United States Patent:  5,985,325

Assignee:  American Home Products Corporation (Madison, NJ)

Filed:  May 29, 1998

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 OF THE INVENTION

Methods of drug delivery are designed to deliver an acceptable dosage of the medication to the patient. In the case of oral formulations, it is highly desirable to provide a dosage form which meets this criteria and which can be effectively administered, preferably self-administered, in either clinical or non-clinical situations.

The present invention concerns formulations useful in the oral administration of rapamycin. Rapamycin has been shown to possess immunosuppressive, antirejection, antifungal and antiinflammatory activity in vivo and to inhibit thymocyte proliferation in vitro. Therefore, these formulations are useful in the treatment or inhibition of transplantation rejection such as kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea, small bowel, and skin allografts, and heart valve xenografts; in the treatment or inhibition of graft vs. host disease; in the treatment or inhibition of autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and diseases of inflammation 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.

Rapamycin has also been shown to have antitumor, antifungal, and antiproliferative activities. The formulations of this invention therefore also useful in treating solid tumors, including sarcomas and carcinomas, such as astrocytomas, prostate cancer, breast cancer, small cell lung cancer, and ovarian cancer; adult T-cell leukemia/lymphoma; fungal infections; and hyperproliferative vascular diseases such as restenosis and atherosclerosis.

The present invention, also provides formulations for use in inducing immunosuppression in a mammal in such need.

In general, the formulations of this invention provides an oral tablet dosage form of rapamycin comprising a core which is overcoated with rapamycin, and a sugar coat containing one or more sugars and one or more binders. It is preferred that such dosage tablets contain 0.05-20 mg rapamycin, with it being more preferred that such tablet will contain 0.5-10 mg rapamycin.

The sugar used in the production of the sugar overcoat described in this invention is a sugar product, such as sucrose, derived from beet or cane sources or starch, saccharide, or polysaccharide converted sources, which are considered suitable for preparing the sugar overcoat. When used in preparing the solid dosage form of this invention, it is preferred that the sugar is sucrose.

When binders are used in preparing the rapamycin oral dosage tablets, these can include gum acacia, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, methyacrylate, microcrystalline cellulose, noncrystalline cellulose, polyvinylpyrrolidone (povidone, PVP), cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, lactose, dextrose, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyvinyl alcohol, and sorbitan fatty acid esters.

The dosage tablets described herein provide rapamycin contained in a sugar overcoat that has been overcoated onto a core. The core can either be pharmaceutically inert or can contain a pharmaceutically active agent. As used in describing this invention the term "sugar overcoat" refers to the rapamycin, sugar, and binder which coat the core.

The following provides a preferred formulation for the sugar overcoat of a solid dosage tablet containing 0.05-20 mg rapamycin.

a) rapamycin in an amount from about 0.05-20 mg

b) sucrose in a range from about 50-99% weight of the sugar overcoat

c) one or more binders in a range from about 0.1-10% weight of the sugar overcoat

In the formulations described in this invention, the quantities of the ingredients specified as percentages will vary according to the weight of the sugar overcoat. The sugar overcoat described in this invention will typically weigh about 50-200 mg. Therefore in the above formulation, the quantity of sucrose would be about 25 mg (about 50% weight of the sugar overcoat) for a 50 mg sugar overcoat containing 20 mg rapamycin and 10% (5 mg) binders. Similarly, the percent weight of sucrose in the sugar overcoat can comprise greater than 99% of the sugar overcoat when a 200 mg sugar overcoat contains 0.05 mg rapamycin and 0.1% (0.2 mg) binders.

The following provides a more preferred formulation for the sugar overcoat of a solid dosage tablet containing 0.05-20 mg rapamycin, in which the sugar overcoat contains povidone and microcrystalline cellulose as binders.

a) rapamycin in an amount from about 0.05-20 mg

b) sucrose in a range from about 50-99% weight of the final overcoat

c) povidone in a range from about 0.2-1.0 % weight of the final overcoat

d) microcyrstalline cellulose in a range from about 0.1-3.0 % weight of the final overcoat

A rapamycin containing oral dosage tablet containing the above constituents can be prepared according to the following procedure. In preparing the above formulation, about 40-60 mg water is used in preparing a 100 mg sugar overcoat; the water is subsequently removed during processing. Briefly, rapamycin is either milled using conventional milling techniques, for example with a Fitz or ball mill, or is micronized using conventional micronizing techniques, for example with a Trost or jet mill. Milled rapamycin typically has a 10-400 micron particle size, and micronized rapamycin typically has a 0.5-10 micron particle size. The required quantity of water is heated to around 65-70.degree. C. and sucrose is added, and mixed well until the sucrose is dissolved. The solution is cooled to about 30-40.degree. C. Povidone is added and mixed vigorously until dissolved. Rapamycin is added to the mixture and mixed well to uniformly disperse the rapamycin, Microcrystaline cellulose is added, and the mixture stirred to provide a uniform suspension. Additional water is added if necessary and the suspension is continuously mixed during the coating process. The mixture is spray coated onto a core in small portions, and air dried in between portions, until the desired tablet strength is formed. During the manufacturing process, the majority of the water is removed, such that approximately less than 5% water remains in each tablet. Typically less than 2% residual water is present in each tablet. The rapamycin containing oral dosage tablets can be optionally coated with a color coat followed by a polish coat if desirable. The color coat typically contains a sugar such as sucrose, and a pigment such as titanium dioxide, and the polish coat contains carnuba wax, which can be applied as a dispersion in a solvent, such as mineral spirits.

When the core is a pharmaceutically inert core, it is typically a placebo core which may contain lactose, microcrystalline cellulose, PEG-6000, and other binders and fillers. The core, can be sealed with shellac to prevent disintegration from occurring during the overcoating process. A sucrose coat may also be placed on top of the shellac coat prior to the overcoating process.

The sugar overcoating described in this invention can be prepared to typically weigh about 50-200 mg. Using the process described herein, a 100 mg sugar overcoat containing 0.05-20 mg rapamycin would be made from the following ingredients according to the procedure described above:

a) rapamycin in an amount from about 0.05-20 mg

c) sucrose in an amount from about 50-99 mg

d) povidone in an the amount from about 0.2-1.0 mg

e) microcyrstalline cellulose in an amount from about 0.1-3.0 mg

f) water in an amount from 40-60 mg (mostly removed during processing)

It is contemplated that when the formulations of this invention are used as an immunosuppressive or antiinflammatory agent, they can be administered in conjunction with one or more other immunoregulatory agents. Such other antirejection 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 for inducing immunosuppression or treating inflammatory conditions, lesser amounts of each of the agents may be required to achieve the desired effect. The basis for such combination therapy was established by Stepkowski whose results showed that the use of a combination of rapamycin and cyclosporin A at subtherapeutic doses significantly prolonged heart allograft survival time. [Transplantation Proc. 23: 507 (1991)].

The dosage requirements may vary the severity of the symptoms presented and the particular subject being treated. Projected daily oral dosages of rapamycin would 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. More preferred projected daily doses are 2-5 mg when rapamycin is used in combination therapy, and 5-15 mg when rapamycin is used as monotherapy.

Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages will be determined by the administering physician based on experience with the individual subject treated. In general, the formulations of this invention are most desirably administered at a concentration that will generally afford effective results without causing any harmful or deleterious side effects.

Claim 1 of 9 Claims

1. A rapamycin solid dosage unit which comprises a tablet core and a sugar overcoat; said sugar overcoat comprises

a) rapamycin in an amount from about 0.05-20 mg

b) sucrose in a range from about 50-99% weight of the sugar overcoat

c) povidone in a range from about 0.2-1.0% weight of the sugar overcoat, and

d) microcrystalline cellulose in a range from about 0.1-3.0% weight of the sugar overcoat.

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