CA2258679C - Solid solution of an antifungal agent with enhanced bioavailability - Google Patents

Abstract

A pharmaceutical composition in the form of a substantially amorphous solid solution comprising an antifungal compound of formula (I), wherein X is F; and R1 is formula (1) or an ester or ether of said compound of formula (I); and a soluble or insoluble polymer such as:
povidone or crospovidone, wherein the ratio of said compound to said polymer is about 1:3 to about 1:6 is disclosed.

Description

SOLID SOLUTION OF AN ANTIFUNGAL AGENT WITH
ENHANCED BIOAVAILABILITY
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions in the form of a substantially amorphous composition of matter comprising a tetrahydrofuran azole antifungal (as well as esters and ethers thereof) and a polymer used as a polymer matrix.
WO 95/17407, published June 29, 1995, discloses tetrahyrofuran antifungal compounds of Formula (I):

H _ N.. Ri YR ~_N ~ ~ ~N

N
X ~~
'~N
wherein: X is independently both F or both Cl, or one X is independently F and the other is independently Cl; and R1 is a straight or branched chain (C3 to Cg) alkyl group substituted by one or two hydroxy moieties; and ethers or esters thereof.
WO 95/17407 discloses that examples of suitable compositions of these compounds include solid compositions

2 5 such as tablets and capsules. WO 95/17407 discloses that a solid carrier can be one or mdre substances which 'may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material. WO 95/17407 discloses that in a tablet,

3 0 the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The oral bioavailability of active compounds can vary with the dosage form of the active compound. For example, it is known that solution dosages and suspensions generally give rise to higher bioavailability than capsules or tablets (see Pharmacokinetics Process and Mathematics, ACS Monograph 185, Chapter 5, page 57 (1986), and J.G. Nairn, Remington's Pharmaceutical Sciences, 18th edition (1990)). However, tablets and capsules are more convenient dosage forms, and it would be preferable to have a tablet or capsule dosage form of an active compound that has good bioavailability.
A pharmaceutical composition of the above described antifungal compounds that provides enhanced bioavailability of the antifungal compounds would be a contribution to the art. A
pharmaceutical composition of the above antifungal compounds that can be manufactured in a tablet or capsule form that has greater bioavailability than a suspension would also be a contribution to the art. This invention provides these contributions to the art. Thus, this invention overcomes the problem of making active compounds such as a tetrahydrofuran 2 0 azole antifungal that have a very low aqueous solubility more bioavailable.

SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical 2 5 composition comprising a substantially amorphous solid solution, said solid solution comprising:
(a) a compound of the formula 1:

H - /-\ - !~ N R1 X ''',''O N~N N
R N
O
N~N (I~
X
N
wherein: X is F; and R1 is CH
30 H3C s or an ester or ether of said compound of Formula I; and (b) a polymer selected from the group consisting of:
povidone, crospovidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene oxide, gelatin, carbomer, carboxymethylcellulose, croscarmellose, methylcellulose, methacrylic acid copolymer, methacrylate copolymer, and watei-soluble salts such as sodium and ammonium salts of inethacrylic acid and methacrylate copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and propylene glycol alginate;
wherein the ratio of said compound to said polymer is about 1:3 to about 1:6.
This invention also provides solid dosage forms comprising the solid solution described above. Solid dosage forms include tablets, capsules and chewable tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. A tablet can contain the solid solution blended with at least one disintegrant, a lubricant, a surfactant, and a glidant. The chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavors.
DETAILED DESCRIPTION OF THE INVENTION
Unless stated otherwise, wt % is based on the total weight of the composition such that the sum equals 100 wt %.
Reference to the "compound of Formula I" also includes 3 0 reference to esters, e.g. the glycine ester, and ethers of said compound, unless indicated otherwise.
The term "substantially amorphous solid solution" as used herein means a homogeneous solution of the antifungal = compound of Formula I in a polymer matrix, wherein the 3 5 polymer used as the polymer matrix is (a) soluble polymer (e.g., povidone) wherein the compound of Formula I and the soluble polymer form a homogenous matrix or (b) an insoluble polymer wo 48/00113 PCT1US97/10120

-4-=(e.g., crospovidone, wherein the compound of Formula I is molecularly dispersed in thc crospovidone polymer i.e. matrix).
The term "substantially amorphous" as applied to solid solutions as used herein means that the solid solutions as measured by x-ray diffraction analysis are greater than 90%
amorphous i.e., homogeneous and consist of a single phase.
The present invention includes esters and ethers of the compound of formula I.
For amino acid esters, e.g., the glycine ester of the compound of Formula 1. RI reresents:
s CH 3 H C S O-i-C2 tW?

The compound of Formula I is a tetrahydrofuran antifungal compound whose preparation is described in Examples 24 and 32 of WO 95/I7407, published 29 June 1995;
1 5 The preparation of esters and ethers of the compound of formula I are described in W095/17407, published 29 June 1995 and in W096138443, published 5 December 1996. The glycine estcr of the compound of Formula I is described in Example 33 of commonly owned U. S. Patent 5,661,151.

The substantially amorphous solid solutions of the antifungal compound of Formula I may be prepared by dissolving said antifungal compound and a soluble polymer in a suitable organic solvent and then removing the solvent to give a 25 solid xolution. Said solid solution is a homogeneous matrix of the antifungal compound and the polymer. A preferred pharmaceutical composition contains a solid solution of the antifungal compound of formula I and povidone.
Alternatively, the substantially amorphous solid solutions 30 of the present invention may be produced by dissolving the antifungal compound of Formula I in a suitable organic solvent that will swell an insoluble polymeric matrix, and then absorbing the resulting solution into the insoluble polymeric matrix. The solvent is then evaporated from the resulting 35 mixture. This results in a solid solution that is substantially, i.e.

-5-greater than 90%, in an amorphous state wherein the antifungal compound of formula I is molecularly dispersed in the polymeric matrix.
The preparation of solid solutions from soluble polymers is well known in the art; see, for example, page 173 in Kollidon--polyvinylpyrrolidone for the s pharmaceutical industry by BASF. The preparation of solid solutions from insoluble polymeric matrices are also known in the art, and such preparations are similar to those for drug loading into crosslinked hydrogels; see for example, U.S.
4,624,848 and Lee, P.I., Kinetics of Drug Release from Hydrogel Matrices, Journal of controlled Release, Vol. II, pages 277 to 288 (1985).
io Suitable polymers for use as the polymeric matrix in said solid solution include soluble and insoluble polymers which are selected from the group consisting of povidone, crospovidone, hydroxypropyl methylcellulose, hydroxypropyl-cellulose, polyethylene oxide, gelatin, carbomer, carboxymethyl-cellulose, croscarmellose, methylcellulose, methacrylic acid copolymer, ammonio 15 methacrylate copolymer, cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate and propylene glycol alginate. Crospovidone and croscarmellose are insoluble polymers; povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene oxide, gelatin, carbomer, carboxy-methylcellulose, methylcellulose, methacrylic acid copolymer, methacrylate 20 copolymer, and water soluble salts such as sodium and ammonium salts of methacrylic acid and methacrylate copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and propylene glycol alginate are soluble polymers. All these polymers are well known in the art. Preferably, povidone or crospovidone are used; and more preferably, povidone is used.
25 Povidone represents 1-vinyl-2-pyrrolidinone polymers (polyvinylpyrrolidone) having a weight average ranging from about 12,000 to about 150,00. Generally, the povidone used has a weight average in the range of about 7000 to about 54,000, with about 28,000 to about 54,000, being preferred, and about 29,000 to about 44,000, in particular about 29,000 to about 32,000, 30 being more preferred.

-6-Crospovidone represents water-insoluble synthetic cross-linked homopolymers of N-vinyl-2-pyrrolidinone. Generally, the crospovidone has a particle size of about 20 M to about 250 M, and preferably about 50 M to about 250 M (see, for example, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry by BASF).
The ratio of the antifungal compound of Formula I to polymer is about 1:3 to about 1:6, preferably about 1:3 to about 1:4, and more preferably 1:4.
The composition comprising the solid solution can, optionally, further comprise excipients selected from the group consisting of: disintegrants, lubricants, surfactants, glidants, artificial sweeteners, bulking agents, colorants and one or more fiavorants.
Generally, the composition comprising the solid solution can, optionally, further comprise: about 8 to about 40 wt % of one or more disintegrants, about 0.5 to about 2 wt % of one or more lubricants, about 4 to about 10 wt % of one or more surfactants, about 0.5 to about 5 wt % of one or more glidants, with about 1 to about 2 wt % being preferred; about 1 to about 10 wt % of one or more artificial sweeteners, about 40 to about 60 wt % of one or more bulking agents, about 0.1 to about 10 wt % of one or more colorants (coloring agents), and/or about 1 to about 5 wt % of one or more flavorants (flavoring agents).
2 5 The term "disintegrants" is used herein means any material which is added to pharmaceutical compositions to help break apart such compositions and release the medicament therefrom.
Suitable disintegrants are selected from the group consisting of: croscarmellose sodium (a cross-linked polymer of carboxymethylcellulose sodium, see NF XVII page 1922 (1990)), crospovidone, starches, celluloses, alginates, and gums.
Preferably, the disintegrants are selected from croscarmellose sodium or crospovidone. Preferably, croscarmellose sodium is 3 5 used as the disintegrant in compositions for capsules.
Preferably, crospovidone is used as the disintegrant in compressible tablets. Those skilled in the art will appreciate that it is desirable for compressible tablets to disintegrate

-7-within 30 minutes; therefore, the disintegrant used preferably results in the disintegration of the tablet within 30 minutes. It has been found that disintegrants, such as croscarmellose sodium and sodium starch glycolate, used in amounts of less than 30 wt % did not produce tablets which disintegrated within 30 minutes. It is believed that significantly higher amounts of such disintegrants would result in a tablet that disintegrates within 30 minutes.
The term "lubricant" as used herein refers to a substance added to the dosage form to enable the dosage form, e.g., a tablet, after it has been compressed to release from the mold or die.
Suitable lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and 1 5 the like. Preferably, magnesium stearate is used.
The term "surfactant" as used herein refers to surface active agents, especially non-ionic sufactants i.e. a surfactant that lacks a net ionic charge.
Suitable surfactants include polyether glycols such as Pluronic F-68 (Poloxamer 188), PluronicO F87 (Poloxamer 237), Pluronic F108 (Poloxamer 338), and PluronicO F127 (Poloxamer 407). Preferably, Pluronic F-68 is used. According to BASF
Corporation's Technical Bulletin (1995), Pluronic is a registered tradename for BASF Corporation's block copolymers of ethylene 2 5 oxide and propylene oxide represented by the chernical structure HO(C2H40)a(C3H60)b(C2H40)aH wherein for: (a) Pluronic F-68, a is 80 and b is 27; (b) Pluronic" F87, a is 64 and b is 37; (c) Pluronic F108, a is 141 and b is 44; and Pluronic F127, a is 101 and b is 56. The average molecular weights for 3 0 these block copolymers are: (a) Pluronic F-68, 8400; (b) Pluronic F87, 7700; (c) Pluronic F108, 14600; and Pluronic F127, 12600.
The term "glidants" as used herein refers to a substance, such as an anticaking agent, which improves the flow 3 5 characteristics of a powder mixture.
Suitable glidants include silicon dioxide and talc.
Preferably, silicon dioxide is used.

-8-The term "bulking agent" as used herein refers to substances (which are also called diluents) that usually make up the major portion of the composition or dosage form.
Suitable bulking agents include xylitol, mannitol, compressible sugars, lactose, and microcrystalline celluloses.
Preferably, xylitol is used for chewable tablets.
Suitable artificial sweeteners include saccharin, cyclamates and aspartame.
If desired known flavorants and known FD & C colorants can be added to the composition.
The composition comprising the solid solution can be reconstituted with water for oral administration. In this dosage form the composition can optionally contain known sweeteners, flavorants, colorants and bulking agents.
The composition comprising the solid solution can be produced in solid dosage forms. Solid dosage forms include capsules (e.g., soft gelatin capsules and hard gelatin capsules) tablets (including, for example, coated tablets, gel coated tablets and enteric coated tablets), and chewable tablets. These dosage forms can be produced by methods well known in the art--see for example Lachman et al., The Theory and Practice of Industrial Pharmacy, 2nd Edition, Lea & Febiger, Philadelphia, pages 321-344 and pages 389-404 (1976).
For capsule dosage forms, the compositior, comprising the solid solution generally further comprises disintegrants, lubricants, and, optionally, surfactants. Thus, a composition for use in capsules can comprise about 80 to about 90 wt% of the solid solution , about 8 to about 20 wt% of one or more disintegrants, about 0.5 to about 2 wt% of one or more lubricants, and, optionally, about 4 to about 10 wt% of one or more surfactants.
For example, a composition for use in a capsule dosage form comprises: about 80 to about 90 wt% of the solid solution, about 8 to about 20 wt% of one or more disintegrants and about 0.5 to about 2 wt% of one or more lubricants.
Another example of a composition for use in a capsule dosage form is a composition comprising about 80 to about 90 wt% of the solid solution, about 8 to about 15 wt% of one or

-9-more disintegrants, about 0.5 to about 2 wt% of one or more lubricants, and about 4 to about 10 wt% of one or more surfactants.
In general, the compositions for capsule dosage forms contain the solid solution, one disintegrant, one lubricant, and optionally, one surfactant.
Preferably, the disintegrant in the capsule compositions is croscarmellose sodium.
For a compressible tablet dosage form the composition comprising the solid solution generally further comprises disintegrants, lubricants, surfactants, and glidants. Thus, a composition for use in compressible tablets can comprise about 50 to about 70 wt% of the solid solution, about 25 to about 40 wt% of one or more disintegrants, with about 30 to about 40 wt % of one or more disintegrants being preferred, about 0.5 to about 2 wt% of one or more lubricants, about 2 to about 10 wt%
of one or more surfactants, and about 1 to about 2 wt% of one or more glidants. Preferably, the disintegrant is crospovidone.
More preferably, the disintegrant is crospovidone in an amount of about 30 to about 40 wt %. Most preferably, the disintegrant is crospovidone in an amount of about 25 to about 30 wt % and another disintegrant (preferably croscarmellose sodium) is used in amounts of about 5 to about 10 wt %.
When used as a disintegrant, the crospovidone generally 2 5 has a particle size of about 20 M to about 250 M, with about 50 M to about 250 M being preferred.
In addition to the disintegrant, the compressible tablet also preferably comprises one lubricant, one surfactant and one glidant.
3 0 For chewable tablets, the composition generally comprises about 40 to about 60 wt% of the solid solution, about 40 to about 60 wt% of a bulking agent (e.g., a sugar such as xylitol), and about 0.5 to about 2 wt% of a lubricant, optionally about 1 to about 10 wt % of an artificial sweetener (e.g., sodium saccharin 3 5 or aspartame), and optionally about 0.1 to about 10 wt % of a colorant.
A preferred composition for tablets comprises: (1) about 62.5 wt% of a solid solution comprising (a) a compound of

- 10 -Formula I and (b) povidone, wherein the ratio of said compound to said polymer is about 1:4; (2) about 6.25 wt% of croscarmellose sodium (disintegrant); (3) about 25.5 wt% of crospovidine (disintegrant); (4) about 0.625 wt% of magnesium stearate (lubricant); (5) about 3.125 wt% of Pluronic F-68 (surfactant); and about 2 wt% of silicon dioxide (glidant). More preferably, the povidone has a molecular weight of about 29,000 to about 44,000. A preferred composition is illustrated in Example 13 below.
The examples that follow are intended to exemplify the claimed invention, and such examples should not be construed as limiting the disclosure or the claimed invention.
In the examples that follow, the compound of formula I
(hereinafter "compound I" or "I"):

H
~~~~~~ ~\ - N
F R p NN N~ N a H
s 0 ~3 ~ ~ N.N
F ~
~N
is used; the esters and ethers of I may also be used.

DOSING PROTOCOL FOR DOGS
The formulation to be tested was administered orally to male beagle dogs in a single dose (PO, single). The number of dogs for each test is indicated by the letter "N" followed by an equal sign and a number. Thus, "(N=6)" means the formulation was administered to six dogs. The total amount of the 2 5 compound of Formula I administered was 200 mg given as two capsules or tablets containing 100 mg each, or one 200 mg tablet. The administered dose (tablet, capsule or control suspension) was slowly washed down with 25 mL of water.
Blood samples were taken at 0, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours and 72 hours.
Serum for analysis was obtained after clotting, and centrifugation at 4 C. Serum samples (one per time point) were split and stored at -20 C until bioassayed as described below.

WO 98d00113 PCTNS97110120 - l1 -The feeding schedule for the dogs to be tested was: (1) between noon and 2 PM on the day before drug administration the dogs were fed a half ration of food (15 g/kg); (2) at about 4 PM of the same day as (1) any uneaten food was removed: (3) at about 7:30 AM the next day, about I hour before drug administration, the dogs were fed a half ration of food (15 g/kg):
(4) about 1 hour after feeding began (about 8:30 AM) the uneaten food was removed and the drug was administered; and (3) after the 4 hour time point after drug administration the dogs were fed normally.
Dogs that were fasted were not given food beginning ] 8 hours before drug administration and were fed normally after the 4 hour time poini after drug administration.
Dogs were fed unlcss otherwise indicated.
BIOAVAIIABILITY ASSAY
Smnples of dog serium were collected at selected time intervals. Proteins from the serium samples were precipitated with methanol. The supernatants were analyzed by HPLC/UV
detection procedure using a high pressure liquid chromatograph (Ctg column) equipped with a ultra violet detector. the Cmax and AUC (area under the curve, 0-72 hours) valucs were calculated using standard procedures to determine the bioavailability of the compound in the tested fotmulations. The larger the AUC
value, the greater the bioavailability.
A suspension of the coinpound of Formula I was used as a control The control was made bv suspending 200 mg of the compound of formula I in 4 ml, of a 0.4% (wt/v) solution of methyl cellulosc. The 0.4 % methyl cellulosc solution was madc bv adding 4 grams of mcthyl cellulose to one liter of distilied water and heating at about 80 C with stirring for about 1 112 hours. After about 45 minutcs (of the 1 112 hours), while heating and stirring, 5.6 ml of TweerP80 and 9 grams of NaCI
werc added to the methyl cellulose solution. The resulting solution was autoclaved at about 121 C for about 65 minutes at about 15 lbs. of pressure. The autoclaved solution was cooled for about 30 minutes at room temperature and then stored at * trade-mark 4 C. Gelling occurs at high temperatures, but will clarify when cooled. The solution was stirred or swirled prior to use.
The results of the bioavailability assay are given in terms Of Cmax g/mL and AUC g.hr/mL.
EXAMPLE I
PREPARATION OF SOLID SOLUTION
Composition:
Ingredient g/batch Compound (I) 4.0 Povidone K29/32 16.0 Methylene Chloride 200 mL
Method:
Compound of formula I and the povidione were dissolved in methylene chloride to form a solution. The solvent was evaporated under a hood, and then the residue was dried under a vacuum. The residue was then reduced to fine particles by grinding. The residue was then passed through a 30 mesh screen. The powder was found to be amorphous by x-ray analysis.

PREPARATION OF SOLID SOLUTION

A solid solution was prepared according to the procedure in Example I with the exception that the solution was spray dried using a portable spray drier.

PREPARATION OF SOLID SOLUTION
A solid solution was prepared according to the procedure in Example 2 with the exception that methanol was used as the solvent instead of methylene chloride.

PREPARATION OF SOLID SOLUTION

A solid solution was prepared according to the procedure of Example I with the exception that the solution was dried using a vacuum double drum dryer.

PREPARATION OF SOLID SOLUTION

A solid solution was prepared according to the procedure of Example 4 with the exception that methanol was used as the solvent.

PREPARATION OF SOLID SOLUTION
Composition:
Ingredient /batch Compound (I), 4.0 Povidone K29/32 12.0 Methylene Chloride 200 mL
Method:
Compound (I) and the povidone were dissolved in methylene chloride to form a solution. The solvent was evaporated under a hood, and then the residue was dried under a vacuum. The residue was Teduced to fine particles by grinding. The residue was passed through a 30 mesh screen.
The powder was found to be amorphous by x-ray analysis.

PREPARATION OF SOLID SOLUTION

A solid solution was prepared according to the procedure in Example 6 with the exception that the solution was spray dried using a spray drier.

PREPARATION OF SOLID SOLUTION
A solid solution was prepared according to the procedure in Example 7 with the exception that methanol was used as the solvent instead of methylene chloride.

PREPARATION OF SOLID SOLUTION

A solid solution was prepared according to the procedure of Example 6 with the exception that the solution was dried using a vacuum double drum dryer.

PREPARATION OF SOLID SOLUTION

2 5 A solid solution was prepared according to the procedure of Example 9 with the exception that methanol was used as the solvent.

CAPSULE FORMULATION
Composition Ingredient g/batch Solid Solution ((I):povidone K29/32=1:4) 500 Croscarmellose sodium 50 Magnesium Stearate 5 Total 555 Method:
A solid solution having a ratio of Compound I to povidone of 1:4 was prepared by a procedure similar to that of Example 1.
The solid solution and croscarmellose sodium were mixed in a mixer for about 10 minutes. A premix was formed with the magnesium stearate and about an equal portion of the mixture.
The premix was added to the mixture and the resulting mixture was further mixed for about 5 minutes. The mixture was encapsulated in No. 0 hard shell gelatin capsules.
Bioavailability in Dogs:

Bioavailability Capsule of Ex. 11 Control Suspension Parameters 200 mg Dose (N=6) 200 mg Dose (N=8) Cmax ( /mL) 1.26 0.95 AUC g.hr/mL 60.83 32.5 CAPSULE FORMULATION
Composition:
Ingredient mg/capsule Solid Solution ((I):povidone K29/32=1:4) 500 Croscarmellose sodium 50 Pluronic F-68 25 Magnesium Stearate 5 Total 580 Method:
A solid solution having a ratio of Compound (I) to povidone of 1:4 was prepared by a procedure similar to that of Example 1. The solid solution, croscarmellose sodium and Pluronic F-68 were mixed in a mixer for about 10 minutes. A
premix of magnesium stearate and an equal portion of the mixture was formed. The premix was added to the mixture and the mixture was further mixed for about 5 minutes. The mixture was encapsulated in No. 0 hard shell gelatin capsules.
Bioavailabilitv in Dogs:

Control Capsule Ex. 12 Capsule Ex. 12 Bioavailability Suspension 200 mg Dose 200 mg Dose Parameters 200 mg Dose (N=12) Fed (N=6) Fasted (N=12) Fed Cmax ( /mL) 1.55 2.44 1.55 AUC 66.39 97.25 62.83 hr/mL

EXAMPLES 13. 14 AND 15 TABLET FORMULATIONS
Compositions Ingredient Ex. 13 Ex. 14 Ex. 15 mg/tab mg/tab mg/tab Solid Solution 500 500 1000 ((I):povidone K29/32=1:4) Pluronic F-68 25 50 50 Silicon dioxide 16 16 32 Croscarmellose Sodium 50 50 100 Crospovidone 204 204 408 Magnesium Stearate 5 5 10 Total 800 825 1600 Method:
The solid solution was prepared by a procedure similar to that of Example 2. The solid solution was compacted using a compactor and milled through an 18 mesh screen. The remainder of the excepients, except for the magnesium stearate, were added and mixed in a suitable mixer for about 15 minutes.
A premix of magnesium stearate with an equal portion of the mixture was made. The premix was added to the mixture and mixed for about 5 minutes. The resulting mixture was then compressed into tablets using a single station tablet machine.
Bioavailability in Dogs:

Control Tablet Ex. 13 Tablet Ex. 15 Bioavailability Suspension 200 mg Dose 200 mg Dose Parameters 200 mg Dose (N=6) (N=6) (N=24) Cmax ( /mL) 1.31 1.81 1.33 AUC 53.41 66.31 56.11 gg.hr/mL

CHEWABLE TA LET
Composition:
Ingredient mg/tab Solid Solution ((I): ovidone K29/32=1:4) 1000 Xylitol 990 Magnesium Stearate 20 Total 2010 Method:
A solid solution, made by procedures similar to that of Example 2, was mixed with the xylitol in a suitable mixer for about 10 minutes to form a mixture. A premix was made with the magnesium stearate and an equal portion of the mixture.
The premix was added to the remainder of the mixture and mixed further for about 5 minutes. The mixture was compressed into tablets using a single station tablet machine.

SOLID SOLUTION
Composition:
Ingredient g/batch Compound (I) 10 Crospovidone 40 Meth lene Chloride 50 mL
Method:
Compound (I) was dissolved in methylene chloride. While mixing, the solution of Compound (I) was slowly added to the crospovidone until all the solution was absorbed. The resulting solid solution was vacuum dried. The residue was reduced to fine particles by grinding. The residue was then passed through a 30 mesh screen. The powder was found to be substantially amorphous by x-ray analysis.

CAPSULE FORMULATION
Composition:

Ingredient m /ca sule Solid Solution ((I):povidone K29/32=1:4) 500 Croscarmellose sodium 50 PluronicO F-68 25 Magnesium Stearate 5 Total 580 M th :
A solid solution, made by procedures similar to that of Example 17, was mixed with the above ingredients, except for the magnesium stearate, in a suitable mixer for about 10 minutes. A premix was made of the magnesium stearate and an equal portion of the mixture. The premix was added to the remainder of the mixture and the resulting mixture was mixed for about 5 minutes. The mixture was encapsulated into No. 0 hard shell gelatin capsules.

BioavailabilitX in Dogs:

Bioavailability Control Suspension Capsule of Ex. 18 Parameters 200 mg.Dose (N=24) 200 mg Dose (N=6) Cmax ( /mL) 1.31 2.39 AUC .hr/mL 53.41 95.36 ___ , _ COMPARATIVE EXAMPLE
CAPSULE FORMULATION WITHOUT SOLID SOLUTION
Composition:

Ingredient m /ca sule Compound(I), micronized 100 Microcyrstalline cellulose 178 Sodium lauryl sulfate 22.5 Sodium starch glycolate 45 Magnesium Stearate 4.5 Total 350 Method:
Compound (I) which was micronized, microcystalline cellulose, sodium lauryl sulfate and sodium starch glycolate were mixed together in a suitable mixer for about 10 minutes.
A premix was made of the magnesium stearate and an equal portion of the mixture. The premix was added to the remainder of the mixture and the resulting mixture was mixed for about 5 minutes. The mixture was encapsulated in No. 0 hard gelatin capsules.

Bioavailability in Dogs:

Bioavailability 1 Control Suspension Capsule of Ex. 19 Parameters 200 mg Dose 200 mg Dose (N=8) (N=6) Cmax ( /mL) 0.95 0.95 AUC ptg.hr/mL 32.5 29.72 It is generally recognized that micronized drugs have a higher bioavailability. However, the above data demonstrate that the conventional capsule formulation of Example 19 with its micronized compound, as well as the control suspension of Example 20 hereinbelow with its micronized compound, have a lower bioavailability compared to the solid solution formulations of this invention represented by Examples 11 and 12 and the tablet formulations represented by Examples 13 and 15.

COMPARATIVE EXAMPLE
CONTROL SUSPENSION IN FASTED DOGS

The following data are for fasted dogs.

Bioavailability Control Suspension Control Suspension Parameters 100 mg Dose (with 200 mg (N=5) tartaric acid) 200 mg Dose (N=6) Cmax ( /ML) 0.18 0.33 AUC ~tg.hr/mL 5.21 12.0 The above data demonstrate that the control suspensions of Example 20 have a lower bioavailability in fasted dogs than the control suspensions in fed dogs--see Examples 11, 12, 13, and 18. This difference in bioavailability (fed versus fasted) is much greater with the control suspensions of this Example than with the solid solution compositions of this invention (see Example 12 for example).
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof (e.g. use of esters and ethers of I) will be apparent to those of ordinary 2 5 skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims (8)

CLAIMS:

1. A pharmaceutical composition comprising a substantially amorphous solid solution, said solid solution comprising:
(a) a compound of the formula:
wherein:
each X is F; and R1 is (b) a polymer selected from povidone and crospovidone;
wherein the solid solution comprises about 50 to about 70 wt % of the pharmaceutical composition and wherein the ratio of the compound to the polymer is about 1:3 to about 1:4; and wherein the remaining about 30 to about 50% of the pharmaceutical composition further comprises:
(c) about 25 to about 30 wt % of the disintegrant crospovidone;
(d) about 5 to about 10 wt % of the disintegrant croscarmellose sodium;
(e) about 0.5 to about 2 wt % of the lubricant magnesium stearate;
(f) about 2 to about 10 wt % of a surfactant compound of the formula HO(C2H4 0)80(C3H6O)27(C2H4 0)80H;
(g) about 1 to about 2 wt % of the glidant silicon dioxide;
such that the total wt % is 100% based on the weight of the composition.

2. A pharmaceutical composition according to claim 1, wherein said polymer (b) is povidone.

3. A pharmaceutical composition according to claim 1, wherein said polymer (b) is crospovidone.

4. The composition of claim 2, wherein the molecular weight of the povidone is about 29,000 to about 32,000.

5. The composition of any one of claims 1 to 4, which is in the solid dosage form of a compressible tablet, a chewable tablet or a capsule.

6. A composition of matter comprising:
(A) about 62.5 wt % of a substantially amorphous solid solution, said solid solution comprising:
(a) a compound of the formula I:

wherein each X is F, and R1 is (b) povidone; wherein the ratio of said compound to said povidone is about 1:4;
(B) about 25.5 wt % of the disintegrant crospovidone;
(C) about 6.25 wt % of the disintegrant croscarmellose sodium;

(D) about 0.625 wt % of the lubricant magnesium stearate;
(E) about 3.125 wt % of a surfactant compound of the formula:
HO(C2H4 0)80(C3H6O)27(C2H4 0)80H; and (F) about 2 wt % of the glidant silicon dioxide;
such that the total wt % is 100% based on the weight of the composition.

7. The composition of claim 6, wherein the molecular weight of the povidone is about 29,000 to about 32,000.

8. The composition of claim 6 or 7, which is in the solid dosage form of a compressible tablet, a chewable tablet or a capsule.