Pharmaceutical compositions

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions for oral administration in the form of a solid dispersion. The invention consists in that the composition comprises rapamycin or 33-epichloro-33-desoxycortisol and the carrier medium. The invention provides for oral administration of the solid drug that is acceptable to rapamycin and its derivatives, and the stability of the composition. 2 C. and 13 C.p. f-crystals, 2 ill., table 1.

The present invention relates to oral compositions in the form of a solid dispersion, containing macrolides, for example rapamycin or ascomycin.

Rapamycin is an immunosuppressive lactam macrolide produced, for example, Streptomyces hygroscopicus. The structure of rapamycin is known (Kesseler N. , et al., 1993; Helv. Chim. Acta; 76, 117). Rapamycin is an extremely potent immunosuppressant and has antitumor and antifungal activity. Its applicability as a pharmaceutical preparation, however, limited due to its very low and erratic bioavailability. Moreover, rapamycin almost insoluble in aqueous medium, for example water, which will overwrite the data of 16-O-substituted rapamycin disclosed in WO 94/02136, the contents of which are included in these materials as a reference.

40-O-substituted rapamycin described, for example, in US 5258389 and WO 94/09010 (O-aryl and O-alkyl rapamycin); WO 92/05179 (esters of carboxylic acids); US 5118677 (ester amide); US 5118678 (carbamates); US 5100883 (fluorinated esters); US 5151413 (acetals); US 5120842 (Silovye esters); WO 93/11130 (methyltryptamine and derivatives); WO 94/02136 (methoxy derivatives); WO 94/02385 and WO 95/14023 (alkenyl derivatives), each of which is included in these materials as a reference, 32-O-dihydro or substituted rapamycin are described, for example, in US 5256790 entered in these materials as a reference.

Further, derivatives of rapamycin are described in the PCT application N ER 96/02441, for example, a 32-mesoxerophytic as described in example 1, and 16-Penta - 2-inolex-32(S)-dihydrocapsaicin, as described in examples 2 and 3. The contents of PCT application N ER 96/02441 included in these materials as a reference.

Rapamycin and its structural analogues and derivatives are all called here as "rapamycin".

EP 240773 discloses a solid dispersion composition comprising the substance of the FR - 900506 and water-soluble polymer.

When orally administered to humans hard rapamycin, for example rapamycin, can neimer rapamycin with conventional pharmaceutical excipients; however, the disadvantages associated with these compositions include unpredictable dissolution rate, unstable indicators of biological availability and instability. To date there are no suitable for oral administration of the solid drug that is acceptable to rapamycin and its derivatives.

The present invention is to eliminate the above disadvantages.

This object is achieved by the development of pharmaceutical compositions for oral administration in the form of a solid dispersion containing rapamycin and the carrier medium.

The composition according to the invention provide high bioavailability of a drug that is convenient for the introduction and stable.

Rapamycin used in the compositions according to the invention, can be any rapamycin or its derivatives, for example, as described above, or in the aforementioned patent applications.

Thus, rapamycin, used in solid dispersion compositions according to the invention may be rapamycin or O-substituted derivative in which the hydroxyl group in tsiklogeksilnogo ring substituted rapamycin on-OR1where R1is hydroxyl what-hydroxy)tyramine, 40-O-(3 - hydroxy)properposition, 40-O-[2-(2-hydroxy)ethoxy] tyramine and 40-O-(2-acetamidomethyl)rapamycin. A derivative of rapamycin may be a 26 - or 28-substituted derivatives.

Preferred rapamycin for use in a solid dispersion compositions of the invention include rapamycin, 40-O-(2-hydroxy)tyramine, 32-mesoxerophytic and 16-Penta-2-ynyloxy-32(S)-dihydrocapsaicin. The preferred rapamycin is 40-O-(2-hydroxy)tyramine (hereinafter referred to as compound X).

Numerous derivatives of rapamycin which are used in the compositions of the present invention relate to the structure described as formula a on page 4 of the published application WO 96/13273, the content of which is included in these materials as a reference.

The term solid dispersion, which is used here, should be understood in the meaning of the co-precipitate of rapamycin, e.g. 40-O-(2-hydroxy)tyramine or rapamycin with the medium carrier. In the solid dispersion rapamycin is amorphous or substantially amorphous form and is physically linked to the environment carrier.

The composition of the invention can be administered in any convenient form, for example tablets, capsules, Foreste from about 0.01 to about 30 wt.% based on the weight of composition ( wt.% /wt.), and preferably in quantities of from 1 to 20 wt.%/wt. calculated on the total weight of the composition.

The carrier medium is present in the amount of up to 99.99 wt.%, for example, from 10 to 95 wt.% calculated on the total weight of the composition.

The carrier medium may contain a water-soluble polymer or a cyclodextrin.

In one embodiment according to the present invention, the carrier medium may contain a water-soluble polymer, preferably a derivative of cellulose, such as hypromellose (HPMC), phthalate of hydroxypropylmethylcellulose or polyvinylpyrrolidone (PVP). Good results can be obtained using HPCM with low apparent dynamic viscosity, for example below 100 CPS (at 20oC for 2 wt.% aqueous solution, for example below 50 JV, preferably below 20 SP, for example HPCM 3 SP. HPCM is well known and is described, for example, in the Handbook of Pharmaceutical Excipients, Second Edition, pub. Pharmaceutical Society of Great Britain and American Pharmaceutical Association, 1994, pp.229-232, the contents of which are incorporated herein by reference. A receiver array including a receiver array 3 SP, commercially available under trade name Pharmacoat 603 from Shinetsu.

Preferably a water-soluble polymer is a hypromellose in kolichestvom 1:4.

PVP is available, for example, under the name of Povidone (Handbook of Pharmaceutical Excipients), and the preferred PVP with an average molecular weight between about 8,000 and about 50000 Yes.

In another embodiment, the carrier medium contains:

- hydroxypropylcellulose (HPC) or its derivative. Examples of HPC derivatives include those that have a low dynamic viscosity in an aqueous environment, such as water, for example, below about 400 SP, such as below 150 SP when measured in 2% aqueous solution at 25oC. Preferred derivatives HPC have a low degree of substitution and average molecular weight below about 200,000 Da, such as between 50000 and 150000 Yes. Examples of commercially available HPC include Klucel LF, Klucel EF and Klucel JF from the company Aqualon; and Nisso HPC-L, supplied by Nippon Soda Ltd.;

- polyethylene glycol (PEG). Examples include PEG with an average molecular weight between 1000 and 9000 Yes, for example between about 1800 and 7000, such as PEG 2000, PEG 4000 or PEG 6000 (Handbook of Pharmaceutical Excipients);

- rich poliglecaprone the glycerides, such as those available under the trademark Gelucir, for example Gelucir 44/14, 53/10, 50/13, 42/12 or 35/10 from the company Gattefosse; or/,

- cyclodextrin, for example-cyclodextrin or cyclodextrin.

Examples of the approach is xten; glycosyl- -cyclodextrin; maltose- -cyclodextrin; sulfo- -cyclodextrin, sulfoalkyl esters-cyclodextrin, for example, complex sulfo-C1-4-alkalemia esters. Examples of cyclodextrins include glycosyl- -cyclodextrin and maltose- -cyclodextrin.

The carrier medium may additionally contain water-soluble or water-insoluble sucrose or other suitable carrier or excipient, such as lactose or microcrystalline cellulose. The filler, if present, is typically present in an amount up to about 30 wt.%, for example from 0.5 to 20 wt. %, preferably from about 5 to about 15% by weight of the composition. Microcrystalline cellulose is commercially available under the trade name Avicel, for example from FMC Corporation.

The carrier medium may optionally contain one or more than one surface-active substance, for example non-ionic, ionic, anionic or amphoteric surfactant. Examples of suitable surfactants include:

- polyoxyethylene-polyoxypropylene copolymers and block copolymers, are known, for example, under the trade name Pluronic or Poloxamer, for example, as described in Fiedler N. R. "Lexikon is these materials as a reference. Preferred polyoxyethylene - polyoxypropylene block polymer is Poloxamer 188, supplied by the company BASF;

- the ethoxylated cholesterol, known, for example, under the trade name Solulan, e.g., Solulan C24, commercially available from Amerchol;

- vitamin derivative, for example derivatives of vitamin E, such as the succinate of polietilenglikolmonostearat (TPGS), supplied by Eastman;

- sodium dodecyl sulphate or sodium lauryl sulfate;

- bile acid or its salt, such as cholic acid, glycolic acid or salt, for example Holt sodium; or

lecithin.

If the compositions according to the invention is a surface-active substance (substances), it is typically present in an amount up to about 20%, for example from 1 to 15 wt.%.

In the composition according to the invention can contain one or more than one, baking powder. Examples of disintegrating agents include Polyplasdone (Handbook of Pharmaceutical Excipients), commercially available from ISP; glycolate, starch sodium, commercially available from Generichem; and crosscarmelose sodium under the trademark Ac-di-sol from FMC Corporation. In the composition of this invention can additionally include one or more than Omas.%, for example, from 0.5 to 2 wt. % calculated on the weight of the composition.

It may be useful to include in the composition of the present invention one or more than one, flavouring substance.

According to the present invention obtained good results using the compositions of rapamycin, which do not contain surfactant. Therefore, this invention is described not containing surfactant solid dispersion composition containing rapamycin, as described in this specification.

In the composition according to the invention can be included antioxidants and/or stabilizers in an amount up to about 1 wt.%, for example, between 0.05 and 0.5. %. Examples of antioxidants include: bottled hydroxytoluene, DL - a-tocopherol, propylgallate, ascorbylpalmitate and fumaric acid. Malonic acid is a suitable stabilizer.

In one embodiment of the present invention the composition comprises up to 30 wt.%, for example from 1 to 20 wt.% 40-O-(2-hydroxy)tyramine and up to 95%, for example from 30 to 90 wt.% HPCM.

The mass ratio of rapamycin and a carrier medium in the compositions according to the invention is usually not more than 1:3, preferably less than 1: 4.

Usually rapamycin and the carrier medium is present in a mass ratio to the solvent is from 1:0.1 to 1:20. The solvent can be evaporated, and the rapamycin seaside with the medium carrier. The resulting residue may be dried, for example under reduced pressure, sieved and crushed. Crushed dispersion may be combined with other excipients, for example, compressed into tablets or placed in bags or capsules.

A solid dispersion composition is, what, for example, by mixing, possibly in the presence of a solvent or mixture of solvents.

Alternative solid dispersion according to the invention can be obtained by dry spraying, as described, for example, in theory and Practice of Industrial Pharmacy, Lachmann et al., 1986. The suspension obtained as described above was dispersed through a nozzle into the chamber at a temperature that is supported, for example, from 20 to 80oC. the Solvent is evaporated by passing through the nozzle, and the fine particles are collected.

The composition of the invention after grinding usually have an average particle size of less than about 0.5 mm, for example less than about 350 microns, for example from about 100 to about 300 microns.

Oral compositions according to the invention is suitable for known indications of rapamycin, for example, for the following States:

a) treatment and prevention of rejection of ALLO - or Xeno-transplant of organs and tissues, for example, for the treatment of recipients of e.g. heart, lung, together heart and lung, liver, kidney, pancreatic, skin or corneal transplants. They also indicated for the prevention of disease, graft versus host, such as a consequence of bone marrow transplantation;
C) Her problem in cancer patients and AIDS patients, where traditional chemotherapy will not be affected, because drugs are pushed out of the cells by Pgp. Therefore, compositions useful for increasing the efficacy of other chemotherapeutic agents in the treatment and control States of resistance to many drugs, such as resistant to many cancer drugs and are resistant to many drugs AIDS;

d) treatment of proliferative disorders, such as tumors, hyperproliferative skin diseases, etc.;

(e) treatment of fungal infections;

g) treatment and prevention of inflammation, especially potentiate the activity of steroids;

C) treatment and prevention of infections, especially infections by pathogens with Mip or Mip-like factors;

and treatment of overdose FK-506 and other macrophilin binding immunosuppressants.

When the pharmaceutical composition according to the invention is in the form of a standard dose of, for example, in the form of tablets, capsules, granules or powder, each standard dose will respectively contain between 1 mg and 100 mg of drug substance, more preferably between 10 and 50 mg, for example, 15, 20, 25, or 50 mg This form is a standard dose suitable for introduction from 1 to 5 times a day bywhich must be entered, depends on several factors, such as the desired duration of treatment, and the speed of release of rapamycin.

The applicability of the pharmaceutical compositions can be observed in standard clinical tests in, for example, by well-known figures doses of the active agent, giving the equivalent levels of the active agent in the blood; for example using dosages in the range of from 1 mg to 1000 mg, for example from 5 mg to 100 mg of active agent per day per 75 kg of body weight of an adult or in standard animal models. The increased bioavailability of drug substances provided by compositions can be observed in standard experiments with animals and in clinical trials.

Used dosage form, for example, the tablet may be coated, for example intersolubility shell. Suitable membranes may contain phthalate cellulose acetate, phthalate of hydroxypropylmethylcellulose copolymer polymethylacrylate acid, for example, Eudragit L, S; or succinate of hydroxypropylmethylcellulose.

Rapamycin used in the compositions according to the invention, for example, 40-O-(2-hydroxy)tyramine or rapamycin, may be in crystalline or amorphous form to the way the s rapamycin was crystalline. Thus, rapamycin can be used directly in combination, for example, with solvent and does not require pre-allocation. Another advantage of this invention is that the dissolution rate of solid dispersions higher than the dissolution rate found for crystalline or amorphous rapamycin rapamycin in a simple mixture.

Another object of the invention is a pharmaceutical composition in the form of a solid dispersion containing ascomycin and the carrier medium.

Up to the present time there was not suitable for the oral administration of solid preparations for 33-epichloro-33 - detoxicating. To eliminate this drawback in this invention features a pharmaceutical composition in the form of a solid dispersive containing 33-epichloro-33-desoxycortisol and the carrier medium, and that the carrier medium comprises water-soluble polymer or a cyclodextrin.

The connection 33-epichloro-33-desoxycortisol described in published European application EP 427680 in example 66a.

33-Epichloro-33-desoxycortisol here will be referred to as Compound y

Containing compounds Y the composition of the invention determine who may be present in the composition in an amount of from about 0.01 to about 30 wt.% /mass, and preferably in quantities of from 1 to 20 wt.%/mass.

The carrier medium may contain any of the above components in the above amounts, wt. %. Suitable water-soluble polymers, cyclodextrins and other excipients, for example, surface-active substances, for use in containing 33-epichloro-33-desoxycortisol compositions according to the invention similar to the above.

In a preferred aspect of the present invention the composition is in the form of a solid dispersion containing compound Y, includes the additional surfactant.

The mass ratio of the Y connection to the environment-the media is usually not more than 1:3, preferably less than 1:4.

Ascomycete containing compounds Y, a solid dispersion composition can be prepared by methods similar to the above.

Describes oral compositions containing compounds Y, useful, for example, in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunological diseases. More specifically, the composition of the invention are useful as anti-inflammatory, immunodepressants and antiproliferative agents dla as:

a) prevention and treatment

- rejection of the transplant organ or tissue such as heart, kidney, liver, bone marrow and skin,

- diseases "graft versus host", such as a consequence of bone marrow transplantation,

- autoimmune diseases such as rheumatoid arthritis, systemic erythema nodosum, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes type I and uveitis,

skin manifestations of immunological diseases;

b) the treatment of inflammatory and hyperproliferative skin diseases such as psoriasis, diffuse neurodermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic eczema, Lichen planus, Pemphigus, bullous Pemphigoid, bullous congenital a bullosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, Lupus lupus and acne; and

C) alopecia areata

When the pharmaceutical composition according to the invention is in the form of a unit dose, for example in the form of tablets, capsules, granules or powder, each unit dosage will accordingly contain between 1 mg and 100 mg of drug substance, more preferably between 10 and 50 mg, for example 15, 20, 25, or 50 mg This form of a unit dose suitable for introduction from 1 to 5 times in the data of the invention the composition comprises 30 wt.% connection Y and 70 wt.% HPMC dose, for example, from 10 to 50 mg per day for use in, for example, psoriasis, diffuse atopic dermatitis or contact dermatitis.

The exact number of tracks that must be entered depends on several factors such as the desired duration of treatment, and the speed of release of compound Y.

The applicability of the pharmaceutical compositions containing the compound Y can be observed in standard clinical tests in, for example, by well-known figures doses of the active agent, giving an equivalent level of active agent in the blood; for example using dosages in the range from 1 to 1000 mg, for example from 5 to 100 mg, of active agent per day per 75 kg of body weight of an adult and in standard animal models. The increased bioavailability of drug substances using the compositions can be observed in standard experiments with animals and in clinical trials.

The following are examples of solid dispersion compositions according to the invention.

Example 1

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Connection X - 9,1

HPMC 3 SP - 81,8

Lactose 200 mesh - 9,1

The composition (form A) is obtained by dissolution of rapamycin and environment-Novelli is evaporated and the obtained dry residue is ground into fine powder with an average particle size of < 0,5 mm

Example 2

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Connection X - 16,7

HPMC 3 SP - 66,7

Poloxamer 188 (BASF) - 16,7

The composition (form B) receive as in example 1.

Example 3

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Connection X - 16,7

HPMC 3 SP - 66,7

TGPS*- 16,7

The composition (form C) receive/as in example 1.

*succinate of polietilenglikolmonostearat

Example 4

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Connection X - 10

HPMC 3 SP - 80

Solulan C24 (from Amerchol) - 10

The composition (form D) are obtained as in example 1.

The above composition, form from a to D, can be formed into tablets, placed in capsules or powdered and Packed in bags.

Pharmacokinetics after administration of 40-O-(2-hydroxy)tyramine rats

an Introduction to medicines

0.5 ml of the aqueous dispersion composition of Compound X (equivalent to 4.0 mg of active ingredient per rat) was injected through a tube into the stomach during short inhalation anesthesia with a syringe for now.

b) sampling the blood

One day before the experiment the animals were put in a permanent cannula in the jugular vein. 0.5 ml of venous blood (jugular vein) were collected from each rat and kept in 2.5 ml EDTA tubes. Blood samples from 2 animals (1, 2, 3 and 4, 5 and 6) were pulirula in the General Fund and stored at -80oC to conduct the drug analysis. The samples were taken before administration and after 10 min, 30 min, 60 min, 120 min, 300 min, 480 min and 1440 min after drug administration.

in) Bioanalytica

Blood samples were analyzed using HPLC (liquid chromatography high resolution) with reversed phase.

The table shows the pharmacokinetic data obtained after administration of compound X rats.

Form And gives the result by the level in the blood is higher than with the introduction of compositions containing surface-active substances.

Studies on dogs

The bioavailability study was conducted on a hound dog with a dose of 1 mg/kg of body weight. Hard gelatin capsules containing each 10 mg of the compound X was introduced 8 dogs on the chart 4-number of Latin squares; dogs fed through 6 h after administration of the capsule, and the connection-level X in the blood was determined by cooperator life connection X in the blood is between 10 and 40 hours Observed median peak level of 140 ng/ml and the median AUC level 0-48 h approximately 1600 NGC/ml.

Example 5

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Compound Y - 20

HPMC 3 SP - 80

The composition (form E) obtained by dissolution of the compound Y and a carrier medium in a mixture of ethanol/acetone. Then the solvent is evaporated, and the obtained dry residue is crushed.

Example 6

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h:

Compound Y - 20

HPMC 3 SP - 70

Poloxamer 188 - 10

The composition (form F) are obtained as in example 5.

Example 7

A solid dispersion composition was prepared with the contents of the following ingredients, by weight.h.:

Compound Y - 20

HPMC 3 SP - 75

Sodium dodecyl sulfate - 5

The composition (form G) are obtained as in example 5.

The above composition, form E through G can be formed into tablets, placed in capsules or powdered and Packed in bags.

Pharmacokinetics after administration 33-epichloro-33-detoxicating rats

an Introduction to medicines

0.5 ml of aqueous dispersions of drug composition (equivalent to 4.0 mg ACSA with a syringe of 1 ml, attached to a polyethylene tube. For each composition forms E, F and G were used for 6 animals.

b) sampling the blood

One day before the experiment the animals were put in a permanent cannula in the jugular vein. 0.5 ml of venous blood (jugular vein) were collected from each rat and kept in 2.5 ml EDTA tubes. Blood samples from 2 animals (1, 2, 3 and 4, 5 and 6) were pulirula in the General Fund and stored at -80oC to conduct the drug analysis. The samples were taken before administration and after 10 min, 30 min, 60 min, 120 min, 300 min, 480 min and 1440 min after injection.

in) Bioanalytica

Blood samples were analyzed using HPLC with reversed phase.

The results are presented in Fig. 1 and 2, where the vertical axis data on blood levels of compound Y in ng/ml) on the horizontal axis indicate the time in hours. Fig. 1 shows that the shape of F gives the result by the level in the blood is significantly higher than the blood level observed after the introduction of the form E or form G. Fig.2 shows that the shape of F gives a high result in blood levels with the introduction of food.

Compound Y is in amorphous form in the compositions E, F and G immediately after formation and after 6 months of storage, as opredelit. Under stirring in a solution of 0.2 wt.% sodium dodecyl sulfate in water at a temperature of 37oC it was found that over 80% of the available connection Y is released and dissolves from each powdered composition containing 10 mg of compound Y in 30 min, 92% of the available connection Y is released from the form that is, It is comparable to approximately 5% release after 30 min of an equivalent amount of crystalline compound Y.

1. Pharmaceutical composition for oral administration in the form of a solid dispersion containing rapamycin and the carrier medium.

2. Composition under item 1, in which the carrier medium contains a water-soluble polymer or a cyclodextrin.

3. Composition under item 1, which is selected from rapamycin 40-O-(2-hydroxy)tyramine, 32-desoxyephedrine or 16-Penta-2-ynyloxy-32(S)-dihydrocapsaicin.

4. The composition according to p. 3, in which the polymer is a hypromellose or polyvinylpyrrolidone.

5. The composition according to p. 1, containing up to 30 wt.% rapamycin.

6. The composition according to p. 2, in which the water-soluble polymer is a hypromellose in an amount up to about 95 wt.%.

7. The composition according to p. 2, in which chestno-active substances.

9. Composition under item 1, in which the carrier medium includes a surfactant.

10. The composition according to p. 9 in which the surfactant is a polyoxyethylene-polyoxypropylene block copolymer.

11. The composition according to p. 2, in which the polymer is a hypromellose or polyvinylpyrrolidone.

12. Composition under item 1, in which the carrier medium comprises water-soluble or water-insoluble sucrose.

13. Composition under item 1, in which the carrier medium comprises microcrystalline cellulose.

14. Pharmaceutical composition for oral administration in the form of a solid dispersion containing 33-epichloro-33-desoxycortisol and the carrier medium, and that the carrier medium comprises water-soluble polymer or a cyclodextrin.

15. The composition according to p. 14, further comprises a surfactant.

 

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