 20000 psi and subjected to recycling for up to 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen.

The obtained pharmaceutical composition contained the following main ranges of components (wt.%): 0.5 to 5% of propofol; 0.01 to 3% albumin human serum; 0.1 to 2% vitamin E-TPGS; soy or other oils (0.1%-5%); of 2.25% glycerin; water for injection q.s. to 100; pH 5-8. Optional added deferoxamine (0.001 to 0.1 wt.%).

EXAMPLE 25

This example illustrates the preparation of pharmaceutical compositions containing propofol, albumin, vitamin E-TPGS, 1% lipids and negatively charged component.

The emulsion containing 1% (by weight) of propofol was prepared in the following way. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Surface-active agent, for example, vitamin E-TPGS (0,5%) was added to the aqueous phase. The oil phase consisted of propofol (1 wt.%) and 1% soybean oil. Added a small amount of negatively charged component (0,001%-1%), for example, a phospholipid or a salt of bile acids. Maslany the phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recycling for up to 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen.

The obtained pharmaceutical composition contained the following main ranges of components (wt.%): 0.5 to 5% of propofol; 0.01 to 3% albumin human serum; 0.1 to 2% vitamin E-TPGS; soy or other oils (0.1%-5%); of 2.25% glycerin; water for injection q.s. to 100; pH 5-8. Optional added deferoxamine (0.001 to 0.1 wt.%).

EXAMPLE 26

This example illustrates the preparation of pharmaceutical compositions containing propofol, albumin, vitamin E-TPGS, 1% lipids and negatively charged component (sodium deoxycholate).

The emulsion containing 1% (by weight) of propofol was prepared in the following way. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Surface-active agent, for example, vitamin E-TPGS (0,5%) was added to the aqueous phase. The oil phase consisted of propofol (1 wt.%) and 1% soybean oil. Added a small amount of negatively charged component (0,001%-1%), for example, detox Holt sodium. The oil phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recycling for up to 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen.

The obtained pharmaceutical composition contained the following main ranges of components (wt.%): 0.5 to 5% of propofol; 0.01 to 3% albumin human serum; 0.1 to 2% vitamin E-TPGS; soy or other oils (0.1%-5%); of 2.25% glycerin; water for injection q.s. to 100; pH 5-8. Optional added deferoxamine (0.001 to 0.1 wt.%).

EXAMPLE 27

This example illustrates the preparation of pharmaceutical compositions containing propofol, albumin, vitamin E-TPGS, 1% lipids and negatively charged components (phospholipids, bile salts, polyaminoamide etc).

The emulsion containing 1% (by weight) of propofol was prepared as follows. The aqueous phase was prepared by adding glycerol (to 2.25 wt.%) and albumin human serum (0.5%) in water for injection, and which to dissolve. The aqueous phase was passed through a filter (filter 0.2 µm). Surface-active agent, for example, vitamin E-TPGS (0,5%) was added to the aqueous phase. The oil phase consisted of propofol (1 wt.%) and 1% is oevag oil. Added a small amount of negatively charged component (0,001%-1%), for example, phosphatidylcholine. The oil phase was added to the aqueous phase and homogenized at 10,000 rpm./minutes within 5 minutes the Primary emulsion is homogenized at high pressure 20000 psi and subjected to recycling for up to 15 cycles at 5°C. Alternatively, used a separate passage through the homogenizer. The final emulsion was filtered (filter 0.2 μm) and stored in nitrogen.

The obtained pharmaceutical composition contained the following main ranges of components (wt.%): 0.5 to 5% of propofol; 0.01 to 3% albumin human serum; 0.1 to 2% vitamin E-TPGS; soy or other oil with 0.1%-5%); of 2.25% glycerin; water for injection q.s. to 100; pH 5-8. Optional added deferoxamine (0.001 to 0.1 wt.%).

EXAMPLE 28

This example demonstrates the binding of propofol to albumin.

The binding of propofol to albumin was determined as follows. The solubility of propofol was tested in water and in a solution containing albumin. 250 μl of propofol was added to 10 ml of water or solution of albumin and which was for 2 hours in a scintillation vial. Then the solution was transferred into a centrifuge tube with 15 ml polyethylene and kept at 40°C for approximately 16 hours. In samples of water and solutions of albumin were analyzed number is the amount of propofol. The solubility of propofol in the water, as defined, 0.12 mg/ml solubility of propofol in the albumin solution was dependent on the concentration of albumin and increased to 0.44 mg/ml, while the concentration of albumin was 2% (20 mg/ml). The solutions were ultrafiltrable through a filter with a MWCO CD and filtrates analyzed the amount of propofol. It was found that for a solution of propofol/water 61% of propofol could be recovered in the filtrate, while for solution propofol/albumin only 14% was recovered in the filtrate, which indicates a significant binding of propofol to albumin. Based on these results, the addition of albumin to pharmaceutical compositions containing propofol, leads to a decrease in the number of unbound propofol due to the binding of albumin with propofol.

EXAMPLE 29

This example illustrates the decrease in unbound propofol in the pharmaceutical composition when filtering/contact with the membrane.

As observed in the experiments described in example 28, filtration or ultrafiltration pharmaceutical compositions containing propofol, led to a decrease in the number of unbound propofol. Diprivan and pharmaceutical composition prepared according to the present invention containing albumin, each of which contained 1% propofol (10 mg/ml), ultrafi trevali using membrane 30 KD. The number of unbound propofol in the filtrate was measured using HPLC. The concentration of unbound propofol in the filtrate was approximately 17 μg/ml for Diprivan, while the concentration of unbound propofol in the filtrate for the pharmaceutical compositions according to the invention was approximately 7 µg/ml. the Results correspond to an effective decrease in unbound propofol, with a ratio of more than 2 to pharmaceutical compositions containing propofol and albumin.

EXAMPLE 30

This example illustrates the introduction of a pharmaceutical composition containing propofol and albumin, people.

Random clinical trial double-blind sang and danced for comparison unwanted skin sensations from pharmaceutical compositions containing propofol and albumin, with the pharmaceutical composition of commercially available drug of propofol Diprivan. The tests were carried out in accordance with acceptable clinical practice, and from individuals consent was obtained on the basis of full information. Adult individuals of both sexes were suitable to participate if they had apparently normal skin without damage on the back of the hands.

Drugs, initially stored in the refrigerator, brought to room temperature, and 10 μl of the drugs slowly put ignoreme is but on the back of both hands of the individual. Noted the overall reaction and feelings on their hands from drugs. The results of this study are summarized in table 1.

Table 1
How to verify an individual% of individuals with sensations from ABI-propofol% of individuals with feelings of Diprivan
Slight warmth or a burning or stinging feelingNo sensationsSlight warmth or a burning or stinging feelingNo sensations
grade 10100,07525

EXAMPLE 31

This example demonstrates the use of deferoxamine as an antioxidant in pharmaceutical compositions containing propofol.

Pharmaceutical compositions comprising propofol and deferoxamine mesilate and contains twin or TPGS, and kept at 4°, 25° or 40°C in order to investigate the effect of nelfinavir deferoxamine in preventing oxidation of propofol. For these drugs was measured concentration of propofol after dlitelnogo the time to determine the antioxidant activity of deferoxamine. The data presented below in tables 2 and 3 as % efficiency relative to the zero time.

Table 2
The medicine albumin/twin
1 month storage
Temperature4°C25°C40°C
Control100%88%48%
0,01% Def101%89%61%
0,1% Def103%89%64%

Table 3
The medicine albumin/TPGS
1 month storage
Temperature4°C25°C40°C
Control 99%73%42%
0,01% Def99%87%55%
0,1% Def99%85%58%

Under these conditions deferoxamine was effective to reduce oxidation of propofol. The effect was more pronounced at higher temperatures. No significant oxidation did not occur at 4°C. This study was conducted using tubes that were not inert or were coated with Teflon.

EXAMPLE 32

This example illustrates internal-lung delivery of a pharmaceutical composition comprising paclitaxel and albumin (ABI-007).

The purpose of this study was to determine the period of the presence of [3H]ABI-007 in blood and selected tissues after intratracheal instillation in rats Sprague Dawley.

Target preparation for intratracheal dose, which was administered to the animals was calculated based on the volume of a dose of 1.5 ml per kg of body weight. The metering device consisted of micropulverized Penn-Century (model 1A-1B; Penn-Century, Inc., Philadelphia, PA; acquired from DeLong Distributors, Long Branch, NJ)attached to the sealing injectors with Swarovski nozzle volume of the IOM 1 ml. Corresponds to the amount of dosage of the drug was placed in the metering device, the completed device was weighed and recorded its weight. The catheter was introduced into the trachea shot the animal, micropolarization part of the metering device was placed into the trachea through the catheter and injected dose. After a dose of empty dosing device is re-weighed and the dose was calculated as the difference of the mass measuring device before and after a dose. The average dose for all animals was 4,7738±0,0060 (CV 1,5059) mg of paclitaxel per kg of body weight.

The blood samples in the amount of approximately 250 µl were taken from under jugular vein cannula in rats JVC at the following predefined points in time after dose: 1, 5, 10, 15, 30 and 45 minutes (min) and 1, 4, 8 and 24 hours (h). The blood samples taken after 24 hours and blood samples taken from dead animals after 10 min, 45 min and 2 h, were taken by puncture of the heart shot at killing. All blood samples analyzed for total radioactivity was distributed in a pre-weighed test tubes for samples, and these tubes for the sample was re-weighed, and the weight of each sample was calculated by subtraction. In blood samples collected from the jugular vein, and the aliquot of blood in 250 ál collected from animals at umerle the AI, analyzed the total tritium content.

For all rats, the maximum concentration of tritium in the blood was observed after 5 min (0,0833 h) after administration of the dose. The half-life of tritium defined in the time interval from 4 h to 24 h, ranged from 19,73 h to 43,02 o'clock it Should be noted that this interval includes only three of the data, which can be calculated for the variability of this parameter. Value expressed cleansing blood from tritium was of the order of 0.04 l/H. the Results of these experiments are shown below in table 4.

Table 4
Compartmental analysis of tritium concentration in blood (mg×EQ./l) versus time profiles in rats after intratracheal injection of [3H]ABI-007
Mean±SD
Cmax(mg×EQ./l)near 1.615±0,279
Tmax(h)
t½beta (h)
0,0833±0,0
to 33.02±1,99

AUClast (mg×EQ×h/l)7,051±1,535
Cl/F (l/h)0,0442±0,0070
Fa (idocument) 1,229±0,268

The average blood concentration of radioactivity derived from [3H]ABI-007, after intravenous dose rats were analyzed as a function of time, in order to assess the bioavailability of tritium obtained by intratracheal introduction of [3H]ABI-007. This analysis resulted in AUC values for 24 hours (AUClast), component 6,1354 mg×EQ×h/L. Based on these data, the radioactivity originating from intratracheal dose of [3H]ABI-007 is extremely bioavailable. Data analyses are based on total radioactivity.

Tritium originating from [3H]ABI-007, quickly absorbed after intratracheal injection. The average absorption and elimination half-life (half-life k01 and k10 half-life, respectively) tritium in blood after intratracheal dose of [3H]ABI-007 (mean±SD) was 0,0155±0,0058 h and 4,738±0,366 h, respectively. The average apparent clearance of tritium in blood was 0,1235±0,0180 l/h (see table 4 above).

Tritium originating from [3H]ABI-007 after intratracheal injection, was absorbed and distributed. The dynamics of the tritium concentrations in the blood are well described dvukhkomponentnoi model with an average absorption and half-life 0,0155 and 4,738 h, respectively. Approximately 28% entered casinohotel in the lungs after 10 min after intratracheal dose. Maximum, less than 1% of the dose found in other tissues, with the exception of the gastrointestinal tract, in all analyzed time points.

Based on the results of previously conducted studies intravenous dose of [3H]kapcsolatTM([3H]Capxol™]), the bioavailability of tritium originating from intratracheal dose was 1,229±0,268 (mean ± SD) for the three animals in this dose group. It should be noted, however, that this assessment of bioavailability based on total radioactivity. Suddenly that paclitaxel is delivered to the lung by using compositions with albumin according to the invention, can quickly become bioavailable, indicating excellent transport across the pulmonary endothelium. Reported no toxicity in animals, which was unexpected since pulmonary delivery of cytotoxic agents are known to cause pulmonary toxicity.

A fair amount of radioactivity present in the gastrointestinal tract (including the content) through 24 h after dose (27% intratracheal dose). The presence of tritium in the gastrointestinal tract is probably the result of biliary excretion or clearance of tritium from the respiratory tract by mucociliary clearance, resulting from swallowing.

EXAMPLE 33

This example illustrates the IP is the study of nozzles Aerotech II and Pari for pulmonary delivery of pharmaceutical compositions, containing paclitaxel and albumin.

The study was performed using the pharmaceutical composition of paclitaxel with albumin ABI-007 under the following conditions: room temperature (20-23°C), relative humidity (48-54%), ambient pressure (629 mm Hg), the feed stream spray (10 l/min forAerotech II; 7 l/min forPari), total feed flow (28.3 l/min), the pressure drop in the nozzle (23 lb/in2forAerotech II; 32 lb/in2forPari), duration (from 15 to 60 seconds), sample volume (1.5 ml), the concentration of paclitaxel, ABI-007 (5, 10, 15 and 20 mg/ml).

Both spray Aerotech II and Pari provide acceptable overall efficiency (30%-60%) in cases, when ABI-007 was restored to a concentration in the range of 5-15 mg/ml Effectiveness of nebulizer Pari had a higher efficiency of the nozzle than the nozzle Aerotech II. The effectiveness of nebulizer Pari decreased to some extent by increasing the concentration of ABI-007. Watched an excellent fraction of fine particles (74%-96%). Spray Aerotech II contained the fraction of fine particles of a higher order than the Pari nebulizer. The fraction of fine particles is not concentration dependent.

Nebulizer Pari gave 100 mg of paclitaxel in less than 30 minutes using a solution of ABI-007 at a concentration of 15 mg/ml have crucified the spruce Aerotech II gave 100 mg of paclitaxel in about 65 minutes using a solution of ABI-007 at a concentration of either 10 mg/ml, or 15 mg/ml Stability performance was tested on both sprayers Aerotech II and Pari. The concentration of aerosol and effectiveness of both nozzles were stable until the drug is not ended. At a concentration of 15 mg/ml nebulizer Pari consumed the drug two times faster than the spray Aerotech II, and were given a higher aerosol concentration than the concentration of aerosol spray Aerotech II.

In conclusion, the preparation of nanoparticles of paclitaxel/albumin (ABI-007) showed excellent bioavailability in rats, with the introduction of the lung by. There were no apparent signs of early toxicity of the administered dose. Pulmonary delivery of paclitaxel in nanoparticles (ABI-007) can be carried out using conventional sprayers.

EXAMPLE 34

In this example, the described internal-lung delivery of pharmaceutical compositions containing albumin and rapamycin. The purpose of this study was to determine the pulmonary absorption of rapamycin after intratracheal infusion to rats Sprague-Dawley compared to intravenous injection.

Target preparation for intratracheal dose, which was administered to the animals was calculated on the basis of the dose volume of 1 ml per kg of body weight. Intratracheal dosing device consisted of micropulverized Penn-Century (model 1A-1B; Penn-Century, Inc., Philadephia, PA; acquired from DeLong Distributors, Long Branch, NJ)attached to the sealing injectors with Swarovski nozzle with a volume of 1 ml Corresponds to the amount of dosage of the drug was placed in the metering device, the completed device was weighed and recorded its weight. The catheter was introduced into the trachea shot the animal, micropolarization part of the metering device was placed into the trachea through the catheter and injected dose. After a dose of empty dosing device is re-weighed and the dose was calculated as the difference of the mass measuring device before and after a dose.

The sample volume in the amount of 250 μl were taken out in the jugular vein cannula in rats in the following predefined points in time after dose: 1, 5, 10, 15, 30 and 45 minutes (min) and 1, 4, 8 and 24 hours (h). All analyzed blood samples were distributed in a pre-weighed test tubes for samples, and these tubes for the sample was re-weighed, and the weight of each sample was calculated by subtraction. The collected blood samples were analyzed by the total concentration of rapamycin using LC/MS/MS.

Unexpectedly, the results showed no significant difference in blood concentrations of rapamycin delivered to the lung by in comparison with the intravenous route. Bioavailability of rapamycin delivered to the lung by using the pharmaceutical composition, containing albumin, as calculated, amounted to 109%, indicating excellent transport across the pulmonary endothelium.

EXAMPLE 35

This example illustrates the distribution in the tissue albumin with rapamycin after the introduction of intra-lungs pharmaceutical composition comprising rapamycin and an albumin, prepared according to the present invention. The purpose of this study was to determine the pulmonary absorption of rapamycin tissue after intratracheal infusion to rats Sprague-Dawley compared to intravenous injection.

Target preparation for intratracheal dose, which was administered to the animals was calculated on the basis of the dose volume of 1 ml per kg of body weight. The metering device consisted of micropulverized Penn-Century (model 1A-1B; Penn-Century, Inc., Philadelphia, PA; acquired from DeLong Distributors, Long Branch, NJ)attached to the sealing injectors with Swarovski nozzle with a volume of 1 ml Corresponds to the amount of dosage of the drug was placed in the metering device, the completed device was weighed and recorded its weight. The catheter was introduced into the trachea shot the animal, micropolarization part of the metering device was placed into the trachea through the catheter and injected dose. After a dose of empty dosing device is re-weighed and the dose was calculated as the difference of the masses desiroush the device before and after a dose.

Samples were taken from brain, lung and liver from three rats per group at time 10 minutes, 45 minutes, 2 hours and 24 hours. Samples were collected and analyzed in General the concentration of rapamycin using LC/MS/MS. The results indicate that the concentration of rapamycin in the lung tissue more in cases where carried out pulmonary delivery compared to intravenous delivery. However, the total concentration of rapamycin in the brain is smaller in cases where carried out intratracheal (IT) delivery compared to intravenous (IV) delivery. In the liver, as it turned out, there was no difference in the concentration of rapamycin in IT or IV delivery. On the basis of these results, pulmonary delivery of rapamycin may be appropriate to treat conditions (i.e., the transplantation of the lung), when high local concentration of rapamycin would be beneficial.

EXAMPLE 36

This example demonstrates how oral delivery of a pharmaceutical composition comprising paclitaxel and albumin (ABI-007).

To determine the oral bioavailability of paclitaxel after oral forced feeding of rats used tritium-labeled ABI-007. After a night food restrictions 5 rats were given paclitaxel in the composition of ABI-007 dose of 5.5 mg/kg (Group A), and 5 rats (Group B) had previously received cyclosporine (5.0 mg/kg), the Le followed the reception of paclitaxel in the composition of ABI-007 dose of 5.6 mg/kg Pharmacokinetic analysis of blood samples obtained through 0,5, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours was performed after determination of radioactivity in blood samples by oxidation. Oral bioavailability was determined by comparison with previously obtained data on intravenous. The results are shown below in table 5.

Table 5
The average AUC 0-24, Cmax, Tmaxand % absorption originating from3H-paclitaxel radioactivity after oral administration
GroupThe treatmentDose/mg/kgAUC 0-24 (µg×EQ×h/ml)Absorption (%)Cmax(mg/kg) (μg×EQ/ml)Tmax(h)
AndABI-007 in physiologists CPM solution5,5/RHO(R)2,9244,30,2451

InABI-007 in physiology (CPM) solution with CsA5/RO(C),
5,6/RHO(R)
8,02121, 1millionof 0.5650,5

The value of AUC 0-24 IV (6,06 µg×h/ml) and dose IV (5.1 mg/kg) was used to calculate the percentage of absorption (data based on dose IV ABI-007).

44% oral bioavailability was shown for only one of ABI-007. This bioavailability is much more than what has been shown for other drugs paclitaxel. Bioavailability was increased to 121%, if the animals were given cyclosporine (CsA). This is expected, since CsA is a known agent for the suppression of the p-glycoprotein pump, which usually prevents the absorption of compounds such as paclitaxel LCD tract. More than 100% bioavailability can be explained by re-absorption after biliary excretion of paclitaxel in LCD tract. Other known suppress or enhance the absorption of the agents can also be used for this purpose.

EXAMPLE 37

This example illustrates the improved penetration of paclitaxel in red blood cells and tumor cells by introduction of a pharmaceutical composition comprising paclitaxel and albumin.

Fragments of tumor human breast MX-1 implanted subcutaneously Nude mice. Pharmaceutical composition comprising paclitaxel and albumin (paclitaxel with albumin"), as described previously, and Taxol, prigot the wheelie using 3H-paclitaxel to a specific activity of 25 µci/mg of paclitaxel. 20 mg/kg isotope-labeled paclitaxel with albumin or Taxol was administered in saline solution intravenously, when tumor volume was increased to approximately 500 mm3. Plasma, blood and tumor tissue were collected and analysed them in radioactivity after 5, 15 and 30 minutes and 1, 3, 8 and 24 hours after injection. Pharmacokinetics in tumor (AUC and constant absorption) were analyzed using WinNonlin, Pharsight, USA.

Paclitaxel with albumin showed rapid distribution into red blood cells (RBC), as shown by the rapid decrease in the ratio of radioactivity in plasma/blood to less units after intravenous drugs. Full distribution of RBC occurred within 1 h after administration of paclitaxel with albumin. In contrast, the distribution of paclitaxel prepared as Taxol, RBC was much slower and incomplete to more than 8 hours

Paclitaxel with albumin showed a rapid distribution in the tumor tissue with a constant absorption (Ka), which amounted to a value of 3.3 times greater than that of Taxol. Kawas 0,43 h-1and 0.13 h-1for paclitaxel with albumin and Taxol, respectively. A quick capture of paclitaxel resulted in a higher value of 33% of tumors of the eve AUC of paclitaxel with albumin, than for Taxol. AUC values were 3632 NCI*h/g and 2739 NCI*h/g for paclitaxel with albumin and Taxol, respectively.

EXAMPLE 38

This example demonstrates the safety of a pharmaceutical composition comprising paclitaxel and albumin injected mice.

Nude mice received increasing doses of paclitaxel with albumin or Taxol daily for 5 successive days. Survival was deferred on axis of the graph against dose to determine LD50. Survival was significantly increased for paclitaxel with albumin compared with Taxol (p=0,017, ANOVA). LD50for paclitaxel with albumin and Taxol, as calculated, was 47 mg/kg/day and 30 mg/kg/day for the scheme once a day × 5, respectively. At the dose level of 13.4 mg/kg/day and paclitaxel with albumin and Taxol was well tolerated with 1% of deaths (1 death of 72 mice) and 4% (2 death of 47 mice), respectively. At the dose level of 20 mg/kg/day was observed by 1% mortality for paclitaxel with albumin (1 death of 72 mice) compared with 17% mortality for Taxol (8 death of 47 mice) (p=0,0025). At the dose level of 30 mg/kg/day observed 4% mortality for paclitaxel with albumin (3 death of 72 mice) compared with 49% mortality for Taxol (23 death of 47 mice) (p<0,0001).

POR THE MEASURES 39

This example demonstrates a new mechanism of transport of paclitaxel through endothelial cells (EC) microvessels for the compositions of paclitaxel with albumin.

Nanoparticles and compositions of albumin to paclitaxel may accumulate in tumor tissue due to the EPR effect, which is the result of the "germination" of vessels in the tumor. Specific for albumin gp60 receptor (Albondon), the transport of albumin across the EU by transcytosis are activated receptors in caveola on the cell surface. This mechanism transcytosis are activated allows the transport of albumin to paclitaxel in subject interscalene space. In contrast, cremophor in Taxol inhibited the binding of paclitaxel to albumin, greatly reducing the transport of paclitaxel in the tumor. Additionally, receptors gp16 and gp30 was also involved in the intracellular transport of modified albumin containing bound paclitaxel, leading to increased binding of paclitaxel with endothelial cells with large protivoallergennymi action compared with Taxol.

EXAMPLE 40

This example illustrates the increase in endothelial transcytosis are activated pharmaceutical compositions containing paclitaxel and albumin compared to Taxol.

Endothelial cells of the microvasculature of the human lung (HLMVEC) raised to the listing is placed in the hole of the tablet for transcytosis are activated. The pharmaceutical composition according to the invention, containing paclitaxel and albumin or Taxol containing fluorescent paclitaxel (flomax) at a concentration of 20 μg/ml, was added to the upper wells for transcytosis are activated.

Transport of paclitaxel via transcytosis are activated from the upper compartment into the lower compartment was continuously recorded using fluorimetry. Also used a control containing only flomax without albumin. Control vlatacom has not shown any transport, confirming the integrity of the fixed monolayer HLMVEC. Transport of paclitaxel from the composition of albumin to paclitaxel was significantly faster than that of paclitaxel from Taxol in the presence of 5% HAS (physiological concentration). Constant velocity transport (Kt) for the composition of albumin to paclitaxel and Taxol was 1,396 h-1and 0.03 h-1, respectively. The total amount of paclitaxel, transported across the monolayer was three times higher for the composition of albumin to paclitaxel than for Taxol

EXAMPLE 41

This example illustrates the improved binding of endothelial cells (EC) pharmaceutical compositions containing paclitaxel and albumin compared with Taxol.

Endothelial cells of the umbilical vein of a person (HUVEC) were grown in 96-well titration the microplate. One expert is ment carried out the reaction of paclitaxel (paclitaxel, tagged flomax-Oregon green) with HUVEC in the presence of increasing concentrations of cremophor EL/EtOH, which is the filler for Taxol. In another experiment carried out the reaction of the pharmaceutical composition comprising albumin and flomax and composition of Taxol with vlatacom with HUVEC at different final concentrations. The binding of paclitaxel with cells inhibited by cremophor. Inhibition was evident with IC500,02% cremophor EL/EtOH.

It was shown that the concentration of cremophor preserved during chemotherapy with Taxol for at least 24 hours. Hence, this corresponds to the process ofin vivo. In all the analyzed concentrations of a significant amount of paclitaxel from the composition of albumin to paclitaxel was associated with the cells. Compared to this, for Taxol observed a slight binding or did not observe any binding.

EXAMPLE 42

This example illustrates the improved binding of albumin to pharmaceutical compositions containing paclitaxel and albumin compared with Taxol.

Albumin human serum (HSA) immobilizerpower on the plastic tablet for ELISA. Carried out the reaction of paclitaxel (paclitaxel, labeled flomax-Oregon green) with immobilized HSA in the presence of increasing concentrations of cremophor EL/EtOH. Another is xperimenta carried out the reaction of the pharmaceutical composition, containing albumin to paclitaxel and vlatacom and composition of Taxol with vlatacom with immobilized HSA at a final concentration of 20 mg paclitaxel/ml the Binding of paclitaxel to albumin inhibited by cremophor. Inhibition was evident with IC500,003% cremophor EL/EtOH. This concentration of cremophor, as shown, is maintained during chemotherapy with Taxol for at least 24 hours. Hence, this corresponds to the process ofin vivo. With appropriate pharmacological concentrations of paclitaxel (20 mg/ml), a significant amount of paclitaxel from the composition of albumin to paclitaxel was associated with immobilized HSA. Compared to this, did not observe any binding to Taxol.

EXAMPLE 43

This example illustrates the increased transfer of paclitaxel with albumin to pharmaceutical compositions containing paclitaxel and albumin compared with Taxol.

Composition of Taxol with vlatacom and albumin to paclitaxel and vlatacom was mixed with either 5% HSA in Hanks buffer or serum at a concentration of 20 μg/ml, 40 μg/ml and 80 μg/ml of the Mixture was immediately separated in native 3-14% polyacrylamide gel and determined the number associated with albumin paclitaxel using scanning fluorimetry. The transfer of paclitaxel to HSA was faster for the composition of the ALB is mine with paclitaxel compared with Taxol.

More paclitaxel moved together with HAS during electrophoresis when either serum or 5% HSA incubated with the composition of albumin to paclitaxel and vlatacom or composition of Taxol with vlatacom. Under the action of 5% HSA, 45%, 60% and 33% more of paclitaxel were moved from the HSA for the composition of albumin to paclitaxel and vlatacom than for the composition of Taxol with vlatacom at 20 μg/ml, 40 μg/ml and 80 μg/ml, respectively. Under the action of human serum 121%, 31% and 83% paclitaxel were moved from the HSA for the composition of albumin to paclitaxel and vlatacom than for the composition of Taxol with vlatacom at 20 μg/ml, 40 μg/ml and 80 μg/ml, respectively. The value of Cmaxfor ABI-007 at a concentration of 260 mg/m2approximately 20 μg/ml, therefore, this process is an important processin vivo.

EXAMPLE 44

In this example demonstrate that the glycoprotein gp60 receptor responsible for binding and transcytosis are activated albumin to paclitaxel.

Composition fluorescently labeled paclitaxel (flotaki) with albumin interact with endothelial cells of the microvessels in the culture. Fluorescent staining was observed under the microscope on the basis of shimmering areas that, as postulated, was the gp60 receptor that binds albumin to paclitaxel. These results confirmed the using albumin, labeled with rhodamine, which was located together with flickering fluorescence of paclitaxel.

EXAMPLE 45

In this example demonstrate that increasing amounts of albumin may compete for binding of paclitaxel.

Albumin was immobilizerpower on titration the microplate. Fluorescent paclitaxel was added to the wells and measured the binding of paclitaxel using the scanning fluorimetry. Increasing amounts of albumin was added to the wells and measured the level of inhibition of binding of paclitaxel with immobilized albumin. The data showed that as the increased number of added albumin, observed a corresponding decrease in the binding. Similar effect was observed when binding to endothelial cells. Such data indicates that a higher concentration of albumin inhibits the binding of paclitaxel. Thus, the preferred are compositions according to the invention, containing lower amounts of albumin.

EXAMPLE 46

In this example demonstrate that lower amounts of albumin in the pharmaceutical compositions according to the invention produce stable compositions.

In order to investigate whether lower amounts of albumin to affect the stability of pharmaceutical com is osili according to the invention, there were prepared compositions of albumin to paclitaxel with small amounts of albumin. It was found that these compositions are also stable, as compositions with higher amounts of albumin in the study for several months at different temperatures (2-8°C, 25°C and 40°C) efficiency of paclitaxel, education, pollution, particle size, pH, and other typical parameters of stability. Thus, compositions with lower amounts of albumin are preferred, as they can significantly reduce the cost and to allow the binding to the cell and transport into the cell.

EXAMPLE 47

In this example demonstrate a pharmaceutical composition comprising albumin and paclitaxel with a high ratio of albumin to paclitaxel.

30 mg of paclitaxel was dissolved in 3.0 ml of methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (3 wt./vol.%) (which corresponds to the ratio of albumin and paclitaxel, equal to 27). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm./minutes (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi, along with recirculation of the emulsion in those who tell, at least 5 cycles. The resulting system was transferred into a rotary evaporator, and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes. The resulting dispersion was translucent, and the typical average diameter of the obtained particles of paclitaxel were in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours the resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization.

It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting. When compared with the toxicity of paclitaxel dissolved in drugs with cremophor, the pharmaceutical composition according to the invention containing albumin, showed significantly lower toxicity.

EXAMPLE 48

In this example demonstrate a pharmaceutical composition comprising albumin and paclitaxel with a low ratio of albumin to paclitaxel.

In particular, 300 mg of paclitaxel was dissolved in 3.0 ml of methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (5 wt./vol.%) (which corresponds to cootes is of albumin and paclitaxel, equal to 4.5). If necessary, was added deferoxamine. The mixture is homogenized for 5 minutes at low rpm./minutes (Vitris homogenizer, model Tempest I.Q.) in order to obtain a primary emulsion, and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi along with recirculation of the emulsion for at least 5 cycles. The resulting system was transferred into a rotary evaporator, and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes. The resulting dispersion was translucent, and the typical average diameter of the obtained particles of paclitaxel were in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours the resulting clot was easily restored to the original dispersion by adding sterile water or saline. The particle size after recovery remained the same as before lyophilization. The final ratio of albumin/paclitaxel provided by adding the required quantity of albumin to obtain a final ratio of albumin/paclitaxel 9:1. This ratio can be determined by means of HPLC.

It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example in no way the meters are not limiting. When compared with the toxicity of paclitaxel dissolved in drugs with cremophor, the pharmaceutical composition according to the invention containing albumin, showed significantly lower toxicity.

EXAMPLE 4 9

In this example demonstrate a pharmaceutical composition comprising albumin and paclitaxel, with an intermediate ratio of albumin and paclitaxel.

In particular, 135 mg of paclitaxel was dissolved in 3.0 ml of methylene chloride. The solution was added to 27.0 ml solution of albumin human serum (5 wt./vol.%). If necessary, was added deferoxamine. In order to obtain a primary emulsion, the mixture is homogenized for 5 minutes at low rpm./minutes (Vitris homogenizer, model Tempest I.Q.) and then transferred to the high-pressure homogenizer (Avestin). Emulsification was carried out at 9000-40000 psi along with recirculation of the emulsion for at least 5 cycles. The resulting system was transferred into a rotary evaporator, and quickly remove the methylene chloride at 40°C under reduced pressure (30 mm Hg) for 20-30 minutes. The resulting dispersion was translucent, and the typical average diameter of the obtained particles of paclitaxel were in the range 50-220 nm (Z-average, Malvern Zetasizer). Next, the dispersion liofilizirovanny within 48 hours the resulting clot was easily restored to the original dispersion, adding sterile the th water or saline. The particle size after recovery remained the same as before lyophilization. The calculated ratio (wt./wt.) albumin and paclitaxel in the composition according to the invention is approximately 10.

It should be understood that the number, types, and quantitative relationships of drugs, solvents, proteins used in this example are in no way limiting. When compared with the toxicity of paclitaxel dissolved in drugs with cremophor, the pharmaceutical composition according to the invention containing albumin, showed significantly lower toxicity.

EXAMPLE 50

This example illustrates the treatment of rheumatoid arthritis in animal models, the composition of albumin to paclitaxel.

Caused by the action of collagen model of arthritis in rats Louvain used to test therapeutic effect of the composition of albumin to paclitaxel on arthritis. In order to assess the severity of arthritis was controlled by the size of the paws of experimental animals.

Once arthritis has developed fully (usually 9-10 days after injection of collagen), the experimental animals were divided into two groups, which intraperitoneally received either paclitaxel albumin with 1 mg/kg given once a day (q.o.d), or albumin to paclitaxel 0.5 mg/kg + predni what he is 0.2 mg/kg, given once a day (q.o.d) (combined treatment) for 6 doses, then one dose per week for three weeks. The size of the paws was measured at the beginning of treatment (day 0) and every time they introduced the drug. One group received only saline as control. By the end of the experiment, the group receiving albumin to paclitaxel, reached reduce the size of the feet by 42%in the group of combined treatment shows a decrease in the size of the legs by 33%, while in the control group observed an increase in the size of the paws approximately 20% in comparison with the time when they began treatment.

In conclusion, the composition of albumin to paclitaxel demonstrated a therapeutic effect on arthritis. The combination of albumin to paclitaxel, probably localized in the hearth artricheskogo damage due to transport through a mechanism mediated by the receptor, such gp60.

EXAMPLE 51

This example illustrates the use of compositions of albumin with paclitaxel for the treatment of cardiovascular restenosis.

Stents, paclitaxel eluting cause animals incomplete healing and, in some cases, the loss of stable suppression neointimal growth in the arteries. In this study, we tested the effectiveness of new compositions of albumin to paclitaxel in from the retenu with systemic delivery to reduce restenosis in the stent.

Restored saline albumin to paclitaxel analyzed for 38 new Zealand white rabbits, which were introduced bilateral stents in the iliac artery. Doses of albumin to paclitaxel (dose of paclitaxel from 1.0 to 5.0 mg/kg) was administered as an intra-arterial infusion over 10 minutes; control animals received filler (0,9% saline solution).

In the chronic experiment with the subsequent observation of 5.0 mg/kg of albumin to paclitaxel was given at the stenting with or without intravenous repeat dose of albumin to paclitaxel 3.5 mg/kg every 28 days; these studies were completed in 3 months. After 28 days, the average neointimal thickness decreased (p≤0,02) at the dose of paclitaxel with albumin ≥2.5 mg/kg signs of slow healing. The effectiveness of a single dose of paclitaxel albumin with 5.0 mg/kg, however, was lost for 90 days. In contrast, the second re-dose albumin to paclitaxel 3.5 mg/kg, which was given 28 days after stenting, has led to a steady reduction neointimal thickness 90 days (p≤0,009 in comparison with a single dose of paclitaxel albumin with 5.0 mg/kg and control) with almost full neointimal healing.

Although systemic injection of albumin to paclitaxel reduces neointimal growth after 2 days, a single repeat dose was required for stable neointimal suppression. Thus, the composition according to the invention suitable for the treatment of cardiovascular diseases such as restenosis. The composition according to the invention containing the pharmaceutical agent other than paclitaxel, for example, rapamycin, other taxanes, epothilone and so on all suitable for treating restenosis in blood vessels or grafts, artificial blood vessels, such as vessels used for arterial-venous access in patients requiring hemodialysis.

1. The pharmaceutical composition containing the water-insoluble pharmaceutical agent and a pharmaceutically acceptable carrier, in which the pharmaceutical agent is a paclitaxel pharmaceutically acceptable carrier comprises albumin, where the ratio (wt./wt.) albumin to not water soluble pharmaceutical agent is 9:1, the pharmaceutical composition comprises nanoparticles comprising the water-insoluble pharmaceutical agent and albumin, where the nanoparticles have a particle size less than 200 nm.

2. The pharmaceutical composition according to claim 1, which is dehydrated.

3. The pharmaceutical composition according to claim 2, which is freeze-dried.

4. The pharmaceutical composition according to claim 1, which I have is liquid.

5. The pharmaceutical composition according to claim 4, which further comprises a saline solution.

6. The pharmaceutical composition according to claim 1 which is sterile.

7. The pharmaceutical composition according to claim 1, which is a standard dose.

8. The pharmaceutical composition according to claim 1, which is a few doses.

9. The pharmaceutical composition according to claim 1, which is contained in a sealed container.

10. The pharmaceutical composition according to claim 1, which further comprises deferoxamine.

11. The pharmaceutical composition according to claim 1, in which albumin is a serum albumin of a person.

12. The pharmaceutical composition according to claim 1, in which paclitaxel is present in an amount of from 0.1 to 1 wt.%.

13. The pharmaceutical composition according to any one of claims 1 to 12, where the pharmaceutical composition is prepared for use in the treatment of cancer.

14. The pharmaceutical composition according to item 13, where the cancer is a cancer of the breast.

15. The pharmaceutical composition according to item 13, where the cancer is a lung cancer.

16. The pharmaceutical composition according to any one of claims 1 to 12, where the pharmaceutical composition is for parenteral administration.

17. The pharmaceutical composition according to any one of claims 1 to 12, where the pharmaceutical composition is intended for intravenous, vnutriarterialnah the introduction, intra-lungs injection, oral administration, inhalation, intravesical injection, intramuscular, intratracheal injection, subcutaneous injection, intraocular injection, intrathecal injection or percutaneous injection.

18. The pharmaceutical composition according to 17, where the pharmaceutical composition is intended for intravenous administration.

19. The pharmaceutical composition according to 17, where the pharmaceutical composition is intended for intravesical injection.

20. The pharmaceutical composition according to 17, where the pharmaceutical composition is intended for intrathecal injection.

21. The pharmaceutical composition according to any one of claims 1 to 12, where the pharmaceutical composition is intended for use in humans.

22. The pharmaceutical composition according to any one of claims 1 to 12, where the pharmaceutical composition is intended for injection.

23. The method of delivery of water-insoluble pharmaceutical agents representing paclitaxel, individual, providing an introduction to the individual a pharmaceutical composition according to any one of claims 1 to 12.

24. The method according to item 23, where the individual has cancer.



 

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3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of the general formula I , and its pharmaceutically acceptable salts, where R1, R2 and R3 represent hydrogen, D, E, G, J and L represent CH; n equals to an integer number 1 or 2; W represents oxygen; R4 represents C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, where the said C1-6alkyl is possibly substituted with one substituent, independently selected from a group, consisting of hydrogen, C1-4alkyl, C3-6cycloalkyl and C3-6cycloalkenyl; Y represents carbonyl; R5 represents C1-6alkyl, C1-6alkoxy or C3-4heteroaryl, which represents a heterocyclic aromatic ring, containing 1-2 heteroatoms, selected from nitrogen and oxygen. The invention also relates to a pharmaceutical composition based on a formula I compound, application of the formula I compound and a method of prevention, treatment of alleviation of a disease, associated with abnormal angiogenesis.

EFFECT: obtained are novel compounds useful in treatment of diseases associated with unregulated angiogenesis, such as cancer, as well as skin and eye diseases.

13 cl, 3 tbl, 11 ex

FIELD: biotechnology.

SUBSTANCE: method comprises isolation of mononuclear cells (MNC) from peripheral blood of a patient, separation of cells to adherent and non-adherent fractions, addition of the adherent fraction to the MNC of growth factors, loading of the dendritic cell with antigens of tumour lysate in vitro, the stimulation of maturation of dendritic cells for the next day. At that, the obtained immature DCs are added to lysate-autologous tumour cells at a dose of 100 mcg/ml, and after 48 hours within the subsequent 24 hours the rf-tumour necrosis factor-alpha is applied at a dose of 25 ng/ml. Then, the co-culture is carried out of mature dendritic cells activated with lysate and the non-adherent fraction of MNC at a ratio of 1:10 in the presence of recombinant human interleukin-12 at a dose of 10 ng/ml and the recombinant human interleukin-18 at a dose of 100 ng/ml.

EFFECT: invention enables to improve the level of cytotoxic and interferon-producing activity of antigen-activated dendritic cells while reducing the duration of their culture.

4 tbl

FIELD: medicine.

SUBSTANCE: invention concerns an agent for preventing malignant diseases representing rhodanine derivatives of general formula (1) .

EFFECT: high efficacy.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid pharmaceutical product for oral administration which contains a photosensitiser representing a compound of general formula I:

wherein R1 represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and each R2 independently represents a hydrogen atom or optionally a substituted alkyl group or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. The above pharmaceutical product is presented in the form of a tablet, a pill or a capsule having an enteric and gastroresistant coating, or in the form of the tablet or the capsule containing a number of balls, drops, granules or mini-pills with an enteric and gastroresistant coating. The above coating disintegrates in the lower gastrointestinal tract. The invention also refers to using the above photosensitiser in preparing the solid pharmaceutical product applicable in photodynamic treatment or diagnostics of a cancer condition in the lower gastrointestinal tract. What is also described is a photodynamic method of treating or diagnosing the cancer condition in the lower gastrointestinal tract by administering the solid pharmaceutical product containing the photosensitiser.

EFFECT: invention provides photosensitiser delivery to the lower gastrointestinal tract, and homogenous distribution of the photosensitiser in the target region, thereby improving the response to photodynamic treatment or diagnostics.

20 cl, 2 dwg, 2 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to a method for preparing an anticancer vaccine agent for treating solid tumours. The method for preparing the anticancer vaccine agent for treating solid tumours consisting in sampling of a raw tumour material, mixing and homogenisation in a buffer solution, multiple centrifugation with residue sampled; the residue is suspended in an acid buffer, mixed, neutralised, centrifuged; the supernatant is collected, enriched and purified with a combination of salt deposition and chromatography on an immobilised protein A or G; the prepared solution is passed through columns with immobilised human immunoglobulins IgG and human placental immobilised proteins; the prepared antibodies are subject to enzymatic treatment to prepare Fab- or F(ab)2-fragments used to immunise animals; immune antibodies are prepared and used to recover the total immunoglobulin fraction to be passed through the columns with the immobilised human immunoglobulins IgG and immobilised human placental proteins; the solution passed through the columns is subject to immunoaffinity chromatography on the columns with immobilised immunoglobulins prepared earlier at the stage of purification and enrichment; the end products specifically bound by the latter types of the columns are eluted with a solution dissociating antigen-antibody complexes, concentrated, filtered through antimicrobial filters, mixed with an adjuvant.

EFFECT: preparation prepared by the method described above enables providing higher clinical effectiveness in solid tumours treatment.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2-{4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}-N-methylacetamide and its salts, such as hydrobromide, hydrochloride, methane sulfonate, ethane-1,2-disulfonate. The invention also relates to a medication and a pharmaceutical composition based on the said compound and its salts for inhibition of ATP-ase activity of HSP90.

EFFECT: novel compound and its salts, which can be applied in medicine for cancer treatment, are obtained.

23 cl, 10 ex

FIELD: medicine.

SUBSTANCE: food ration is added with multi-component natural concentrated food products (NCFP) with high concentrations of biologically active substances (BAS) of herbal (HNCFP) and (or) protein-herbal (PHNCFP) raw material, for the purpose of nutritional support of sportsmen doing various sports, their individual physiological requirements; that results in recovering a set of characteristics of physiological functions and qualities determining a degree of activity of morphofunctional body systems, activities of daily living and professional performance, with providing preventing donozological and pathological conditions, achieving high sport scores. The above food products can be presented by NCFP Antitox and NCFP SportAtiv-2.

EFFECT: invention provides easier exercise tolerance and recovery thereafter, improving health in sportsmen.

5 cl

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