Drugs rapamycin for oral administration

 

(57) Abstract:

The invention relates to pharmacology and medicine, in particular to the preparation of solid dosage forms of the drug rapamycin, which includes a core and a sugar coating. This coverage includes rapamycin, sucrose and one or more binders. The technical result of the invention is to provide the safest and most convenient dosage form providing modified release of rapamycin. 3 S. and 13 C.p. f-crystals, 1 table.

The invention relates to preparations containing rapamycin or a pharmaceutically acceptable salt of rapamycin, suitable for oral administration to stimulate immunosuppression and treatment of rejection in transplantation, painful reactions of the recipient on transplantat, autoimmune diseases, inflammatory diseases, solid tumors, fungal infections, T-cell leukemia/lymphoma in adults and hyperproliferative vascular disorders.

Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus, which was first discovered as an antifungal agent. It prevents the growth of fungi such as Candida albicans and Microsporum gupseum. Rapamycin, it is. reported in the Canadian Journal of Physiological Pharmacology, 55, 48-51 (1977) on the immunosuppressive properties of rapamycin relative to experimental allergic encephalitis and arthritis in adults. In 1989 Calne, R. Y., and others [Lancet, 1989, 2, pp. 227[ and Morris R. E. and Meiser B. M. [Medicinal Science Research, 1989, 17, pp. 609-10] independently reported the efficacy of rapamycin in inhibiting rejection in vivo when transplanted allograft. After describing the properties of rapamycin on immunosuppression and inhibition of rejection was followed by many articles and began clinical studies on the use of rapamycin in inhibiting rejection in transplantation in humans.

It is known that rapamycin itself [U.S. Patent 4885171] or in combination with picibanil (picibanil) [U.S. Patent 4401653] antineoplastic activity. R. Martel and others [Can. J. Physiol. Pharmacol. 55, 48 (1977)] revealed that rapamycin is effective in models of experimental allergic encephalomyelitis model of multiple sclerosis; in the model of arthritis in adults, models of rheumatoid arthritis and inhibits the formation of IgE-like antibodies (IgE-like antibodies).

Effects of rapamycin on immunosuppression disclosed in FASEB 3, 3411 (1989). It is known that cyclosporine A (Cyclosporin A and FK-506, other macrocyclic say the Oia transplant [FASEB 3, 3411 (1989); FASEB 3,5256 (1989); R. Y. Calne, etc., Lancet 1183 (1978)].

It is known that rapamycin inhibits graft rejection in mammals [U.S. Patent 5100899], and that rapamycin, its derivatives and prodrugs suitable for the treatment of pulmonary inflammation [U.S. Patent 5080899], systemic lupus erythematosus (U.S. Patent 5078899], inflammatory skin diseases such as psoriasis [U.S. Patent 5286730], inflammatory bowel disease [U.S. Patent 5286731], ocular inflammation [U.S. Patent 5387589] , hyperproliferative vascular disorders, such as restenosis [U.S. Patent 5512781 and 5288711], carcinomas [U.S. Patent 5206018 and 4885171] and cardiac inflammatory diseases [U.S. Patent 5496832] and to prevent attacks insulin-dependent diabetes mellitus [U.S. Patent 5321009]. In addition, it is shown that rapamycin is useful in the treatment of T-cell leukemia/lymphoma [European Patent Application 525960 A1] and in the treatment of eye inflammation [U.S. Patent 5387589].

It turned out that due to poor solubility in oil and water are satisfactory only some drugs rapamycin. U.S. patents 5516770 and 5530006 reveal drugs rapamycin for intravenous administration. U.S. patents 5536729 and 5559121 disclose liquid preparations is a (esterified 28 and 43 of the regulations) suitable as antifungal agents [U.S. Patent 4316885], and they are used to obtain water-soluble prodrugs of rapamycin [U.S. Patent 4650803]. Recently changed the terms of the numbering of the atoms for rapamycin; now according to the nomenclature of Chemical Abstracts described above esters would be derived for the 31 - and 42-positions. U.S. patent 5118678 reveals carbamates rebamipide that are useful as immunosuppressants, anti-inflammatory, antifungal and anticancer agents. U.S. patent 5100883 discloses fluorinated esters of rapamycin. U.S. patent 5118677 discloses esters amides (amide esters) of rapamycin. U.S. patent 5130307 reveals complex amino esters (aminoesters) rapamycin. U.S. patent 5117203 reveals the sulfonates and sulfonate rapamycin. U.S. patent 5194447 reveals sulfanilamide rapamycin.

The most important immunosupressants, currently used for the inhibition of rejection in the transplantation of allografts organs in humans, is SANDIMMUNE (cyclosporine). Cyclosporine is a polypeptide consisting of 11 amino acids. The drug SANDIMMUNE (IV) is a sterile ampoule, which contains (per ml) 50 mg cyclosporine, 650 mg CremophorEL and alcohol Ph Helv. (32,9% by volume) (under nitrogen). To introduce this M dextrose for injection (Dextrose Injection). [Pnysicians' Desk Reference, edition 45, 1991, pp. 1962-64, Medical Economics Company, Inc.]. Currently, clinical trials for the inhibition of rejection in the transplantation of allografts organs in the human subject also macrolide molecule labelled FK506, which has certain structural similarities with rapamycin. FK506 isolated from Streptomyces tsuskubaensis and described in U.S. Patent 4894366 (Okuhara and others) from 16 January 1990. R. Venkataramanan and others in Transplantation Proceedings, 22 1, Suppl. , 1, pp. 52-56 (February 1990) report that the drug FK506 for intravenous injection in the form of FK506 solution 10 mg/ml in polyoxyethylene castor oil (HCO-60, surfactant and alcohol. Preparation for intravenous injection should be diluted with saline or dextrose and use as an infusion over 1-2 hours.

Physicians' Desk Reference [edition 45, 1991, pp. 2119, Medical Economics Company, Inc.] indicates that SANDIMMUNE (cyclosporine) is available as capsules of 25 mg and 100 mg and solution for oral administration in 50 ml bottles. 25 mg capsules contain 25 mg of cyclosporine, USP and alcohol, USP, digidrirovanny up to a maximum of 12.7% by volume. 100 mg capsules contain 100 mg of cyclosporine, USP and alcohol, USP, digidrirovanny up to a maximum of 12.7% by volume. Capsules for oral administration is alizirovannaya (glycolysed) glycerides), red iron oxide, sorbitol, titanium dioxide and others. Solution for oral administration is available as a 50 mg bottles containing 100 mg of cyclosporine, USP and alcohol Ph. Helv. (12,5% by volume) dissolved in olive oil. Ph. Helv. /Labrafil M 1944 CS (polyoxyethylene oleic glycerides) as a carrier, which before the oral use should be diluted with milk, chocolate milk or orange juice.

IMURAN (azathioprine, from Burroughs Wellcome Co., Research Triangle Park, N. C.) is another immunosuppressant for oral administration, which are prescribed by itself or in combination with other immunosuppressants. Physicians' Desk Reference [edition 45, 1991, pp. 785-787, Medical Economics Company, Inc.] defines azathioprine 6-[1-methyl-4-nitroimidazol-5-yl)thio]purine, which is prepared for oral administration in tablet form with the shell containing 50 mg of azathioprine and inactive ingredients: lactose, magnesium stearate, potato starch, povidone and stearic acid.

Methods of drug delivery are intended for delivery to the patient an acceptable dose. In the case of preparations for oral administration is highly desirable to provide a dosage form of the drug, which satisfies these criteria by themselves.

The present invention relates to drug rapamycin, orally applicable. It is known that rapamycin has immunosuppressive activity, the activity of anti-rejection, anti-fungal and anti-inflammatory activity in vivo and inhibits proliferation of thymocytes in vitro. Therefore, these drugs suitable for the treatment or inhibition of rejection in the transplantation of allografts, such as kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea, small intestine and skin, and heart valve xenografts; in the treatment or inhibition of painful reactions transplantat against the owner; for the treatment or inhibition of autoimmune diseases such as lupus, rheumatoid arthritis, diabetes, myasthenia gravis and multiple sclerosis; and inflammatory diseases such as psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease, pulmonary inflammation (including asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis and the like; and eye uveitis.

It is also known that rapamycin has antitumor, antifungal and entirelife is her including sarcomas and carcinomas such as astrocytomas, prostate cancer, breast cancer, small cell lung and ovarian cancer; T-cell leukemia/lymphoma in adults; fungal infections, and hyperproliferative vascular diseases such as restenosis and atherosclerosis.

The present invention also includes preparations for use to stimulate the immune suppression in need of this mammal.

Mostly the drugs of this invention to provide a dosage form of rapamycin in the form of tablets for oral administration, characterized in that it includes a core, which is coated with rapamycin, and sugar coating containing one or more sugars and one or more binders. Preferably, such dosed tablets contain 0.05 to 20 mg of rapamycin, more preferably, such tablets contain 0.5 to 10 mg of rapamycin.

This invention relates also to a method for producing dosage forms of rapamycin in the form of tablets for oral administration, characterized in that it comprises a coating on the core suspension of rapamycin in an aqueous solution containing one or more sugars and one or more binder, and drying, as long as the cores on the CSOs in this invention the sugar coating, is a sugar product, such as sucrose, the product of processing sugar beet or cane, or food processing sources of starch, saccharide or polysaccharide which are considered suitable to produce sugar coating. For preparing solid dosage forms of this invention it is preferable that the sugar was sucrose.

If you are getting dosed tablets rapamycin for oral administration using a binder, they may include a resin of acacia, tragakant, stearic acid, gelatin, casein, lecithin (phosphatides), calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, the phthalate hypromellose, methyl acrylate, microcrystalline cellulose, noncrystalline cellulose, polyvinylpyrrolidone (povidone, PVP), cetosteatil alcohol, cetyl alcohol, paraffin based atilovykh esters (cetyl ester wax), dexterity (dextrates, dextrin, lactose, dextrose, glycerol monooleate, glyceryl the monostearate, glyceryl palmitostearate, alkyl ethers of polyoxyethylene, polyethylene glycols, polyoxyethylene derivatives of castor oil, polyoxyethylene, polivi is according to the invention provides rapamycin, contained in a sugar coating, which is deposited on the core. The kernel can be any pharmaceutically inert or may contain pharmaceutically active agent. Used in this description, the term "sugar coating" refers to rapamycin, sugar and a binder, which cover the core.

The following preferred composition of the sugar coating of solid dosage tablets containing 0.05-20 mg of rapamycin:

(a) rapamycin in an amount of about 0.05 to 20 mg;

b) sucrose in an amount of about 50-99 wt.% sugar coating;

C) one or more binders in an amount of about 0.1 to 10 wt.% sugar coating.

In the preparations according to the invention are specified in percent number of ingredients vary depending on the weight of sugar coating. Sugar coating according to the invention typically weighs approximately 50-200 mg. Therefore, in the above preparation the quantity of sucrose is about 25 mg (about 50 wt.% sugar coating) for 50 mg sugar coating containing 20 mg of rapamycin and 10% (5 mg) binder. Similarly, the weight percent of sucrose in sugar coating can be more than 99% of the sugar coating, then 200 mg sugar coating containing 0.05 mg rapamycin is dosed tablets containing 0.05-20 mg of rapamycin in which the sugar coating contains as a binder povidone, microcrystalline cellulose:

(a) rapamycin in an amount of about 0.05 to 20 mg;

b) sucrose in an amount of about 50-99 wt.% final coating;

C) povidone in an amount of about 0.2 to 1.0 wt.% final coating;

g) microcrystalline cellulose in the range of about 0.1-3.0 wt.% final coating.

Dosed tablets for oral administration containing rapamycin and having the above composition can be prepared as follows. Upon receipt of the above drug use about 40-60 mg water to prepare 100 mg sugar coating, and thereafter the water is removed in the production process. In short, rapamycin or grind using conventional technology of grinding, for example in the mill fitza (Fitz) or ball mill, or grind on the micron mill using conventional technology micron grinding, for example by means of a mill Outer (Trost) or jet mill. Grind rapamycin typically has a particle size of 10-400 μm, and rapamycin reduced to the micron mill typically has a particle size of 0.5 to 10 microns. Number of Etwor cooled to approximately 30-40oC. Add the povidone and vigorously stirred until dissolution. To this mixture rapamycin and mixed well until a homogeneous dispersion of rapamycin. Add microcrystalline cellulose and the mixture is stirred, providing a homogeneous suspension. If necessary, additional water is added during the coating suspension is continuously stirred. This mixture is sprayed on the core of the small portions and dried in the air between the coating portions until until you get a tablet with the required concentration. In the production process the main quantity of water removed, so each tablet remains less than approximately 5% water. Usually each tablet is less than 2% of residual water. If desired, the dosage of tablets for oral administration containing rapamycin, optional you can put the color coating, asetem gloss finish. Colored coating usually contains sugar, such as sucrose, and a pigment such as titanium dioxide, and a glossy coating contains Carnauba wax, which can be applied in the form of a dispersion in a solvent such as mineral spirits.

If the engine is pharmaceutically inert, it is usually the core of placebo, which moretwat using shellac to prevent the destruction of the coating process. Before applying the outer coating can also on top of the shellac coating of sucrose.

Described in this invention the sugar coating may have a normal weight of about 50-200 mg of Applying the described method, receive 100 mg of sugar coating containing 0.05-20 mg of rapamycin from the following ingredients by following the procedure as described above:

(a) rapamycin in an amount of about 0.05 to 20 mg;

b) sucrose in an amount of about 50-99 mg;

C) povidone in an amount of about 0.2 to 1.0 mg;

g) microcrystalline cellulose in an amount of about 0.1 to 3.0 mg;

d) water in the amount of 40-60 mg (mostly removed during processing).

In the case when the preparations according to the invention are used as immunosuppressants or anti-inflammatory agents, can be applied in combination with one or more immunoregulatory agents. Such chemotherapeutic agents, anti-rejection include, but are not limited azathioprine, corticosteroids such as prednisolone and methylprednisolone, cyclophosphamide, cyclosporine A, FK506, OCT-3, and ATG. When combining one or more drugs of the present invention with other drugs or agents for the incentive of the agent to achieve the desired effect. The Foundation of such combination therapies were installed Stepkowski, whose results show that the use of a combination of rapamycin and cyclosporine a in subtherapeutic doses significantly extends the lifetime of allotransplanted heart [Transplantation Proc. 23:507 (1991)].

The dose can vary depending on the severity of existing symptoms and patient. Daily dose of rapamycin should be 0.05 to 25 mg, preferably 0.5 to 10 mg if rapamycin is used in combination therapies, and 1-25 mg if replicia used in monotherapy. The preferred daily dose is 2-5 mg if rapamycin is used in combination therapies, and 5-15 mg if rapamycin is used in monotherapy.

Usually start treatment with small dosages less than the optimum dose of this compound. Then increase the dose to optimally achievable effect under the circumstances. The exact dosage for a particular patient is determined by the physician based on his experience. In General, the most desirable to take the drugs of the present invention at a concentration, which usually provides effective results without causing any harmful or harmful side effects.

Following the receipt and evaluation of the submitted examples of solid dosage tablets rapamycin.

EXAMPLE 1

The method of obtaining and evaluating 3.0 mg dosage tablets rapamycin for oral administration, contains 100 mg of sugar coating.

Formula:

Ingredient* - Number, mg

Rapamycin - 3,06

Sucrose - 97,41

Povidone - 0,510

Microcrystalline cellulose - 1,020

Water - 54,92

* These numbers include over 2% in the expense of production losses.

Instructions to receive:

1. Heat the water to 65-70oC, add the saccharose and mix well to dissolve. The solution is cooled to about 30-40oC.

2. Add povidone and vigorously stirred until dissolution.

3. To the mixture add minced or chopped micron mill rapamycin and mixed well to obtain a homogeneous dispersion of rapamycin.

4. Add the microcrystalline all the s on pharmaceutically inert core and between the coating portions are dried in the air.

Assessment

Six Cynomolgus monkeys mokeus below as a-C, enter the above drug at the dose of 3 mg of rapamycin on the monkey and then determine the concentration of rapamycin in the serum at the indicated time after dose (see table).

The results show that a concentration of rapamycin is found in the serum after administration presents dosed tablets for oral administration of the present invention.

EXAMPLE 2

According to the procedure described in Example 1, receive 0.5 mg dosed pill rapamycin for oral administration, contains 100 mg of sugar coating. The following quantities of ingredients used.

Formula:

Ingredient* - Number, mg

Rapamycin - 0,510

Sucrose - of 99.96

Povidone - 0,510

Microcrystalline cellulose - 1,020

Water - 54,92

*These numbers include over 2% in the expense of production losses.

EXAMPLE 3

According to the procedure described in Example 1, receive 1.0 mg dosed pill rapamycin for oral administration, contains 100 mg of sugar coating. The following quantities of ingredients used.

Formula:

Ingredient* - number 1,020

Water - 54,92

* These numbers include over 2% in the expense of production losses.

EXAMPLE 4

According to the procedure described in Example 1, get 5.0 mg dosage tablet rapamycin for oral administration, contains 100 mg of sugar coating. The following quantities of ingredients used.

Formula:

Ingredient* - Number, mg

Rapamycin - 5,10

Sucrose - 95,37

Povidone - 0,510

Microcrystalline cellulose - 1,020

Water - 54,92

*These numbers include over 2% in the expense of production losses.

EXAMPLE 5

According to the procedure described in Example 1, receive 7.5 mg dosage tablet rapamycin for oral administration, contains 100 mg of sugar coating. The following quantities of ingredients used.

Formula:

Ingredient* - Number, mg

Rapamycin - 7,65

Sucrose - 92,82

Povidone - 0,510

Microcrystalline cellulose - 1,020

Water - 54,92

*These numbers include over 2% in the expense of production losses.

EXAMPLE 6

According to the procedure described in Example 1, receive 10 mg dosed pill rapamycin for oral administration, contains 100 mg Sahar* - Number, mg

Rapamycin - 10,2

Sucrose - 90,27

Povidone - 0,510

Microcrystalline cellulose - 1,020

Water - 54,92

*These numbers include over 2% in the expense of production losses.

1. Solid dosage form of a rapamycin-containing core and a sugar coating, and the specified sugar coating contains (a) rapamycin in an amount of about 0.05 to 10 mg,

(b) sucrose in an amount of about 50-99 weight. % sugar coating and

(C) as a binder povidone derivative of cellulose in an amount of about 0.1 to 10 weight. % sugar coating.

2. Dosage form under item 1, characterized in that the average particle size of rapamycin is 0.5 to 400 microns.

3. Dosage form under item 1, characterized in that as binders contains povidone in an amount of about 0.2 to 1.0 weight. % final coating and microcrystalline cellulose in an amount of about 0.1 to 3.0 weight. % final coating.

4. Dosage form under item 3, wherein the povidone is contained in an amount of about 0.5 weight. % the specified sugar coating.

5. Dosage form under item 4, wherein the microcrystalline cellulose is contained in the amount of approx shall rapamycin is contained in the amount of approximately 6.5 mg, (b) sucrose is contained in an amount of about 95 to 99 weight. % the specified sugar coating, (b) povidone is contained in an amount of about 0.5 weight. % the specified sugar coating and (d) microcrystalline cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

7. Dosage form under item 3, characterized in that (a) rapamycin is contained in an amount of about 1 mg, (b) sucrose is contained in an amount of about 94-99 weight. % the specified sugar coating, (b) povidone is contained in an amount of about 0.5 weight. % the specified sugar coating and (d) microcrystalline cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

8. Dosage form under item 3, characterized in that (a) rapamycin is contained in an amount of about 3 mg, (b) sucrose is contained in an amount of about 90-99 weight. % the specified sugar coating, (b) povidone is contained in an amount of about 0.5 weight. % the specified sugar coating and (d) microcrystalline cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

9. Dosage form under item 3, characterized in that (a) rapamycin is contained in an amount of about 5 mg, (b) sucrose contained in the EU. % the specified sugar coating, (d) microcristalina cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

10. Dosage form under item 3, characterized in that (a) rapamycin is contained in an amount of about 7.5 mg, (b) sucrose is contained in an amount of about 80-97 weight. % the specified sugar coating, (b) povidone is contained in an amount of about 0.5 weight. % the specified sugar coating, (d) microcrystalline cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

11. Dosage form under item 3, characterized in that (a) rapamycin is contained in an amount of about 10 mg, (b) sucrose is contained in an amount of about 75-96 weight. % the specified sugar coating, (b) povidone is contained in an amount of about 0.5 weight. % the specified sugar coating, (d) microcrystalline cellulose is contained in an amount of about 1 weight. % the specified sugar coating.

12. The method of obtaining dosed tablets rapamycin for oral administration under item 1, which comprises spraying on the engine suspension of rapamycin in an aqueous solution containing sucrose and with povidone, microcrystalline cellulose, and drying until the bath tablets rapamycin for oral administration by p. 1, namely, that includes obtaining a sugar coating for the following stages: (a) grinding or crushing on the micron mill to obtain rapamycin with an average particle size of 0.5 to 400 microns, (b) adding sucrose to enough water to dissolve sucrose; however, the specified water has a temperature of 65-70o(C) cooling the solution to 30-40o(G) adding povidone and stirring until the dissolution, (d) adding to the solution of crushed rapamycin and stirring until a homogeneous dispersion, (e) adding one or more additional binder and mixing until a homogeneous suspension, coating the core and the drying up until the kernel will not napisano the required amount of rapamycin.

14. The method according to PP. 12 and 13, characterized in that the amount of sucrose is about 50-99 weight. % the dried coating.

15. The method according to p. 13, characterized in that the number used as the binder is povidone is approximately 0.2-1 wt. % the dried coating.

16. The method according to p. 13, characterized in that the number used as a binder microcrystalline cellulose is approx

 

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