WO2008083192A2

WO2008083192A2 - Methods and formulations for improved bioavailability of antiprogestins

Info

Publication number: WO2008083192A2
Application number: PCT/US2007/088891
Authority: WO
Inventors: Joseph Podolski
Original assignee: Repros Therapeutics Inc
Current assignee: Repros Therapeutics Inc
Priority date: 2006-12-28
Filing date: 2007-12-27
Publication date: 2008-07-10
Anticipated expiration: 2009-06-28
Also published as: NO20092271L; WO2008083192A3; EP2094275A2; EA200970646A1; JP2010514793A; WO2008083192A8; ECSP099536A; MX2009006912A; CA2672888A1; AU2007339820A1; TW200831110A; CO6190605A2; AR064697A1; CL2007003855A1; KR20090086470A

Abstract

Compositions comprising an antiprogestin and having improved bioavailability are provided. In one aspect, compositions comprising particles of an antiprogestin deposited on a carrier substrate are provided. In another aspect, compositions comprising a micronized antiprogestin are provided. Also provided is the use of compositions comprising an antiprogestin and having improved bioavailability for the treatment of endometriosis, uterine fibroids, dysmenorrhea, and meningiomas.

Description

METHODS AND FORMULATIONS FOR IMPROVED BIOAVAILABILITY OF ANTIPROGESTINS

FIELD OF THE INVENTION

[0001] The present invention relates generally to compositions with improved bioavailability comprising at least one antiprogestin. More particularly, the present invention relates to compositions with potent antiprogestational activity, minimal antiglucocorticoid activity and improved bioavailability, comprising a 19- norprogesterone I derivative and optionally a pharmaceutically acceptable exicipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present application claims the benefit of U.S. Provisional Patent Application Nos. 60/882,423, filed December 28, 2006 and 60/885,372, filed January 17, 2007, the contents of each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0003] There have been numerous attempts over the past few decades to prepare steroids with antihormonal activity. It has been generally recognized for some years, that antiprogestational steroids would find wide applicability in population control, while antiglucocorticoids would be extremely valuable in the treatment of, for example, Cushing's syndrome and other conditions characterized by excessive endogenous production of cortisone.

[0004] For purposes of contraception, it would be advantageous to have compounds which possess antiprogestational activity without (or with minimal) antiglucocorticoid activity. Although there have been a number of attempts to modify the mifepristone structure in order to obtain separation of the antiprogestational activity from the antiglucocorticoid activity, this goal has not yet been fully achieved. As such, there remains a need in the art for the development of new formulations comprising steroids which possess antiprogestational activity with minimal antiglucocorticoid activity. [0005] U.S. Patents 6,861,415 and 6,900,193, both incorporated herein by reference, disclose new compounds which possess antiprogestational activity with minimal antiglucorticoid activity. The compounds are steroid derivatives, and more specifically they are structural modifications of 19-norprogesterone I, such as 17-α- substituted-1 1 -β-substituted-4-aryl and 21 -substituted 19-norpregnadienedione, and are poorly soluble in water. Therefore, a need remains in the art to develop formulations comprising antiprogestins, in particular steroid derivatives, with increased solubility and improved bioavailability.

SUMMARY OF THE INVENTION

[0006] The present invention provides new formulations with potent antiprogestational activity, preferably minimal antiglucocorticoid activity and improved bioavailability.

[0007] In one aspect of the invention, the new formulations are produced by finely- spraying a non-aqueous solution of the antiprogestin onto a carrier substrate. The resulting formulation comprises antiprogestin particles deposited on relatively larger particles of carrier substrate.

[0008] In another aspect of the invention, the new formulations comprise micronized antiprogestin particles.

[0009] Preferably, the antiprogestin is a compound having the following general formula I:

[00010] Wherein: R¹ is a functional group including, but not limited to, —

OCH₃, -SCH₃, — N(CH₃)₂, -NHCH₃, -NC₄H₈, -NC₅H₁₀, -NC₄H₈O, -CHO, -CH(OH)CH₃, C(O)CH₃, — O(CH₂)2N(CH₃)₂, — O(CH2)₂NC₄H₈ and —

R² is a functional group including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl and — OC(O)R₆, wherein R6 is a functional group including, but not limited to, alkyl (e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g., -CH₂OCH₃) and alkoxy (-OCH₃); R³ is a functional group including, but not limited to, alkyl (e.g., methyl, methoxymethyl, etc.), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, vinyloxy, etc.), and acyloxy; R⁴ is a functional group including, but not limited to, hydrogen and alkyl; and X is a functional group including, but not limited to, =0 and =N — OR⁵, wherein R⁵ is a member selected from the group consisting of hydrogen and alkyl. [00011] Also provided are compositions comprising particles of an antiprogestin, such as any compound of general formula I, and a surfactant. The surfactant is preferably a polyglycolysed glyceride, such as an unsaturated polyglycolysed glyceride, a saturated polyglycolysed glyceride, GELUCIRE 33/01, GELUCIRE 35/10, GELUCIRE 37/02, GELUCIRE 44/14, LABRAFIL and LABRASOL. [00012] The composition may further comprise a polyethylene glycol (PEG).

Representative polyethylene glycols include, but are not limited to, PEG200, PEG400, PEG600 and PEG2000. A weight ratio of polyglycosylated glyceride to polyethylene glycol (PEG) of from 5: 1 to 1 : 1 is preferred

[0010] Also provided, are compositions comprising particles of an antiprogestin, preferably any compound of general formula I, a polyglycolysed glyceride and peceol (glyceryl monooleate). A weight ratio of polyglycolysed glyceride to peceol of from 9: 1 to 1 :4 is preferred.

[0011] The compositions may possess potent antiprogestational activity with minimal antiglucocorticoid activity in combination with improved bioavailability. Therefore, the compositions may be suitable for long term use in the treatment of human endocrinological disorders or other conditions in steroid-sensitive tissues. Specific conditions for treatment include, but are not limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroid, meningioma and metastatic breast cancer. Other uses include, but are not limited to, contraception, including emergency post-coital contraception and inducement of cervical ripening.

[0012] Also provided is the use of any of the compositions of the present invention in the manufacture of a medicament for treatment of human endocrinological disorders or other conditions in steroid-sensitive tissues as described herein, including but not limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroid, meningioma and metastatic breast cancer.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In one aspect, the present invention provides a composition comprising a carrier substrate and a deposit on said carrier substrate, said deposit comprising particles of an antiprogestin, preferably a steroid derivative with the following general formula I:

[0014] In formula I, R¹ is a functional group including, but not limited to, — OCH₃, -SCH₃, —N(CH₃)₂, -NHCH₃, -NC₄H₈, -NC₅Hi₀, -NC₄H₈O, -CHO, -CH(OH)CH₃, -C(O)CH₃, — O(CH₂)₂, — N(CH₃)₂, — O(CH₂)₂NC₄H₈, and -0(CHa)₂NC₅H]_O. R² is a functional group including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl and — OC(O)R⁶, wherein R⁶ is a functional group including, but not limited to, alkyl (e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g., -CH₂OCH₃) and alkoxy (-0CH₃). R¹ is a functional group including, but not limited to, alkyl, hydroxy, alkoxy and acyloxy. R is a functional group including, but not limited to, hydrogen and alkyl. Finally, X is a functional group including, but not limited to, =0 and =N — OR⁵, wherein R⁵ is a member selected from the group consisting of hydrogen and alkyl. [0015] In another aspect, the present invention provides a composition comprising micronized particles of an antiprogestin, preferably a steroid derivative with general formula I. [0016] The term "alkyl" refers to a branched, unbranched, monovalent hydrocarbon radical having from 1-12 carbons. When the alkyl group has from 1-6 carbon atoms, it may be referred to as a "lower alkyl." Representative alkyl radicals include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i- butyl (or 2-methylpropyl), etc. As used herein, the term alkyl encompasses "substituted alkyls." A substituted alkyl refers to alkyl further containing one or more functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen (i.e., alkylhalos, e.g., CF₃), hydroxy (e.g., hydroxymethyl), amino, alkylamino, acylamino, acyloxy, alkoxy (e.g., methoxymethyl), mercapto and the like. These groups may be attached to any carbon atom of the lower alkyl moiety.

[0017] The term "alkoxy" may refer to a — OR group, where R is a lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl. Suitable alkoxy radicals include, for example, methoxy, ethoxy, phenoxy, t-butoxy (e.g., methoxyethoxy, methoxymethoxy, etc.), etc.

[0018] The term "acyloxy" may refer to an organic radical derived from an organic acid by the removal of a hydrogen. The organic radical can be further substituted with one or more functional groups such as alkyl, aryl, aralkyl, acyl, halogen, amino, thiol, hydroxy, alkoxy, etc. An example of such a substituted organic radical is glycinate (e.g., -OC(O)CH₂NH₂). Suitable acyloxy groups include, for example, acetoxy, i.e., CH3COO — , which may be derived from acetic acid, formyloxy, i.e., H(CO)O — , which may be derived from formic acid and cypionyloxy, which may be derived from 3-cyclopentylpropionic acid.

[0019] The term "halogen" may refer to fluorine, bromine, chlorine and iodine atoms. The term "hydroxyl" may refer to the group — OH. The term "acyl" may denote groups — C(O)R, where R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein. The term "aryl" may refer to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently, or linked to a common group such as an ethylene or methylene moiety. The aromatic ring(s) may include phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-l -ethyl, and may contain a heteroatom, such as thienyl, pyridyl and quinoxalyl. The aryl group may also be substituted with halogen atoms, or other groups such as nitro, carboxyl, alkoxy, phenoxy, and the like. Additionally, the aryl group may be attached to other moieties at any position on the aryl radical which would otherwise be occupied by a hydrogen atom (such as 2-pyridyl, 3-pyridyl and 4-pyridyl). [0020] The term "alkyl carbonate" may refer to the group — OC(O)OR, where R is alkyl, substituted alkyl, aryl, or substituted aryl as defined herein. [0021] The term "S-alkyl" may refer to the group — SR, where R is lower alkyl or substituted lower alkyl. The term "S-acyl" may refer to a thioester derived from the reaction of a thiol group with an acylating agent. Suitable S-acyls include, for example, S-acetyl, S-propionyl and S-pivaloyl. S-acyl may refer to such thioesters regardless of their method of preparation. The terms "N-oxime" and "N-alkyloxime" may refer to the group =N — OR⁵, wherein R⁵ is, for example, hydrogen (N-oxime) or alkyl (N-alkyloxime). The oximes can consist of the syn-isomer, the anti-isomer or a mixture of both the syn- and anti-isomers.

[0022] Representative compounds within formula I, include those in which R¹ is — N(CH₃)₂; those in which R² is hydrogen, halogen or alkoxy; those in which R³ is acyloxy; those in which R⁴ is alkyl (e.g., methyl and ethyl); and those is which X is =O and =N — OR⁵, wherein R⁵ is hydrogen or alkyl. Additional compounds include those in which R¹ is -N(CHa)₂; R² is halogen; R³ is acyloxy; and R⁴ is alkyl, such where R² is F, Br or Cl; and R⁴ is methyl. Also included are compounds in which R¹ is — N(CH₃)₂; R² is alkyl; R³ is acyloxy; R⁴ is alkyl; and X is =0. Also included are compounds in which R¹ is — N(CH₃)₂; R² is alkoxy; R³ is acyloxy; R⁴ is alkyl; and X is =0. Additional compounds are those in which R is methoxy or ethoxy; and R is acetoxy or methoxy. Also included are compounds in which R¹ is — N(CH₃); R is hydroxy; R³ is acyloxy; R⁴ is alkyl; and X is =0. Also included are compounds in which R¹ is — N(CH₃)₂; R² and R³ are both acyloxy; R⁴ is alkyl; and X is =0. Additional compounds are those in which R² and R³ are both acetoxy. Also included are compounds in which R¹ is — N(CH₃)₂; R is S-acyl; R is hydroxy or acyloxy; R is alkyl; and X is =0. Also included are compounds in which R¹ is — N(CH₃)₂; R is cypionyloxy; R³ is acetoxy; R⁴ is alkyl; and X is =O. Also included are compounds in which R¹ is — N(CH₃^; R² is methoxy; R³ is acetoxy; R⁴ is alkyl; and X is =0 and =N — OR⁵, wherein R⁵ is, for example, hydrogen or alkyl (e.g., methyl, ethyl, etc.). Also included are compounds in which R¹ is — N(CH₃)₂; R² and R³ are both acetoxy; R⁴ is alkyl; and X is =0 and =N — OR⁵, wherein R⁵ is, for example, hydrogen or alkyl (e.g., methyl, ethyl, etc.).

[0023| Exemplar compounds include, but are not limited to, 17α-acetoxy-l lβ-[4- (N,N-dimethylamino)phenyl]-21 -methoxy- 19-norpregna-4,9( 10)-diene-3 ,20-dione (CDB-4124) with the following structural formula:

[0024] Another exemplar compound is 17α-acetoxy-l lβ-[4-(N,N- dimethylamino)phenyl]-19-noφregna-4,9-diene-3,20-dione (CDB-2914) with the following structural formula:

CH₃

[0025] Other exemplar compounds include, but are not limited to, 17α-acetoxy-21- chloro- 11 β-(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy-21 -bromoro- 11 β-(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9- diene-3,20-dione; 17-,21-diacetoxy-l lβ-(4-N,N-dimethylaminophenyl) 19-norpregna- 4,9-diene-3,20-dione; 17α-hydroxy-21-acetylthio-l lβ-(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy-21 -acetylthio- 1 1 β-(4-N,N- dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione; 17α-acetoxy-21 -ethoxy- 1 l β-(4N,N-dimethylaminophenyl)-19-noφregna-4,9-diene-3,20-dione; 17α-acetoxy- 21 -methyl- 1 1 β-(4-N,N-dimethylamino-phenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy-21 -methoxy- 1 1 β-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene- 3 ,20-dione; 17α-acetoxy-21 -ethoxy- 1 1 β-(4-N,N-dimethylaminophenyl)- 19- norpregna-4,9-diene-3,20-dione; 17α-acetoxy-21 -(3'-cyclopentylpropionyloxy) 1 lβ- (4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy-21 - hydroxy- 1 1 β-(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17α,21-diacetoxy-l 1 β-(4-N,N-dimethylaminophenyl) 9-norpregna-4,9-diene-3,20- dione 3-oxime; 17α-acetoxy-21 -methoxy- 11 β-(4-N,N-dimethylaminophenyl)- 19- norpregna-4,9-diene-3,2-dione 3-oxime; and 17α,21-diacetoxy-l lβ-[4-(N- methylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione. [0026] Also included are those compounds in which R¹ is — N(CHa)₂, — NC₄Hs, -NC₄H₁₀, -NC₄H₈O, -C(O)CH₃, — O(CH₂)₂N(CH₃)₂, — O(CH₂)2NC₄H₈, ~O(CH₂)₂NC₃Hi₀, and — O(CH₂)₂NC₅Hi₀; those in which R² is hydrogen, alkyloxy, alkoxy, -SAc, -SCN, — OC(O)CH₂N(CH₃)₂, and -OC(O)R⁶, wherein R⁶ is a functional group including, but not limited to, alkyls (e.g., — CH₂CH₃), alkoxy esters (e.g., — CH₂OMe) and alkoxys (e.g., — OCH₃); those in which R³ is alkyl, alkoxy, acyloxy and hydroxy; those in which R⁴ is alkyl (e.g., methyl and ethyl); and those is which X is =0 or =N — OR⁵, wherein R⁵ is hydrogen or alkyl. Also preferred are compounds in which R¹ is — N(CH₃)₂; R² is hydrogen; R³ is methoxymethyl; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — N(CHa)₂; R² is hydrogen; R³ is -OC(O)H, -OC(O)CH₂CH₃ or -OC(O)C₆Hi₃; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — NC₄Hs, — NC₅Hi_O, — NC₄H₈O, -C(O)CH₃ or -SCH₃; R² is hydrogen; R³ is acetoxy; R⁴ is methyl; and X is =O. Also included are compounds in which R¹ is — N(CH₃)₂ or — NCsH₁₀; R² is hydrogen; R³ is methoxy; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is -NC₅Hi₀ or -C(O)CH₃; R² and R³ are both acetoxy; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — C(O)CH₃; R² is — SAc; R³ is acetoxy; R⁴ is methyl; and X is =O. Also included are compounds in which R¹ is — C(O)CH₃, -N(CH₃)₂, -NC₄H; or -NC₅Hi₀; R² and R³ are both methoxy; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — NC₅Hi_O, — C(O)CH₃ or -O(CH₂)₂N(CH₃)₂; R² is methoxy; R³ is acetoxy; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — N(CH₃)₂; R² is — OC(O)CH₂CH₃, -OC(O)OCH₃, -OC(O)OCH₂OCH₃, -OCH=CH₂, — OC(O)CH₂N(CH₃)₂ or — SCN; R³ is acetoxy; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is -N(CH₃)₂; R² is -OC(O)H; R³ is -OC(O)H; R⁴ is methyl; and X is =0. Also included are compounds in which R¹ is — N(CH₃)₂; R² is -OC(O)H; R³ is hydroxy; R⁴ is methyl; and X is =0. Also included are compounds in which R is — NC₅Hi₀; R² is hydrogen; R³ is acetoxy; R⁴ is methyl; and X is =N — OR⁵, wherein R⁵ is hydrogen. Also included are compounds in which R¹ is — N(CHs)₂ or — NC₅H10; R² is hydrogen or methoxy; R³ is methoxy or ethoxy; R⁴ is methyl; and X is =N — OR⁵, wherein R⁵ is hydrogen.

[0027] Exemplar compounds also include, but are not limited to, 17α-acetoxy-l 1 β-[4- (N,N-dimethylamino)phenyl]-21 -methoxy- 19-norpregna-4,9( 10)-diene-3,20-dione; 17α-formyloxy- 1 1 β-[4-(N,N-diethylamino)phenyl]- 19-norpregna-4,9-diene-3 ,20- dione; 17α-propionoxy-l l β-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene- 3,20-dione; 17α-heptanoyloxy-l l β-[4-(N,N-dimethylamino)phenyl]-19-norpregna- 4,9-diene-3,20-dione; 17α-methoxymethyl-l l β-[4-N,N-dimethylamino)phenyl]-19- norpregna-4,9-diene-3,20-dione; 17α-acetoxy- 1 1 β-(4-N-pyrrolidinophenyl)- 19- norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy- 11 β-(4-N-piperidinophenyl)- 19- norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy- 1 1 β-(4-N-morpholinophenyl)- 19- norpregna-4,9-diene-3,20-dione; 17α-acetoxy 1 lβ-(4-acetylphenyl)-19-noφregna-4,9- diene-3,20-dione; 17α-acetoxy- 1 lβ-(4-methylthiophenyl)-19-norpregna-4,9-diene- 3 ,20-dione; 17α-methoxy- 1 1 β-[4-(N,N-dimethylamino)phenyl]- 19-noφregna-4,9- diene-3 ,20-dione; 17α-methoxy- 1 1 β-(4-N-piperidinophenyl)- 19-noφregna-4,9-diene- 3,20-dione; 17α,21 -diacetoxy-1 1 β-(4-N-piperidinophenyl)- 19-norpregna-4,9-diene- 3 ,20-dione; 17α,21 -diacetoxy- 1 1 β-(4-acetylphenyl) 19-noφregna-4,9-diene-3 ,20- dione; 17α-acetoxy- 1 1 β-(4-acetylphenyl)-21 -thioacetoxy- 19-norpregna-4,9-diene- 3 ,20-dione; 17α,21 -dimethoxy- 1 1 β-[4-(N,N-dimethylamino)phenyl]- 19-norpregna- 4,9-diene-3 ,20-dione; 17α,21 -dimethoxy- 1 1 β-(4-N-pyrrolidinophenyl)- 19-norpregna- 4,9-diene-3,20-dione; 17α,21 -dimethoxy- 1 1 β-(4-N-piperidinophenyl) 19-norpregna- 4,9-diene-3 ,20-dione; 17α,21 -dimethoxy- 1 1 β-(4-acetylphenyl)- 19-norpregna-4,9- diene-3 ,20-dione; 17α-acetoxy- 1 1 β-(4-acetylphenyl)21 -methoxy- 19-norpregna-4,9- diene-3,20-dione; 17α-acetoxy-l lβ-{4-[2'-(N,N-dimethylamino)ethoxy]phenyl}-21- methoxy- 19-norpregna-4,9-diene-3,20-dione; 17α,21 -diformyloxy- 1 1 β-[4-(N,N- dimethylamino)phenylj- 19-norpregna-4,9-diene-3,20-dione; 17α-acetoxy- 1 1 β-[4- (N ,N-dimethylamino)phenyl]-21-propionyloxy-19-norpregna-4,9-diene-3 ,20-dione; 17α-acetoxy- 11 β- [4-(N,N-dimethylamino)phenyl]-21 -(2 '-methoxyacetyl)oxy- 19- norpregna-4,9-diene-3,20-dione; 17α-acetoxy-21 -hydroxy- 11 β- [4-(N ,N- dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione-21 -methyl carbonate; 17α-acetoxy- 1 1 β-[4-(N,N-dimethylamino)phenyl]-21 -( 1 '-ethenyloxy)- 19-norpregrιa- 4,9-diene-3 ,20-dione; 17α-acetoxy-l l β-[4-(N,N-dimethylamino)phenyl]-21-(2'-N,N- dimethylamino)acetoxy-19-norpregna-4,9-diene-3,20-dione; 17α-acetoxy-l l β-[4- (N,N-dimethylamino)phenyl]-21-thiocyanato-19-norpregna-4,9-diene-3,20-dione; 17α-acetoxy-l lβ-(4-N-piperidinophenyl)-19-norpregna-4,9-diene-3,20-dione 3- oxime; 17α-methoxy-l l β-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene- 3,20-dione 3-oxime; 17α-methoxy-l lβ-(4-N-piperidinophenyl)-19-norpregna-4,9- diene-3,20-dione 3-oxime; and 17α,21 -dimethoxy- 11 β-[4-(N ,N- dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione 3-oxime. [0028] Although compounds with general formula I are preferred, any known antiprogestin can be used in the practice of this invention for its known antagonist effect on the progesterone receptor. Examples of such antiprogestins include, but are not limited to, onapristone (1 l β-(p-(dimethylamino)phenyl)-17α-hydroxy-17-(3- hydroxypropyl)-13α-estra-4,9-dien-3-one), mifepristone (1 l β-(4- dimethylaminophenyl)-17β-hydroxy-17-(prop-l-ynyl)-estra-4,9-dien-3-one), lilopristone (l lβ-(p-(dimethylamino)phenyl)-17β-hydroxy-17-((Z)-3- hydroxypropenyl)estra-4,9-dien-3-one) and ZK 230 211. Further examples of antiprogestins include those disclosed in U.S. Patent Nos. 4,814,327, 4,829,060, 5,089,635, 6,339,098, 6,391,907 and 6,417,214, the contents of which are hereby incorporated by reference in their entirety.

[0029] The absorption of an antiprogestin, preferably a compound having general formula I, into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal in the form of particles spray-deposited on a solid substrate or in the form of micronized particles. For example, the particles may be relatively small, thus providing a large surface area which leads to increased dissolution and bioavailability.

[0030] In one embodiment, a composition is provided comprising particles of an antiprogestin, preferably a compound of formula I, deposited on a carrier substrate, The average diameter of a particle may be from about 50 nanometers (nm) to about 20,000 nm, although particles of any size having favorable dissolution and/or bioavailability profiles are within the scope of the invention. Preferably the average particle diameter is from about 50 nm to about 1000 nm, more preferably from about 200 nm to about 900 nm, most preferably from about 300 nm to about 800 nm. The average particle diameter may fall anywhere within the range of 50 nm and 20,000 nm, or may be less than 50 nm or greater than 20,000 nm. Preferably, at least 90% of the particles have a diameter less than 10,000 nm.

[0031] According to the present invention, a composition comprising particles of an antiprogestin, preferably a compound having general formula I, deposited on a carrier substrate, is formed by spraying a solution of said compound in at least one solvent onto carrier substrate particles under conditions that allow for a substantial amouni of solvent to be removed from said solution, such that particles of said compound having the desired size, preferably an average particle diameter of less than about 20,000 ran, are deposited on the carrier substrate.

[0032] Optionally, a surfactant may be present in the solution to be sprayed. According to the invention, a "surfactant" is a surface active agent which displays wetting, detergent or soap-like qualities as those agents are understood by those of ordinary skill in the art. Thus the term "surfactant" as used herein, represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, simethicone, ocoxynol, dioctyl sodium sulfosuccinate, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinate, fatty alcohols such as lauryl, cetyl, and steryl, glycerylesters, cholic acid or derivatives thereof, lecithins and phospholipids. Preferably, the surfactant, if present, is a polyglycolyzed glyceride. [0033] The carrier substrate is preferably a water-soluble compound or polymer. Carrier substrates useful in the present invention include, but are not limited to, saccharides, such as sugars (for example, lactose or sucrose) and sugar alcohols (for example, mannitol, or sorbitol), starches, flour, cellulose preparations and/or salts such as carbonates, bicarbonates and phosphates, for example tricalcium phosphate or calcium hydrogen phosphate. Sugars and sugar alcohols useful as carrier substrates include xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, lactose and the like. Preferably the sugar or sugar alcohol has a molecular weight less than 500 and is capable of easily dispersing and dissolving in water, thus improving the dissolution rate of the antiprogestin, preferably a compound of general formula I. More preferably, the sugar is lactose having particle size range from about 10 μm to about 3 mm. Polymers suitable as carrier substrates include, without limitation, polymers and copolymers of polyvinyl acohol, polyvinyl pyrrolidinone, polysaccharide polymers, acrylate polymers, methyacrylate polymers, phthalate polymers, polyvinyl acetate, polyethylene oxide, polypropylene, polyester and polyamide films. Cellulose preparations suitable as carrier substrates include, without limitation, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and ethyl cellulose. According to the present invention, one part by weight of an antiprogestin, preferably a compound having general formula I, is combined with about one to about 50 parts, preferably about 2.5 to about 20 parts, more preferably about 5 to about 10 parts by weight, of a carrier substrate.

[0034] For spray deposition, antiprogestins, preferably compounds of general formula I, can be dissolved in a non-aqueous solvent or mixed solvents, including mixtures of non-aqueous solvents as well as mixtures of non-aqueous and aqueous solvents. Useful non-aqueous solvents include, without limitation, alcohols, halogenated alkanes, dialkylketones and aromatic solvents. Particularly useful solvents include ethanol, preferably 95% ethanol, isopropyl alcohol, methylene chloride, chloroform, acetone, methylethyl ketone and toluene. Suitable solvents have the property of dissolving the antiprogestin, preferably a compound of general formula I, to a useful concentration, which should be at least about 0.5% (w/v), preferably at least about 2% (w/v), more preferably in the range of 5% to 10% (w/v) or greater than 10% (w/v). Typically, an antiprogestin, preferably a compound of general formula I, will be dissolved at a concentration that is well below its solubility limit. [0035] Spray deposition of antiprogestins, preferably compounds having general formula I, may be performed by any method known in the art. The design and operation of the sprayer can vary many characteristics of the final product, such as particle size and size distribution, bulk and particle densities, porosity, moisture content, flowability and friability. Preferably, the design and operation of the sprayer is such to ensure that the dried particles of the compound have an average particle size of less than or equal to about 20 microns. One of ordinary skill in the art will be able to adjust parameters to achieve similar results with sprayers that are available in the art. For example, spray deposition of antiprogestins, preferably compounds having general formula I, may be performed by electrostatic jet spray deposition. In this method, the solution comprising an antiprogestin, preferably a compound of general formula I, and optionally comprising a surfactant, is metered into an apparatus which projects a fine spray of droplets which are concentrated on a particular area of the substrate through the use of a defined area electrostatic field. [0036] Also useful are commercially available fluid-bed apparatus equipped with an insert for top spray (droplets are sprayed from the top) or bottom spray using a Wurster-type column, or tangential spray using a rotor disk (droplets are sprayed from a side of the bottom). In a Wurster fluid-bed apparatus, carrier substrate particles are entrained in a high velocity gas and pass through the Wurster column where fine droplets of solution comprising an antiprogestin, preferably a compound of general formula I, and optionally a surfactant are sprayed from a jet nozzle. The gas stream is heated to allow the evaporation of the solvent from the sprayed solution. The result is to deposit a plurality of particles of an antiprogestin, preferably a compound of general formula I, (and optionally a surfactant) onto a carrier substrate. Particularly useful is the Vector FL-M-I fluid bed system equipped with a 6 inch Wurster column. [0037] Regardless of the spray method used to obtain formulations of the present invention, the diameter of the droplets of solution that is sprayed and the speed at which the droplets collide with the carrier substrate during spraying and drying should be controlled so as to minimize aggregation of the sprayed particles as well as aggregation of the carrier substrate.

[0038] The amount of compound, solvent(s) and optional surfactant used for spraying are optionally chosen so that the resulting compound particles have the desired particle size which is preferably no more than 20 microns, more preferably less than or equal to 2 microns, most preferably less than or equal to 1 micron. [0039] Particle size analysis may be carried out using any technique known in the art. For example, a laser diffraction technique using photo correlation spectroscopy (Nicomp C370) may be used. The results are reported in terms of volume- weighted mean diameter. Volume- weighted mean diameter is defined as follows: (Σnd⁴)/(∑nd³) where n=the number of particles in a size interval characterized by a diameter "d". Remington's Pharmaceutical Sciences, 18^th edition, Mack Publishing Company, Easton, Pa. (1990).

[0040] The solution to be sprayed may comprise a surfactant such as a polyglycolysed glyceride. The absorption of spray deposited particles of an antiprogestin, preferably a compound having general formula I, into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal as a formulation with a polyglycolysed glyceride. Thus, a composition is provided comprising a carrier substrate and a deposit on said carrier substrate, wherein said deposit comprises particles of an antiprogestin, preferably a compound of formula I, and a polyglycolysed glyceride. The composition may further comprise a polyethylene glycol (PEG), such as a polyethylene glycol with molecular weight in a range from 200 to 35000 or such as PEG with molecular weight 400 (PEG400). Alternatively, the composition may further comprise Peceol, a readily dispersible, solubilizing agent comprised primarily of a mixture of mono- and diglycerides of oleic acid that closely resembles the end products of intestinal lipid digestion (Hauss et al. 1998. J. Pharm. ScL 87: 164-169).

[0041] "Polyglycolysed glycerides" may be a mixture of mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters, which may be of molecular weight between 200 and 600, where appropriate of free glycerol and free PEG, whose HLB (Hydrophile-Lipophile Balance) value may be adjusted by the length of the PEG chain, and whose melting point is adjusted by the length of the chains of the fatty acids, of the PEG and by the degree of saturation of the fatty chains, and hence of the starting oil; examples of such mixtures are GELUCIRE. Another suitable saturated polyglyocylsed glyceride is LABRASOL, a mixture of polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate.

[0042] In another embodiment, the present invention provides compositions comprising micronized particles of an antiprogestin, preferably a compound of general formula I, wherein the average particle diameter is less than 20 microns. Preferably, the average particle diameter is between 0.5 and 20 microns. For example, the average particle diameter may be 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1, 1 1.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or may fall anywhere within the range of 0.5 and 20 microns. More preferably, at least 90% of the particles have a diameter less than 10 microns.

[0043] Micronization of compounds having general formula I may be performed by any method known in the art. For example, micronization of compounds having general formula I may be performed in a radiator mill (jet air micronizer). Pinned disc mills or hammer mills can also be used. U.S. Patent Nos.: 2,032,827 and 4,018,388 disclose micronization techniques and machines and are hereby incorporated by reference in their entirety. The time of milling or grinding will be a function of the capacity and type of apparatus used.

[0044] Other methods of micronization useful in the present invention include the aerosol solvent extraction system (ASES) described, for example, in Steckel, et al, "Micronizing Steroids for Pulmonary Delivery by Supercritical Carbon Dioxide," Int. J. of Pharmaceutics, (1997), Vol. 152, No. 1, pp. 99-1 10 (incorporated herein by reference), which describes the preparation of a number of steroids in a spraying solution containing 1% (w/w) of the drug in an organic solvent such as dichloromethane, methanol or a mixture of both. The spraying solution was sprayed into supercritical dioxide and median particle size was determined to be in most cases under 5 microns. The addition of a surface active agent added to the spraying solution resulted in larger sized particles. Such micronized particles may be administered by any available route of administration.

[0045] Other preferred methods for preparing micronized drugs of the present invention are described in the U.S. Patent Nos.: 7,148,212; 7,029,700; 5,952,008; 5,855,913; 5,851 ,453; 5,874,064; 5,874,029; 5,833,891 ; 5,043,280; and 4,384,975, all of which are incorporated herein by reference in their entirety. [0046] Particle size analysis may be carried out using any technique known in the art. For example, a Coulter Counter, Model TA 2, which is an automatic apparatus for analyzing particle size distribution of powders, may be used. This apparatus makes it possible to detect particles independently of their form, density or color and measurement of the size is a direct function of their volume and thus of their mass. [0047] Micronization may be performed in the presence of a surfactant such as a polyglycolysed glyceride. The absorption of micronized particles of a compound having general formula I into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal as a formulation with a surfactant. Thus, in a related embodiment, the present invention provides a composition comprising micronized particles of a compound of general formula I, a polyglycolysed glyceride and optionally a pharmaceutically acceptable carrier. The compositions may further comprise a polyethylene glycol (PEG), such as a PEG with molecular weight in a range from 200 to 35000 or such as a PEG with molecular weight 400 (PEG400). Alternatively, the composition may further comprise ethanol or Peceol. Micronization in the presence of an oily excipient such as a polyglycolysed glyceride may be carried out more easily than in the dry or aqueous phase in that overheating of the compound is avoided, as is the need for cooling and lubricating during the micronization process.

[0048] The compositions may possess potent antiprogestational activity and minimal antiglucocorticoid activity, combined with improved absorption, which may render these compositions suitable for oral administration.

[0049] The compositions can be advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat meningioma; to treat uterine leiomyonas, to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; to induce cervical ripening, for hormone therapy; and for contraception.

[0050] The compositions having antiprogestational activity may also be characterized by antagonizing the effects of progesterone. As such, the compositions may be of particular value in the control of hormonal irregularities in the menstrual cycle, for controlling endometriosis and dysmenorrhea, and for inducing menses. In addition, the compositions can be used as a method of providing hormone therapy either alone or in combination with estrogenic substances in postmenopausal women, or in women whose ovarian hormone production is otherwise compromised. [0051] Moreover, the compositions can be used for control of fertility during the whole of the reproductive cycle. For long-term contraception, the compositions can be administered either continuously or periodically depending on the dose. In addition, the compositions may be of particular value as post-coital contraceptives, for rendering the uterus inimical to implantation, and as "once a month" contraceptive agents.

[0052] A further important utility for the compositions lies in their ability to slow down growth of hormone-dependent tumors and/or tumors present in hormone- responsive tissues. Such tumors include, but are not limited to, kidney, breast, endometrial, ovarian, and prostate tumors, e.g., cancers, which may be characterized by possessing progesterone receptors. In addition, such tumors include meningiomas. Other utilities of the compositions include the treatment of fibrocystic disease of the breast and uterine. [0053] The compositions can be administered to any warm-blooded mammal such as humans, domestic pets, and farm animals. Domestic pets include dogs, cats, etc. Farm animals include cows, horses, pigs, sheep goats, etc.

[0054] The amount of active ingredient that can be combined with an optimal carrier material to produce a single dosage form will vary depending upon the disease treated, the mammalian species, and the particular mode of administration. For example, a unit dose may comprise between 0.1 milligram and 1 gram of the active ingredient or between 0.001 and 0.5 grams. However, the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy.

[0055] The compositions can be administered by a variety of methods. For example, the compositions can be administered via the oral route in a form of solutions, suspensions, emulsions, tablets, including sublingual and intrabuccal tablets, soft gelatin capsules, including solutions used in soft gelatin capsules, aqueous or oil suspensions, emulsions, pills, lozenges, troches, tablets, syrups or elixirs and the like. [0056] The compositions can be also administered as an implant including SILASTIC and biodegradable implants or via intramuscular and intravenous injections. [0057] The compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents. Tablets containing the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients, which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid and talc. Tablets can be uncoated or, alternatively, they can be coated by known methods to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0058] Formulations for oral use can also be presented as hard gelatin capsules wherein the particles of the active ingredient deposited on a carrier substrate are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein particles of the active ingredient deposited on a carrier substrate are mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0059] Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (erg., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g. polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.

[0060] Oil suspensions can be formulated by suspending particles of the active ingredient deposited on a carrier substrate in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0061] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can be formulated from the active ingredients in admixture with a dispersing, suspending and/or wetting agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present. [0062] The pharmaceutical composition can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening and flavoring agents. [0063] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0064] The pharmaceutical composition can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. [0065] The compound can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [0066] They can also be administered by in intranasal, intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations.

[0067] Compounds administered by the topical route can be administered as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. [0068] The invention will be described in greater detail by way of the following specific, but not limiting, examples.

Example 1. Preparing a Composition Comprising Particles of a Compound of General Formula I in Admixture with Lactose

[0069] A biologically effective amount of a compound of general formula I, e.g. CDB-4124 or CDB-2914, is dissolved in a suitable solvent, e.g., ethanol, with slight warming to 30° C. The solution is sprayed onto 1 kg of lactose in, e.g., a Vector FL-

M-I fluid bed system equipped with a 6 inch Wurster column. The spray rate, static

inlet pressure and inlet temperature are adjusted such that particles of the compound of general formula I have the desired average particle diameter, preferably less than 20 microns, as measured by e.g, laser diffraction technique using photo correlation

spectroscopy.

Example 2. Preparing a Composition Comprising Particles of a Compound of General Formula I in Admixture with Lactose and GELUCIRE 44/14,

PEG400

[0070] A biologically effective amount of a compound of general formula I, e.g.,

CDB-4124 or CDB-2914, is dissolved in a suitable solvent, e.g., ethanol, with slight

warming to 30° C. PEG400 and GELUCIRE 44/14 is then added to the solution in the 2.87: 1 ratio of GELUCIRE 44/14 to PEG400. The solution is sprayed onto 1 kg of lactose in, e.g., a Vector FL-M-I fluid bed system equipped with a 6 inch Wurster

column. The spray rate, static inlet pressure and inlet temperature are adjusted such

that particles of the compound of general formula I have the desired average particle diameter, preferably less than 20 microns, as measured by e.g, laser diffraction technique using photo correlation spectroscopy. Example 3. Preparing a composition comprising micronized particles of a compound of general Formula I

[0071] A jet air pulverizer such as a Spiral-Mill (fluid energy mill) manufactured by

Schering, AG, West Germany, is used to micronize a compound of general Formula I,

e.g. CDB-4124 or CDB-2914. Milling occurs due to a strong continuous acceleration and decelaration of the feed stock by expanding nitrogen gas within the cylindrical milling chamber. Collisions occur constantly between the particles, resulting in comminution. A cyclone separator is used to internally classify the material. The

finest particles leave the milling chamber through a central outlet, whereas the larger particles continue circling in the mainstream around the periphery. The fineness of the micronized material is controlled by adjusting the feed rate, milling gas pressure, and the angle of the gas jets. The air speed in the mill is about 300-500 meters per

second. Due to the high air speed, the compound is in the mill for a period of time

less than about 10 seconds, depending on the particle size of the starting material.

Micronized compound consisting of particles preferably have an average particle diameter of less than 20 microns are optionally combined with pharmaceutically acceptable excipients.

Example 4. Preparing a composition comprising GELUCIRE 44/14, PEG400 and micronized particles of a compound of general Formula I in a capsule form

[0072] PEG400 is heated to 50⁰C, GELUCIRE 44/14 is then added in the 2.87:1 ratio of GELUCIRE 44/14 to PEG400. The mixture is then heated with good mixing until GELUCIRE 44/14 is melted to completion. Micronized particles of a compound of general Formula I are then added to the concentration of 3.42%. The solution is then held at 50⁰C for 30 minutes. Empty pre-weighted capsules were then filled with the solution at the target weight of net fill of 365 mg per capsule. Example 5. Preparation of Micronized Antiprogestin Compositions Using ASES [0073] Antiprogestins according to the present invention may be prepared by using the aerosol solvent extraction system (ASES) described, for example, in Steckel, et al., "Micronizing Steroids for Pulmonary Delivery By Supercritical Carbon Dioxide," Int. J. of Pharmaceutics, (1997), Vol. 152, No. 1, pp. 99-1 10, (incorporated herein by reference). The compounds of the present invention are prepared in a spraying solution containing 1 % (w/w) of the drug in an organic solvent such as dichloromethane, methanol or a mixture of both. Other suitable organic solvents are also well known in the art. The spraying solution is then sprayed into supercritical carbon dioxide and median particle size is determined. In most cases particle size is expected to be around 5 microns. The addition of a surface active agent added to the spraying solution will result in larger sized particle.

Claims

CLAIMS:What is claimed is:

1. A composition comprising a carrier substrate and a deposit on said carrier

substrate, said deposit comprising particles of a compound having the general

formula:

wherein:

R¹ is a member selected from the group consisting of — N(CHs)₂, — NHCH₃, —

NC₄H₈, --NC₅H₁₀, and — NC₄H₈O; R² is a member selected from the group consisting of hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl, and — OC(O)R⁶, wherein R⁶ is a member selected from the group consisting of alkyl, alkoxy ester and alkoxy; R³ is a member selected from the group consisting of alkyl-alkoxy, alkoxy and acyloxy; R is a member selected from the group consisting of hydrogen and alkyl;

X is a member selected from the group consisting of =0 and =N — OR⁵, wherein

R³ is a member selected from the group consisting of hydrogen and alkyl.

2. The composition of claim 1, wherein said compound is 17α-acetoxy-l 1 β-[4- (N,N-dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9(10)-diene-3,20- dione.

3. The composition of claim 1 , wherein said compound is 17α-acetoxy-l lβ-[4- (N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione.

4. The composition of claim 1 wherein the compound has the structural formula:

5. The composition of claim 1 wherein the compound has the structural formula:

CH₃

6. The composition of claim 1, wherein the deposit further comprises a surfactant.

7. The composition of claim 6, wherein the surfactant is a polyglycolysed glyceride.

8. The composition of claim 7, wherein the polyglycolysed glyceride consists of Cs- C|8 glycerides and polyethylene glycol esters.

9. The composition of claim 7, wherein the polyglycolysed glyceride is selected from the group consisting: GELUCIRE 35/10, 37/02, 44/14, 50/13, WL

2514CS and LABRASOL.

10. The composition of claim 7 further comprising polyethylene glycol (PEG).

1 1. The composition of claim 7 further comprising PEG400.

12. The composition of claim 7, further comprising peceol.

13. The composition of claim 1, wherein said particles have an average particle diameter of from about 50 nanometers to about 20 microns.

14. The composition of claim 13, wherein said average particle diameter is from about 200 nanometers to about 900 nanometers.

15. The composition of claim 13, wherein said average particle diameter is from about 300 nanometers to about 800 nanometers.

16. The composition of claim 15, wherein at least 90% of said particles have a diameter less than 10 microns.

17. The composition of claim 1, wherein the carrier substrate is selected from the group consisting of: xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, lactose, polyvinyl acohol, polyvinyl pyrrolidinone, polysaccharide polymers, acrylate polymers, methyacrylate polymers, phthalate polymers, polyvinyl acetate, polyethylene oxide, polypropylene, polyester, polyamide films, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and ethyl cellulose.

18. A composition comprising micronized particles comprising a compound having the general formula:

wherein:

NC₄H₈, -NC₅Hi₀, and — NC₄H₈O; R² is a member selected from the group consisting of hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl, and — OC(O)R⁶, wherein R⁶ is a member selected from the group consisting of alkyl, alkoxy ester and alkoxy; R³ is a member selected from the group consisting of alkyl-alkoxy, alkoxy and acyloxy;

R⁴ is a member selected from the group consisting of hydrogen and alkyl; X is a member selected from the group consisting of =0 and =N — OR⁵, wherein R⁵ is a member selected from the group consisting of hydrogen and alkyl.

19. The composition of claim 18, wherein said compound is 17α-acetoxy- 1 1 β-[4- (N,N-dimethylamino)phenyl]-21 -methoxy- 19-norpregna-4,9( 10)-diene-3 ,20- dione.

20. The composition of claim 18, wherein said compound is 17α-acetoxy- 1 lβ-[4- (N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione.

21. The composition of claim 18 wherein the compound has the structural formula:

22. The composition of claim 18 wherein the compound has the structural formula:

23. The composition of claim 18. wherein the composition further comprises a polyglycolysed glyceride.

24. The composition of claim 23, wherein the polyglycolysed glyceride is selected from the group consisting of: GELUCIRE 35/10, 37/02, 44/14, 50/13, WL

2514CS, and LABRASOL.

25. The composition of claim 23 further comprising polyethylene glycol (PEG).

26. The composition of claim 25 wherein the PEG is PEG400.

27. The composition of claim 23 further comprising ethanol.

28. The composition of claim 23 further comprising peceol.

29. The composition of claim 18, wherein said micronized particles have an average particle diameter of from about 0.5 microns to about 20 microns.

30. The composition of claim 29, wherein said average particle diameter is less than 10 microns.

31. The composition of claim 30, wherein at least 80% of said micronized particles have a diameter less than 10 microns.

32. A capsule for oral use, comprising a composition according to claim 1 or claim 18.

33. A tablet for oral use, comprising a composition according to claim 1 or claim 18.

34. A method of producing an antiprogestational effect in a patient, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

35. A method of inducing menses in a patient, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

36. A method of treating endometriosis, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

37. A method of treating dysmenorrhea, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

38. A method of treating endocrine hormone-dependent tumors, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

39. A method of treating meningiomas, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

40. A method of treating uterine fibroids in a patient, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

41. A method of inhibiting uterine endometrial proliferation in a patient, said method comprising administering to said patient an effective amount of the composition of claim 1 or claim 18.

42. A method of inducing labor, said method comprising administering to a patient an effective amount of the composition of claim 1 or claim 18.

43. A method of contraception, said method comprising administering to a patient an effective amount of the composition of claim 1 or claim 18.

44. A method of post-coital contraception, said method comprising administering to a patient an effective amount of the composition of claim 1 or claim 18.