Pharmaceutic compositions

Description of the invention

The present invention relates to an oral pharmaceutical composition containing a solid dispersion in co-precipitated form which includes a macrolide antibiotic such as rapamycin or ascomycin, and a method of preparing the pharmaceutical composition.

Rapamycin is an immunosuppressive lactam macrolide antibiotic produced e.g. by Streptomyces hygroscopius. The structure of rapamycin is given in Kesseler. H. et. al, 1993, Helv. Chim. Acta, 76: 117. Rapamycin is an extremely potent immunosuppressant and has also been shown to have anti-tumor and anti-fungal activity. Its usefulness as a pharmaceutical, however, is limited by its low and variable bioavailability. Moreover, rapamycin is highly insoluble in aqueous media making it very difficult to form stable galenic compositions. A number of rapamycin derivatives are known. Certain 16-O substituted rapamycins are disclosed in WO 94/02136, which is incorporated herein by reference. Rapamycins substituted at the 40-O position are described e.g. in US 5,252,389 and WO 94/09010 (O-aryl and O-alkyl rapamycins), WO 92/05179 (carboxylic acid esters), US 5118,677 (amide esters), US 5,118,678 (carbamates), US 5 100,883 (fluorinated esters), US 5,151,413 (acetals), US 5,120,842 (silyl ethers), WO 93/11130 (methylene rapamycins and derivatives thereof), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives), all of which are incorporated herein by reference. 32-O-dihydrorapamycins or other 32-O substituted rapamycins are described, for example, in US 5,256,790 herein by reference.

Further rapamycin derivatives are described in the patent application PCT / EP96 / 02441, for example 32-deoxyrapamycin is described in example 1, and 16-pent-2-ynyloxy-32 (S) -dihydrorapamycin is described in examples 2 and 3. Content of the application Patent PCT / EP96 / 02441 is incorporated herein by reference.

Both rapamycin and its structurally similar analogs and derivatives are referred to herein by the common term "rapamycin".

Document EP 240 773 discloses a solid suspension composition containing the substance FR-900506 and a water-soluble polymer.

When administered orally to humans, solid rapamycin, e.g., rapamycin, may not be absorbed into the bloodstream to any great extent. Simple mixtures of rapamycin, e.g. rapamycin, with conventional pharmaceutical excipients are known; however, disadvantages of these compositions include unpredictable dissolution rates, irregular bioavailability profiles, and instability. To date, there is no way to formulate solid state formulations of rapamycin and its derivatives so that they can be conveniently administered.

The present invention relates to a pharmaceutical composition for oral administration containing a solid dispersion in a co-precipitated form.

The essence of the invention is that the solid dispersion comprises rapamycin or a rapamycin derivative and a carrier medium, said carrier medium containing a water-soluble polymer.

Preferably, the rapamycin derivative is selected from the group consisting of 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxyrapamycin and 16-pent-2-ynyloxy-32 (S) -dihydrorapamycin.

Preferably, the polymer is hydroxypropyl methylcellulose or polyvinylpyrrolidone.

Preferably, the composition comprises up to 30% by weight of rapamycin or a rapamycin derivative.

Preferably, the water-soluble polymer is hydroxypropyl methylcellulose with a content of up to about 95% by weight.

Preferably, the weight ratio of rapamycin derivative to polymer is less than 1: 4.

Preferably, the composition is surfactant free.

Preferably, the composition according to the present invention is in the form of a unit dose.

In another preferred embodiment, the composition is in the form of a tablet.

In a further preferred embodiment the composition is in the form of a capsule.

In yet another preferred embodiment the composition is in the form of a solid dispersion.

Preferably, the polymer is polyvinylpyrrolidone.

Preferably the composition additionally comprises water-soluble sucrose.

In another preferred embodiment, it additionally comprises microcrystalline cellulose

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In yet another embodiment, the composition further comprises a polyoxyethylene-polyoxypropylene block copolymer or copolymer.

The invention also relates to a process for the preparation of a pharmaceutical composition containing rapamycin or a rapamycin derivative and a carrier medium.

The essence of the invention is that a rapamycin or rapamycin derivative is suspended in a solvent, then one or more carrier components are combined with the solvent, and the suspension is spray dried to form a pharmaceutical composition.

Preferably, the pharmaceutical composition is then formulated into a unit dose form.

In another preferred embodiment, the pharmaceutical composition is then formulated into a tablet.

In yet another preferred embodiment, the pharmaceutical composition is then formed into a capsule.

In a further embodiment of the invention, the rapamycin or rapamycin derivative is formed as a dispersion co-precipitated by spray drying.

Preferably, an organic solvent or a mixture of organic solvents is used as the solvent.

Preferably, the components of the carrier include a polyoxyethylene-polyoxypropylene block copolymer or copolymer.

In another preferred embodiment, the components of the carrier include polyvinylpyrrolidone.

In yet another preferred embodiment, the components of the carrier include microcrystalline cellulose.

In a further preferred embodiment, the components of the carrier include water-soluble sucrose.

The invention also relates to a pharmaceutical composition for oral administration comprising the solid dispersion in co-precipitated form.

The essence of the invention is that the solid dispersion contains 33-epi-chloro-33-deoxyascomycin and a carrier medium, said carrier medium containing a water-soluble polymer.

Preferably, the water-soluble polymer composition comprises hydroxypropyl methylcellulose.

Preferably, the composition additionally comprises a surfactant.

Preferably, the composition comprises a polyoxyethylene-polyoxypropylene block copolymer as a surfactant.

The compositions of the invention provide the drug substance with high bioavailability, are convenient to administer and are stable.

The rapamycin used in the compositions of the invention may be any rapamycin or a derivative thereof, for example one of those disclosed above in the aforementioned patent applications.

Thus, the rapamycin used in the solid suspension compositions of the invention may be rapamycin or an O-substituted derivative thereof, in which the hydroxyl group of the rapamycin cyclohexyl ring is replaced with -OR1, in which R1 is a hydroxyalkyl radical, a hydroxyalkoxyalkyl radical, an acylaminoalkyl radical, or an acylaminoalkyl radical. an aminoalkyl radical; e.g. such as described in WO94 / 09010, e.g. 40-O- (2-hydroxy) ethyl rapamycin, 40-O- (3-hydroxy) propyl rapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethyl rapamycin and 40-O- (2-acetoaminoethyl) -rapamycin. The rapamycin derivative may be a substituted derivative at position 26 or also at position 28.

Rapamycins recommended for use in the solid dispersions of the invention include rapamycin, 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxyrapamycin, and 16-pent-2-ynyloxy-32 (S) -dihydrorapamycin. A particularly preferred rapamycin is 40-O- (2-hydroxy) ethyl rapamycin (hereinafter referred to as compound X).

The numbering of the rapamycin derivatives as used herein refers to the structure disclosed in Formula A on page 4 of WO 96/13273, the contents of which are incorporated herein by reference.

The term solid dispersion as used herein refers to a co-precipitate of rapamycin, e.g. 40-O- (2-hydroxy) ethyl rapamycin or else rapamycin with a carrier medium. In the solid dispersion, rapamycin is in an amorphous or largely amorphous form and is physically bound to the carrier medium.

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The compositions of the present invention may be administered in any convenient form, e.g.

in sachets.

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

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

The carrier medium comprises a water-soluble polymer, preferably a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate or else polyvinylpyrrolidone (PVP). Good results have been obtained with HPMC having a low apparent dynamic viscosity, e.g. below 100 mPaa measured at 20 ° C for a 2% by weight aqueous solution, e.g. below 50 mPa · s, preferably below 20 mPa · s, for example HPMC with a viscosity of 3 mPa · s. Hydroxypropylmethylcellulose (HPMC) is well known and is described, for example, in the Handbook of Pharmaceutical Excipients, Second Edition, Publisher: UK Pharmaceutical Society and American Pharmaceutical Society, 1994, pages 229 to 232, the content of which is contained in the minor description. by reference. HPMC, including HPMC 3 mPa.s are commercially available from Shinetsu under the tradename Pharmacoat 603.

PVP is commercially available under the trade name Povidon (Handbook of Pharmaceutical Excipients), PVP having an average molecular weight of from 8,000 to 50,000 is preferred.

In another embodiment, the carrier medium comprises the following components:

- hydroxypropyl cellulose (HPC) or derivatives thereof. Examples of HPC derivatives include those that have a low dynamic viscosity in aqueous media, e.g. water, e.g. less than approximately 400 mPa · s, e.g. less than 150 mPa · s measured at 25 ° for an aqueous solution with a concentration of 2 % by weight. Recommended HPCs have a low degree of substitution and have an average molecular weight of less than approximately 200,000, e.g. from 50,000 to 150,000. Examples of commercially available HPCs include products from Aqualon under the tradename Klucel LF, Klucel EF or Klucel JF, and products from Nippon Soda Ltd. under the tradename Nisso HPC-L;

- polyethylene glycol (PEG). Examples include polyethylene glycols which have an average molecular weight of between 1000 and 9000, e.g. between 1800 and 7000, for example PEG 2000, PEG 4000 or PEG 6000 (Handbook of PharmaceuticalExcipients);

a saturated polyglycolized glyceride available under the trade name Gelucir, e.g. Gelucir 44/14, 53/10, 50/13, 42/12 or 35/10 as a product from Gatlefosse; or

- cyclodextrin, e.g. b-cyclodextrin, a-cyclodextrin. Examples of suitable b-cyclodextrins include methyl-b-cyclodextrin; dimethyl-b-cyclodextrin; hydroxypropyl-b-cyclodextrin; glycosyl-b-cyclodextrin; maltosyl-b-cyclodextrin; sulfo-b-cyclodextrin; b-cyclodextrin sulfoalkylethers, e.g. sulfoC1-4 alkyl ethers. Examples of α-cyclodextrins include glucosyl-α-cyclodextrin and maltosyl-α-cyclodextrin.

The carrier medium may also contain sucrose, which is either water-soluble or insoluble, and other acceptable carriers or fillers, such as lactose or also microcrystalline cellulose. The filler, if present, is typically up to 30% by weight, e.g., 0.5 to 20% by weight, preferably from about 5 to about 15% by weight based on the total weight of the composition. Microcrystalline cellulose is commercially available, for example, as a product of FMC Corporation under the trade name Avicel.

The carrier medium may also contain one or more surfactants, for example, a nonionic surfactant, an ionic surfactant, an anionic surfactant, or an amphoteric surfactant. Examples of suitable surfactants include:

-polyoxyethylene and polyoxypropylene polymers and their block copolymers known, for example under the trade names Pluronic or Poloxamer, for example as described in: Fiedler, HP "Lexikon der Hilfsstoffe for Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, 0- 7960 Aulendorf, 3rd edition, revised and expanded (1989), the contents of which are hereby incorporated by reference. A preferred polyoxyethylene / polyoxypropylene block copolymer is from BASF under the trade name Poloxamer 188;

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

vitamin derivatives, for example vitamin E derivatives such as ethylene glycol tocopherol succinate (TPGS) commercially available from Eastman;

- sodium dodecyl sulfonate or sodium lauryl sulfonate;

bile acid or a salt thereof, e.g. cholic acid, glycolic acid or a salt thereof, e.g. sodium cholate; or - lecithin.

When surfactants are present in the compositions of the present invention, they are present in the compositions in an amount of up to about 20%, for example from 1 to 15% by weight.

One or more disintegrants may be added to the compositions of the present invention. Examples of disintegrants include Polyplasdon (Handbook of Pharmaceutical Excipients) commercially available from ISP, sodium starch glycolate commercially available from Generichem, and croscarmellose sodium commercially available from FMC Corporation under the trademark Ac-di-sol. A lubricant such as magnesium stearate or colloidal silica or more of such lubricants may also be added to the composition of the present invention in an amount of up to about 5% by weight, e.g., 0.5 to 2% by weight.

It may also be desirable to include one or more perfumes in the compositions of the present invention.

The authors of the present application have obtained good results using rapamycin compositions free of surfactants.

Antioxidants and / or stabilizers may also be added to the compositions of the present invention in amounts up to about 1% by weight, for example from 0.05 to 0.5% by weight. Examples of antioxidants include butylated hydroxytoluene, DL-α-tocopherol, propyl gallate, ascorbil palmitate, and fumaric acid. Malonic acid is in turn a suitable stabilizing agent.

In one embodiment of the present invention, the composition comprises up to 30% by weight, e.g. from 1 to 20% by weight of 40-O- (2-hydroxy) ethyl rapamycin, and up to 95%, e.g. from 30 to 90% by weight of HPMC.

Generally, in the compositions of the present invention, the weight ratio of rapamycin to carrier medium will not exceed 1: 3, preferably less than 1: 4.

In another of its aspects, the present invention provides a method of making a solid dispersion composition, as described in the description below.

In one embodiment, the compositions of the present invention can be prepared by reconstituting rapamycin and the carrier medium in a solvent or solvent system or suspending them in such a system. The solvent may be a single solvent or a solvent system, and the order in which the rapamycin and the carrier medium in the solvent are reconstituted or suspended in the solvent may also vary. Suitable solvents for use in preparing the solid dispersion compositions of the present invention may be organic solvents such as alcohols, e.g., methanol, ethanol, or isopropanol; esters, e.g. ethyl acetate; ethers, e.g. diethyl ether; ketones, e.g. acetone, or else halogenated hydrocarbons, e.g. dichloroethane. A convenient mixture of solvents is ethanol / acetone with a weight ratio of ethanol to acetone from about 1:10 to about 10: 1, for example, 5: 1.

Typically, rapamycin and the carrier medium are present in a weight ratio to the solvent of from 1: 0.1 to 1:20. The solvent can be evaporated and the rapamycin co-precipitated with the carrier medium. The resulting sludge may be dried, for example in vacuo, screened and ground. The ground dispersion can be combined with other excipients and then, for example, compressed to make tablets or filled into sachets or gelatin capsules.

In another embodiment, the solid dispersion compositions may be prepared by melting a carrier medium to form an alloy and then combining the carrier medium with rapamycin. e.g. by stirring, optionally in the presence of a solvent or solvent mixture as described herein.

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Alternatively, the solid dispersions of the present invention may be prepared using spray-drying techniques such as are described, for example, in the monograph: Theory and Practice of Industrial Pharmacy, Lachmann et al. 1986. A slurry formed as described above is dispersed by a nozzle into a chamber having a temperature of, for example, 20 to 80 ° C. As it passes through the nozzle, the solvent is evaporated and the finely dispersed particles are collected.

When milled, the compositions of the present invention typically have an average particle size of less than about 0.5 mm, such as less than 350 mm, such as from about 100 to about 300 mm.

The oral compositions of the present invention are useful in the known indications of rapamycin use, e.g.

a) Treatment and prevention of rejection of intraspecific or interspecific organ or tissue transplantation, e.g. in the treatment of heart, lung, heart to lung, liver, kidney, pancreas, skin or cornea transplant recipients. The indication is also the prevention of graft-versus-recipient diseases such as the consequence of bone marrow transplantation.

b) Treatment and prevention of autoallergic diseases and inflammations, in particular inflammations whose etiology includes an autoallergic component such as arthritis (e.g. rheumatic arthritis, chronic progressive arthritis or degenerative arthritis) or rheumatic diseases. Specifically, the autoallergic diseases against which the agents of the present invention can be used include haematological autoallergic diseases (including e.g. haemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, tissue sclerosis, Wegener's Hodgkin, dermatomyositis, chronic active hepatitis, severe muscle weakness, psoriasis, Stevisten Johnson's syndrome, idiopathic oral cavity, autoallergic inflammatory bowel disease (including e.g. ulcerative colitis or Crohn's disease), endocrine-related eye diseases, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mallitus type I), uveitis (both anterior and posterior) ), dry keratitis and conjunctivitis and spring and / or allergic keratitis and conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with or without associated nephrotic syndrome, including, e.g., spontaneous nephrotic syndrome or minimal lesion nephropathy) and juvenile dermatomyositis.

c) Treatment and prevention of asthma.

d) Treatment of multi-drug resistance (MOR). MOR is a particular problem in cancer and AIDS patients who do not respond to conventional chemotherapy because the drug is pumped out of the cell with Pgp. These compositions are, therefore, useful for improving the efficacy of other chemotherapeutic agents in the treatment and control of multiple drug resistance conditions, such as drug-resistant cancer or drug-resistant AIDS syndrome.

Treatment of proliferative disorders, e.g. tumors, hyperproliferative skin disorders and the like,

Treatment of fungal infections.

g) Treatment of inflammation and prevention of such conditions, in particular by enhancing the action of steroids.

h) Treatment of infections and prevention of infections, in particular infections with a pathogenic component including Mip and the like.

i) Treatment of overdosage with FK-506 or other macrophilin binding immunosuppressants.

Where the composition of the present invention is in unit dosage form, e.g. tablets, capsules, granules or powder, it is convenient for each unit dose to contain between 1mg and 100mg of the drug substance, preferably the amount is between 10mg. a 50 mg; for example 15, 20.25 or 50 mg. Such unit doses are suitable for administration from 1 to 5 times a day, depending on the particular treatment goal, phase and the like.

The exact amount of the composition to be administered depends on many factors, for example, the duration of the treatment desired and the rate of release of rapamycin into the body.

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The utility of pharmaceutical compositions can be tested by standard clinical tests, for example, in known indications of doses of active ingredient yielding equivalent blood levels of that ingredient; for example using doses ranging from 1mg to 1000mg, e.g. from 5mg to 100mg of active ingredient per 75kg adult in standard animal models. The increased bioavailability of the drug substance administered in these compositions can be demonstrated by standard animal testing and clinical trials.

The dosage form used, e.g. tablets, can be coated, for example with an enteric coating. Suitable coatings may contain cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polymethacrylic acid copolymer, e.g. Eudragit L, S, or else hydroxypropyl methylcellulose succinate.

The rapamycin used in the compositions of the present invention, e.g., 40-O- (2-hydroxy) ethyl rapamycin or rapamycin, may be in crystalline or amorphous form prior to forming the solid dispersion. An advantage of the invention is therefore that rapamycin need not be in a crystalline form. It can therefore be used directly in conjunction with, for example, a solvent, and does not need to be isolated first. Another advantage of the invention is that the dissolution rates of the solid dispersion are higher than the dissolution rates measured for either crystalline rapamycin or amorphous rapamycin in simple mixtures.

To date, no solid formulations of 33-epi-chloro-33-deoxy-ascomycin are available that could be conveniently administered orally.

The chemical compound 33-epi-chloro-33-deoxy-ascomycin is described in published European patent application EP 427 680 as example 66a.

Hereinafter, 33-epi-chloro-33-deoxy-ascomycin will be referred to as compound Y.

Compositions of the invention containing compound Y provide high bioavailability, are convenient to administer, and are stable.

Compound Y may be present in the composition in an amount from about 0.01 to about 30% by weight, preferably from about 1 to about 20% by weight.

The carrier medium may contain any of the aforementioned ingredients in percentages by weight as set out above. Suitable water-soluble polymers, cyclodextrins or other excipients, e.g. surfactants, that can be used in compositions with 33-epi-chloro-33-deoxy-ascomycin are as set out above.

A surfactant composition containing compound Y in the form of a solid dispersion as described herein is preferred.

The weight ratio of compound Y to carrier medium is generally not greater than 1: 3, preferably less than 1: 4.

Example 1

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

Compound X 9.1

HPMC 3 mPa 2 s 81.8

Lactose particles passing through a 9.1 screen of 200 mesh over a length of 2.54 cm of screen mesh

This composition (Form A) was prepared by dissolving rapamycin and carrier medium in an ethanol / acetone mixture. Absolute ethanol was used in a weight ratio of 1: 1 to acetone. The solvents were then evaporated and the obtained dry residue was ground to a fine powder with an average particle size <0.5 mm.

Example 2

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

Compound X 16.7

HPMC 3 mPa · s 66.7

Poloxamer 188 (BASF) 16.7

This composition (Form B) was prepared in an analogous manner to that of Example 1.

Example 3

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

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Compound X 16.7

HPMC 3 mPa · s 66.7

TPGS * 16.7 * tocopherol and ethylene glycol succinate

This composition (Form C) was prepared in a manner analogous to the composition of Example 1.

Example 4

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

Compound X 10

HPMC 3 mPa ^ s 80

Solulan C24 (Amerchol companies) 10

This composition (Form D) was prepared in an analogous manner to that of Example 1.

The above formulation forms A to D can be formed into tablets, filled into capsules or crushed and packaged in sachets.

Pharmacokinetics of 40-O- (2-hydroxy) ethyl rapamycin following administration to rats.

a) Drug administration

0.5 ml of the aqueous dispersion of compound X (corresponding to 4.0 mg active ingredient / rat) was administered by gastric intubation using a 1 ml syringe fitted with a polyethylene tube, during a short period of inhalation anesthesia of the rats. Six animals were used for each form of compositions A, S, C, and D.

b) blood sampling

The day before the experiment in question, the animals were inserted into a Vena jugularis vein with a permanent cannula. 0.5 ml of venous blood of Vena jugularis was collected from each rat and stored in tubes containing 2.5 ml of EDTA. Animal blood samples were paired (1 and 2 rats, 3 and 4 rats, and 5 and 6 rats) and stored at -80 ° C until drug assay was performed. Samples were taken prior to drug administration and then 10 minutes, 30 minutes, 60 minutes, 120 minutes, 300 minutes, 480 minutes, 1440 minutes after drug administration.

c) bioanalyst

Blood samples were analyzed by high performance liquid chromatography (HPLC) using reversed phase.

The table below shows the pharmacokinetic data collected after administration of Compound X to rats.

Tabe la

Summary profiles (average of 2-3 pools)

<td colspan="5">Blood concentration (ng / ml)</td>

<td> 0</td><td> 7</td><td> 7</td><td> 7</td><td> 7</td>

<td> 0,17</td><td> 118</td><td> 117</td><td> 85</td><td> 68</td>

<td> 0,5</td><td> 422</td><td> 131</td><td> 125</td><td> 74</td>

<td> 1</td><td> 375</td><td> 129</td><td> 96</td><td> 66</td>

<td> 2</td><td> 277</td><td> 82</td><td> 89</td><td> 54</td>

<td> 5</td><td> 573</td><td> 92</td><td> 58</td><td> 39</td>

<td> 8</td><td> 496</td><td> 66</td><td> 45</td><td> 34</td>

<td> 24</td><td> 93</td><td> 30</td><td> 34</td><td> 30</td>

<td>Cmax (ng / ml)</td><td> 573</td><td> 135</td><td> 131</td><td> 81</td>

<td>Tmax (hrs)</td><td> 5,00</td><td> 0,50</td><td> 0,50</td><td> 0,50</td>

<td>AUC 0-8 h [(ng / ml) h</td><td> 3502</td><td> 720</td><td> 565</td><td> 376</td>

<td>AUC 0-24 h [(ng / ml) h</td><td> 8213</td><td> 1487</td><td> 1192</td><td> 886</td>

Administration of the drug in form A resulted in higher blood levels of the drug than after administration of a surfactant containing composition.

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Research on dogs.

Following the above promising results, studies of relative bioavailability were further conducted in beagle dogs using a dose of 1 mg / kg body weight administered under fasting conditions. Hard gelatin capsules each containing 10 mg of Compound X were administered to eight dogs in a four-way Latin square; the dogs were fed 6 hours after administration of the capsules and blood levels of the drug were measured over the next 48 hours. Similar blood concentration profiles for Compound X were observed in all dogs with the terminal half-life of Compound X in the blood ranging from 10 to 40 hours. Median peak levels of 140 ng / ml and median AUC 0-48h levels of approximately 1600 ngh / ml were observed.

Example 5

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

Compound Y 20

HPMC 3 mPa ^ s 80

This composition (Form E) was prepared by dissolving Compound Y and the carrier medium in an ethanol / acetone mixture. The solvents were then evaporated and the resulting dry residue was ground.

Example d 6

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

Compound Y 20

HPMC 3 mPa ^ s 70

Poloxamer188 10

This composition (Form F) was prepared in a manner analogous to the composition in Example 5.

Example d 7

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

Relationship Y

HPMC 3 mPa.s sodium lauryl sulfonate

This composition (Form G) was prepared in a manner analogous to the composition of Example 5.

The above formulation forms E to G can be formed into tablets, filled into capsules or crushed and packaged in sachets.

Pharmacokinetics of 33-epi-chloro-33-deoxy-ascomycin after administration to rats.

a) Drug administration

0.5 ml of an aqueous dispersion of the drug composition (corresponding to 4.0 mg active ingredient / rat) was administered by gastric intubation using a 1 ml syringe fitted with a polyethylene tube during a brief period of inhalation anesthesia of the rats. Six animals were used for each form of compositions E, F and G.

b) blood sampling

The day before the experiment in question, the animals were inserted into a Vena jugularis vein with a permanent cannula. 0.5 ml of venous blood of Vena jugularis was collected from each rat and stored in tubes containing 2.5 ml of EDTA. Animal blood samples were paired (1 and 2 rats, 3 and 4 rats, and 5 and 6 rats) and stored at -80 ° C until drug assay was performed. Samples were taken prior to drug administration and then 10 minutes, 30 minutes, 60 minutes, 120 minutes, 300 minutes, 480 minutes, 1440 minutes after drug administration.

c) bioanalyst

Blood samples were analyzed by high performance liquid chromatography (HPLC) using reversed phase.

The results are presented graphically in Figures 1 and 2, where ng / ml (vertical axis) is plotted against hours (horizontal axis). Figure 1 shows that administration of form F leads to significantly higher blood levels of the drug than the levels observed after administration of form F or G. Figure 2 shows that administration of form F leads to high blood levels of drug when it is co-administered with the administration of a meal.

Compound Y is found in an amorphous form in compositions E, F and G as determined by x-ray examination both at the time of formulation and after six months.

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Forms E, F and G were tested for their respective digestion rates. When stirred in a 0.2% (w / w) solution of sodium dodecyl sulfonate in water at 37 ° C, it was found that after 30 minutes more than 80% of the available compound Y was released and reconstituted from each of the ground compositions containing 10 mg of Y. 92% of the available Y compound is released. For comparison, after 30 minutes, only 5% of this compound is released from an equivalent amount of crystalline compound Y.