Cci-779 for amphicyte lymphoma treatment

FIELD: medicine.

SUBSTANCE: according to the invention, method involves introduction of Paramycin 42 ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779). In addition, the invention refers to applications of CCI-779 in producing a medicinal agent for amphicyte lymphoma.

EFFECT: application of the invention ensures amphicyte lymphoma treatment.

9 cl, 3 ex


The prior art INVENTIONS

The present invention relates to the use of ester rapamycin 42 with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) for the treatment or inhibition of lymphoma mantle cell.

Ester of rapamycin 42 with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an ester of rapamycin. Rapamycin, also known as sirolimus is a macrocyclic trinovum antibiotic produced by Streptomyces hygroscopicus. In U.S. patent 5362718 and 6277 983 describes how to obtain and use complex hydroxyamino rapamycin, including CCI-779.

Described that CCI-779 has in vitro and in vivo activity against some types of tumor cells. It is assumed that CCI-779 inhibits terms of progression of the tumor or the time of tumor recurrence. This mechanism of action is more typical cytotoxic funds than for cytotoxic agents and similar to the mechanism of action of sirolimus.

CCI-779 is associated with the cytoplasmic protein FKBP (FK-binding protein) and forms a complex, which inhibits the enzyme mTOR (target of rapamycin in mammals, also known as FKBP12-rapamycin - associated protein [FRAP]). Inhibition of the activity of mTOR kinase causes in different pathways of signal transduction of inhibi the Finance, including cytokine-stimulated cell proliferation, translation of mRNA for several key proteins that regulate the G1 phase of the cell cycle, and interleukin(IL)-2-induced transcription, leading to inhibition of cell cycle progression from G1 to S.

Lymphoma of mantle cell, B - lymphocytic tumor located in the mantle zone of lymph nodes, represents a unique subtype of non-Hodgkin lymphoma (NHL), which is characterized by a specific chromosomal translocation gene bcl-1 (t (11; 14)(q13:q32)) and the subsequent overproduction of the gene product cycline D1. Protooncogene bcl-1 (responsible for the development of b-cell lymphoma/leukemia) represents one of the five genes customers chromosome 11, translatemouseevent in MCL (lymphoma of the mantle cells), but it is the only gene expressed in MCL. It is believed that at least a partial cause of some oddities in the behavior of cells MCL is the unique character of lymphocytes, and in particular the site of bcl-1, located in chromosome 14.

About 10% of all cases of NHL presents MCL. The average age of onset is the age of about 60 years, and most often the disease occurs in men [Decaudin, D., et al., Leuk Lymphoma 37: 181-4(2000)]. Usually patients at a late stage there is often involvement of areas outside of the lymph nodes. For example,identify some patients significant lymphocytosis may be mistaken for chronic lymphocytic leukemia [Wong .F., et al., Cancer 86: 850-7 (1999)]. In other patients revealed multiple polyps in the colon, which can cause gastrointestinal bleeding [Hashimoto, Y., et al., Hum Pathol 30: 581-7 (1999)]. Another unusual manifestation of disease is extensive splenomegaly and minimal lymphadenopathy [Molina T.J., et al., Virchows Arch 437: 591-8 (2000)]. It has been shown that patients with MCL, in contrast to patients with other low histological indicators, the prognosis was significantly worse, and the average time of survival was 3-4 years [Weisenburger, D.D., et al., Am J Hematol 64: 190-6 (2000); Hiddemann, W., et al., Journal of Clinical Oncology 16: 1922-30 (1998); Samaha, H., et al., Leukemia 12: 1281-7, (1998); Callea, V., et al., Haematologica 83: 993-7 (1998)].

Treatment of MCL remains problematic, despite the availability of purine nucleoside analogues, transplantation of stem cells and monoclonal antibody therapy with rituximab. Each of these techniques can give carcinogenic effects in MCL, but the disease usually recurs and requires additional therapy. Regimens that can be considered the treatment of choice in patients with newly diagnosed, untreated MCL does not exist. Most patients used a combination of rituximab and chemotherapy - usually R-CHOP therapy (rituximab-cytoxan, adriamycin, oncovin (vincristine), prednisone), or a combination of purine nucleoside analogues and rituximab. Patients motoringfile use of high therapeutic doses of supporting stem cell, at first remission usually undergo transplantation.

Complete remission (CR) when such treatment is achieved in less than 50% of patients with MCL, and a small number of patients have long-term remission. In the normal course of events the patient responds to chemotherapy, but usually the effect is partial, short time to progression [Oinonen R., et al., European Journal of Cancer 34: 329-36 (1998)].

Lymphoma of the mantle cells remains a difficult disease to treat with the occurrence of relapses, and usually the treatment of patients is carried out in multiple schemes with short term progression between treatment.


In the present invention it is proposed to use CCI-779 for the manufacture of a medicinal product for the treatment or inhibition of lymphoma mantle cell from the subject.

In one aspect, the present invention is a pharmaceutical composition for the treatment or inhibition of lymphoma, mantle cell, which in a standard dosage form includes CCI-779 pharmaceutically acceptable carrier.

In another aspect, the present invention is a pharmaceutical pack containing a course of treatment of lymphoma mantle cell for one individual mammal, containing reservoir with CCI-779 in a standard dosage form.

From the following detail is inogo description of the present invention will become apparent other aspects and advantages of the present invention.

DETAILED description of the INVENTION

The present invention thus provides a method and kits that are useful in the treatment or inhibition of lymphoma mantle cell.

Used according to the present invention the term "treatment" means the treatment of a mammal with lymphoma mantle of cells by securing the said mammal an effective amount of CCI-779 in order to inhibit lymphoma in a mammal, destruction lymphoma or palliative treatment of lymphoma.

Used according to the present invention, the term "inhibition" refers to the inhibition of occurrence of lymphoma or progression of lymphoma mantle cell from a mammal having such a disease or prone to the development of this disease, providing the specified mammal an effective amount of CCI-779.

Used according to the present invention, the term "software" means or direct introduction of CCI-779 or the introduction of a prodrug, derivative, pharmaceutical salt or analogue CCI-779, which will form an effective amount of CCI-779 in the body. Everywhere in this detailed description and in the claims the term "CCI-779" covers CCI-779 and such prodrugs, derivatives, pharmaceutical salts or its analogs, which provide an effective amount of CCI-79 subject.

Getting CCI-779 is described in U.S. patent 5362718 referenced by the present invention. Regiospecific synthesis of CCI-779 described in U.S. patent 6277983 referenced by the present invention. However, other regiospecificity method of synthesis of CCI-779 is described in patent application U.S. 10/903062, filed July 30, 2004, and parallel international patent application PCT/US2004/22860, filed July 15, 2004.

Although the present invention illustrates the use of CCI-779, it is assumed that in the present invention instead of CCI-779 can be applied to other rapamycin. The term "rapamycin" defines a class of immunosuppressive compounds which contain basic rapamycine the core. Rapamycine of the present invention include compounds which, while maintaining the immunosuppressive properties, as derived rapamycin kernel can be chemically or biologically modified. Accordingly, the term "rapamycin" includes esters, ethers, oximes, hydrazones and hydroxylamine rapamycin, and rapamycin modified with, for example, by restoring or oxidation, functional groups rapamycin kernel. The term "rapamycin" also includes pharmaceutically acceptable salts rapamycin, capable of forming such salts due to the content of acidic or basic functional groups.

Rapamycin compounds preferably are selected from rapamycin, [brand of sirolimus Rapamune™, Wyeth, Madison, NJ], or 42-O-(2-hydroxy)tyramine. Other suitable rapamycin include, for example, AR [Ariad], FK-506, RAD001 (everolimus) and TAFA-93, which is a prodrug of rapamycin [Isotechnika Inc].

The ability of CCI-779 treatment or inhibition of lymphoma mantle cell was determined in a clinical trial. Treated 18 patients (mean age 72 years, ranging from 38 to 89 years) intravenous CCI-779 dose of 250 mg / 1, 8, 15, and 22 days 4-week treatment cycle, up to a maximum of 12 cycles. In 15 of these patients had stage IV, 2 patients had stage III, and 1 patient was stage II. The overall rate of response was 44.4% (confidence interval CI 95%; 24%-68%), and thus in this group of patients met the criteria for early sign of efficiency. In one patient there was complete response (CR), and 7 patients had a partial response (PR). Only in 3 patients the progression was observed before the end of the cycle. Based on the results obtained in this clinical trial, shows the usefulness of CCI-779 in the treatment or inhibition of lymphoma mantle cell.

It is assumed that the application of CCI-779 in the treatment or inhibition of lymphoma mantle cell of the subject will be provided with weekly doses what RowKey from 10 to 250 mg CCI-779 in a week. Usually treatment consists of a monthly cycle, which consists of weekly dose, you can choose a weekly or fortnightly cycles. Can be the subject of from one to twelve continuous cycles. Alternatively, the subject may undergo one cycle, stop the treatment, and then to pass the next cycle.

Oral or intravenous infusion are the preferred routes of administration, thus intravenous administration is the preferred route. It is assumed that the initial intravenous dose is typically ten times less than the oral dose. For example, an intravenous dose may range from 10 mg/week up to 175 mg/week, or 20 mg/week up to 150 mg/week, or more preferably, from 25 mg/week up to 75 mg/week; whereas oral dose can vary from 100 mg/week up to 250 mg/week, 125 mg/week up to 225 mg/week, or 150 mg/week, 200 mg/week. Accurate dosages for oral, parenteral, nasal or endobronchial injection will be determined by the attending physician based on the experience of treatment of a specific subject.

Usually, in General, the treatment will begin with small dosages less than the optimum dose of the compound. Further dose increase, while when the circumstances will not achieve an optimal effect. Then dose neobyazatel is lower during the week, two weeks or cycle, if this is desirable or necessary.

The pharmaceutical composition preferably is a standard dosage form, such as tablets, capsules, or syringe ampoule or syringe-pens. In this form, the composition is divided into the standard dose containing appropriate quantities of the active component; standard dosage form can be packaged compositions, for example packaged powders, vials, ampoules, prefilled syringes or containing fluid bags. Standard dosage form can be, for example, directly capsule or tablet, or it can constitute an adequate number of any such compositions in packaged form.

Oral formulations containing the active compounds of the present invention may contain any conventional oral forms, including tablets, capsules, pills to slow dissolution in the buccal pocket, lozenges, lollipops and fluids of the oral cavity, suspensions or solutions. Capsules may contain mixtures of active compounds (compounds) with inert fillers and/or diluents such as pharmaceutically acceptable starches (e.g., grain, potato or manioc starch), sugars, artificial sweeteners, phoroshop the EIT cellulose, such as crystalline and microcrystalline cellulose, flour, gelatin, resin, etc. Tablets can produce conventional compression, wet granulation or by means of dry granulation, and utilize pharmaceutically acceptable diluents, binding tools, lubricants, dezintegriruetsja substances, means of surface modification (including surfactants), suspendresume or stabilizing means comprising magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum Arabic, xanthan resin, sodium citrate, silicate complexes, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar, but not limited to the above. The preferred means of surface modification include nonionic and anionic means of surface modification. Typical examples of means of surface modification include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, esters sorbitan, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, aluminosilicate magnify triethanolamine, but not limited to the above. Oral compositions of the present invention can use standard formulations with delayed or slow release to change the absorption of the active compounds (compounds). Oral compositions can also comprise an active component enlisted with water or fruit juice, containing, if necessary, adequate solubilization or emulsifiers. Preferred oral compositions for complex ether (rapamycin 42 with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid disclosed in published patent application US 2004-0077677 A1 (also USSN 10/663506)referenced by the present invention.

In some cases it may be desirable to use compounds in the form of an aerosol directly into the respiratory tract.

The compounds may also be administered parenterally or intraperitoneally. As a free base or pharmacologically acceptable salts, solutions or suspensions of these active compounds can be produced in water, respectively, mixed with a surfactant such as hydroxypropylcellulose. The dispersion can be produced in glycerol, liquid polyethylene glycol and mixtures thereof in oils. Under normal conditions of storage and use of these formulations contain preservatives to prevent the growth of microorganisms.

Farmaceuticas what their form, suitable for injection include sterile aqueous solutions or dispersions and sterile powders for extemporanea preparation of sterile injectable solutions or dispersion. In all cases, the dosage form must be sterile and must be so liquid that the introduction through the syringe was easy. It must be stable under conditions of manufacture and storage and must be resilient against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures, and vegetable oil. Preferred compositions for injection of ester rapamycin 42 with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid are disclosed in US patent 2004-0167152 (also USSN 10/626943)referenced by the present invention.

In the present embodiment, a composition for injection, useful in the present invention, provides a co-solvent concentrate CCI-779, which contains, as described above, parenterally acceptable solvent, antioxidant, and containing a parenteral composition of CCI-779, composed of CCI-779, parenterally acceptable solvent, antioxidant, resbaladeros and surfactant. Any useful in the present invention, a given composition may contain many ingredients of the components of each class. For example, parenterally acceptable solvent may include Nesporova solvent, an alcohol solvent, or a mixture thereof. Examples of suitable Nesporova solvents include, for example, dimethylacetamide, dimethylsulfoxide or acetonitrile, or a mixture thereof. "Alcohol solvent" may contain one or more alcohol as the alcohol component of the solvent composition. Examples of solvents useful in the compositions of the present invention, without limitation, include ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, or a mixture thereof. These co-solvents are particularly desirable, as the decomposition by oxidation and lactoovo decay occurs in these co-solvents to a lesser extent. Additionally, for the more flammable the product can be combined ethanol and propylene glycol, with an increased amount of ethanol in the mixture usually results in greater chemical stability. The preferred concentration of ethanol in the mixture is from 30 to 100% volume ratio (vol./vol.).

In the present embodiment, the stability of CCI-779 in a parenterally acceptable alcohol co-solvent surface which agrees by adding to the composition of an antioxidant. Acceptable antioxidants include citric acid, d,l-α-tocopherol, BHA (butylacetamide), BHT (butylacetyl), monothioglycerol, ascorbic acid, propylgallate and mixtures thereof, but are not limited to the above.

Parenteral formulations useful in this embodiment of the present invention will typically contain antioxidant component (s) in concentrations in the range of about 0.001% to 1% of a ratio of weight to volume (weight/vol.), or from 0.01% to 0.5% weight./about. concentrate co-solvent, although it may be desirable and more low or high concentrations. A particularly desirable type of antioxidant is d,l-α-tocopherol, and it is used in a concentration of from 0.01 to 0.1% wt./about. with the preferred concentration of 0.075 wt%./about. concentrate co-solvent.

In some embodiments, the implementation of the antioxidant component of the composition of the present invention also exhibits chelate forming activity. Examples of such chelat forming means include, for example, citric acid, acetic acid and ascorbic acid (which, in the present compositions can act as a classical antioxidant and as a chelate forming agent). Other hepatoblastoma tools include such materials which are able to bind with metal ions in solution, such as ethylenediaminetetraacetic to the slot (EDTA), its salts or amino acids such as glycine, which can increase the stability of CCI-779. In some embodiments, the implementation of components with chelat forming activity included in the compositions of the present invention as the only antioxidant component. As a rule, when acting as chelat forming means, such connecting metal components are used in the lower limit of the range of concentrations of the antioxidant component provided by the present invention. In one example, citric acid improves the stability of CCI-779 when used in concentrations of less than 0.01 wt%./about. Higher concentrations are less sustainable solutions and, thus, are less desirable as a food for long term storage in liquid form. Additionally, such hepatoblastoma tools can be used in combination with other antioxidants as the fraction of the antioxidant component of the present invention. For example, acceptable composition may also contain citric acid and d,l-α-tocopherol. Specialists in the art can easily determine optimum concentrations for selected antioxidants on the basis of the information provided in the present invention.

Preferably, in some embodiments, the manufacture of parenteral formulations, the floor of the EIT in the present invention, precipitation CCI-779 after dilution water intravenous fluids or blood, is prevented by using a surfactant contained in the diluting solution. The most important component of the diluent is a parenterally acceptable surfactant. One particularly desirable surfactant is Polysorbate 20 or Polysorbate 80. However, experts in the art can readily select other suitable surfactants from among the salts of bile acids (taurocholate, glycocholate, Khalatov of deoxycholate etc)that are not necessarily connected with lecithin. Alternatively, as the surfactant in the solvent can be used ethoxylated vegetable oils, such as pegylated castor oil [for example, such as castor oil, PEG 35, which is commercially available, for example under the name Cremophor EL, BASF], vitamin E tocopherol propylene glycol succinate (Vitamin E TGPS) copolymer and block polyoxyethylene-polyoxypropylene, as well as other members of the family of polysorbates, such as Polysorbate 20 or Polysorbate 60. Other components of the solvent may include water, ethanol, polyethylene glycol 300, polyethylene 400, 600 polyethylene, polyethylene 1000 or mixture containing one or more of these glycols, propylene glycols and other parenterally acceptable co-solvents or funds, the reg is arousih osmollnosti solution, such as sodium chloride, lactose, mannitol or other parenterally acceptable sugar, polyols and electrolytes. It is assumed that the surfactant will contain from 2 to 100 wt%./about. dilution of the solution, from 5 to 80 wt%./about., from 10 to 75 wt%./about., from 15 to 60% wt./about., and preferably at least 5 wt%./about., or at least 10 wt%./about. dilution of the solution.

Parenteral composition, useful in the present invention, can be produced in the form of monoester, or, preferably, it can be produced in the form of a co-solvent concentrate containing CCI-779, an alcohol solvent, and an antioxidant, which is subsequently combined with a diluent containing a diluting solution and a suitable surfactant. Before using the concentrate of the co-solvent is mixed with a diluent containing a diluting solution and surfactant. When CCI-779 is manufactured according to the present invention in the form of a concentrate of co-solvent concentrations of CCI-779 contained in the concentrate may be from 0.05 mg/ml, 2.5 mg/ml, from 5 mg/ml, from 10 mg/ml or 25 mg/ml to about 50 mg/ml Concentrate can be mixed with a diluent to a ratio of approximately 1 part concentrate to 1 part diluent that will result in the parenteral formulations having concentrations of CCI-779 from 1 mg/ml, from 5 mg/ml, 10 mg/ml, 20 mg/ml to about 25 mg/ml, for Example, the concentration of CCI-77 parenteral composition may be from about 2.5 to 10 mg/ml In the scope of the present invention also includes the use of compositions having lower concentrations of CCI-779 in concentrate co-solvent, and the composition in which the ratio is greater than one part concentrate to 1 part diluent, for example, the ratio of the volume of the concentrate: diluent of about 1:1,5, 1:2, 1:3, 1:4, 1:5 or 1:9.about. and so on, until the parenteral compositions of CCI-779, having a concentration of CCI-779 to the lowest level of detection.

Typically, the antioxidant may range from about 0.0005 to 0.5% weight./about. composition. Surfactant, for example, may be from about 0.5% to about 10% wt./about. composition. The alcohol solvent may, for example, be from about 10% to about 90% wt./about. structure.

Parenteral formulations useful in the present invention, can be used for producing a pharmaceutical form suitable for administration in the form of direct injection or in the form of additions to the sterile infusion fluids for intravenous infusion.

With the purpose of disclosing the present invention means that the transdermal introduction includes all types of insertion through the surface of the body and through the inner integument of the natural openings of the body, including epithelial tissues and mucous membranes. Such introduction can be carried out using compounds of the present invention or their pharmaceutically reception is controlled salts, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

Transdermal introduction can be performed using a transdermal patch containing the active compound and inert to the active compound of the media, non-toxic to skin and contribute to the delivery means for systemic absorption into the bloodstream through the skin. The media can take many forms, such as creams and ointments, pastes, gels and the occlusive device. Creams and ointments can be viscous liquids or semisolid emulsions of the type oil-in-water" or "water in oil". Can be suitable paste containing absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient. To release the active ingredient into the bloodstream, you can use a variety of occlusive devices, such as a semi-permeable membrane that covers containing the active ingredient reservoir with the carrier or without a carrier, or a matrix containing the active ingredient. Other occlusive devices known in the literature.

Formulations of suppositories can be manufactured from conventional materials, including cocoa butter, with the addition of waxes or without the addition of waxes to change the melting point of suppositories, the glycerin. You can also use water-soluble bases suppositories, such as glycols with different molecular weights.

The components of the present invention can be represented as a set. Thus, the present invention includes a product containing CCI-779 for use in the treatment or inhibition of lymphoma mantle cell I in need thereof of a mammal subject. The present invention also includes a pharmaceutical pack containing a course of treatment of lymphoma mantle cell for one individual mammal subject, this package contains CCI-779 or 42-O-(2-hydroxy)ethyl rapamycin in a standard dosage form. In one embodiment, the product contains CCI-779 in ready for the introduction of a form. Alternatively, the product may contain CCI-779 in the form of a concentrate which can be mixed with a suitable diluent, optionally contained in the specified product. In yet another embodiment, the product contains CCI-779 in solid form and, optionally, a separate container with a suitable solvent or carrier for CCI-779. Other kit components, for example, instructions for thinning, mixing and/or product introduction, information about other contained substances, syringes, needles, etc. will be easily understood by professionals in this area of technology.

Follow what their examples are illustrative, but not limiting the present invention.

EXAMPLE 1. Antitumor activity of CCI-779 for relapsed lymphoma mantle of cells: phase II trials conducted by the North Central cancer care team (North Central Cancer Treatment Group).

For lymphoma of mantle cell (MCL) is characterized by the translocation t(11; 14), leading to overproduction cycline D1, involved in the synthesis pathway phosphatidylinositol-3-kinase (PI3K). This study investigated whether CCI-779, which inhibits the PI3K path-level target for rapamycin in mammals (mTOR), to cause carcinogenic effects in patients with MCL.

A. Patients and methods

The study was conducted by a joint team from the North Central cancer treatment (North Central Cancer Treatment Group NCCTG). Patients met the conditions of this test, if they have previously received treatment and had a relapse. The number of prior courses of therapy were not in any limit for the test. All histological analyses the main pathological studies confirmed the presence of lymphoma mantle cell. Tested positive for cyclin-Dl demanded immunohistochemical investigation or detection of translocation t(11; 14) by the method of fluorescent in situ hybridization (FISH). Patients were required to have disease measurable by the size of the lymph is systematic nodes or tumor formation, average of ≥2 cm or malignant limfotsitoz with absolute lymphocyte count (ALC) ≥5000; life expectancy component of ≥3 months, by health status in ECOG (Eastern Cooperative Oncology Group, Eastern cooperative Oncology group)of 0.1 or 2; the absolute number of neutrophils (ANC) ≥1000; platelet count ≥75000; hemoglobin ≥8 g/DL; serum creatinine, constituting ≤2 times upper limit of normal (UNL); serum bilirubin ≤1.5 to UNL; serum cholesterol ≤350 mg/DL; and triglycerides ≤400 mg/DL. Patients had to be free of lesions of the Central nervous system and HIV infection.

Patients were administered a constant dose of 250 mg CCI-779, diluted with 250 ml of saline solution and deliver intravenous (IV) over 30 minutes. Pre-patients/introduced diphenhydramine dose of 25-50 mg Treatment was designed for a week, and the cycle was considered to be 4 weeks. Each week we conducted a complete blood count and have introduced a full dose if platelet count was ≥50000 and ANC was ≥1000, and there were 3 levels not hematological toxicity (using option 2 common criteria toxicity NCI - NCI Common Toxicity Criteria version 2). Patients who do not comply with the criteria for re-treatment, supported the indicated dose to recovery, and the ATEM dose modified to a constant dose of 175, 125, 75, or 50 mg should Not have been prophylactically applied to the white cell growth factors in patients as a maintenance treatment, they can be used in patients with neutropenia at the discretion of the physician. Perhaps the use of erythropoietin.

After 1, 3, and 6 cycles conducted a survey of patients, and the response was evaluated according to the international working criteria. [.D.Cheson, et ah, "Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas", Journal of Clinical Oncology, Vol.17, Issue 4 (April), 1999: 1244]. Patients who were detected constant progression, or patients who have the disease after 6 cycles sustained, continued participation in the trial. Patients who had a complete remission (CR) or partial remission (CR) within 6 months should receive 2 cycles of treatment after POR or treatment for all 12 months in the case of the Czech Republic and then be observed without additional therapy.

One-step test in phase II, with interim analysis was performed for the proportional evaluation of previously treated patients with lymphoma of the mantle cells, under the CR or improvement after treatment with CCI-779. This test was designed to test the null hypothesis that the true level of response in most cases was 0.05. The lowest level of response that would indicate that a specific group of patients of a particular mode which was udalsa additional study, was $ 0,20. The project was developed based on the parameters and assumptions of a two-phase project Min-Simon™, but building it is not suspended for an interim analysis. For this research project required a maximum of 32 measurable patient, and in this draft interim analysis was performed after were recruited 18 patients, and they were followed for at least 24 weeks. In this group of patients were included in 3 patients (for a maximum total number of 35 patients), to explain the reasons for any inconsistencies with the requirements, removal from testing before the introduction of drugs or serious violations. However, for evaluation criteria conclusion on this project used only the first 32 patients, measurable. Was the need for surveillance in the time analysis of at least one response in the first 18 measurable patients to continue to grow. By the time the final research only took four or more responses to determine that this confirms further evaluation in this group of patients. Calculate the ratio of the responses were calculated 90% exact binomial confidence intervals (CI) for the true level of response (all suitable the x criteria recruited patients) with the assumption that the distribution of the number of responses was binomial.

Duration of response was defined as the time from date registered response prior to the date of progression. Controlled patients who interrupted treatment due to other reasons (for example, adverse reactions, discontinue treatment), at that time. Time to progression was defined as the time from the moment of registration until the date of progression. Patients who died without evidence of disease progression were censored at the time of their last evaluation. If the patient died without confirmation of progression of the disease, it was considered that the patient has the disease progressed to the point of death, if there was not enough evidence to conclude that at the time of death progression was not observed. Time of termination of active treatment was defined as the time from registration to the date of making the decision to cancel the active patient. In patients who continued treatment at the time these studies were censored at the time of their last evaluation. Full survival was defined as time from registration to death due to any cause. Each distribution of these critical points in time before the event was estimated using the method of Kaplan-Meier [JM Blad and DG Altman, "Survival probabilities (the Kaplan-Meier method)", BMJ, 317 (7172):1572 (Dec 1998)].

B. characteristics of the patients

The total number of patients selected for this test was 35 people. One patient was non-compliant criteria after the pathological examination revealed negative staining for cyclin-Dl, although histological analysis was consistent with MCL. Mostly the patients were older adults, with an average age of 70 years (range from 38 to 89 years). The majority of patients (91%) had stage IV disease and had previously been repeatedly the treatment, having an average of 3 previous course of therapy (mean 4; range 1 to 11). Most patients unsuccessfully applied rituximab, alkylating agents such as cyclophosphamide and anthracyclines, such as doxorubicin. More than half of the patients received purine nucleoside analogues.

C. Clinical results

The overall response (ORR) was 38% (13/34; 90% CI: 24-54%) 1 PR, and 12 partial remissa. The response of the tumor occurred quickly, with an average time to response, comprising 1 month (variability from 1 to 8). Eight responses came after the evaluation of the first cycle, 3 responses were recorded after 3 cycles, and 1 response noted th the 4 and 8 months of assessment. The average duration of response for these 13 respondents was 5.7 months (95% CI: 4-13,2 months). At the time of these studies, in 3 patients continued to be treated.

The average life expectancy of patients was 11 months (variability from 6.7 to 24.6 months). Overall, 29 patients showed disease progression, and 22 patients died. Patients without confirmation of death on the background of the progression of the disease was not. The average time to progression was 6.2 months (95% CI: 3.8 to 9.4 months). The average total survival was 12 months (95% CI: 6.7 months before the not-yet-happening of the time).

D. safety and tolerability

All 35 patients were included in the study analysis of safety and tolerability. During infusion over 30 minutes CCI-779 was well tolerated and did not reveal any significant toxicity. The main reason for dose reduction was thrombocytopenia, rapidly reversible by removing medicines typically only one week. Only three patients required platelet transfusion, and four patients required red cell transfusions. Thirteen patients showed infection 3 levels without concomitant neutropenia; two patients experienced neutropenia on the background of fever, and three had the infection (3 levels) with neutropenia. One patient developed right-sided lower motor paralysis of the facial nerve (bell's palsy) and alterations in mental status, and he moved NMR scanning and analysis of the cerebrospinal fluid, which did not confirm the hallmark of MCL. The experts concluded that it was idiopathic bell's palsy, which was in fact the final decision. It was impossible to establish or exclude a possible relationship with CCI-779. In patients with impaired acuity was diagnosed with retinitis due to the reactivation of cytomegalovirus infection (CMV). In the anamnesis the patient had CMV retinitis before you enroll in this trial, but at the beginning of the test, the infection was not obvious.

The most frequent side effects at all levels were thrombocytopenia (100%), hyperglycemia (91%), anemia (66%), neutropenia (77%), increased triglycerides (77%), inflammation of the mucous membranes (71%), weakness (66%), infection without concomitant neutropenia (63%), rash (51%), nausea (49%), weight loss (46%), the rise of AST, pathological change of taste (43%), loss of appetite (40%), hypercholesterolemia (40%) and sensory neuropathy (37%). Do not report about any phenomenon level 5 (i.e. death during treatment).

In terms of tolerability of the treatment regimen only 4 patients completed the trial according to the developed scheme (1 PR, 2 PD and 1 patients is NT stable disease, who completed all 12 cycles). Of the remaining 28 patients stopped treatment, one patient performed an alternative therapy without progression, 7 patients stopped treatment due to side effects, 4 the patient refused further treatment, one patient excluded from testing due to other medical problems, and in 15 patients in therapy there was progress. It is noted that those patients who refused further treatment or discontinued treatment due to other medical problems, continued this mode of treatment is largely due to the adverse reactions of low level and significantly reduce quality of life. The average time of treatment was 3.7 months (95% CI: 3-6,2 months).

Dose reduction was required at all, but especially 4 patients. Nine patients could receive 250 mg weekly for an average of 2.5 cycles (variability from 1 to 8); the other required a lower dose in the first cycle. Two of 6 patients who received more than one cycle, eventually took lower doses. The average dose received during a month of testing, was 175 mg all patients; 125 mg in patients with a response; and 175 mg in patients who had no response.

Patients who had a response and continue to receive CCI-779 for a long period is, experienced pathological change of taste, which led to decreased appetite and weight loss. One patient with partial response was observed weight loss level 3 due to dysgeusia, and he was not able to start re-treatment with CCI-779. Although inflammation of the mucosa was normal, but identified two cases 1 or 2 level.

It is known that CCI-779 may cause thrombocytopenia, and in this test it was indeed the most frequent side effect. There were several reasons for thrombocytopenia was frequently encountered in this test. First, patients could be included in the Protocol with thrombocytopenia 1 level (≥75000) and get a 100% dose of CCI-779 in the number of platelets, comprising ≥50000 hours (level 2). Secondly, were recruited for this trial patients had previously undergone severe therapy, and thirdly, in most patients there was infiltration of the bone marrow cells MCL, what was the reason for the weakening of reserves in the bone marrow.

The only means of CCI-779 had significant antitumor activity in case of relapse MCL. This test showed that CCI-779 has therapeutic utility.

Example 2. Antitumor activity of low-dose only means of CCI-779 in case of recurrence of lymphoma mantle cell

In the phase II trials CCI-779 were ZAR is registered eleven patients with MCL (4 unresponsive patient 7 patients with relapse in the age range from 55 to 85 years) and were treated as described above in example 1 with the exception that they received a 10 times lower dose than in example 1, 25 mg/week. Eight patients (73%) had stage 4, two (18%) had stage 3 and 4 patients (36%) identified ≥2 newslove area. Patients had received prior therapy, on average, 3 times (variability from 1 to 7), and 3 patients were immune to his last treatment.

The overall level of response was 64% (7/11) 7 the Czech Republic (64%).

Example 3. Dose of CCI-779, referred to in Example 1 or Example 2, Packed in capacity to provide treatment of the patient

All specific documents included in the present invention with reference. Specialist in the art will recognize that minor modifications described in the variants of implementation of the conditions and methods described in this invention may be varied without departure from the present invention. Such minor modifications and variations are within the scope of the present invention, which is defined by the following claims.

1. A method of treating or inhibiting lymphoma mantle of cells in a mammal, in need thereof, which includes an introduction to the specified mammal an effective amount of ester of rapamycin-42 3-Ki-the Roxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779).

2. The method according to claim 1, in which CCI-779 administered intravenously.

3. The method according to claim 1, in which CCI-779 administered weekly from one to twelve months.

4. The method according to claim 1, in which CCI-779 administered in a dose of from 10 to 100 mg per week.

5. The method according to claim 1, in which CCI-779 administered intravenously at the dose of 25 mg per week.

6. The method according to claim 1, in which CCI-779 administered orally at a dose of 100 mg to 250 mg per week.

7. The use of ester of rapamycin-42 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) for the manufacture of a medicinal product for the treatment or inhibition of lymphoma mantle of cells in the subject.

8. The use according to claim 7, in which CCI-779 presented in preparative form for intravenous administration.

9. The use according to claim 7, in which CCI-779 presented in preparative form for oral administration.


Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medical products, particularly to application of compound of formula I where A stands for O, R stands for hydrogen or lower alkyl, and Z stands for O to prepare a medicinal agent for treatment of cancer disease chosen from primary cancer of Fallopian tube; primary peritoneal cancer and colorectal cancer progressing after Irinotecan therapy. Besides the invention concerns the pharmaceutical composition including specified compound, therapy of specified diseases and commercial package. formula (I).

EFFECT: agent is characterised with improved effectiveness.

13 cl, 7 ex

FIELD: medicine.

SUBSTANCE: there is described oral pharmaceutical composition containing 9,10-dehydroepothilone combined with a pharmaceutically acceptable carrier. According to the second version, the oral pharmaceutical composition contains trans-9,10-degihydroepothilone D and a pharmaceutically acceptable carrier containing hydroxypropyl-β-cyclodextrine, ethanol and propylene glycol. The concentrate for injection contains 9,10-degihydroepothilone D in the pharmaceutically acceptable carrier.

EFFECT: good bioavailability of epothilone D.

21 cl, 4 ex

FIELD: medicine.

SUBSTANCE: prevention of carcinogenic action of diethyl nitrosamine in experimental animals is ensured by introduction of kaskorutol dosed 0.4 g/kg within 9 months as an anticarcinogen, while diethyl nitrosamine is introduced in a dose 100 mg/l 5 days after introduction of kaskorutol within 4 months.

EFFECT: reduced carcinogenic action of diethyl nitrosamine due to inhibition of blastomogenic process, lowered level of lipid peroxidation, improved activity of antioxidant enzymes.

2 tbl, 8 dwg, 1 ex

FIELD: pharmacy.

SUBSTANCE: antineoplastic preparation which coordination compound on the magnesium gluconate base wherein the ligands are chosen from the group consisting of γ-aminobutyric acid (GABA), 3-hydroxy-GABA, ethylendiaminotetraacetic acid and ethylenglycoltetraacetic acid or binary salt chosen from the group consisting of magnesium butyrogluconate, oxymagnesium butyrogluconate, magnesium glucarate-gluconate, calcium butyrogluconate, calcium oxybutyrogluconate, calcium glucarate-gluconate and their combinations.

EFFECT: claimed preparations exert the apoptotic and antiproliferative effect retaining the civilised cells.

4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used in therapy of epidermoid skin cancer without metastases in regional lymph nodes. Said therapy is ensured by close-focus roentgenotherapy of total focal dose 6000 R. The irradiation course is followed with over- and subfascial introduction of Klein solution in tumour projection in a dose 20 ml. Then tumour-associated fascia is removed by endoscopic or surgical technique at the distance at least 1 cm from the irradiation zone.

EFFECT: method allows ensuring greatest possible therapeutic radicalism, removing lymphatic capillaries and postcapillaries assisting in dissemination of cancer cells, reducing metastasis probability with maintaining the cosmetic effect.

2 ex

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new biologically active high-immunotropic compound -N,N'-(sulphonyldi-1,4-phenylene)bis[(N",N'"-dimethyl)methyliminomethane]1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-5-pyrimidinesulphonate of formula stated below to be used in treatment of, e.g., patients suffering from leprosy, allergic dermatosis, dermatitis herpetiformis. .

EFFECT: new compound is characterised with useful biological activity.

2 tbl, 1 ex

FIELD: medicine; oncology.

SUBSTANCE: in treatment of breast cancer in mammal introduction of rapamicine esters with aromatase inhibitor in form of combination o in pharmaceutical composition is realised. As rapamicine esters CCI-779 or 42-O-(2-hdroxy)ethylrapamicine is introduced, as aromatase inhibitor - letrozole in subtherapeutic doses.

EFFECT: enhancing anti-tumor effect due to synergetic effect resulting from combination of definite rapamicine ester with particular aromatase inhibitor.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: composition contains the compound blocking the cyclic state G1, and the antiviral agent that inhibits or reduces HIV penetration into mononuclear cells. The compound blocking the cyclic state G1 is chosen from the group consisting of sodium butyrate, afidicoline, olomucine, roscovitine, tocopherols, tocotrienols, hydroxyurea and rapamycine.

EFFECT: invention ensures reducing receptor site number for HIV penetration into T-cages and increasing in antiviral agent activity.

14 cl, 9 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the amorphous form of the 42-ester of rapamycin and 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid. The invention also relates to methods of obtaining the amorphous form and to pharmaceutical compositions containing this amorphous form and having immunosuppressive, anti rejection, antifungal, antiphlogistic and antiproliferative activity.

EFFECT: increased solubility and bioavailability.

24 cl, 7 dwg, 6 tbl, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: lyophilised preparation forms and solutions CCI-779 are available for production of lyophilised preparation forms CCI-779. The specified solutions consist of CCI-779 and solvent chosen from dimethylsulfoxide, acetonitrile, ethanol, isopropanol, tert-butyl alcohol and their mixtures. Besides, methods of lyophilised preparation forms CCI-779 preparation and restoration are offered.

EFFECT: improved storage stability and preservation of initial activity.

21 cl, 10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: CCI-779 cosolvent concentrate includes 0.05 to 50 mg/ml of CCI-779, alcohol solvent and 0.001 to 1.0 wt % per volume of antioxidant component. Invention also claims parenteral composition including the described concentrate and method of its obtainment.

EFFECT: improved storage and dissolution stability of the concentrate.

25 cl, 9 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: medicine.

SUBSTANCE: traditional treatment includes operative intervention with additionally detected phase of menstrual cycle for women of childbearing age. In case disease is developed in late folliculin phase, Clopidogrel is introduced orally in single dose 75 mg in the day of operation. Then alveolar process from vestibule of mouth cavity is covered with bolsters impregnated with 0.2% 5-oxy 4-methyluracyl in 10% dimethylsulphoxide within 15-20 minutes up to 5 times a day. And since the second day after operation phonophoresis method is applied daily in amount 10-20 ml within 5-7 minutes during 5 days.

EFFECT: provides improved rheological and coagulation properties of blood, correction of oral immunity that is accompanied with reduction of inflammatory process and short-term tissue regeneration after surgical intervention.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel form of the crystalline clopidogrel naphthalenesulfonate with formula Ia: for which the powder X-ray diffraction scanning reveals the principal peaks with the I/I0 values more than 10% at 2θ=6.7, 8.2, 8.5, 12.4, 13.0, 13.5, 16.8, 17.2, 18.9, 19.6, 20.2, 21.2, 22.3, 22.9, 23.2, 23.6, 24.7, 25.0, 25.3, 25.8, 27.0, 27.5, 28.0, 28.6, 32.1, 32.5, 34.7. and monohydrate crystalline clopidogrel 1,5-naphthalenesulfonate with formula (Ib) for which the powder X-ray diffraction scanning reveals the principal peaks with the I/I0 values more than 10% at 2θ=7.6, 9.7, 10.7, 11.0, 12.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27.3, 28.4, 29.0, as well as to the method of their production and to their pharmaceutical composition.

EFFECT: increased stability of compounds.

10 cl, 8 dwg, 9 tbl, 4 ex

FIELD: medicine; stomatology.

SUBSTANCE: suppurative focus is opened and drained, antibacterial, desensitising therapy is prescribed. Menstrual cycle phase is detected for women of childbearing age and if disease is developed at late folliculin phase hydrofluor is singly injected dosed 75 mg in addition. And 10-20 ml of 0.2% 5-oxy-4-methyluracil in 10% dimethylsulphoxide is introduced in vestibule of oral cavity. Then each jaw is daily exposed with ultrasonic vibrator within 5 minutes running by continuous gliding circular motion. Treatment course is 5 days.

EFFECT: improved treatment efficiency; improved tissue regeneration; as well as prevention of postoperative complications.

1 tbl, 1 ex

Oral compositions // 2326654

FIELD: medicine.

SUBSTANCE: described solid pharmaceutical formulation for oral introduction contains granulated material consisting of 42-ester of rapamicine with 3-hydroxy-2-(hydroxymethyl)-2-methyl propionic acid in amount from approximately 1 weight % to approximately 30 weight %, water-soluble polymer, such as polyvinylpyrrolidone (PVP) in amount from approximately 1 weight % to approximately 40 weight %, surface-active substance, such as sodium lauryl sulphate in amount from approximately 1 weight % to approximately 8 weight %, antioxidant in amount from approximately from 0.001 weight % to 3 weight % and pH regulating agent.

EFFECT: provides high bioavailability of non-micronised composition.

16 cl, 3 tbl, 2 ex

FIELD: antibiotics, pharmacy.

SUBSTANCE: invention relates to stabilization of rapamycin or rapamycin derivative with immunosuppressive properties and sensitive to oxidation. Method for stabilization involves addition of antioxidant to the purified rapamycin in small concentrations - below 1% as recalculated for rapamycin mass. Also, invention relates to a solid mixture containing rapamycin and antioxidant taken in the catalytic amount. Antioxidant represent preferably 2,6-di-tert.-butyl-4-methylphenol. The stabilized rapamycin shows high stability against oxidation, it can be stored as formulation without package before it's the following treatment and can be used in an unmodified form for preparing the required galenic composition.

EFFECT: improved stabilizing method.

14 cl, 3 dwg, 2 ex