MXPA99011518A - Rapamycin formulations for oral administration - Google Patents

Abstract

This invention provides rapamycin solid dosage unit which comprises a core and a sugar overcoat, said sugar overcoat comprising rapamycin, one or more sugars, and one or more binders.

Description

FORMULATIONS OF RAPAMYCIN FOR ORAL ADMINISTRATION DESCRIPTION OF THE INVENTION This invention relates to formulations containing rapamycin, or pharmaceutically acceptable salts of rapamycin, which are useful in oral administrations for inducing immunosuppression and for treatment of transplant rejection, host disease against grafting, autoimmune diseases, inflammation diseases, solid tumors, fungal infections, leukemia disorders in adult T cells / lympholas and hyperproliferative vascular.

BACKGROUND OF THE INVENTION Rapamycin is a macrolide antibiotic produced by Streptomyomyces hygroscopius, which was first discovered for its properties as an antifungal agent. This adversely affects the growth of fungi such as Candida albi cans and My crosporum gypseum. Rapamycin, its preparation and its antibiotic activity are described in U.S. Pat. No. 3,929,992, issued December 30, 1975, to Surendra Sehgal et al. In 1977 Martel, R. R. REF .: 32123 et al. report immunosuppressive properties of rapamycin against experimental allergic encephalitis and adjuvant arthritis in the Canadian Journal of Physiological Pharmacology, 5_5, 48-51 (1977). In 1989, Caine, R. Y. et al., In Lancet, 1989, no. 2 P. 227 and Morris, R.E. and Meiser, B.M. in Medicinal Science Research, 1989. No. 17. P. 609-10, the effectiveness of rapamycin is separately reported in inhibiting rejection in vi ve in allograft transplantation. They have followed numerous articles describing the immunosuppressive and rejection inhibition properties of rapamycin, and clinical research has initiated the use of rapamycin in the inhibition of transplant rejection in men. Rapamycin alone (Patent of the States United 4,885,171) or in combination with picibanil (U.S. Patent 4,401,653) have been shown to have antitumor activity. R. Martel et al. [Dog. J. Physiol, Pharmacol. 55, 48 (1977)] describe that rapamycin is effective in the model of experimental allergic encephalomyelitis, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis / and effectively inhibits the formation of IgE-like antibodies.

The immunosuppressive effects of rapamycin have been described in FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, have also been shown to be effective as immunosuppressive agents, therefore useful in the prevention of transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Caine et al., And Lancet 1183 (1978). It has been shown that rapamycin inhibits rejection of transplants in mammals [U.S. Patent 5,100,899]. Rapamycin, its derivatives and prodrugs have also been shown to be useful in the treatment of pulmonary inflammation [U.S. Patent 5,080,899], systemic lupus erythematosis [U.S. Patent 5,078,899], skin disorders in an inflammatory as psoriasis [U.S. Patent 5,286,730], immunoinflammatory large bowel disorders [U.S. Patent 5,286,731], ocular inflammation [U.S. Patent 5,387,589], hyperproliferative vascular disorders, such as restenosis [U.S. Patent 5,512,781 and 5,288,711], carcinomas [U.S. Patent Nos. 5,206,018 and 4,885,171], and cardiac inflammatory disease [U.S. Patent 5,496,832]; to prevent in the onset of insulin-dependent diabetes mellitus [U.S. Patent 5,321,009]. Additionally, rapamycin has been shown to be useful in the treatment of adult T cell leukemia / lymphoid [European Patent Application 525,960 Al], and in the treatment of ocular inflammation [U.S. Patent 5,387,589]. Due to its poor solubility in oil and water, only a few formulations of rapamycin have been tested to be satisfactory. U.S. Patents 5,516,770 and 5,530,006 describe the intravenous rapamycin formulations, and U.S. Patents 5,536,729 and 5,559,121 describe. formulations of liquid oral rapamycin. The mono- and diacylated derivatives of rapamycin (esterified at positions 28 and 43) have been shown to be useful as antifungal agents (U.S. Patent 4,316,885) and are used to make water soluble prodrugs of rapamycin (U.S. Patent 4,650,803).

Recently, the different rapamycin convention has been changed; therefore, according to the nomenclature of Chemistry Abstracts, the esters described above may be in positions 31 and 42. U.S. Patent 5,118,678 discloses rapamycin carbamates that are useful as immunosuppressants, anti-inflammatories, antifungals, and agents antitumor. U.S. Patent 5,100,883 describes fluorinated esters of rapamycin. U.S. Patent 5,118,677 describes rapamycin amide esters. U.S. Patent 5,130,307 describes amino esters of rapamycin. U.S. Patent 5,117,203 describes sulfonates and sulfamates of rapamycin. U.S. Patent 5,194,447 describes rapamycin sulfonylcarbamates. The primary immunosuppressive agent currently used to inhibit rejection. in organ allograft transplantation in man it is SANDIMMUNE (ciclosporin). Cyclosporin is a cy polypeptide consisting of 11 amino acids. The intravenous injectable formulation of SA? DIMMU? E (IV) is a sterile vial containing, per ml, 50 mg of ciclosporin, 650 mg of Cremophor® EL and alcohol Ph Helv. (32.9% by volume) (under nitrogen). To administer this mixture it is further diluted with 0.9% Sodium Chloride injection or 5% Dextrose injection before use. (Physicians' Desk Reference, 45th ed, 1991, pp. 1962-64, Medical Economics Company, Inc.) The macrolide molecule designated FK506, which has certain structural similarities to rapamycin, is also currently undergoing ical research to inhibit rejection in Transplantation of allograft organs in humans. FK506 is isolated from Streptomyces tsuskubaensi s and a U.S. Patent No. 4,894,366 to Okuhara et al., Issued January 16, 1990, R. Venkataramanan et al., In Transplantation Proceedings, 22, No. 1, Suppl. ., 1 pp 52-56 (February 1990), reports that the intravenous injectable formulation of FK506 is provided with a 10 mg / ml solution of FK506 in polyoxyethylated resin oil (HCO-60, a surfactant) and alcohol. The intravenous preparation must be diluted with saline or dextrose and administered as an infusion for 1 to 2 hours. The Physicians Desk Reference (45th ed., 1991, p.2119, Medical Economics Company, Inc.), list SANDIMMUNE (cyclosporine) as available in 25 mg and 100 mg resistant capsules and as an oral solution in 50 ml bottles. The 25 mg capsules contain -25 mg of cyclosporin, USP, and alcohol, dehydrated USP, in a maximum of 12.7% by volume. The 100 mg capsules contain cyclosporin, USP, 100 mg and alcohol, USP dehydrated, to a maximum of 12.7% by volume. The inactive ingredients in the oral capsules are corn oil, gelatin, glycerol, Labrafil M 2125 CS (polyoxyethylated glyceride glycerides), red iron oxide, sorbitol, titanium dioxide and other ingredients. The oral solution is available in 50 mg bottles containing cyclosporin, USP, 100 mg of P. Helv. alcohol at 12.5% by volume dissolved in olive oil, Ph. Helv. / Labrafil M 1944 CS (polyoxyethylated oleic glycerides), vehicle that must be further diluted with milk, chocolate milk or orange juice before oral administration. IMURAN (azathioprine, available from Burroughs Wellcome Co., Research Triangle Park, N.C.) is another orally administered immunosuppressive agent prescribed alone or in combination with other immunosuppressive agents. The Physicians' Desk Reference (45th ed., 1991, pp. 785-787, Medical Economics Company, Inc.) lists azathioprine _ as 6- [l-methyl-4-nitroimidazol-5-yl) thiopurine, which is provided for oral administration in heavy tablets containing 50 mg of azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid.

DESCRIPTION OF THE INVENTION The drug delivery methods were designed to deliver an acceptable dose of the drug to the patient. In the case of oral formulations, it is highly desirable to provide a dosage form that meets these criteria and that can be administered effectively, preferably self-administered, either in clinical or non-clinical situations. The present invention relates to formulations useful in oral administration of rapamycin. Rapamycin has been shown to possess immunosuppressive, anti-rejection, antifungal and antiinflammatory activity in vivo and. to inhibit the proliferation of thymocytes in vi tro. Therefore, these formulations are useful in the treatment or inhibition of transplant rejection such as kidney, heart, liver, lung, bone marrow, pancreas (islet cells), corneas, small intestine, and skin allografts, and xenografts. of heart valve; in the treatment or inhibition of graft-versus-host disease; in the treatment or inhibition of autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and inflammation diseases such as psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease, lung inflammation (including asthma, chronic obstructive pulmonary disease, emphysema, acute respiratory distress syndrome, bronchitis and the like), and eye uveitis. Rapamycin has also been shown to have antitumor, antifungal and antiproliferative activities. The formulations of this invention are therefore also useful in the treatment of solid tumors, including sarcomas and carcinomas, such as astrocytomas, prostate cancer, breast cancer, small cell lung cancer, and ovarian cancer; adult T cell leukemia / lymphoid; fungal infections; and hyperproliferative vascular diseases, such as restenosis and atherosclerosis. The present invention also provides formulations for use in the induction of immunosuppression in a mammal in such need. In general, the formulations of this invention provide a purely oral dose of rapamycin comprising a core that is overcoated with rapamycin and a sugar coating containing one or more sugars and one or more binders. It is preferred that such dose tablets contain 0.05-20 mg rapamycin, that it is more preferred that such a tablet contain 0.5-10 mg rapamycin. This invention also provides a process for preparing an oral tablet dosage form of rapamycin which comprises spraying a core with a suspension of rapamycin in an aqueous solution comprising one or more sugars and one or more binders and drying, until the desired amount of rapamycin has been sprayed into the nucleus. The sugar used in the production of the sugar coating described in this invention is a sugar product, such as sucrose, derived from cane or beet sources, or starch, saccharin or converted sources of polysaccharide, which are considered suitable for preparing the sugar. sugar coating. When used in the preparation of the solid dosage form of this invention, it is preferred that the sugar be sucrose. When using binders in the preparation of rapamycin oral dose tablets, these may include acacia gum, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose , hydroxypropylmethylcellulose phthalate, methylacrylate, microcrystalline cellulose, non-crystalline cell, polyvinylpyrrolidone (povidone, PVP), cetostearyl alcohol, cetyl alcohol, cetyl ester wax, dextrates, dextrin, lactose, dextrose, glyceryl monooleate, glyceryl monostearate, palmito-stearate glyceryl, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyvinyl alcohol, and sorbitan fatty acid esters. The dose tablets described herein provide rapamycin contained in a sugar coating that has been coated on a core. The core can be either pharmaceutically inert or it can contain a pharmaceutically active agent. As used in describing this invention, the term "sugar coating" refers to the rapamycin, sugar and binder that coat the core. The following provides a preferred formulation for sugar coatings of a solid dose tablet containing 0.05-20 mg rapamycin. a) rapamycin in an amount of about 0.05-20 mg b) sucrose in a range of about 50-99% by weight of the sugar coating one or more binders in a range of about 0.1-10% by weight of the sugar coating In The formulations described in this invention, the amounts of the ingredients specified as percentages will vary according to the weight of the sugar coating. The sugar coating described in this invention will typically weigh approximately 50-200 mg. Therefore, in the above formulation, the amount of sucrose can be about 25 mg (about 50% by weight of the sugar coating), for a 50 mg sugar coating containing 20 mg of rapamycin and 10% of binders ( 5 mg). Similarly, the sucrose weight percent in the sugar coating may comprise more than 99% of the sugar coating when a sugar coating at 200 mg contains 0. 05 mg of rapamycin and 0.1% of binders (0.2 mg). The following provides a more preferred formulation for sugar coating of a solid dose tablet containing 0.05-20 mg rapamycin, in which the sugar coating contains povidone and microcrystalline cellulose as binders. a) rapamycin in an amount of approximately 0.05 - 20 mg b) sucrose in a range of approximately 50-99% by weight of the final coating c) povidone in a range of approximately 0.2 - 1.0% by weight of the final coating d) cellulose microcrystalline in a range of about 0.1 - 3.0% by weight of the final coating. An oral dose tablet containing rapamycin containing the above constituents can be prepared according to the following procedure. In preparing the above formulation, approximately 40-60 mg of water is used in preparing a 100 mg sugar coating; the water is subsequently removed during processing. Briefly, rapamycin is either comminuted using conventional trituration techniques, for example, with a Fitz or ball mill, or micronized using conventional micronization techniques, for example with a Trost or jet mill. The milled rapamycin typically has a particle size of 10-400 microns, and the micronized rapamycin typically has a particle size of 0.4-10 microns.The required amount of water is heated to about 65-70 ° C, and add sucrose and mix well until the sucrose dissolves, cool the solution to approximately 30-40 ° C. Add povidone and mix vigorously until it dissolves, add the rapamycin to the mixture and mix well to disperse Rapamycin is uniformly added, microcrystalline cellulose is added and the mixture is stirred to provide a uniform suspension Additional water is added if necessary and the suspension is continued to mix during the coating process The mixture is sprinkled over a core in portions small, and air-dried between portions, until the desired tablet concentration is formed.Most of the water is removed during the manufacturing process. such that approximately 5% of water remains in each tablet. Typically, less than 2% residual water is present in each tablet. Oral-dose tablets containing rapamycin can be optionally coated with a colored coating followed by a polishing coating if desired. The color coating normally contains a sugar such as sucrose and a pigment such as titanium dioxide, and the polished coating contains carnauba wax, which can be applied as a dispersion in a solvent, such as mineral spirits. When the core is a pharmaceutically active core it is typically a placebo core which may contain lactose, microcrystalline cellulose, PEG-6000, and other binders and fillers. The nucleus, it can be sealed with schellac to avoid the disintegration that occurs during the coating process. A sucrose coating can also be placed on top of the coating prior to the coating process. The sugar coating in this invention can be prepared to typically weigh about 50-200 mg. - By using the process described herein, a 100 mg sugar coating containing 0.05-20 mg rapamycin of the following ingredients can be made according to the procedure described above: a) rapamycin in an amount of about 0.05-20 mg c) sucrose in an amount of about 50-99 mg d) povidone in an amount of about 0.2-1.0 mg e) microcrystalline cellulose in an amount of about 0.1-3.0 mg f) water in an amount of 40-60 mg (deleted mostly during the process) It is contemplated that when the formulations of this invention are used as an immunosuppressant or anti-inflammatory agent, it may be administered together with one or more other immunoregulatory agents. Such other anti-rejection chemotherapeutic agents, include, but are not limited to, azathioprine, corticosteroids, such as prednisone and methylprednisolone, cyclophosphamide, cyclosporin, A, FK-506, OKT-3, and ATG. By combining one or more of the formulations of the present invention with such other drugs or agents to induce immunosuppression or treatment of inflammatory conditions, lesser amounts of each of the agents may be required to achieve the desired effect.

The basis for such combination therapy is established by Stepko ski whose results show that the use of a combination of rapamycin and cyclosporin A in subtherapeutic doses significantly prolongs the survival time to the allograft of heart [Transplantation Proc. 23: 507 (1991)]. The dose requirements may vary the severity of the present symptoms and the particular subject to be treated. The projected daily oral doses of rapamycin can be 0.05 - 25 mg, with preferred projected daily doses being 0.5 - 10 mg when rapamycin is used in combination therapy and 1 - 25 mg when rapamycin is used as monotherapy. Most preferred daily projected doses are 2-5 mg when rapamycin is used in combination therapy, and 5-15 mg when rapamycin is used as monotherapy. Treatment will usually begin with small doses less than the optical dose of the compound. After this the dose is increased until the optimum effect under the circumstances is reached. Precise doses will be determined by the doctor who administers based on the experience with the treated subject. In general, the formulations of this invention are most desirably administered in an administration that will generally produce effective results without causing any damage or damaging side effects. The oral dose tablet formulation of this invention can also be used to make oral dose tablets containing rapamycin derivatives, including, but not limited to rapamycin esters, carbamates, sulfates, ethers, oximes, carbonates, the like, which also they are described in the patent literature. The following provides the preparation and evaluation of representative examples of solid dose tablets of rapamycin.

EXAMPLE 1 The following shows the preparation and evaluation of an oral dose tablet of rapamycin 3.0 mg containing a 100 mg sugar coating.

Formula Ingredients * Amount Rapamycin 3.06 mg Sucrose 97.41 mg Povidone 0.510 mg Microcrystalline cellulose 1.020 mg Water 54.92 mg * An average of 2% of these amounts are included to take manufacturing losses into account.

Manufacturing Addresses1 The water is heated to about 65-70 ° C and the sucrose is added and mixed well until dissolved. The solution is cooled to approximately 30-40 ° C. Povidone is added and mixed vigorously until it dissolves. The crushed or micronized rapamycin is added to the mixture and mixed well to uniformly disperse rapamycin. The microcrystalline cellulose is added, and the mixture is stirred to provide a uniform suspension. The resulting solution is spray coated into a pharmaceutically inert core portion by portion and air dried between the portions.

Evaluation Six cynomologo monkeys, listed below as A-C, are administered the above formulation in a dose of 3 mg rapamycin per monkey and the following concentrations of rapamycin serum are determined at the indicated time after dosing.

The results obtained demonstrate that serum rapamycin concentrations are observed after administration of a representative oral dose tablet of this invention.

EXAMPLE 2 An oral dose tablet of rapamycin 0.5 mg containing a sugar coating of 100 mg is prepared according to the procedure described in Example 1. The following list lists the amounts of ingredients used.

Formula Ingredients * Amount Rapamycin 0.510 mg Sucrose 99.96 mg Povidone 0.510 mg Microcrystalline cellulose 1.020 mg Water 54.92 mg * An average of 2% of these amounts is included to take manufacturing losses into account.

EXAMPLE 3 An oral dose tablet of rapamycin 1.0 mg containing a 100 mg sugar coating according to the procedure described in Example 1 is prepared. The following lists the amounts of ingredients used.

Formula: Ingredients * Amount Rapamycin 1.02 mg Sucrose 99.45 mg Povidone 0.510 mg Microcrystalline cellulose 1.020 mg Water 54.92 mg * An average of 2% of these amounts are included to take manufacturing losses into account.

EXAMPLE 4 An oral dose tablet of rapamycin 5.0 mg containing a 100 mg sugar coating according to the procedure described in Example 1 is prepared. The following list lists the amounts of ingredients used.

Formula: Ingredients * Amount Rapamycin 5.10 mg Sucrose 95.37 mg Povidone 0.510 mg Microcrystalline cellulose 1.020 mg Water 54.92 mg * An average of 2% of these amounts are included to take manufacturing losses into account.

EXAMPLE 5 An oral dose tablet of rapamycin of 7.5 mg containing a sugar coating of 100 mg is prepared according to the procedure described in Example 1. The following lists the amounts of ingredients used.

Formula Ingredients * Amount Rapamycin 7.65 g Sucrose 92.82 mg Povidone 0.510 mg Microcrystalline cellulose 1.020 mg Water 54.92 mg * An average of 2% of these amounts is included to take manufacturing losses into account.

EXAMPLE 6 An oral dose tablet of rapamycin 10 mg containing a sugar coating of 100 mg is prepared according to the procedure described in Example 1. The following lists the amounts of ingredients used.

Formula Ingredients * Amount Rapamycin 10.2 mg Sucrose 90.27 mg Povidone 0.510 mg CCeelluulloossaa micimicrocrrizissttaalliinnaa 1,020 mg Water 54.92 mg * An average of 2% of these amounts is included to take manufacturing losses into account.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A solid dose unit of rapamycin characterized in that it comprises a core and a sugar coating, the sugar coating comprises: (a) rapamycin, (b) one or more sugars, and (c) one or more binders.

2. The dose unit according to claim 1, characterized in that the average particle size of rapamycin is 0.5-400 microns.

3. A solid dose unit of rapamycin characterized in that it comprises a core and a sugar coating, the sugar coating comprises: a) rapamycin in an amount of "about 0.05-20 mg b) sucrose in a range of about 50-99 % by weight of the sugar coating, and c) one or more binder in a range of about 0.1-10% by weight of the sugar coating.

4. A solid dose unit of rapamycin characterized in that it comprises a core and a sugar coating; the coating comprises: a) rapamycin in an amount of about 0.05 - 20 mg b) sucrose in a range of about 50 - 99% by weight of the final coating c) povidone in a range of about 0.2 - 1.0% by weight of the final coating , and d) microcrystalline cellulose in a range of about 0.1 - 3.0% by weight of the final coating.

5. The dose unit according to claim 4, characterized in that the povidone is contained as approximately 0.5% by weight of the sugar coating.

6. The dose unit according to claim 5, characterized in that the microcrystalline cellulose is contained as about 1% by weight of the sugar coating.

7. The dosage unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 0.5 mg, (b) the sucrose is contained in a range of about 95-99% by weight of the sugar coating (c) the povidone is contained in approximately 0.5% by weight of the sugar coating, and (d) the microcrystalline cellulose is contained as approximately 1% by weight of the sugar coating.

8. The dosage unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 1 mg, (b) the sucrose is contained in a range of about 94-99% by weight of the sugar coating (c) the povidone is contained as approximately 0.5% by weight of the sugar coating, and (d) the microcrystalline cellulose is contained as approximately 1% by weight of the sugar coating.

9. The dosage unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 5 mg, (b) the sucrose is contained in a range of about 0.55- by weight of the sugar coating, (c) the povidone is contained as approximately 0.5% by weight of the sugar coating, and (d) the microcrystalline cellulose is contained as approximately 1% by weight of the sugar coating.

10. The dose unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 5 mg, (b) the sucrose is contained in a range of about 85-98% by weight of the sugar coating (c) the povidone is contained as approximately 0.5% by weight of the sugar coating, and (d) the cellulose at microcrystalline talin is contained as approximately 1% by weight of the sugar coating.

11. The dosage unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 7.5 mg, (b) the sucrose is contained in a range of about 80-97% by weight of the sugar coating (c) the povidone is contained as approximately 0.5% by weight of the sugar coating, and (d) the microcrystalline cellulose is contained as approximately 1% by weight of the sugar coating.

12. The dosage unit according to claim 4, characterized in that (a) the rapamycin is contained in an amount of about 10 mg, (b) the sucrose is contained in a range of about 75-96% by weight of the sugar coating (c) the povidone is contained as approximately 0.5% by weight of the sugar coating, and (d) the microcrystalline cellulose is contained as approximately 156 by weight of the sugar coating.

13. A process for preparing an oral dose tablet of rapamycin according to claim 1, characterized in that it comprises spraying a core with a suspension of rapamycin in an aqueous solution comprising one or more sugars and one or more binders and drying until the amount Desired rapamycin has been sprayed into the nucleus.

14. A process for preparing an oral dose tablet of rapamycin, characterized in that it comprises preparing a sugar coating by employing the following steps: (a) grinding or micronizing rapamycin to provide rapamycin having an average particle size of 0.5-400 microns, (b) add one or more sugars to a sufficient amount of water to dissolve the sugars, the water is at a temperature of 65-70 ° C, (c) cool the solution to 30-40 ° C, (d) add a first binder, and mix until dissolved, (e) add the ground rapamycin to the aqueous solution and mix until uniformly dispersed, (f) optionally add one or more additional binder and stir to provide a uniform suspension, spray the coating in a core and dry until the desired amount of rapamycin has been sprayed into the nucleus.

15. "The process according to claim 13 or claim 14, characterized in that the povidone is a first binder and the microcrystalline cellulose is used in the sugar coating as a second binder.

16. The process according to any of claims 13 to 15, characterized in that the sugar is sucrose.

17. The process according to claim 16, characterized in that the amount of sucrose is about 50-99% by weight of the dried coating.

18. The process according to any of claims 13 to 17, characterized in that the amount of povidone used as a binder is an amount of about 0.2-1% by weight of the dried coating.

19. The process according to claim 18, characterized in that the microcrystalline cellulose is used as a binder in an amount of 0.1-3% of the dry coating.