HK1016081B - Pharmaceutical compositions - Google Patents

Description

Pharmaceutical composition

The present invention relates to oral pharmaceutical compositions comprising a macrolide that is a rapamycin or a solid dispersion of ascomycin.

Rapamycin is an immunosuppressive lactam macrolide that can be produced, such as a hygroscopic streptomyces bacterium. The structure of rapamycin is given in Kesseler, H et al; 1993; helm.chim.acta; 76: 117. rapamycin is a very potent immunosuppressant and also has anticancer and fungicidal activity. Its use as a drug is limited by its low and variable availability of heavies. Furthermore, rapamycin has a low solubility in aqueous solvents, such as water, making it difficult to formulate stable pharmaceutical compositions. A large number of rapamycin derivatives are known. Some 16-O-substituted rapamycin are disclosed in the world intellectual Property organization (WO)94/02136, the contents of which are incorporated herein by reference. 40-O-substituted rapamycin is described in, for example, U.S. Pat. No. 5258389 and WO94/09010 (O-aryl and O-alkyl rapamycin); WO92/05179 (carboxylic acid esters), U.S. Pat. No. 5118677 (amide esters), U.S. Pat. No. 5118678 (carbamate esters), U.S. Pat. No. 5100883 (fluorinated esters), U.S. Pat. No. 5151413 (acetals), U.S. Pat. No. 5120842 (silyl ethers), WO93/11130 (methylene rapamycin and derivatives), WO94/02136 (methoxy derivatives), WO94/02385 and WO95/14023 (alkenyl derivatives), all of which are incorporated herein by reference. 32-O-dihydro or substituted rapamycin is described in U.S. Pat. No. 5256790, which is incorporated herein by reference.

Further rapamycin derivatives are described in Patent Cooperation Treaty (PCT) application No. EP96/02441, such as 32-deoxyrapamycin is described in example 1 and 16-pent-2 alkynyloxy-32 (S) -dihydrorapamycin is described in examples 2 and 3. The contents of PCT application number EP96/02441 are incorporated herein by reference.

Rapamycin and its structurally related analogs and derivatives are hereinafter collectively referred to as "rapamycin".

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

Solid rapamycin orally administered to humans cannot be absorbed in significant amounts in the blood. Mixtures of simple rapamycin with conventional pharmaceutical excipients are known; however, such compositions are disadvantageous in that they have unpredictable dissolution rates, irregular bioavailability and are unstable. There is currently no solid-state formulation of rapamycin or a derivative thereof that is convenient for oral administration.

Accordingly, in one aspect of the present invention, there is provided a pharmaceutical composition comprising a solid dispersion of rapamycin and a carrier medium.

The composition of the present invention provides a medicament which is convenient to administer and stable and has high bioavailability.

Rapamycin for use in the compositions of the present invention may be any rapamycin and derivatives thereof, as disclosed above or as described in the above-mentioned patent applications.

Rapamycin for use in the solid dispersion compositions of the present invention may be rapamycin OR an O-substituted derivative wherein the hydroxyl group of the cyclohexane ring of rapamycin is replaced by an-OR group₁Is substituted in which R₁Are hydroxyalkyl, hydroxyalkoxyalkyl, amidoalkyl and aminoalkyl; 40-O- (2-hydroxy) ethyl-rapamycin, 40-O- (3-hydroxy) propyl-rapamycin, 40-O [2- (2-hydroxy) ethyloxy as described in WO94/09010]Ethyl-rapamycin and 40-O- (2-acetamidoethyl) -rapamycin. Rapamycin derivatives may be 26-or 28-substituted derivatives.

Preferred rapamycin for use in the solid dispersion compositions of the present invention include rapamycin, 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxyrapamycin and 16-pent-2-alkynyloxy-32 (S) -dihydrorapamycin. A more preferred rapamycin is 40-O- (2-hydroxy) ethyl rapamycin (hereinafter referred to as compound X).

The numbering of rapamycin derivatives used in the present invention refers to the structures disclosed in formula A at page 4 of PCT application WO96/13273, the contents of which are incorporated herein by reference.

The term solid dispersion as used herein denotes a co-precipitate with a rapamycin, such as 40-O- (2-hydroxy) ethyl rapamycin or a rapamycin and a carrier medium. In solid dispersions, rapamycin is amorphous or substantially amorphous and is physically associated with the carrier medium.

The compositions of the invention can be administered in any convenient form, such as tablets, capsules, granules or powders in sachets.

Rapamycin is present in the composition in an amount of from about 0.01 to about 30% by weight based on the weight of the composition (% w/w), preferably from 1 to 20% w/w based on the total weight of the composition.

The amount of carrier medium may be up to 99.99% by weight, such as from 10 to 95% by weight based on the total weight of the composition.

In one embodiment, the carrier medium comprises a water soluble polymer, preferably a cellulose derivative such as Hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, or polyvinylpyrrolidone (PVP). Good results can be obtained with HPMC of low performance dynamic viscosity, e.g. less than 100cps in 2% by weight aqueous solution at 20 deg.C, e.g. less than 50cps, preferably less than 20cps, e.g. HPMC 3 cps. HPMC is well known and published in the handbook of pharmaceutical excipients, second edition, the British society of medicine and the American society of pharmaceuticals, 1994, pages 229 to 232, the contents of which are incorporated herein by reference. HPMC, including HPMC 3cps, is available under the trade name Pharmacoat603 from the Shinetsu plant.

PVP, trade name Povidone, is commercially available (handbook of pharmaceutical excipients), preferably a PVP having an average molecular weight of about 8000 to about 50,000 daltons.

In another embodiment the carrier medium comprises

-hydroxypropyl cellulose (HPC) or derivatives thereof. Examples of HPC derivatives include aqueous media such as water, and 2% aqueous solutions below about 400cps, such as below 150cps, at 25 ℃. Preferred HPC derivatives have a low degree of substitution and an average molecular weight of less than 200,000 daltons, such as between 50,000 and 150,000 daltons. Commercially available HPCs are available from Aqualon Inc. under the name Klucel LF, Klucel EF and Klucel JF; nisso HPC-L from Nissan soda;

-a polyethylene glycol (PEG). Examples are average molecular weights between 1000 and 9000 daltons, such as between about 1800 and 7000, such as PEG2000, PEG4000 or PEG6000 (handbook of pharmaceutical excipients);

a saturated polyglycolysed glyceride, commercially available, for example, from the company Gattefoss, under the trade name Gecir, such as Gelucir44/14, 53/10, 50/13, 42/12 or 35/10;

a cyclodextrin, such as beta-cyclodextrin or alpha-cyclodextrin. Suitable beta-cyclodextrins are methyl-beta-cyclodextrin; dimethyl-beta-cyclodextrin; hydroxypropyl-beta-cyclodextrin; glucosyl-beta-cyclodextrin; maltose-beta-cyclodextrin; sulfo-beta-cyclodextrin; sulfo-alkyl ethers of beta-cyclodextrins, e.g. sulfo-C_1-4-alkyl ethers. The alpha-cyclodextrin includes glucosyl-alpha-cyclodextrin and maltose-alpha-cyclodextrin.

The carrier medium may also contain a water-soluble or water-insoluble sucrose or other acceptable carrier or filler such as lactose, or microcrystalline cellulose. Fillers, if any, are generally present in an amount of up to about 30% by weight, such as from 0.5 to 20% by weight, preferably from about 5 to about 15% by weight of the composition. Commercial microcrystalline cellulose Avicel is available from the market, e.g. from FMC corporation.

The carrier medium may also comprise one or more surfactants, such as nonionic, ionic, anionic or amphoteric surfactants. Suitable surfactants are:

polyoxyethylene-polyoxypropylene copolymers and block copolymers, known under the trade name Pluronic or Poloxamer, which is "Lexikon derHilfsstuffe fur Pharmazie, Kosmetik und grenze Gebiete", EditioCantor, D-7960Aulendorf, third revised and expanded edition (1989) in Fiedler, H.P., the contents of which are incorporated herein by reference. One preferred polyoxyethylene-polyoxypropylene block polymer is Poloxamer188, available from BASF corporation;

ethoxylated cholesterol, known by the trade name Solulan, such as Solulan C24 from Amerchol;

vitamin derivatives such as vitamin E derivatives, Tocopherol Polyethylene Glycol Succinate (TPGS) from Eastman;

-sodium lauryl sulfate or sodium lauryl sulfate;

-a bile acid or a salt thereof, such as cholic acid, glycolic acid or a salt, such as sodium cholate; or

Lecithin.

If present in the compositions of the present invention, the amount of surfactant is generally less than about 20%, such as 1 to 15% by weight.

The compositions of the present invention may comprise one or more disintegrants. Examples of disintegrants are the commercial products Polyplasdone (handbook of pharmaceutical excipients) from ISP company; sodium starch glycolate available from Generichem corporation; cross-linked sodium carboxymethyl cellulose available under the trade name Ac-di-sol from FMC. The compositions of the present invention may also include one or more lubricants such as magnesium stearate or colloidal silicon dioxide in an amount of up to about 5% by weight, such as 0.5 to 2% by weight, based on the weight of the composition.

It may be advantageous for the composition of the invention to comprise one or more fragrances.

The present applicant has obtained good results with surfactant-free rapamycin compositions. In another aspect, the present invention provides a solid dispersion of a surfactant-free rapamycin as described herein.

The compositions of the invention may contain antioxidants and/or stabilizers in amounts up to about 1% by weight, such as between 0.05 and 0.5% by weight. Examples of anti-nitrogen agents are butylated hydroxytoluene, DL-alpha-tocopherol, propyl gallate. Vitamin C ester of healtic acid and fumaric acid. Malonic acid is a suitable stabilizer.

In one embodiment of the invention, the composition comprises up to 30 wt%; such as 1 to 20% by weight, 40-O- (2-hydroxy) ethyl rapamycin, and up to 95%, such as 30 to 90% by weight, HPMC.

The weight ratio of rapamycin to carrier medium in the compositions of the invention is generally not more than 1: 3, preferably less than 1: 4.

In another aspect of the present invention, there is provided a method of preparing the solid dispersion composition described herein.

In one embodiment, the compositions of the present invention may be obtained by dissolving or suspending rapamycin and a carrier medium in a solvent or solvent mixture. The solvent may be a single solvent or a mixture of solvents, and the order in which the rapamycin and carrier medium are dissolved and suspended in the solvent may vary. Suitable solvents for preparing the solid dispersion compositions of the present invention may be organic solvents, such as an alcohol, e.g., methanol, ethanol or isopropanol; an ester, such as ethyl acetate; an ether, such as diethyl ether; a ketone, such as acetone; or a halogenated hydrocarbon such as dichloroethane. A convenient solvent mixture is an ethanol/acetone mixture having a weight ratio of ethanol to acetone of from about 1: 10 to about 10: 1, such as from 1: 5 to 5: 1.

The rapamycin and carrier medium are typically present in the solvent in a weight ratio of 1: 0.1 to 1: 20. The solvent can be evaporated and the rapamycin can be co-precipitated with the carrier medium. The residue obtained can be dried, for example under reduced pressure, filtered and triturated. The milled dispersion may be mixed with other excipients, for example, compressed into tablets, or enclosed in sachets or capsules.

In another embodiment, the carrier medium may be thawed, mixed with rapamycin, stirred, and the solid dispersion composition may optionally be prepared with a solvent or solvent mixture.

The solid dispersions of the present invention may also be prepared using spray drying techniques, such as those described by Lachmann et al in the theory and practice of industrial pharmacy, 1986. The suspension obtained as described above is dispersed through nozzles into a chamber maintained at, for example, 20 to 80 ℃. The solvent evaporates while passing through the nozzle, and the dispersed fine particles are collected.

The compositions of the invention have an average particle size, after grinding, of less than 0.5mm, such as less than about 350 μm, for example from about 100 to about 300 μm.

The oral compositions of the present invention are effective against known indications of rapamycin, such as the following afflictions:

a) treatment and prevention of rejection of organ or tissue allografts, such as treatment of recipients of heart, lung, heart-lung, combination, liver, kidney, pancreas, skin or cornea transplants. They are also suitable for preventing graft-versus-host disease, such as after bone marrow transplantation.

b) Can be used for treating and preventing autoimmune diseases and inflammation, especially inflammatory diseases with autoimmune partial etiology, such as arthritis (such as rheumatic arthritis, chronic arthritis, and arthritis deformity) and rheumatism. Specific autoimmune diseases to which the compounds of the invention may be applied include autoimmune haematological disorders (including, for example, haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, sjogren's syndrome, and sprue. Autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and crohn's disease), endocrine ophthalmopathy, graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes type I), uveitis (both pre and post), keratoconjunctivitis sicca and vernal keratoconjunctivitis sicca, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathies), and juvenile dermatomyositis.

c) Can be used for the treatment and prevention of asthma.

d) Treating multidrug resistance (MDR). MDR is particularly problematic for cancer patients and aids patients because they do not respond to conventional chemotherapy and Pgp delivers drugs outside the cell. The compositions of the present invention may be used to enhance the use of other chemical agents in the treatment and management of multi-drug resistant diseases such as multi-drug resistant cancer or multi-drug resistant AIDS.

e) Treating proliferative diseases, such as tumor and dermatosis.

f) Treating fungal infection.

g) Treatment and prevention of inflammation, in particular enabling steroids to potentiate their action.

h) Treatment and prevention of infections, in particular infections with pathogens having a Mip or Mip-like factor.

i) Treatment of overdoses of FK-506 and other conjugated immunosuppressants.

The pharmaceutical composition of the present invention may be prepared in unit dosage forms such as tablets, capsules, granules, powders, each containing 1mg to 100mg of the drug, more preferably, 10 to 50 mg; such as 15, 20, 25 or 50 mg. Such dosage forms are suitably administered from 1 to 5 times per day, depending on the particular purpose of the therapy, the period of treatment, etc.

The exact amount of composition to be administered will depend on several factors, such as the desired duration of treatment and the release rate of rapamycin.

The efficacy of the combination can be observed by standard clinical trials, e.g. knowing the amount of active agent given the blood content of the corresponding active agent; for example, dosages between 1mg and 1000mg are used, such as 75kg adult and standard animals simulating dosages of 5mg to 100mg per day. The improved bioavailability of the drug substance by the present compositions can be observed in standard animal tests and clinical trials.

The dosage form used, e.g. tablet form, may be covered with a coating. Suitable coatings include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; a polymethacrylic acid copolymer, such as Eudragit l.s; or hydroxypropyl methylcellulose succinate.

Rapamycin, such as 40-O- (2-hydroxy) ethyl rapamycin or rapamycin, used in the compositions of the present invention may be crystalline or amorphous prior to being formed into a solid dispersion. One advantage of the present invention is that rapamycin need not be crystalline. Rapamycin can be used directly with a solvent without prior isolation. Another advantage of the present invention is that solid dispersions dissolve at a rate greater than crystalline or amorphous rapamycin in a simple mixture.

In another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of an ascomycin and a carrier medium.

Among the ascomycins suitable for use in the solid dispersion compositions of the present invention are ascomycins or derivatives thereof, such as 33-epichloro-33-desoxyascomycin.

There is currently no solid formulation of 33-epichloro-33-desoxy-ascomycin that is convenient for oral administration. Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a solid dispersion of 33-epichloro-33-desoxy-ascomycin and a carrier medium.

In example 66a of European application EP427680, the compound 33-epichloro-33-deoxy-ascomycin is described.

33-Epichloro-33-deoxy-ascomycin will be referred to as compound Y.

The composition of the ascomycin of the invention, such as compound Y, has high bioavailability of the drug, is convenient to take and is stable.

The amount of ascomycin, e.g. compound Y, in the composition is from about 0.01 to about 30% w/w, preferably from 1 to 20% w/w.

The carrier medium may contain any of the components already mentioned above in amounts of% by weight as described above. Suitable water-soluble polymeric cyclodextrins, and other excipients such as surfactants, may be employed in the compositions of 33-epichloro-33-desoxy-ascomycin of the present invention.

In a preferred aspect, the present invention provides a composition as described herein comprising a surfactant and a solid dispersion of a ascomycin such as compound Y.

The ratio of ascomycin to carrier medium is generally not more than 1: 3, preferably less than 1: 4.

The solid dispersions of ascomycin, for example of compound Y, can be prepared in the same manner as already described.

The oral composition of compound Y disclosed in the present invention is useful for the treatment of cutaneous manifestations of immune-mediated dermatitis and skin hyperproliferation. More particularly, the compositions of the present invention are useful as anti-inflammatory and immune control agents and as anti-skin proliferation agents, for the prevention and treatment of inflammation and conditions requiring immunosuppression, such as

a) Prevention and treatment of

Rejection of organ or tissue transplants, such as heart, kidney, liver, bone marrow and skin,

graft-versus-body disease, such as after bone marrow transplantation,

autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashinoto's thyroid disease, multiple sclerosis, myasthenia gravis, type I diabetes and uveitis,

-cutaneous symptoms of immune mediated diseases;

b) preventing and treating hyperproliferative skin diseases, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermic bullous, urticaria, angioneurotic edema, vasculitis, erythema, cutaneous eosinophilia, erythematous wolfiscus and acne and

c) alopecia areata.

When the pharmaceutical composition of the invention is in a unit dose, such as tablet, capsule or powder, each unit dose may comprise from 1mg to 100mg of drug, more preferably between 10 and 50 mg; for example 15, 20, 25 or 50 mg. Such dosage forms are suitable for administration 1 to 5 times per day, depending on the particular purpose of the therapy, the stage of treatment, etc.

In one embodiment of the invention, the composition comprises 30% by weight of compound Y and 70% by weight of HPMC, e.g. for the treatment of psoriasis, atopic dermatitis or contact dermatitis in an amount of 10 to 50mg per day.

The exact amount of composition to be administered will depend on several factors, such as the desired treatment time and the release rate of compound Y.

The efficacy of the composition containing compound Y can be observed by standard clinical trials, given the corresponding blood active dose as the known active dose; such as 75kg of active agent per day in an amount of 1mg to 1000mg per day for adults and standard animal models. The improved bioavailability of the drug of the compositions of the present invention is observed in standard animal tests and clinical trials.

The following examples are only illustrative of the solid dispersion combinations of the present invention.

Example 1

A solid dispersion composition was prepared containing the following components (parts by weight):

compound X9.1

HPMC3 cps 81.8

Lactose 200 mesh 9.1

Rapamycin and a carrier medium are dissolved in an ethanol/acetone mixture to form a composition (form a). The solvent used was evaporated off in a weight ratio of 1: 1 anhydrous ethanol and acetone, and the resulting dried residue was ground to a fine powder with an average particle size of < 0.5 mm.

Example 2

A solid dispersion composition was prepared containing the following components (parts by weight):

compound X16.7

HPMC 3cps 66.7

Poloxamer188 (ex BASF) 16.7

Composition type (B) was prepared in a similar manner to the examples.

Example 3

A solid dispersion was prepared containing the following components (parts by weight):

compound X16.7

HPMC 3cps 66.7

TPGS* 16.7

Composition (form C) was prepared in a similar manner as in example 1.

Tocopheryl polyethylene glycol succinate

Example 4

A solid dispersion composition was prepared containing the following components (parts by weight):

compound X10

HPMC 3cps 80

Solulan C24 (from Amerchol) 10

Composition (form D) was prepared in a similar manner as in example 1.

The above A-D form of the composition can be made into tablet, capsule, or powder and filled into sachet.

Pharmacokinetics in rats after administration of 40-O- (2-hydroxy) ethyl rapamycin

a) Medicine taking

0.5ml of an aqueous dispersion of the composition containing compound X (corresponding to 4.0mg of active ingredient per mouse) was administered by gastric intubation during brief inhalation anaesthesia using a 1ml injection tube connected to a polyethylene tube. Six animals were used for each composition of forms A, B, C and D.

b) Blood sampling sample

One permanent cannula was inserted into the jugular vein of the animal the day before the experiment. 0.5ml of venous blood (jugular vein) was collected from each mouse and stored in 2.5ml EDTA tubes. Blood samples (1 and 2, 2 and 4, 5 and 6) from both animals were pooled and stored at-80 ℃ until drug analysis. Blood samples were taken before dosing, 10 min, 30 min, 60 min, 120 min, 300 min, 480 min and 1440 min after dosing.

c) Biological analysis

Blood samples were analyzed by reverse phase high pressure liquid chromatography.

Table 1 gives the pharmacokinetic numbers collected after compound X administration in rats.

TABLE 1

Brief introduction to the summary (average of 2-3 pooled samples)

Blood concentration
					Time (h)	Type A	Type B	C type	D type
0	7	7	7	7
					0.17	118	117	85	68
0.5	422	131	125	74
					1	375	129	96	66
2	277	82	89	54
					5	573	92	58	39
8	496	66	45	34
					24	93	30	34	30
CMaximum of(ng/ml)	573	135	131	81
					TMaximum of(hr)	5.00	0.50	0.50	0.50
AUC0-8h[(ng/ml).h]	3502	720	565	376
					AUC0-24h[(ng/ml).h]	8213	1487	1192	886

Type A causes blood levels to be higher than those obtained by administration of surfactant-containing compositions.

Study in dogs

Following the promising results above, a relative bioavailability study was conducted on tethered swine-free dogs at a dose of 1mg/kg body weight. Each hard capsule containing compound X10mg was administered to 8 dogs using a 4-way latin square design; after 6 hours of administration, the dogs were fed and the amount of compound X in the blood was measured over 48 hours. All dogs were observed to have the same blood concentration profile for compound X, with a limit half-drain in the blood of compound X within 10 to 40 hours. A medium peak level of 140ng/ml was observed, with a medium AUC level of about 1600ng.h/ml in 0-48 hours.

Example 5

A solid dispersion composition was prepared containing the following components (parts by weight):

compound Y20

HPMC 3cps 80

The composition (form E) was prepared by dissolving Compound Y and the carrier medium in an ethanol/acetone mixture. The solvent was evaporated and the resulting dried residue was triturated.

Example 6

A solid dispersion composition was prepared containing the following components (parts by weight):

compound Y20

HPMC 3cps 70

Poloxamer188 10

The composition (form F) was prepared in the same manner as in example 5.

Example 7

A solid dispersion compound was prepared containing the following components (parts by weight):

compound Y20

HPMC 3cps 75

Sodium lauryl sulfate 5

Composition (form G) was prepared in the same manner as in example 5.

The above compositions of forms E to G can be made into tablet, capsule or powder and filled into sachet.

Pharmacokinetics of 33-epi-chloro-33-dechlorinated-ascomycin in rats

a) Medicine taking

An aqueous dispersion of 0.5mi pharmaceutical composition (equivalent to 4.0mg active ingredient/mouse) was administered by gastric intubation while briefly anaesthetised by inhalation using a 1ml syringe attached to a polyethylene tube. Six animals were used for types E, F and G of each composition.

b) Blood sampling sample

One permanent cannula was inserted into the jugular vein of the animal the day before the experiment. 0.5ml of venous blood (jugular vein) was collected from each mouse and stored in 2.5ml EDTA tubes. Blood samples (1 and 2, 3 and 4, 5 and 6) from both animals were pooled and stored at-80 ℃ until drug analysis. Blood samples were taken before dosing, 10 min, 30 min, 60 min, 120 min, 300 min, 480 min and 1440 min after dosing.

c) Biological analysis

Blood samples were analyzed by reverse phase high pressure liquid chromatography.

The results are plotted in figures 1 and 2, wherein ng/ml (ordinate axis) is plotted against time (hours) (abscissa axis). Figure 1 shows that the level of form F in the blood is significantly higher than the level of form E or form G after administration. Figure 2 shows that form F is high in blood when taken with food.

Compound Y was amorphous as determined by X-ray diffraction at the time of formation of compositions E, F and G and after 6 months of storage.

Forms E, F and G were tested for their relative rates of dissolution. In an aqueous solution of 0.2 wt% sodium lauryl sulfate with stirring at 37 deg.C, it was found that, after 30 minutes, more than 80% of compound Y was released and dissolved in each polishing composition containing 10mg of compound Y. 92% of compound Y is liberated from form E. For comparison, about 5% was released after 30 minutes from an equal amount of crystalline compound Y.

Claims (10)

1. An oral pharmaceutical composition in the form of a solid dispersion comprising rapamycin and a carrier medium.

2. A composition according to claim 1 wherein the carrier medium comprises a water-soluble polymer or a cyclodextrin.

3. A pharmaceutical composition according to claim 1 or 2, wherein the rapamycin is selected from 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxyrapamycin or 16-pent-2 alkynyloxy-32 (S) -dihydrorapamycin.

4. A composition according to claim 3 wherein the polymer is hydroxypropylmethylcellulose or polyvinylpyrrolidone.

5. A composition according to any preceding claim which comprises up to 30% by weight rapamycin.

6. A composition according to any one of claims 2, 3 or 4 wherein the water soluble polymer is hydroxypropylmethylcellulose and is present in an amount of up to about 95% by weight.

7. A composition according to any one of claims 2 to 6 wherein the ratio of rapamycin to polymer is less than 1: 4.

8. A composition according to any one of the preceding claims which is free of surfactant.

9. An oral pharmaceutical composition in the form of a solid dispersion comprising 33-epichloro-33-desoxy-ascomycin and a carrier medium comprising a water-soluble polymer or a cyclodextrin.

10. The composition of claim 9, further comprising a surfactant.