CA2150554A1 - Cyclodextrin and polymer based drug delivery system - Google Patents

Abstract

Pharmaceutical compositions comprising a therapeutic agent, an effective stabilizing amount of carboxy-containing polymer and cyclodextrin, in an aqueous medium, wherein said cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ?, ? and ?-cyclodextrin, modified or unmodified; and methods for stabilizing and solubilizing a therapeutic agent in a pharmaceutial composition, comprising combining said therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, said cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ?, ? and ?-cyclodextrin, modified or unmodified.

Description

-wo 94/12217 215 0 ~ 5 4 PCT/US93/11651 CYCLODEXTRIN AND POLYI~IER
BASED DRUG DELIVERY SYSTEM

F~LD OF IHE INVENTION
The present invention relates to pharm~ceutical formulations comprising cyclodextrin or cyclodextrin derivatives, carboxy-co,-~ining polymers and therapeutic agents. The invention further relates to topical ophthalmic compositions comprising therapeutic agents, particularly, amino-substituted sterold therapeutic agents, lightly cross-linked carboxy-containing polymers and selected cyclodextrin derivatives. The invention further relates to methods of stabilizing and solubilizing amino-substituted steroid therapeuticagents in formulations using cyclodextrin derivatives, in combination with carboxy-containing polymers.

BACKGROUND

Some valuable therapeutic agents (drugs) are difficult to use because of their low stability in water or body fluids. Some therapeutic agents suffer from stability problems and they can cause irritation. Drug instability can limit the usefulness of pharm~reufir~l compositions containing them by shortening the shelf-life of the formulations and/or requiring stringent controlof storage conditions. The insolubility of some therapeutic agents can seriously hamper efforts to utilize the compounds to their full potential because low solubility limits their bioavailability. Some aminosteroids illustrate these problems because they tend to be unstable and to have low solubility in aqueous environments such as body fluids. Instability of aminosteroids occurs primarily as a consequence of their antioxidative ~r~e~ lies. Because they are potent antioxidants, the aminosteroids are especially sensitive to oxidative degradation. Moreover, these compounds are -WO 9~/12217 ` , - PCT/US93/11651 .

2 1 ~ 4 2 subject to hydrolytic degradation and rearrangement. There is thus a need for improved pharm~celltir~l compositions comprising therapeutic drugs with agents that stabilize and solubilize the pharmaceutical compositions and ameliorate irritation. Providing compositions that deliver the therapeutic agentS to a target site over a prolonged period of time is also an objective for many applications.

A number of publications are available pertaining to drug delivery systems, cyclodextrin, and drugs combined with cyclodextrin or pharm~eeutir~l vehicles. It has not been suggested, however, that cyclodextrins and carboxy-containing polymers would, when combined, stabilize and solubilize therapeutic agents and be compatible with one another.
It was also not known that aminosteroids disclosed in International Publication No. WO 87/01706 and U.S. Patent No. 5,124,154 (discussed below) would be co-llpatible or stable with the combination of carboxy-cont~ining polymers with cyclodextrins. Publications pertinent to the background of the present invention are identified below.

A variety of col"po~iLions have been formulated to deliver drugs to the eye, skin and other parts of the body in a sllst~ined manner. Sust~ined release ophth~lmic formulations of an ophth~lmic drug and a high molecular weight polymer to form a highly viscous gel, for instance, have been described in Schoenwald et al U.S. Patent No. 4,271,143, issued June 2, 1981 and Schoenwald et al U.S. Patent No. 4,407,792, issued October 4, 1983.
U.K. Patent Application GB 2007091 A, published May 16, 1979, describes an ophthalmic composition in the form of a gel comprising an aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance and an ophthalmic drug, the gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20C.

WO 94112217 21~ ~ ~ 5 ~ PCT/US93/11651 U.K. Patent Application GB 2013084 A, published August 8, 1979, describes an aqueous gel for application to the conjunctival sac of the eye comprising an ophthalmic drug and a polymer having carboxylic or anhydride functional groups and a molecular weight in excess of 1,000,000, such as S carboxypolymethylene, carboxyvinyl and ethylene maleic anhydride polymers.
Robinson U.S. Patent No. 4,615,697, issued October 7, 1986, discloses a controlled release composition and method of use based on a bioadhesive and a treating agent, such as an anti-inflammatory agent. The bioadhesive is a water-swellable, but water-insoluble~ fibrous, cross-linked carboxy-functional polymer having a plurality of repeating units of which about 80 percent contain at least one carboxyl functionality and a cross-linkingagent which is substantially free from polyalkenyl polyethers.

U.S. Patent No. 5,192,535, issued March 9, 1993 and ~ignecl to the ~ccignt~ hereof, describes formulation of lightly cross-linked polymers, preferably ones prepared by suspension or emulsion polymerizing at least about 90% by weight of a carboxyl-cont~ining monoethylenically unsaturated monomer such as acrylic acid with from about 0.1 % to about 5% by weight of a polyfunctional, and preferably difi-n~tion~l, cross-linking agent such as divinyl glycol (3,4-dihydroxy-1,5-heY~ e), having a particle size of not more than about 50 ~m in equivalent spherical diameter, with an ophth~lmic meAir~ment, e.g., the steroid fluorometholone, into suspensions in aqueous medium in which the amount of polymer ranges from about 0.1 % to about 6.5% by weight, based on the total weight of the aqueous suspension, the pH
is from about 3.0 to about 6.5, and the osmotic pressure (osmolality or tonicity) is from about 10 mOsM to about 400 mOsM. These new topical ophthalmic medicament delivery systems have suitably low viscosities which permit them to be easily a(lmini~tered to the eye in drop form, and hence to be comfortably ~dmini~tered in con~i~tent, accurate dosages. These WO 94/12217 ~ PCT/US93/11651 2 1 5 ~ 4 suspensions will rapidly gel in the eye after coming into contact with the eye'stear fluid to a substantially greater viscosity than that of the originally-introduced suspension and thus remain in place for prolonged periods of time to provide sllct~ined release of the ophthalmic medicament. See International Publication Number WO 92/00044 published January 9, 1992 and International Publication No. WO 89/06964, published August 10, 1989.

International Publication No. WO 87/01706, published March 26, 1987, which discloses a number of aminosteroids and their therapeutic use in a variety of contexts, as well as ~(lminictration techniques and dosages, does not disclose treatment or prevention of ophthalmic dice~cec or disorders. Nor does it disclose topical application to the eye or administration by intraocularinjection.

Applicants' U.S. Patent No. 5,124,154, discloses methods and compositions which are ~lecigned to enhance the ability of the tissues of the eye to respond to trauma, to aging, to surgery, to the threat of glaucoma by increasing intraocular pr~s~ulc:, to thepotential loss of vision from progression of macular degeneration and the like by supplementing, both acutely and chronically, the natural ability of the eye to resist oxidative damage. In one aspect, the '154 invention discloses methods and compositions for preventing or treating ophthalmic ~ice~ces or disorders in a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, with an ophth~lmiç~lly effective amount of certain amino-substituted steroids which function as a the-d~ulic agent (particularly an antioxidant agent) is in an inert vehicle, to arrest processes (particularly oxidation processes) ~l~m~ging to the eye.

WO 94/12217 2 ~ 5 ~ 5 ~ 4 PCT/US93tll651 Applicants' U.S. Patent No. 5,124,154 further relates to formulations of aminosteroids with an app-opliate inert vehicle or carrier for prevention or treatment of ophthalmic ~ es or disorders. Topical, intraocular and systemic routes of ~dminictration are described. The term "inert vehicle" is S broadly used in those earlier applications to optionally include adjuvants, preservatives, buffers, demulcents and anything else that is essentially inert relative to the therapeutic function (particularly the antioxidant function) of the aminosteroids as that function relates to eye tissue. Topical form~ ion~
should generally include between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight, of the amino-substituted steroid therapeutic agent in a suitable polymeric carrier. Polymeric carriers include lightly cross-linked carboxy-containing polymers (such as polycarbophil), dextran, cellulose derivatives, polyethyleneglycol 400 and other polymeric demulcents. Other additions taught as desirably included in the topical formulations include lS sodium chloride, EDTA (disodium edetate), surfactants, and preservatives such as BAK (benzalkonium chloride).

Cyclodextrins are cyclic oligos~ch~rides. The most common cyclodextrins are ~-cyclodextrin, which is composed of a ring of six glucose residues; ,6'-cyclodextrin, which is composed of a ring of seven glucose residues; and ~y-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharm~ceutic~l~, and many inclusion complexes with drugs have been reported. ,l~-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility (about 1.8% w/v at 25C) and attendant nephrotoxicity have limited its use in the pharm~eutic~l field.

WO 94/12217 ~ ~ ~ PCT/US93/11651 ~
21~5~ 6 Attempts to modify prope~ lies of the natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)-,~-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-,B-cyclodextrin, hydroxypropyl-,~-cyclodextrin, ~B-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive S review of cyclodextrins and their use in pharm~ceutic~l research, see Pitha et al, in Controlled Drug Delivery~ ed. S.D. Bruck, Vol. I, CRC Press, Boca Raton, Florida, 125-148 (1983). For an even more recent overview, see Uekama et al, in CRC Critical Reviews in Therapeutic Dnlg Carrier Systems, Vol. 3 (1), 1-40 (1987); Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D.D. Breimer and P. Speiser, Elsevier Science Publishers B.V.
(Biomedical Division), 1987, 181-194; and Pagington, Chemistry in Britain, May 1987, 455-458.

Inclusion complexes of ~Y-"B- or ~y-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. These descriptions include those documents s-~mm~rized in Bodor U.S. Patents Nos. 4,983,586 and 5,024,998, incorporated by reference herein in their entireties and relied upon.Particular reference may be made to Lipari U.S. Patent No. 4,383,992, which describes inclusion complexes of ~-cyclodextrin itself with a variety of steroidal hormones (corticosteroids, androgens, anabolic steroids, estrogens and progestagens). The complexes are said to have improved water solubility and increased therapeutic response in the eye. However, as noted above, ,~-cyclodextrin has low aqueous solubility (about 1.8% w/v at 25) with attendant nephrotoxicity.

Hydroxypropyl-~-cyclodextrin and its preparation by propylene oxide addition to ~B-cyclodextrin were described in Gramera et al U.S. Patent No.

3,459,731 over 20 years ago. (Gramera et al also described the analogous preparation of hydroxyethyl-,B-cyclodextrin by ethylene oxide reaction with ,~-wo 94/12217 2 ~ ~ O ~ 9 PCT/US93/11651 cyclodextrin.) Much more recently, Pitha and co-workers have described the improved pr~d~ion of this cyclodextrin derivative and its effects on the dissolution of various drug molecules. Pitha U.S. Patent No. 4,596,795, dated June 24, 1986, describes inclusion complexes of sex hormones, S particularly te~lo~eroile, p~uge~ ulle and estradiol, with specific cyclodextrins, preferably hydroxypropyl-,B-cyclodextrin and poly-,l~-cyclodextrin. The complexes enable the sex hormones to be s~lcce~fully delivered to the systemic circulation via the sublingual or buccal route; the effectiveness of this delivery is believed to be due to "the high dissolution power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure of their complexes with steroids, and their low toxicity and irritancy of mouth tissue". Success with other cyclodextrins, including poly- y-cyclodextrin and hydroxypropyl-~y-cyclodextrin, have also been noted in the Pitha patent. See also Pitha et al, J. Pharm. Sci.. Vol. 74, No. 9, September 1985, 987-990, concerning the same and related studies. Pitha et al also describe in the J.
Pharm. Sci. publication the storage stability of tablets containing a testosterone/hydroxypropyl-,B-cyclodextrin complex and the lack of toxicity of the cyclodextrin derivative itself, as well as the importance of the amorphous nature of the cyclodextrin derivatives and their complexes with drugs in improving dissolution p~u~llies.

The improved, optimized preparation and purification of hydroxypropyl-,B-cyclodextrin has been described by Pitha et al, International Journal of Pharm~reutics, 29, 73-82 (1986). In the same publication, the authors have described increased water solubility for 32 drugs in concenL.~ted (40 to 50%) aqueous solutions of hydroxypropyl-~-cyclodextrin; among the drugs for which the authors have reported improved solubilization are dexamethasone, estradiol, estriol, ethinylestradiol-3-methyl ether, ethisterone,17-methylte~ le~o.le norethindrone, progesterone, spironolactone and testosterone. The authors inrlir~ted this to be an extension of their earlier WO 9~/12217 ' . PCT/US93tll651 21~05~ 8 work with hydroxypropyl-,B-cyclodextrin, which was previously found effective for oral ~mini~tration of the sex hormones to humans. Their later work reported in Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986), has also been described in Pitha U.S. Patent No. 4,727,064, dated S February 23, 1988. That patent claims a composition cont~ining an amorphous complex of cyclodextrin and a drug, and a method of producing a stabilizing amorphous complex of a drug and a mixture of cyclodextrins comprising (1) dissolving an intrinsically amorphous mixture of cyclodextrin derivatives which are water soluble and capable of forming inclusion complexes with drugs in water; and (2) solubilizing lipophilic drugs into aqueous media to form a solution and form a solubilized drug/cyclodextrin complex. The patent describes the preparation of various substituted amorphous cyclodextrins, including hydroxypropyl-,B-cyclodextrin and hydroxypropyl-~y-cyclodextrin, the latter by analogous conden~tion of propylene oxide and y-cyclodextrin.

Uekama et al, CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), 1-40 (1987), have described the characteristics of various cyclodextrins, including hydroxypropyl-~-cyclodextrin. The authors have presented data showing improved solubilization in water in the presence of 15 mg/mL of hydroxypropyl-,~-cyclodextrin for the drugs carmofur, diazepam, digitoxin, digoxin, flull)iplufe,l, indomethacin, isosorbide dinitrate, phenytoin, prednisolone, plug~Lelune and testc sterone. Uekama et al have indic~t~i that cyclodextrins at sufficiently high concentrations cause hemolysis, and that the methylated cyclodextrins have higher hemolytic activity than the natural cyclodextrins. Hydroxypropyl-,~-cyclodextrin is said to cause hemolysis bçginning at 4.5 mM. The authors have further indicated that palell~eldl lmini~tration of large doses of cyclodextrins should be avoided, but that " y-cyclodextrin and hydroxypropyl-~B-cyclodextrin seem to be useful in drug wo 94/12217 21 S O ~ 5 ~ PCT/US93/11651 solubilization for injections and liquid preparations used for mucous membranes. "

JANSSEN PHARMACEUTICA N.V.'s International Patent Application No. PCT/EP84/00417, published under International Publication No. W085/02767 on July 4, 1985, has described pharmaceutical compositions comprising inclusion compounds of drugs, which are unstable or only sparingly soluble in water, with partially etherified ,B-cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups. Among the cyclodextrin derivatives contemplated is hydroxypropyl-~B-cyclodextrin, while the drugs include nonsteroidal anti-rheumatic agents. steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole and triazole. Pharmaceutical compositions described in WO 85/02767 include oral, parenteral and topical formulations, with 4 to 10%
solutions of cyclodextrin derivatives being used to solubilize various drugs.
Improved solubilities of indomethacin, digitoxin, proge~ une, dexamethasone, hydrocortisone and diazepam using 10% hydroxypropyl-,6'-cyclodextrin are reported.

The preparation of amorphous water-soluble cyclodextrin derivatives, including 2-hydroxyethyl-,~-cyclodextrin,3-hydroxypropyl-~B-cyclodextrin and 2-hydroxypropyl-~y-cyclodextrin, is described by Irie et al, Pharmaceutical Research, Vol. 5, No. 11, 1988, 713-717. That report also addresses the distribution of the substituents among the glucose residues of the cyclodextrin ring.

A pharm~ utical evaluation of hydroxyalkyl ethers of ,~-cyclodextrin has been reported by Yoshida et al, International Journal of Pharm~celltics 46, 1988, 217-222. Aqueous solubilities, surface activities, hemolytic activity and local irritancy are r~l)Gl led. The data suggest that hydroxyal~yl-~B-Wo g~/12217 PCT/uS93/11651 2150~5~ lO

cyclodextrins overcome many of the undesirable characteristics of ,~-cyclodextrin usage in pharm~rellticals.

JANSSEN PHARMACEUTICA N.V.'s European Patent Application No. 86200334.0, published under EPO Publication No. 0197571 on October 15, 1986, describes y-cyclodextrin derivatives which are ~y-cyclodextrin substituted with C,-C6 alkyl, hydroxy Cl-C6 alkyl, carboxy C,-C6 alkyl or C,-C6 alkyloxycarbonyl C,-C6 alkyl or mixed ethers thereof. Among the specific derivatives named are hydroxypropyl- y-cyclodextrin and hydroxyethyl-~-cyclodextrin. Compositions comprising the cyclodextrin derivatives and a drug are also described. See also coll~s~)onding Muller United States Patent No. 4,764,604, dated August 16, 1988.

Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D.D.
Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomef~
Division), 1987, 181-194, has described the effects on bio-pharrn~ceulir,~l properties of maltosyl and glucosyl cyclodextrin derivatives, as well as hydroxypropyl and other hydrophilic cyclodextrin derivatives, including enhanced drug absorption. The my~h~ni~m of enhancing drug absorption is described and the appale.~t stability constants for inclusion complexes of various drugs with ,6'-cyclodextrin, dimethyl-,~'-cyclodextrin, hyd.op,upyl-,~-cyclodextrin and maltosyl-,~'-cyclodextrin are given. Drugs studied with these cyclodextrins include prednisolone, progesterone, spironolactone and testosterone.
Koizumi et al, Chem. Pharm. Bull. 35 (8), 3413-3418 (1987), have reported on inclusion complexes of poorly water-soluble drugs with glucosyl cyclodextrins, namely 6-O-(Y-D-glucosyl-~-CD (G,-~-CD), 6-O-cY-D-glucosyl-,B-CD (G,-,B-CD) and 6A, 6D-di-O-cY-D-glucosyl-,~-CD (2G,-~-CD).

-wo 94/12217 21~ n 5 5 ~ PCT/US93/11651 11 , Okada et al, Chem. Pharm. Bull. 36(6), ~176-2185 (1988), have reported on the inclusion complexes of poorly water-soluble drugs with maltosyl cyclodextrins, namely 6-O-cY-maltosyl-cx-CD (G2-cY-CD), 6-O-~-maltosyl-~'-CD (G2-,l~-CD), 6-O-o~-maltosyl- y-CD (G2-~y-CD), 6-O-~-maltotriosyl-~-CD (G3-cY-CD), 6-O-~-maltotriosyl-,B-CD (G3-~-CD) and 6-O-a!-maltotriosyl-~y-CD (G3- y-CD).

Yamamoto et al, in International Journal of Pharmaceutics 49, 163-171 (1989), have described physicochemical properties of branched ~'-cyclodextrins such as glucosyl-,B-cyclodextrin, maltosyl-,B-cyclodextrin and dimaltosyl-~-cyclodextrin, and their inclusion characteristics. Those authors report that thebranched ~-cyclodextrins are better solubilizers for poorly water-soluble drugs and have less hemolytic activity than ~-cyclodextrin itself, and they suggest that glucosyl-,~-cyclodextrin and maltosyl-k'-cyclodextrin may be espe~ lly useful in ~Jarelltel~l prepal~lions.

J~p~n~se Kokai 63-135402 (TOKUYAMA SODA KK), published June 7, 1988, describes compositions consisting of maltosyl-,B-cyclodextrin and at least one of digitoxin, nifedipine, flurubiprophene, isosorbide nitrate, phenytoin, progesLeloi1e or testosterone. The compositions have improved water solubility and reduced erythrocyte destruction, are safe for humans and can be used as injections, eye drops, syrups, and for topical and mucous membrane application.

J~p~nese Kokai 62-281855 (DAIKIN KOGYO KK), published December 7, 1987, describes stable, water-soluble inclusion compounds of maltosyl-~-cyclodextrin with a variety of vitamins and hormones, e.g. steroid hormones such as prednisolone, hydrocortisone and estriol. These lipophilic vitamins and hormones can thus be used as aqueous solutions.

wO 94/12217 ~ PcT/uss3/11651 2~5~54 12 J~r~nese Kokai 63-036793 (NIKKEN CHEM KK), published February 17, 1988, describes the preparation of dimaltosyl-~-cyclodextrin and its general use in medicines.

S J~p~nçse Kokai 62-106901 (NIKKEN CHEM KK), published May 18, 1987, describes the p,c~pal~ion of diglucosyl-,B-cyclodextrin and its general use for pharm~r~uti~l~.

J~r~n~se Kokai 61-236802 (NIKKEN CHEM KK), published October '2, 1986, describes the preparation of maltosyl- y-cyclodextrin and its general use with drugs.

J~r~nese Kokai 61-197602 (NIKKEN CHEM KK), published September 1, 1986, describes the preparation of maltosyl-~-cyclodextrin and its expected use in m~icines.

J~r~nese Kokai 61-070996 (NIKKEN CHEM KK), published April 11, 1986, describes the p,epaldtion of maltosyl-~-cyclodextrin and its general use in pharmaceuticals.
J~p~n.ose Kokai 63-027440 (SANRAKU OCEAN), published February 5, 1988, describes co.-.positions containing a water-insoluble or slightly soluble drug together with glucosylated branched cyclodextrin.
Among the drugs mentioned are steroid hormones.
J~p~n~se Kokai 62-164701 (SHOKUHIN SANGYO BIO), published July 21, 1987, describes the p,~a,~tion of diglucosyl-~-cyclodextrin and its general use in me~icine WO 9~/12217 215 0 ~ 5 4 PCT~US93/11651 J~p~n~Pse Kokai 62-003795 ('rOKUYAMA SODA KK), published January 9, 1987, describes production of glucose and maltoligo~cch~ride (2-4 glucose units) derivatives of cY-, ,~- and y-cyclodextrin and their use as stabilizers for pharm~euti(~
s Bodor U.S. Patents Nos. 5,0`02,935, issued March 26, 1991, and 5,017,566, issued May 21, 1991, relate to stabilizing the reduce~, dihydropyridine forms of dihydropyridine ~ pyridinium salt redox systems for brain-targeted drug delivery by complexation with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ,B- and y-cyclodextrins. The compleY~Ps also provide a means for increasing the ratio of initial brain to lung concentrationsof drug, leading to decreased toxicity. In selected instances, improved water solubilities are noted as well. In a ~rerelled aspect, the redox system is a redox carrier system and the reduced, dihydropyridine form can be ~,ese"ted by the formula [D-DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine ~ pyridinium salt redox carrier. The "centrally acting" drug species is broadly defined and includes many classes of drugs, including steroids and, specifically, anti-in~ oly adrenal cortical steroids such as hydlocolLisone, bet~methesone, cortisone, del~mPth~one, fl~lm~th~onP, fluprednisolone, meprednisone, methyl prednisolone, prednisolone, prednisone, triamicinolone, cortodoxone, fludrocortisone, flurandrenolone ~cetonide (flurandrenolide), par~mPth~one and the like. The "dihydropyridine carrier" or "[DHC]" is defined as any nontoxic carrier moiety comprising, cont~ining or including the dihydropyridine nucleus, the only critPrinn being capacity for BBB peneLldLion and in vivo oxidation to the CO~ onding qual~l"aly pyridium salt. Among the specific redox carrier drugs for complexation with cyclodextrins in accord WO 94/12217 ' , ~ PCT/US93/11651 215~5~

with the Bodor ~a~n~ are a number of steroid dcl;va~ s, in~ ing the d~livali.~cs of desmeth~c~...e and hydlocu~ olle shown belaw:

C~2C 4~d C~33 c =0 H3_ L___OH
HO ~ _ _ CH3 15 ~/
o~
9-flouro-11~, 17-diLy~u~
methyl-21-{[(1-methyl-1,4-dihydro-pylidin-3-yl)carbonyl]o~y}pregna-1,4-diene-3,20-dione (de~ameth~ ~on e-CDS) C3201C~

C--O

HO ~__ OH
H3C ¦ ¦
40 ~' ~
~
11~, 17-diL~rd~ y-2l-{[(l-methyl-1,4-dik~,~u~,.idi.l-3-yl)~l,u~l]-~y}pregn ~ e.,c-3,20-dione (h~L~ L~l.c-CDS) SIJ~STITUTE SHEET ~RULE 26) WO 94/12217 215 0 ~ 5 q PCT/US93/11651 The aforenoted Bodor patents propose complexation with the specific cyclodextrin derivatives named in the preceding paragraph as a means for overcoming the stability problems from which the dihydropyridine-cont~ining redox compounds suffer; the patents note that even in the dry state, the redox compounds are very sensitive to oxidation as well as to water addition. Such complexation is also proposed in the Bodor patents as a means for providing better brain to lung ratios of the redox compounds by preventing their precipitation out of solution at the injection site or in the lungs. Successful solubilization of a number of redox compounds is noted; however, Bodor indicates that such results are not universal. For example, in the case of estradiol, the redox derivative has about the same solubility in aqueous 50%
hydroxypropyl-,B-cyclodextrin as has the parent drug; in the case of norethindrone, the redox drug has less than 1 % of the solubility in aqueous 50% hydroxypropyl-,B-cyclodextrin displayed by the parent drug.
Bodor U.S. Patents Nos. 4,983,586, issued January 8, 1991, and 5,024,998, issued June 18, 1991, relate to pharnl~elltic~l formulations for pal~,lte.~l use. Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ,~- and ~y-cyclodextrins, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral ~dmini~tration. The pa-~-lte~l solutions contain from about 20%
to about 50% of the selected cyclodextrin(s). The drugs may be the dihydropyridine forms of dihydropyridine ~ pyridinium salt redox systems (as noted above in connection with the Bodor '935 and '566 patents) or other poorly soluble or unstable drugs of many types, including steroids. Anti-infl~mm~tory steroids such as dexamethasone, hydrocortisone and prednisolone are mentiolled WO 94/12217 ~ . - ; - PCT/US93/11651 .

21505~ ~

Recently, the solubilizing and stabilizing effects of hydroxypropyl-~-cyclodextrin (HP~CD) on drugs have been reviewed by Thorsteinn Loftsson, Pharm. Zt~. Wiss. 4/136: 5-10 (1991). Solubility enhancement for many drugs in water has been accomplished by means of complexation with HP~CD. The solubility of dexamethasone was increased 5,500 times and intravenous ~Aminictration of the dey~meth~cone-Hp~cD complex gave higher initial plasma levels of deY~meth~cone than those obtained after dex~m~h~cQne phosphate dosing. The authors further note that transdermal/topical nonocclusive aqueous vehicle systems are suggested to avoid side-effects of occlusive systems, and that the improved water solubility of many lipophilic drugs in aqueous HP,~CD solutions makes the nonocclusive systems possible. Transdermal delivery of the steroids 17~-estradiol, hydrocortisone and tP~c~leruile in aqueous HP~CD solutions have been reported. See also Loftsson et al, Acta Pharm. Nord. 1(4), 185-193 (19~9), which describes the effects of 2-hydroxypropyl-~-cyclodextrin on the aqueous solubility of drugs, including dexamethasone, and the transdermal delivery of 17,B-estradiol. It has also been suggested that the hydroxy-propyl derivatives of betacyclodextrin could be useful in solubilizing amino-substituted steroid therapeutic agents of the type disclosed in the aforementioned International Publication No. WO 87/01706 and U.S. Patent No. 5,124,154.

As previously noted, the literature has not suggested that hydroxyalkylated or branched cyclodextrin derivatives would be con~aLible with lightly crocclink~d carboxy-cont~ining polymers or that this combination of materials could be used to stabilize and solubilize pharnl~eut~
formulations of therapeutic agents to provide remarkably stable compositions whose drug release rate could be finely controlled.

O 94/12217 2 ~ PCT/US93/11651 S~JMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a therapeutic agent, an effective stabilizing amount of carboxy-S containing polymer and cyclodextrin in an aqueous medium. The cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ~ and ~y-cyclodextrin, modified or nonmodified.

It further provides a method for stabilizing and solubilizing a therapeutic agent in a pharma(~eutical formulation, comprising combining the therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize the the~ ic agent. The cyclodextrin is sele~ted from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ~"B- and y-cyclodextrin, modified or nonmodified.

The present invention further provides a method for stabilizing and solubilizing an amino-substituted steroid therapeutic agent in a pharm~ceutica'lformulation, comprising combining the therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize the therapeutic agent. The cyclodextrin is selected from the group conci~ing of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of cY, ,l~- and ~y-cyclodextrin, modified or nonmodified.

In yet another aspect, the present invention provides a pharm~euti~l composition comprising an amino-substituted steroid therapeutic agent sele~t~d from the group consisting of the C20 through C26 aminosteroids of the formula WO 9~/12217 PCT/US93/11651 : 18 2l~as~

XI hereinbelow, and the pharm~l~eutically acceptable salts, hydrates and solvates thereof, an effective stabilizing amount of a carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, in an aqueous medium. The cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of a!, ~- and y-cyclodextrin, modified or nonmodified.

DETAILED DESCRIPIlON OF THE INVENTION AND THE
PREFERRED EMBODIMENTS
This invention compris~s pharm~eutical preparations cont~ining a combination of carboxy-containing polymers and a molecular inclusion chemical entity, cyclodextrin or a derivative of cyclodextrin, particularly ,~-hydroxypropyl cyclodextrin, as a vehicle for delivering therapeutic agents.
Drugs used in the formulation can be hydrophobic organic compounds with little solubility and they may be labile. The drug can also be a peptide or protein from either a recombinant process or synthetic process, or a water soluble drug. The advantages of the invention are most apparent, however, in connection with drugs having low solubility in water or body fluids and/or instability problems.

The combination of the present invention can be made without experiencing adverse consequences of incompatibility of the components. For instance, the improved solubility effect of the present invention might have been neg~t~d by the polymer colll~Ling for the drug. In addition to n~g~ting the desired improvement in solubility, and therefore bioavailability, undersirable ~recil)iLaLion or agglomerated of particles may have occurred.

The me~h~ni~m of the present invention is not fully understood and may be different for different thel~uLic agents. It is believed, however, that .

, "~o 94/12217 PCT/US93/11651 21~0~S l stabilization of the drug may be achieved by cyclodextrin through molecular inclusion of the drug in the cyclodextrin ring or by ionic attractive forces between the drug and cyclodextrin. The polymer component of the present invention, in most inst~nces, provides the greatest stabilizing influence. For some drugs, particularly those that are positively charged, an ionic interactionmay be formed between the drug and the polymer. This interaction may stabilize labile portions of the drug.

The drug can be partially or completely solubilized by ~-hydroxypropyl cyclodextrin and/or other modified and nonmodified cyclodextrins. The term partial solubilization refers to ~ degree of solubilization in excess of the normal solubility for the particular drug. Increasing the solubility of therapeutic agents typically also reduces irritation that would otherwise be experienced. The degree of solubilization can be controlled by the type and weight fraction of the cyclodextrin and the manufacturing procedures used and the formulation. Although the present invention may incorporate drugs that are highly soluble in water and body fluids, the fullest advantage of the solubilizing effect of cyclodextrin will be realized in connection with drugs that have low solubility in water or body fluids.
Soluble drugs may be released from gels containing formulations of the present invention, through diffusion. Insoluble drugs can be solubilized by the cyclodextrin and diffused out of the polymeric gel or be released from it as the surrounding co.ll~onents of the formulation erode. By b~l~ncing the ratio between the solubilized and insoluble form of the drug in the formulation, the release profile of the drug from the delivery system can be mod~ tPd.

The amounts of cyclodextrin, carboxyl-containing polymer and drug may be varied to accommol~tP different applications. Other characteristics WO 94/12217 PCT/US93/11651 ~
2~5~4 such as pH and osmolality may also be tailored to suit requirements of particular applications. In general, however, a stabilized, solubilized drug delivery system will be an aqueous suspension at a pH of from about 3 to about 9, preferably about 5 to about 8. For ophthalmic applications an 6 osmotic pies~ulc; of from about 10 to about 400 mOsM is desirable.
Generally, formulations may contain up to about 10%, more preferably about 0.1% to about 6.5% by weight, of the sllcpçncion~ of a lightly cross-linked, carboxyl-containing polymer. Cyclodextrin may be present in amounts from about 1% to about 50%. Suspensions of the present invention may have a wide range of viscosities, but many formulations may have a viscosity of from about 1,000 to about 100,000 centipoises. For ophthalmic applications the viscosity will preferably be about 1,000 to about 30,000 centipoises for drops and about 30,000 to about 100,000 centipoises for ribbons. Viscosities greater than about 100,000 centipoises are ordinarily apl)ro~ iate for topical routes of~dminictration other than ophthalmic, e.g. dermal and local routes such as nasal, buccal, rectal and vaginal, but viscosities for these applications may also, in some inct~nces, be lower than 100,000 centipoises.

In topical pharmaceutical formulations of the present invention, the polymer ranges from about 0.1 to about 10%, preferably about 0.1% to about 6.5 % and more preferably about 0.5 to about 2 % . The cyclodextrin preferably makes up about 1 to about 50%, more preferably about 5% to about 25%, dçpçn-iing on drug loading. Therapeutic agents (drugs) will ordinarily make up about .01% to about 10% by weight of the composition, preferably about 0.1% to about 5% of the composition.

The lightly cross-linked carboxy-cont~ining polymers for use in the present invention are lightly cross-linked polymers of acrylic acid or the like and are, in general, well-known in the art. See, for example, Robinson U.S.
Patent No. 4,615,697, and International Publication No. WO 89/06964, ~wo 91/12217 21~ 0 5 S ~ PCT/US93/11651 referred to hereinabove. These polymers are also described in United States Patent 5, 192,535.

Suitable polymers are ones prepared from at least about 90% and preferably from about 95% to about 99.9% by weight, based on the total weight of monomers present, of one or more carboxyl-containing monoethylenically unsaLuldted monomers. Acrylic acid is the pre~e,led carboxyl-containing monoethylenically unsaturated monomer, but other unsaturated, polymerizable carboxyl-cont~ining monomers, such as methacrylic acid, ethacrylic acid"~-methylacrylic acid (crotonic acid), cis-~x-methylcrotonic acid (angelic acid), trans-~-methylcrotonic acid (tiglic acid), ~-butylcrotonic acid, c~-phenylacrylic acid, o~-benzylacrylic acid, cY-cyclohexylacrylic acid"B-phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinn~mic acid), umbellic acid (p-hydroxycoumaric acid), and the like can be used in addition to or instead of acrylic acid. The most p~er~lled polymers are lightly cross-linked carboxy polymers. As will be understood from the present disclosure, however, soluble carboxy polymers that are not cross-linked may also be used. Examples of soluble polymers of the present invention that are not cross-linked include polyacrylic acid polymers and polymethacrylic acid polymers. Such polymers may be made by known methods.

Preferred polymers are lightly cross-linked by using a small percentage, i.e., less than about 5%, such as from about 0.01% to about 5%, and preferably from about 0.2% to about 3%, based on the total weight of monomers present, of a polyfunctional cross-linking agent. Included among such cross-linking agents are non-polyalkenyl polyether difunctional cross-linking monomers such as divinyl glycol; 3,4-dihydroxy-hexa-1,5-diene; 2,5-dimethyl-l ,5-hPY~liPnP; divinylbenzene; N,N-diallylacrylamide; N,N-diallylmeth~rrylamide and the like. Also included are polyalkenyl polyether WO 9~/12217 22 PCT/US93/11651 0 2~5~

cross-linking agents containing two or more alkenyl ether groupings per molecule, preferably alkenyl ether groupings containing terminal H2C=C<
groups, prepared by etherifying a polyhydric alcohol containing at least four carbon atoms and at least three hydroxyl groups with an alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like; see, e.g., Brown U.S. Patent No. 2,798,053. Diolefinic non-hydrophilic macromeric cross-linking agents having molecular weights of from about 400 to about 8,000, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products, and reaction products of isocyanate terrnin~t~d prepolymers derived from polyester diols1 polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the cross-linking agents; see, e.g., Mueller et al U.S. Patents Nos. 4,192,827 and 4,136,250.
The lightly cross-linked polymers can of course be made from a carboxyl-containing monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a cross-linking agent or agents.
They can also be polymers in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxyl-cont~ining monoethylenically unsaturated monomer or monomers has been replaced by one or more non-carboxyl-col "i. i n i ng monoethylenically unsaturated monomerscont~ining only physiologically (and, where a~plup~iate, ophthalmologically) innocuous substituents, including acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octylmeth~.rylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vinylpyrrolidone, and the like; see Mueller et al U.S.
Patent No. 4,548,990 for a more extensive listing of such additional monoethylenically ~In~~ d monomers. Particularly preferred polymers are lightly cross-linked acrylic acid polymers wherein the cross-linking monomer -~To 94ll22l7 215 0 5 S ~ PCTtUS93/11651 is 2,3-dihydroxyhexa-1 ,5-diene or 2,5-dimethylhexa-1 ,5-diene.

An especiallyplefel.ed lightlycross-linked carboxy-cont~iningpolymer for use herein is polycarbophil, particularly NOVEON AA-1, a carboxyl-cont~ining polymer prepared by suspension polymerizing acrylic acid and divinyl glycol. NOVEON AA-1 (also called Carbopol 976) is commercially available from The B.F. Goodrich Company. A different p~re~ d lightly cross-linked carboxy-containing polymer for use herein is Carbopol 974P
which is prepared using a different polyfunctional cross-linking agent (of the polyalkenyl polyether type).

The lightly cross-linked polymers used in practicing this invention are preferably prepared by slls~n~ion or emulsion polymerizing the monomers, using conventional free radical polymerization catalysts, to a dry particle sizeof not more than about 50 ~m in equivalent spherical diameter; e.g., to provide dry polymer particles ranging in size from about 1 to about 30 ~m, and preferably from about 3 to about 20 ~m, in equivalent spherical ~ meter.
In general, such polymers will range in molecular weight estimated to be greater than about 250,000 and preferably greater than about 2,000,000.
The cyclodextrins conle",plated for use herein are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of,B-cyclodextrin and the corresponding derivatives of y-cyclodextrin. The hydroxyalkyl groupings may contain one or more hydroxyl groups, e.g. hydroxypropyl (2-hydroxypropyl, 3-hydroxypropyl), dihydroxypropyl and the like. The glucosyl, maltosyl and maltotriosyl derivatives may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl. Various IllLl~lules of the cyclodextrin derivatives may be used as well, e.g. a ",i~lureof maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein include hydroxypropyl-~B-cyclodextrin (HPCD or HPBCD), .

W O 94/12217 PCTrUS93/11651 21~ 4 -; _ hydroxyethyl-,B-cyclodextrin (HEBCD), hydroxypropyl- y-cyclodextrin (HPGCD), hydroxyethyl- y-cyclodextrin (HEGCD), dihydroxypropyl-,B-cyclodextrin (2HPBCD), glucosyl-~-cyclodextrin (G,-~3-CD or G,BCD), diglucosyl-,~-cyclodextrin (2GI-k'-CD or 2G,BCD), maltosyl-,~-cyclodextrin S (G2-,B-CD or G2BCD), maltosyl- y-cyclodextrin (G2- y-CD or G2GCD), maltotriosyl-,~-cyclodextrin (G3-~-CD or G3BCD), maltotriosyl- y-cyclodextrin (G3- y-CD or G3GCD) and ~lim~l~osyl-~B-cyclodextrin (2G,-,B-CD or 2G2BCD), and mixtures thereof such as maltosyl-,~-cyclodextrin/dimaltosyl-,B-cyclodextrin.
Hydroxypropyl-~-cyclodextrin for use in the compositions and methods of the present invention is commercially available. Altematively, it can be prepared by known methods, especially by use of the optimized procedure of Pitha et al, Intemational Joumal of Pharmaceutics, 29, 73-82 (1986) or by modifications thereof as described in Bodor U.S. Patent No. 5,017,566 and related Bodor patents referred to hereinabove. The other hydroxyalkyl cyclodextrins inten(led for use herein can also be prepared by known procedures, e.g. as described by Pitha et al or Bodor. The cyclodextrins obtained in this manner are intrinsically amorphous mixtures; see Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990 and Pitha U.S.
Patent No. 4,727,064.

The other cyclodextrins intended for use in the present invention, i.e.
the glucosyl, maltosyl and maltotriosyl derivatives of c~ - and ~y-cyclodextrin, modified or nonmodified, are branched cyclodextrins which are highly soluble in water as co-l,pal~d to the parent cyclodextrins. These branched cyclodextrins can be produced by microbiological processes from the parent cyclodextrins. Glucosyl-,~-cyclodextrins can be obtained from the mother liquor of a large-scale ,B-cyclodextrin synthesis with Bacillus ohbensis cyclom~lto(lextrin glucanotransferase; see Koizumi et al, Chem. Pharm. Bull., ~o 94/12217 2 ~ i 4~ PCT/US93/11651 35 (8), 3413-3418 (1987) and reference cited therein. Maltosyl and - maltotriosyl ,~- and y-cyclodextrins can be prepared from the parent cyclodextrin and maltose or maltotriose through the reverse action of Pseudomonas isoamylase or Klebsiella aerogenes pullulanase, while glucosyl-~-cyclodextrin can be prepared by enzymatic hydrolysis of maltosyl-~-cyclodextrin; see Okada et al, Chem. Pharm. Bull., 36 (6), 2176-2185 (1988) and references cited therein. The preparation of maltosyl-~B-cyclodextrin by reacting maltose with ,B-cyclodextrin in the presence of pullulanase is also described in Japanese Kokai 61-287902, published Dec. 13, 1986, and J~p~ne~e Kokai 61-197602, published Sept. l, 1986. A mixture of maltosyl-~B-cyclodextrin and various flim~ltosyl-~B-cyclodextrins may be conveniently employed. See also Kainuma et al U.S. Patent No. 4,668,626, issued May 26, 1987.

A variety of drugs may be used in formulations of the present invention. Useful therapeutic agents include, but are not limited to:
demulcents (for relief of "dry eye"), antibiotics, antivirals, steroids, amino-substituted steroids, including anti-inflammatory agents, peptides, polypeptides, cardiotonics, antihypertensives, or antioxidants, antiallergics, alpha- and betaadrenergic blocking agents, ophthalmic medicaments such as ~nti~t~ract agents, collagenase inhibitors, antiglaucoma agents and ophthalmic antiinfl~mm~tory agents, ophthalmic lubricating agents, ophthalmic topical or regional anesthetic agents, antiretinopathy agents, etc.

More specific therapeutic agents believed suitable for use in the present invention include drugs such as idoxuridine, carbachol, beth~nechol, timolol, atenolol, labetolol, metoprolol, nadolol, oxprenolol, pindolol, sotalol, betaxolol, acebutolol, alprenolol, levobunolol, p-aminoclonidine, dipivefrin, epinephrine, phenylephrine, phospholine, aceclidine, ~erner~ m, cyclopentolate, homatropine, scopolamine, pilocarpine, ethacrynic acid, WO 9~112217 ~ PCT/US93/11651 ~
2 ~ 26 furosemide, amiloride, bacitracin, neomycin, polymyxin, polymyxin B, gramicidin, gentamycin, penicillins, erythromycin, slllf~ret~mide, tobramycin, trospectomycin, vancomycin, ciprofloxacin, perfloxacin, olfloxacin, enoxacin, naphazoline hydrochloride, clindamycin, isofluorophate, fluorometholone, dexamethasone, hydrocortisone, fluorocinolone, medrysone, methylprednisolone, fluticasone propionate, betamethasone, estradiol, ibuprofen, flurbiprofen, naproxen, esters of ibuprofen, flurbiprofen, naproxen, ketorolac, suprofen, intt;lrer~ils, cromolyn, gancyclovir, aminozolamide, all trans-retinoic acid (Vitamin A) and the nontoxic, pharmaceutically acceptable salts thereof. Pro-drug counterparts are also within the scope of the present invention.

Topical or regional anesthetic agents include ones used duling ophthalmic surgery or other ophthalmic procedures, such as lidoc~ine, cocaine, benoxinate, dibucaine, proparacaine, tetracaine, etidoc~ine, procaine, hexylcaine, bupivacaine, mepivacaine, prilocaine, chloroprocaine, ben70c~ine, tetracaine, and the like, as well as their acid forms.

The drugs that may be ~dminictered include inorganic and organic drugs that can be transported across a vessel, for example, drugs acting on the central nervous system such as hypnotics and sedatives, mixtures thereof such as pentobarbital sodium, phenobarbital, secobarbital, thiopental, etc.;
heterocyclic hypnotics such as dioxopiperidines, and glutarimides; hypnotics and sedatives such as amides and ureas exemplified by diethylisovaleramide and a bromo-isovaleryl urea; and hypnotic and sedative urethanes and ~liculf~n~$; narcotic antagonists such as naloxone and cyclazocine; psychic energizers such as isoc~ox~zid, ni~l~mide, phenelzine, imipramine, tranylcypromine and paragylene; tranquilizers such as chlolup,o~ ine, p~ 7;i-~, fluphen~7inP, reserpine, deserpidine; meprobamate and benzodiazepines such as chlol.lia~epoxide; anticonvulsants such as primidone, ~:VO 94/12;!17 2 1 5 0 5 ~ ~ PCT/US93/11651 diphenylhydantoin, ethyltoin, phenetruide and ethosuximide; muscle relaxants and anti-parkinson agents such as mephenesin, methocarbomal, trihexylphenidyl, biperiden and levo-dopa, also known as L-dopa and L-,~-3-4dihydroxyphenyl~1~nine; analgesics such as morphine, codeine, S meperidine and nalorphine, antipyretics and anti-infl~mm~tory agents such as aspirin, salicylamide and sodium salicylamide; local anesthetics such as procaine, lidocaine, n~ep~ine, piperocaine, tetracaine, and dibucane;
~nti.~p~modics and antiulcer agents such as atropine, scopolamine, methscopolamine, oxyphenonium, papaverine and prostaglandins such as PGEI, PGE2, PGFI,,, PGF23, and PGA; anti-microbials such as penicillin, tetracycline, oxytetracycline, chlortetracycline, and chloramphenicol;
sulfonamides; anti-malarials such as 4-aminoquinolines, 8-aminoquinolines and pyrimeth~mine; antivirals including idoxuridine, hormonal agents such as prednisolone, prednisolone acetate, cortisone, cortisol and triamcinolone;
androgenic steroids, for example methyltestosterone and fluoxmesterone;
estrogenic steroids, for example, 17 ~-estradiol and ethinyl estradiol;
progestational steroids, for example, 17 ~-hydroxyproge~L~une acetate, 19-nor-ploge~.~erone, norethindrone and progesterone; sympathomimetic drugs such as epinephrine, amphetamine, ephedrine, and norepinephrine;
cardiovascular drugs, for example, procainamide, amyl nitrite, nitroglycerin, dipyridamole, sodium nitrate, and mannitol nitrate; diuretics, for example, chlorothiæide, and flllmethi~7.ide; antiparasitic agents such as bephenium hydroxynaphthoate, dichlorophen, dapsone and enitabes; neoplastic agents such as mechloreth~mine, uracil mustard, S-fluorouracil, 6-thioguanine, and procarbæine; hypoglycemic drugs such as insulin, isophane insulin suspension, protamine zinc insulin suspension, globin zinc insulin, extended insulin zinc suspension, and other like insulins derived from animal and synthetic origin including tolbutamide, acetohexamide, tolazamide, and chlo,~.,.,pamide; nutritional agents, for example vitamins such as ascorbic acid, essential amino acids, essential elements such as iron, and es.senti~l fats;

WO 94/12217 PCTIUS93/11651 ~
215~S ~

. . , ophth~lmic drugs such as pilica~ e base, piloca~ e hydlochloride, pilocal~iue nitrate, eserine, eserine salicylate, atropine sl.lf~te, homatropine, and eucall~iue, and proteius or peptides such as human epirlerm~l growth factor (hEGF), aFGF, bFGF, IL,lra, TGF-~B and S g~mm~ tel~ron. The above drugs are further described in "The ph~rmr, -l^gical Basis of Therapeutics," edited by Goo 1~n~n and Gilman, published by The M~r.mill~n Culllpally.

Com~ouuds believed to be of particular interest in the plcsellt 10 invention include [4(N-hy~L~Ay~o)-2R-i~ u~yl-3~(thienyl-thiomethyl) -succinyl]-~phenylalanine-N-metLylA .. . i~le, ((5)-4-methyl-2-[methyl-[4-(2-methyl-;...i~lA,o[4,5-C]pyridin-1-y1methyl)-benzene sulphonyl]-acetate, dexamethasone, e~ylLroluy~ and Lydl~c~ one.

In the pl~sent invention, the amino-sul~s~ ted steroid therapeutic agents employed are the C20 through C26 aminosteroids of formula XI
(esl)ecially those which eA~hibit anti~y~ nt LuncLious)~ as set forth in International Publication No. WO87/01706 and in applicants' U.S. Patent No. 5,124,154, all of which are incorporated by lefercl,ce herein in their eulilcLes and relied upon. The intended aminosteroids have the formula Rll ~f R16 RIO ~ /
_ ~ - (XI ) R5 ~ j~

ST~TlJTE SHEtT ~RUL~ ~6~

~wo 94112217 215 0 S 5 i PCT/US93/11651 where:
(A-I) R6 is cY-R61:~'-R62, Rlo is ~-RIol ~7-Rlo2 and R7 is c~-H:~-H, where one of R6l and R62 is -H, and the other is -H, -F, or Cl-C3 alkyl, R,02 is -CH3,Rlo, and R5 taken together are -(CH,)2-C(-R33)-CH= or S -CH-CH-CO-CH=, where R33 is =O or ~-H:,l~-OR34 or c~-OR34:~-H, where R34 is -H, -P( = O)(OH)2, -CO-CH3, -CO-C~H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2Hs;
(A-II) R5 is C~-Rs3:,B-R5~, R6 iS ~-R63:~-R64~ Rlo iS ~X-RI03 ~-R104 and R7 is ~-H:~-H, where one of R63 and R64 is -H, and the other taken together with one of R53 and R54 forms a second bond between C5 and C6, R~04 is -CH3, R,03 and the other of~ Rs3 and R54 taken together are -(CH2)2-C(H)(OH)-CH2- or -(CH2)2-C[H][OP(=O)-(OH)21-CH,-;
(A-III) Rlo and R5 taken together are =CH-CH=
C(OR3)-CH= where R3 is -H, -P(=O)(OH)2, Cl-C3 alkyl, -CO-H, C2-C4 alkanoyl or benzyl, R6 is ~-R65:~B-R66 where one of R65 and R66 is -H, and the other is -H, -F, or Cl-C3 alkyl and R7 is ~-H:~-H;
(A-IV) Rs is CY-R57:,B-Rs8, R6 is cy-R67:,l~-R68~ R7 is c~-H:~-H and Rlo is ~-RI07:,B-Rl08, where one of R57 and R58 is -H, R,07 and the other of Rs7and R5% taken together are -(CH,)2-C(=R33)-CH2, where R33 is as defined above, R,08 is -CH3, where one of R67 and R6~ is -H and the other is -H, -F, or C,-C3 alkyl;
(A-V~ R6 is R69 R6~o~ R7 iS R79:R7l0, Rlo iS
cY-RIog:Rlolo, where one of R69 and R6lo is -H and the other taken together withone of R79 and R7~0 forms a second bond between C6 and C7, and the other of R79 and R7,0 is -H, Rlolo is -CH3, Rlog and R5 taken together are -(CH2)2-C(=R33)-CH= or -CH=CH-CO-CH=, where R33is as defined above; where:
(C-I) R" is a-RI~:,B-Rll2, where one of Rll, and Rll2 is taken together with Rg to form a second bond between C9 and C" and the other of Rll, and Rll2 is -H;
(C-II) Rg is -Cl and Rll is =O or cY-H:,~-RIl4 where Rll4 is -Cl 2 ~ , . PCT/USs3/11651 . . . 30 or -OH;
(C-III) R9 is -H or -F and R" is =O or cY-RIl5:,B-R~l6, where one of Rlls and Rll6 is -H, and the other of R"5 and Rll6 is -H, -OH or C,-C,2 alkoxy;
S (C-IV) R9 is -H or -F and Rl, is cY-O-CO-RIl,:~-H, where R"7 is (A) C,-C3 alkyl, (B) C,-C,2 alkoxy, (C) furanyl, (D) -NR,22RI23, where one of Rl~2 and Rl23 is -H, methyl or ethyl and the other is -H, C, ,C4 alkyl or phenvl, (E) -X3-Xl, where X3 iS -O- or a valence bond, where Xl is phenyl optionally substituted with 1 through 2 -Cl, -Br, Cl-C3 alkoxy, -COOH, -NH2, C,-C3 alkylamino, di(CI-C3)alkylamino, where the alkyl groups are the same or different, l-pyrrolidinyl-, 1-piperidinyl, 1-heY~methylenimin~ -, 1-heptamethylenimino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3;
where:
(D-I) R,6 is R,6~:R,62 and R,7 is Rl7l:RI72, where one of R,6, and R,62 is -H or -CH3 and the other taken together with one of R,7l and Rln forms a second bond between Cl6 and Cl7, and the other of R,7, and Rl72 is -C(=Z)-(CH2)n-NR2lR2,0, where Z is =O, =CH2 or Rl79:-H where R,79 is -H
or -CH3, where n is 0 through 6, where (A) R2, is (1) -(CH2)m-NR2ll-X~, where m is 2, 3 or 4, where R2~l is -H or Cl-C3 alkyl, where X2 is: [A]
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R2,2, being the same or different, where R2l2 is (i) -F, ~0 94/12217 215 0 5 5 ~ PCT/US93/116~1 (ii) -Cl, (iii) -Br, (iv) C,-C5 alkyl, (v) -cH2-cH =CH2, (vi) -Xl, where X, is as defined above, (vii) -NR2~3R2l3 where the R2l3 s are the same or different and are -H, Cl-c3 alkyl or -CH2-CH =CH2, (viii~) ~CH2~(CH2)q~CH2~N-~
where the atoms marked with an asterisk (*) are bonded to each other resnlting in the formation of a ring, where q is 1 through 5, (viii,B) CH2-CH2-(CH2)C-G-(CH2)d-CH2-CH2-N-- where the atoms marked with an asterisk (*) are bonded to each other resnlting in the formation of a ring, where G is -O-, -S-, -SO-, -SO2- or -NHR2~4, where R2l4 is -H, Cl-C3 alkyl, or Xl as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, [a]
(ix) 3-pyrrolin-1-yl, [b]
(x) pyrrol-l-yl optionally substituted with Cl-C3 alkyl, [c]
(xi) piperidin-l-yl optionally substituted with 1 or 2 C,-C3 alkyl, [d]
(xii) 1,2,3,6-tetrahydro-pyridin-1-yl, [e]
(xiii) l-hexamethyleneimino cont~ining a 3- or 4- double bond or 3- and 5-double bonds, [f~
(xiv) 1 ,4-dihydro- 1 -pyridinyl substituted in the 4 position by two C~-C3 alkyl being the same or WO 9~/12217 PCT/US93/11651 ~
2 ~ 3 different, [g]

(xv) -OH, (xvi) C,-C3 alkoxy, (xvii) -NR2l7-(CH2)e-Q where Q is 2-pyridinyl where R2,7 is -H or C,-C3 alkyl and e is 0 through 3 (1) (xviii) pyridin-2-, 3- or 4-yl, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R2l2 asis defined above, , (4) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R2l2 as is defined above, (5) (d) pyrimidin-2-yl optionally substituted at the 4- and/or 6- position with 1 or 2 R2l2 as is defined above, (6) (e) pyrazin-2-yl optionally substituted with 1 or 2 R2l2 as is defined above, (7) (f) imidazol-2-yl optionally substituted in the 1 position with Cl-C3 alkyl or -X" where Xl is as defined above, and further optionally substituted with 1 or 2 R2l2 as defined above, ~8) (g) 1,3,4-triazol-2-yl optionally substituted in the 1 position with Cl-C3 alkyl or -Xl, where Xl is as defined above, and further optionally substituted with R2l2 as defined above, (9) (h) imid~7Ql-4- or 5-yl optionally substituted in the 1 position with C,-C3 alkyl or -X" where Xl is as defined above, and further optionally substituted with 1 or 2 R2~2 as defined above, (10) ~WO 94/12217 215 Q ~ 5 ~ PCT/US93/11651 (i) benzo[b]thien-2-yl, (12a) (j) indol-2-yl, (12b) (k) benzo[b]thiazol-2-yl, (12c) (I) benzimidazol-2-yl, (12d) S (m) 4-[2-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]ethyl]piperazinyl, (13) (n) 1,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with R2l2 as is defined above, (14) (2) ( 1 -piperazinyl)-(C~-C4)alkyl optionally substituted in the 4- position with -Xl or -X, as defined above, [B]
(3) -X2, as defined above, [O]
(4) -(CH2)m-X~ where m is as defined above and where X4 iS
(a) -O-CH2CH2-Y, where Y is C,-C3 alkylamino, di(C,-C3)alkylamino where the alkyl groups are the same or different, C3-C6 alkyleneimino, optionally substituted with 1 or 2 Cl-C3 alkyl, (b) -NR220CH2CH2-Y, where R220 is -H or C,-C3 alkyl and Y is as defined above, (c) -(CH2)o-N(R220)-X2, where g is 2, 3 or 4, and where R220 and X2 are as defined above, [H]
(S) -(CH2)m-NR222R223, where R222 is -H or Cl-C3 alkyl and R223 is -Xl or-X2 as defined above, or R222 and R223 are taken together with the ~t~hed nitrogen atom to form a saturated mono-nitrogen C3-C6 heterocyclic ring and where m is as defined above, t (6) -(CHCH3)b-(CH2)fR224, where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R224 is phenyl substituted with 1 through 3 -OH, Cl-C3 alkoxy, -NR225R226 where R22s and R226 are the same or different and are -H, Cl-c3 alkyl or are taken together with the attached niL,og~n atom to form a C4-C7 cyclic amino 2 1 5 ~

ring, [J]
(7) -(CH2)i-X2, where i is 1 through 4 and X1 is as defined above, [K]
(8) (1-piperazinyl)acetyl substituted S in the 4-position by X2 where X2 is as defined above, [L]
(9) (1-piperazinyl)carbonylmethyl substituted in the 4- position by -X2 where X2 is as defined above, and [M]
(B) R2,0 is (1) -H, (2) C~-C3 alkyl, (3) Cs-C7 cycloalkyl, (4) -(CH2)n,-NR",-X2, where m, R2ll and X. are as defined above, [A]
(S) ( 1-piperazinyl)-(C2-C4)alkyl optionally lS substituted in the 4- position with -X, or -X2 as defined above, [B]
(6) -(CH2)",-X4, where m and X4 are as defined above, [H]
(7) -(CH2)m-NR222R223, where m, R222 and R223 are as defined above, [I]
(8) -(CHCH3)b-(CH2)fR22~, where b, f and R224 are as defined above, [J]
(C) R2l and R2,0 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-1-pyrrolidinyl optionally as the Cl-C3 alkyl ester or as a pharm~eutic~lly acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperidinyl optionally as the Cl-C3 alkyl ester or as a pharmaceutically acceptable salt [C-2]
(3) 2-(carboxy)-1-hexamethylenPimino optionally ~0 94/12217 215 0 ~ ~ 4 PCT/US93/116~1 as the Cl-C3 alkyl ester or as a pharm~ el1ti~1ly acceptable salt, tc-3 (4) 2-(carboxy)- 1 -heptamethylene-imino optionally as the C,-C3 alkyl ester or as a pharm~e~ltirally acceptable 5 salt, [C-4]
(5) l-piperazinyl substituted in the 4- position with R228-CO-(CH2)j- where R228 is -X" -NR229Xl or 2-furanyl, where R229 is -H or C,-C3 alkyl, where j is 0 through 3 and X, is as defined above, [D]

(6) l-piperazinyl substituted in the 4- position with X2-(CH2)j-, where X2 and j are as defined above, [E]

(7) l-piperazinyl substituted in the 4- position with Xl-(CH2)j-, where Xl and j are as defined above, [F]

(8) 4-hydroxy-1-piperidinyl substituted in the 4- position with Xl as defined above, [G]

(9) 1-piperazinyl substituted in the 4- position with X2-NR229-CO-(CH2)j-, where X2, R229 and i are as defined above; [Nl (D-II) Rl6 is cY-Rl63:~B-Rl64 where one of Rl63 and Rl64 is -H and the other is -H, -F, -CH3 or -OH, and Rl7 is -CH-(CH2)p-NR2lR2l0, where p is 1 or 2, where R2l and R2l0 are as defined above;
(D-III) R,6 is ~-RI65:,B-Rl66 and Rl7 is ~-RI75:~B-Rl76, where Rl65 is -H, -OH, -F or -CH3 and Rl66 is -H, -OH, -F, or -CH3, with the proviso that at least one of Rl65 and Rl66 is -H, where Rl7s is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-Xl, where Xl is as defined above, and where Rl76 is -C(=Z)-(CH~)n-NR2,R2,0, where Z, n, R2l and R2l0 are as defined above;
(D-IV) the 16,17-acetonide of a compound where Rl65 is -OH, Rl66 is -H, Rl75 is -OH and Rl76 is -C(=Z)-(CH2)n-NR2lR2l0, where Z, WO 9~/12217 PCT/US93/11651 ~

215~$~ 36 n, -R2l and R2,0 are as defined above;
and pharm~ceutic~lly acceptable salts thereof, and hydrates and solvates thereof;
with the following overall provisos that:
S (I) one of R,6, or R,62 is taken together with one of R,7, or R,72 to form a second bond between Cl6 and Cl7, only when Rlo is a-R,0,:,B-R,02, c~-RI03:~-Rl04, Ix-R,07:~-R,08 or ~-R~09:~-R~olo, (II) R,7 is -CH-(CH2)p-NR2,R2,0, only when Rlo is cY-R~ol ~-Rl02~ a-R~03:~-R~04, ~X-Rl07:~-Rl08 or ~-R~09 ~-Rlolo~
(III) R5 and Rlo taken together are =CH-CH=C(OR3)-CH=, only when Rl7 is cY-RI75:,~-Rl76 or the 16,17-acetonide of a co",pou,~d where Rl6 is a-OH:~-H and Rl7 is ~x-OH:,l~-C(=Z)-(CH2)n-NR2,R2,0, and (IV) Rs is CY-R57:~-R58, only when R~7 is ~x-R~75:~5-R~76 or cx-OH:~B-C-(=Z)-(CH2)n-NR21R2l0, or the 16,17-acetonide thereof.
More ple~ll~d are the C2, ~minost~roids of formula XI, especially those which inhibit lipid peroxidation. Most preferred are the 21-[4-(substituted-4-pyrimidinyl)-1-piperazinyl]-steroids, such as U-74006 (21-[4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16a-methylpregna-1,4,9(11)-triene-3,20-dione), and the 21-[4-(substituted-2-pyridinyl)-l-pi~~ yl]-steroids, such as U-74500 (21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-pi~l;~inyl]-16~-methylpregna-1,4,9(11)-triene-3,20-dione)andU-75412(21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16cY-methylpregna-1,4,9(11)-triene-3,20-dione), all, when in the unform~ ted state, preferably as a solid, preferably cryst~lline, preferably relatively non-hygroscopic and pharm~eutically acceptable salts, such as the meth~n~sulfonate salt of U74006 (U-74006F), the hydrochloride of U-74500 (U-74500A), and the hydrochloride or maleic acid salt of U-75412 (U-75412A and U-75412E, resl)ec~ ely); See Br~lghl~r et al, Biochemical Pharrnacology 37: 3853-3860 (1988). The ~0 94/12217 21~ 0 5 5 4 PCT/US93/11651 following are ~lu~hali~`e structures ~ N N ~N

N
C_O <~

~ CH3 Il I

0~
C~I3 - S02 - OH

CE~2 N N ~ N _ CH2CH3 C O
~ CH2CH3 ~ 3 O ~J C~3 HCl SUBSTITUTE SHEET (RULE 26) WO 94/12217 PCT/US93/11651 ~
2~.S~s ~ 38 CH3 lH2 NH

IJ
C _ O N ~/

~\
~~
0~

HCI

The above-prefelled amino steroids are all exemplified as 21-substituted-16a -mell~ gna-1,4,9(11)-triene-3,2û-diones. However, the steroidal portion of these may be modified without substantially altering their preferred nature. Thus, a class of preferred C2l amino-substituted 30 steroids may be represented by the formula I, below StJBSTITUTE SHEET (RULE 26) I

C O
0 , C~qd~

~/ (I) ~

b where:
a' is selected from the group 1,2-dihydro (saturated) and 1,2-dehydro (1,2-double bond);
b' is selected from the group 6a-H, 6~-methyl and 6a-flouro;
c' is selected from the group 9,11-dihydro (saturated), 9(11)-dehydro (double bond), 9a-H-lla-OH-11~3-H,9a-H-ll~-OH-llcr-H,9a-H-ll-keto,9~-F-11~3-OH-lla-H and 9a-F-ll-keto;
d' isselectedfromthegroup 16a-methyl-16~-H-17a-H, 16,B-methyl-16a-H-17a-H, 16-H2-17c~-H, 16-H-16,17-dehydro (double bond), and 16-methyl-16,17-dehydro. Less preferably, a 17~-OH group can be present in~te~rl of 17a-H when d' is not 16-H-16,17-dehydro or 16-methyl-16,17-dehydro;
and where:
X'is selecte-l from the complex 21-amino substituents Xl and X2 where Xl is ~ N
N N _~/ N
f' SU~STITUT~ SHEE~ ~RUL~ 26) W O 94/12217 PCT~US93/11651 ~

?~5~

and S X2 iS -- N N ~

where e' and f' may be the same or different and are selected from the 10group: H,NHR1' and NR1'R2', where R1' and R2' are C1 to C3 lower aLt~yl or R1' and R2', taken toget_erwith N, co~ te a hetero~y.;lic ring;
preferably 1-ethyleneimino, 1-trimethyleneimino, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl and 1-(4-methyl)pipelazL--yl.

15Ph~ çel~tically acceptable salts of the aminosteroids of formula (XI) are frequently preferred over the fee base form because the salts are more soluble in water and form cr~stals which are better suited to ph~ cel~tical use. Preferred salts are those ~,~palcd by reacting the free base of the aminosteroid of formula (XI) with an ~p,~ te1y 20 stoichiometrical amount of a ph~ çe~tically acceptable acid such as hrdlc,chloric, hydroiodic, hydlobrol~ic, phosphoric, sulfuric, acetic, citric, lactic, succinic, benzoic, pamoic, salicylic, cyclohexanes~llf~rnir7 methanesulfonic, ~-toluenesulfonic, naphthalenesulfonic, malic, o~alic, fumaric or the like. Plcielled salts are those of L~dlocllloric, 25 methanesulfonic, maleic and fumaric acids.

Equivalent to the steroids of formula (XI) and t_eir ph~ ce~tically acceptable acid addition salts for the purposes of l:his invention are the ph~ centically acceptable Lydlates or solvates thereof, 30 in which form they can be i~ol~tetl SUBS~ITlJTE SHEET IRULE 26~

WO 9~/12217 215 0 ~ 5 4 PCT/US93/11651 The aminosteroids can be ~(lminictered by a variety of routes for the treatment or prevention of a variety of conditions, as noted in International Publication No. WO 87/01706. For particular routes of ~minictration, certain characteristics of the lightly cross-linked polymers need to be carefully controlled. Thus, for example, aqueous suspensions containing polymer particles ~lepared by snspencion or emulsion polymerization whose average dry particle size is al)prGeiably larger than about 50 ~m in equivalent spherical mett~r are less comfortable when administered to the eye than suspensions otherwise identical in composition containing polymer particles whose equivalent spherical diameters are, on the average, below about S0 ,um. It has also been discovered that lightly cross-linked polymers of acrylic acid or the like ~lGpa,ed to a dry particle size appreciably larger than about 50 ~m in equivalent spherical diameter and then reduced in size, e.g., by mech~nically milling or grinding, to a dry particle size of not more than about 50 ,um in equivalent spherical di~meter do not work as well as polymers made by suspension or emulsion polymerization.

In some prGfGllGd embodiments of the invention, the particles have a narrow particle size distribution within a lO,L~m band of major particle size distribution which contains at least 80%, more preferably at least 90%, most preferably at least 95% of the particles. Also, there is no more than 20%, preferably no more than 10%, and most preferably no more than 5% particles of a size below 1 ~m. The presence of large amounts of such fines has been found to inhibit the desired gelation upon eye contact. Apart from that, the use of a monodispersion of particles will give maximum viscosity and an increased eye residence time of the ophthalmic medicament delivery systems for a given particle size. Monodisperse particles having a particle size of 30 ~m and below are most plGf~ d. Good particle packing is aided by a narrow particle size distribution.

Wo 94/12217 PCT/US93/11651 æ~a55 4 42 Aqueous solutions and suspensions for liquid oral ~mini~tration will typically contain between about 0.05 and 5.0% by weight, preferably between 0.1 and 2.0% by weight of the amino-substituted steroid therapeutic agent;
that suitable adjuvants which may be used as carriers to provide wetability and stability include propylene glycol, lightly cross-linked carboxy-cont~ining polymers such as polycarbophil, ethyl cellulose, hydroxypropyl cellulose and methyl cellulose; and that other additives, including sodium edetate, methyl and propyl parabens, flavoring agents and colorants may also be employed, if desired. Examples 7 and 8 in the parent and grandparent applications detail the preparation of topical compositions containing the aminosteroid U-74006F, U-74500A or U-75412A and a polycarbophil (NOVEON AA-l). A viscosity of 5,000 cps or greater is noted in Example 7. Sodium chloride, EDT~, sodium hydroxide and, optionally, the preservative benzalkonium chloride are also present in the col"po~ilions.
In accordance with the invention, a stabilized sust~in~d release aminosteroid delivery system comprises an aqueous suspension at a pH of from about 3 to about 9 (preferably 5 to 8) and an osmotic pressure of from about 10 to about 400 mOsM cont~ining from about 0.1% to about 6.5% by weight, based on the total weight of the suspension, of a lightly cross-linked, carboxyl-containing polymer prepared by polymerizing one or more carboxyl-cont~ining monoethylenically unsaturated monomers and less than about 5%
by weight of a cross-linking agent, such weight percentages of monomers being based on the total weight of monomers polymerized. Typically, the suspension has an initial viscosity of from about 1,000 to about 30,000 centipoises and is ~rlminictrable to the eye in drop form, or in the form of a ribbon at a viscosity of from about 30,000 to about 100,000 centipoises, but considerably higher viscosities are acceptable for topical routes of ~lmini~tration other than ophthalmic, e.g. dermal, and local routes such as nasal, buccal, rectal and vaginal. The polymer has an average particle size WO 94/12217 21 ~ ~ ~ S ~ PCT/US93/11651 of not more than about 50 ~Lm, preferably not more than about 30 ~Lm, in equivalent spherical ~ meter. In the case of topical ophthalmic delivery systems, the pH of the suspension is from about S to about 9. The viscous gel can remain in the eye for a prolonged period of time so as to release the S aminosteroid therapeutic agent contained therein in suct~ined fashion.

The polymer is preferably prepared from at least about 50% by weight, more preferably at least about 90% by weight, of one or more carboxyl-containing monoethylenically unsaturated monomers. Desirably, the polymer is prepared by suspension or emulsion polymerizing acrylic acid and a non-polyalkenyl polyether difunctional cross-linking agent to a particle size of notmore than about 50 ,~Lm, preferably not more than about 30 ~m, in equivalent spherical ~i~meter. A l,refelled cross-linking agent is divinyl glycol. It may be desirable to replace up to about 40% by weight of the carboxyl-cont~ining monoethylenically unsaturated monomers by one or more non-carboxyl-cont~ining monoethylenically unsaturated monomers cont~ining only physiologically (and, where al,~,opliate, ophthamologically) innocuous substitllentc The osmotic pressure is preferably achieved by using a physiologically (and, where a~prop,iate, ophthalmologically) acceptable salt in an amount of from about 0.01 % to about 1 % by weight, based on the total weight of the suspen~ions. A pler~llcd salt is sodium chloride.

~minostt~roid of formula (XI) may be present in desired therapeutic amount, preferably from about 0.01 % to about 10 % by weight, based on the total weight of the suspension. Preferred aminosteroids include U-74006, U-74500, U-75412, U-74006F, U-74500A, U-75412A and U-75412-E and aminosteroids of forumula I.

WO 94/12215 ~ PCT/US93/11651 In a ~ ed method of preparing stable sustained release topical ophthalmic delivery systems, the foregoing suspensions are prepared and packaged at the desired viscosity of from 1,000 to about 30,000 centipoises, for ~tlminictration to the eye in drop form. Upon ~minictration to the eye, viscous gel remains in the eye for a prolonged period of time so as to release in a sllst~in~d fashion the aminosteroid entrapped therein.

The present invention thus provides a stable ophth~lmic delivery system that not only has the benefits of administration in drop form, but also does not suffer from bre~down limitations due to administration at a viscosity suitable for drops. Through ~(lm, inistration at a viscosity such that the suspension can be reliably administered in drop form, but which actually increases when the suspension is so administered, controlled release of aminosteroid medicament is significantly enhanced.
As mentioned above, viscosities substantially over 30,000 cps are generally not suitable for drops; also, viscosities over 100,000 are generally not suitable as ribbons. When the viscosities are substantially lower than 1,000 cps, the ability of the gel to sustain itself after contact with tears is impeded. When a suspension at a pH of from about 3 to about 6.5 and an osmotic plessure of from about 10 to about 400 mOsM contacts the tear fluid, there is an increased gelation with a pH change. As will be appreciated, tear fluid is at a higher pH of about 7.2 to about 7.4. With the pH increase, carboxylic acid (COOH) undergoes a sodium replacement (to COONa), and the sodium form dissociates, causing the polymer to expand.

The relationships between the degree of cross-linking and between the degree of cross-linking and particle siæ can become quite important variables.
Re~use the particles are present in a suspension, the degree of cross-linking is ne~es.s~rily high enough to avoid substantial dissolution of the polymer. On Wo 94/12217 215 0 ~ ; PCT/US93/11651 the other hand, since rapid gelation may be achieved at the time of a pH
change, the degree of cross-linking is necçss~rily low enough to permit gelation. Moreover, if the polymer particle size is too large, in~ ced swelling can tend to fill voids between large particles that are in contact with one another, rather than causing gelation.

If the polymer were in a dissolved state, as it would be if there were insufficient cross-linking because the ratio of cross-linker to monomer was too low, particle size would be basically irrelevant. In a suspension, particle siæ
can be relevant to comfort. However, it has been found that in the system of the present invention, the small particle size and light cross-linking synergistically yield rapid gelation to a subst~n~i~lly increased viscosity whenthe pH changes such as when compositions of the present invention contact tears fluid. In fact, above the 50 ,um size this advantage of subst~nti~lly increased viscosity is not realized. Moreover, at the 50 ~Lm size, there is alsoreasonably good eye comfort.

In a most preferred form of the invention, the particles are not only subject to the upper size limits described above, but also to a narrow particle siæ distribution. Such use of a monodispersion of particles, which aids in good particle packing, yields a maximum increased viscosity upon contact of the suspension with the tears and increases eye re~idenre time. At least about 80%, more preferably at least about 90% and most preferably at least about 95%, of the particles should be within a no more than about 10 ~m band of major particle size distribution, and overall (i.e., considering particles both within and outside such band) there should be no more than about 20%, preferably no more than about 10% and most preferably no more than about 5% fines (i.e., particles of a size below 1 ~m). It is also p~re..ed, as the average particle size is lowered from the upper limit of 50 ~m, more preferably 30 ~m, to lower sizes such as 6 ~m, that the band of major particle wo 94/12217 - ~ PCT/US93/11651 ) 2~3~ ~ 46 size distribution be also narrowed, for example to S ~Lm. Preferred sizes for particles within the band of major particle distribution are less than about 30 ,um, more preferably less than about 20 ,um, most preferably from about l ~Lm to about S ,um.

It is apparent that, while the stable suct~ined delivery systems rli~cuc~ed above are uniquely well-suited to ophthalmic ~lmini~tration~ the same systems can be used for topical tre~tmen~ of skin and mucous membrane by local application to tissue in need of treatment, such as dermal, nasal, vaginal and rectal tissues. However, various features of the systems designed for ~rimini~tration to the eye can be modified in order to produce systems which are even better suited to the contemplated non-ophthalmic route of adrnini~tration. For example, larger amounts of cross-linking agents and/or higher pH levels may be utilized to provide more viscous gels suited for longer retention on the skin or in body cavities. Furthermore, when it is desired to combine in a single composition the sn~t~ined release and prolonged retention prope.Lies of the aminosteroid su~pen~ions described above with the immP~ te release which aminosteroid solutions would provide, or when i~ is desired to simply achieve the more immediate release and greater penetration possible with solutions, be it for ophthalmic or other route of ~mini~tration, yet other modific~tiQns of the invention can be made as described in more detail hereinbelow.

As noted hereinabove, the stable compositions obtained in accord with the foregoing dçt~ilPd description provide for sustained release of the aminosteroid, by virtue of the fact that the aminosteroid is in suspension;
prolonged retention at the site of application can also be readily provided by these compositions by virtue of their viscosity. However, immPAi~tP release of the ~minos¢çroid and greater penetration (e.g. through the cornea or skin, in the case of ophth~lmic or dermal application, respectively) are sometimes WO 94/12217 215 0 5 ~ ~ PCT/US93/11651 desired, either in combination with or instead of the suct~ined release/prolonged retention properties. The present invention provides for modification of the method and compositions described above in order to achieve these goals. Speci~lc~lly, the aminosteroid can be partially or S completely solubilized in the ~minosttoroid/lightly cross-linked carboxy-cont~ininp: polymer forrnulations by using an amount of cyclodextrin (as defined and discussed in detail hereinabove) sufficient to at least partially solubilize the aminosteroid. Addition of cyclodextrin reduces irritation topically and ocularly. Moreover, if desired, sufficient cyclodextrin can be utilized to subst~nti~lly completely solubilize the aminosteroid. The degree of solubilization can be contro~led and the mixed solution/suspension or complete solution which results is stable to degradation. The cyclodextrin used can be any of the hydroxyalkylated or branched derivatives of ,B- and y-cyclodextrins identified hereinabove. However, hydroxypropyl-~-cyclodextrin is presently ~l~fell~d.

When compositions of the present invention are suspensions or formulations intPn(led for ~lminictration to the eye, particle size and viscosity of the polymers, may be less important particularly when the therapeutic agent is completely solubilized. The cyclodextrin-containing compositions of the present invention can be adapted for topical tre~tment of skin and mucous membrane by local application to tissue in need of treatment, such as dermal, nasal, vaginal and rectal tissues. The dosage loading for compositions of the present invention may vary depending on the drug used, the route of ~iminictration selected and other factors f~mili~r to those skilled at methods of formulating pharm~ceutic~l compositions.

In a typical method for stabilizing and partially or completely solubilizing ~minost~roids in accord with the present invention, the selected cyclodextrin (e.g. hydroxypropyl-,B-cyclodextrin) is employed in an amount WO 94/12217 ;. ~ PCT/US93/11651 ~
2~5a~5~ 48 sufficient to solubilize at least a portion of the aminosteroid in the final formulation; the cyclodextrin is thus utilized in an amount which is generally from about 1.0 to about 20.0% or 30.0% by weight of the total composition, but much larger amounts of cyclodextrin (e.g. up to about 50% by weight) may be used when complete solubilization is desired, depending on the insolubility of the particular aminosteroid selected, the amount of aminosteroidto be solubilized and the solubilizing power of the selected cyclodextrin. The weight ratio of cyclodextrin to aminosteroid can range from about 1:1 to about 500:1. The selected polymer is generally used in an effective stabilizing amount of from about 0. 1 % to about 2 % by weight of the final composition, although additional polymer (up to about 6.5% by weight) can be present, if desired. This amount can also to ~,~plessed as a weight to weight ratio of polymer to aminosteroid from about 1:10 to about 20:1. Generally, the cyclodextrin is dissolved in water, then the polymer is slowly dispersed therein and stirred (typically, for a period of from about 15 minutes to 2 hours). Sodium chloride (from about 0 to 0.9% by weight) is added to adjust osmolality and, optionally, EDTA may be added to complex metal ions. The reslllt~nt mixture is generally heated (e.g. autoclaved) for a period of from about 30 to about 90 minutes, then cooled. It is pl~fell~d to adjust the pH of the mixture to be above about 6. This may be done by addition of a suitable base such as sodium hydroxide. Separately, the aminosteroid (from about 0.01 to about 10.0% by weight of the total composition) is dissolved in a strong acid solution (e.g. aqueous hydrochloric acid) and that solution is combined with the polymer/cyclodextrin solution, the pH is adjusted to around pH 6-7 with sodium hydroxide, and water is added as neces~ry to bring the total volume to 100%. Compositions obtained in this manner can be solutions or mixed sus~-n~ions/solutions; the degree of solubilization is controlled by the concentr~tion of the cyclodextrin component. A le~resentative formulation prepared as described in EXAMPLE 1 hereinbelow, having a 1% w/w concentration of the l~lGse~l~tive aminosteroid U-74006F which is ~0 94/12217 215 0 5 5 4 PCT/US93/11651 approximately 75% solubilized, will be stable at room te~ dture and at 40C over a three month storage period. There is no significant loss of aminosteroid concentration at either temperature. In this case, it is believed that stability results from the stability of the non-dissolved aminosteroid, theinteraction of the aminosteroid with the polymer as discussed above in relation to the non-cyclodextrin compositions, and the molecular inclusion of the aminosteroid by the cyclodextrin. Solubili_ation is of course due primarily to the presence of cyclodextrin. The main reason the aminosteroid is stable in both formulations appears to be the presence of the cross-linked polymer and its ionic interaction with the ~minosteroid.

The aminosteroids of formula XI are useful in the treatment of a variety of medi~l conditions in warm-blooded ~nim~lc, including humans.
The present invention provides pharm~ eutical compositions for adminictration in the tre~tmçnt or prevention of the various conditions for which the aminosteroids are known to be useful, e.g. from International Publication No.
WO 87/01706, and from U.S. Patent No. 5,124,154. Briefly, such conditions include spinal trauma; head injury (mild, moderate or severe); subarachnoid hemorrhage (including theassociated cerebral vasospasm); skin graft rejection;
ischemic stroke; excessive mucous secretion; ~cthm~; muscular dystrophy;
shock (hemorrhagic, septic or tr~l~m~tic); cardiac toxicity induced by anti-cancer agents such as adriamycin; Parkinsonism, ~l7h~imçr's disease and other neurological disorders of a degenerative nature; severe burns; ARDS;
multiple sclerosis; organ damage occurring during reperfusion following transplant; o~eo~ ~hlitis, rhP~m~toid arthritis and other infl~mm~tory ~licç~ces;
dermatological disorders such as infl~mm~tion and psoriasis; immunological nephrotic syndrome; allergic reactions; systemic lupus erythematosis;
atherosclerosis; emphysema; met~ct~cPs and tumor growth; cluster headaches, ulcers indllce~ by stress; complications from radiation damage, brain tumors and damage after myocardial infarction; and burns and wounds (to promote WO 94/12217 - ~ PCT/US93/116~1 ~

21~055 4 50 healing). The aminosteroids are further known to be useful in the prevention of damage following cardiopulmonary resuscitation, cardiac infarction and neurological or cardiovascular surgery; in the treatment and prevention of many of the conditions for which glucocorticoid pharm~euticals are known to be useful (some of which are listed hereinabove); in the trP~tment or prevention of ophthalmic ~lice~cps or disorders such as cataracts, glaucoma or the risk of glaucoma associated with significantly elevated intraocular pressure, infl~mm~tory eye disease, retinal eye disease, intraocular pressure rise due to uveitis, post-infarct ambolus, traumatic eye injury (such as blunt trauma compression injury, hyphema, surgical trauma, etc.), neovascular or ischemic eye disease (conditions in the eye involving ischemia such as corneal edema from prolonged wearing of contact lenses and the like), bullous kPr~titi~, dry eye including keratitis sicca, alkali burn and conditions arisingfrom transplantation of ocular cells.

The folegoillg is not meant to imply that each of the aminosteroids of formula XI is useful for every condition noted above. However, one skilled in the art can readily ascertain which aminosteroids are useful for which purposes, for example, using assay procedures referred to in International Publication No. WO 87/01706.

Routes of ~rlminictration~ frequency of ~11minictration and dosage levels vary with the particular therapeutic agent selected, condition being treated, severity of the condition, size, weight and age of the patient and other well-known factors. Typical dosage ranges for intravenous or intramuscular injection of ~minosteroids include from about 0.05 to about 100 mg/kg/day, one to four times daily. The dosages will vary, of course, with the compound s~lected Obviously, sl~spencion and solutions can be ~iminictPred by other routes as well including topical (e.g., ophth~lmic, dermal or vaginal), introcular, nasal and rectal ~dmini~tration.

~Wo 94/12217 2 1 5 0 5 S 4 PCT/US93/11651 Topical adminictration to the skin is generally preferred for the treatment of many dermatological conditions, particularly skin infl~mm~tion and psoriasis, but particularly serious dermal conditions may require systemic ~lminictration, alone or in conjunction with topical treatment. Here again, the specific dosages selected will vary somewhat depending on the drug selected and other factors noted above.

In the case of ophthalmic conditions, topical administration is preferable when the target of the treatment is located in or near the anterior chamber of the eye. By contrast, because the flow of aqueous humor is from the ciliary body (behind the iris) forward towards the cornea before it exits through the trabecular meshwork and Schlemm's canal, penetration of drugs to the back of the eye when ~rlminict~red topically to the front of the eye occurs with some difficulty. It is therefore often more effective to ~clminicterdrugs intended for the tre~tment of uveal and retinal ~lice~ces by the systemic route where access to the eye occurs through the choroid plexus, or by the intravitreal route. Some of the more severe eye ~lise~cPs affect those targets which are difficult to treat effectively by the topical route and they can be associated with markedly impaired vision or blindness. Accordingly, the topical route is plefelled for convenience of individual patient self-lminictration, and the intraocular and systemic routes are preferred for surgical and presurgical ~lminictration.

In order to maintain an ocularly adequate therapeutic level of drug in the back of the eye where surgery is not involved, or has been concluded, the present invention also conte...plates the treatment of an ophthalmic disease by ~lminictration of a thel~peu~ically effective amount of amino-substituted steroid antioxidant agent (including salts, hydrates or solvates), by oral or intramuscular routes, in addition to the convenient topical route or by intraocular injection.
.

WO 94/12217 52 PCT/US93/11651 ~

2lsass l Aqueous solutions, aqueous suspensions, ointments, and gels are preferably used for topical formulations, e.g. for ophthalmic or dermal ~mini~tration. The aqueous formulations may also contain liposomes for creating a reservoir of dissolved amino-substituted steroid therapeutic agent S for contact with the tear film. Particularly ~ felled among topicalformulations are gels, which enhance pre-corneal retention and protect the amino-substituted steroids from degradation without the inconvenience and impairment of vision associated with ointments.

Topical formulations should generally include between 0.01 and 10%
by weight, preferably between 0.1 and 5 % by weight, of the amino-substituted steroid therapeutic agent, together with the amounts of polymer and/or cyclodextrin noted hereinabove, in an aqueous medium.

Other additives which are desirably included in the topical formulations include sodium chloride, EDTA (disodium edetate), pH adjusters, buffers, surfactants, and preservatives like BAK (benzalkonium chloride).
A~mini~tration of the formulation to the eye or skin will typically be carried out between one and four times a day, depending on the particular problem being treated.

Formulations for ocular injection, intramuscular injection, oral ~(~mini~tration and other routes can be formulated in accord with techniques well-known to those skilled in the art of pharmaceutical formulations. The amounts of thçlAl~ulic agent, polymer and cyclodextrin as noted hereinabove may typically be included in an aqueous medium; and as in the case of topical formulations, other additives may be included just so long as they do not interfere with the stabilization (and solubilization, when desired) and are ~ro~u~iate for the selectçd route of ~(~mini~tration. See, for example applicants' parent application referenced hereinabove, and Rçmington's ~Wo 94/12217 2 15 0 ~ 5 ~ PCT/US93/11651 Pharmaceutical Sciences seventeen edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985) which is incorporated herein by reference in its entirety and is relied upon.

The following examples are given for illustrative purposes only and should in no way be construed as limiting the subject matter presently disclosed and cl~im~d.

A 100 g batch of pharm~eutical composition may be prepared as described below:

INGREDIENTCONCENTRATION (% w/w) Aminosteroid U-74006F 1.0 %
Polycarbophil 976 (Noveon AA-l)1.0%
2-Hydroxypropyl-~B-cyclodextrin20.0%
EDTA 0. 1%
Hydrochloric Acid, 0.2 N 12.5 %
Sodium Hydroxide, 2 Nto adjust pH
Water,q.s.to 100%

The cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for injection. The polymer is dispersed in the cyclodextrin solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes. The mixture is autoclaved for 45 minutes at 121C, then allowed to cool to room temperature. The aminosteroid (1 g) is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid. The aminosteroid solution is added to the cyclodextrin/polymer mixture by sterile filtration. ThepH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the final weight of the formulation is adjusted to 100 g sterile water by sterile filtration. The formulation is sealed under a blanket of filtered nitrogen. The 2 ~ 5 ~ 54 aminosteroid is extensively solubilized in the resultant composition, but about 25% of the steroid rem~ined undissolved: The pH is physiological and the osmolality is slightly hypotonic.

S The resultant composition is of particular interest for topical treatment of ophthalmic conditions. Use of about 30 g of 2-hydroxypropyl-~-cyclodextrin in the above procedure is expected to substantially completely solubilize the aminosteroid.

The foregoing example can be repeated, substituting or adding one or more other aminosteroid therapeu~tic agents selected from the C20 through C26 aminosteroids of the formula XI structure (especially those which exhibit antioxidant functions), and pharm~elltically acceptable salts, hydrates, or solvates thereof. One such agent is U-77372E. The structure of U-77372E, 21-[4-(4,6-bis-(2-pyridinyl)triazin-2-yl)-1-piperazinyl]-16~-methylpregna-1,4,9(11)-triene-3,20-dione methanesulfonate, may be obtained from the description in Braughler et al, Biochemical Pharmacolo~y 37:3856 (1988).

A 100 g batch of pharm~-eutic~l composition may be prepared as described below:

INGREDIENT CONCENTRATION
(5)-4-methyl-2-{methyl-[4-(2-methyl- 0.3 %
imi~7O[4,5-C]pyridin-l-ylmethyl)-benzene sulphonyl]-amino}pentanoic acid ethyl ether (BB-882) Polycarbophil (Noveon AA-1) 1.3 %
2-Hydroxypropyl-,l~-cyclodextrin (HPBC) 15.0 %
EDTA 0.1 %
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%

-Wo 94/12217 215 0 5 5 4 PCT/US93/11651 The HPBC (15 g) is dissolved in approximately 60 g of sterile water for injection. The polymer is dispersed in the HPBC solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes. The mixture is autoclaved for 20 minutes at 121C, then allowed to cool to room tem~ ture. BB-882 is a PAF-antagonist useful as an antiinflamatory therapeutic agent. BB-882 (.3 g) is dissolved in 12.5 g of 0.2 N hydrochloric acid. The BB-882 solution is added to the HPBC/polymer mixture by sterile filtration while mixing. The pH is adjusted to about 6.0 with 2 N sodium hydroxide solution and the final weight of the formulation is adjusted to l00 g with sterile water by sterile filtration.

E~XAMPLE 3 A 100 g batch of pharm~reutical composition may be prepared as described below:
INGREDIENT CONCENTRATION
[4(N-hydroxyamino)-2R-isobutyl-3S- 0.3 %
(thienyl-thiomethyl)-succinyl] -L-phenyl~l~nine-N-methylamide (BB-94) Polycarbophil (Noveon AA-1) 1.3 %
2-Hydroxypropyl-,B-cyclodextrin (HPBC)15.0 %
EDTA 0.1%
Hydrochloric Acid, 0.2 N 12.5 %
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%

The HPBC (15 g) is dissolved in approximately 60 g of sterile water for injection. The polymer is dispersed in the HPBC solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes. The mixture is autoclaved for 20 minutes at 121C, then allowed to cool to room telllpelature. BB-94 is a collogenase inhibitor.
The BB-94 (.3 g) is dissolved in 12.5 g of 0.2 N hydrochloric acid. The aminosteroid solution is added to the HPBC/polymer mixture by sterile wo g~/12217 PcT/US93/11651 ~
~15~55 ~ 56 filtration. The pH is adjusted to about 6.0 with 2 N sodium hydroxide solution. The final weight of the formulation is adjusted to 100 g with sterile water.
,, ' A 100 g batch of pharm~reutical composition may be prepared as described below:

INGREDIENT CONCENTRATION
Levobunalol HCl 1.0%
Polycarbophil (Noveon AA-l) 1.3%
2-Hydroxypropyl-,~-cyclodextrin (HPBC)15.0%
EDTA 0. 1%
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%

The HPBC (15 g) is dissolved in approximately 60 g of sterile water for injection. The polymer is dispersed in the HPBC solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes. The mixture is autoclaved for 45 minutes at 121C, then allowed to cool to room temperature. Levobunolol HC 1 is an ~ntigl~l~coma therapeutic agent. The levobunolol HCl (1 g) is dissolved in 12.5 g of water of pH 7.2. The levobunolol HC1 solution is added to the HPBC/polymer ~ ulc by sterile filtration. The pH is adjusted to about 6.0 with 2 N sodium hydroxide solution by sterile filtration. The final weight of the formulation is adjusted to 100 g with sterile water by sterile f1ltration.

A 100 g batch of pharm~r-eutir~l composition is prepared as described below:

wo 94/12217 215 0 5 5 ~ PCT/US93/11651 .

In~redient Concentration L-Asparaginyl-L-Leucyl-Glycyl-L- 1 %
Valyl-S-Acet~midomethyl-L-Cystein~mide Acetate (CBT-101) Polycarbophil (Noveon AA- 1 ) 1 %
Sodium Glycocholate 1%
2-Hydroxypropyl-~-cyclodextrin 4 %
(HPBC) Sodium Chloride (NaCl) 0.34%
Disodium Acetate (EDTA) 0.1%
Sodium Hydroxide, 10 N. to adjust pH
Water for iniection, q.s. to 100%

The polymer is dispersed in approximately 60 g of sterile water for injection, stirred for 1 hour at 400 rpm. Then 0.1 g of EDTA is added and stirred for 15 minutes, 0.34 g of NaCl is added and stirred for 15 minutes, 1 g of sodium glycocholate is added to the mixture, and stirred for 15 minutes. The mixture is autoclaved for 45 minutes at 121 C, then allowed to cool to room temperature. Dissolve HPBC (4 g) in 15 g of sterile water for injection, then add 1 g of CBT-101 to the HPBC solution. Add the CBT-101/HPBC solution to the polymer mixture by sterile filtration. The pH is adjusted to about 7-0 with 10 N. sodium hydroxide solution by sterile filtration. The final weight of the formulation is adjusted to 100 g with sterile water by sterile filtration.
CBT-101 is useful in tre~tment of glaucoma.

wo 94/12217 PCT/US93/11651 2`~50~5~ 58 Although only plefell~d embodiments are specifically illustrated and described herein, it will be appreciated that many modifications and variations of the present invention are possible in light of the above teaching and within the purview of the appended claims without departing from the spirit and intended scope of the invention.

A 100 g batch of pharmaceutical composition may be prepared as described below:

INGREDIENTCONCEN~RATION (% w/w) Aminosteroid U-74006F 1.0%
Carbopol 910 2.0%
2-Hydroxypropyl-,B-cyclodextrin20.0 %
EDTA 0.1%
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 Nto adjust pH
Water, q.s. to 100%

The cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for injection. The polymer is dispersed in the cyclodextrin solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes. The mixture is autoclaved for 45 minutes at 121C, then allowed to cool to room temperature. The aminosteroid (1 g~
is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid. The aminosteroid solution is added to the cyclodextrin/polymer mixture by sterile filtration. ThepH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the final weight of the formulation is adjusted to 100 g sterile water by sterile filtration. The formulation is sealed under a blanket of filtered nitrogen.

Claims (49)

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising a therapeutic agent, an effective stabilizing amount of carboxy-containing polymer and cyclodextrin, in an aqueous medium, wherein said cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .alpha., .beta. and .gamma.-cyclodextrin, modified or nonmodified.

2. The composition of claim 1, wherein the cyclodextrin is present in an amount sufficient to at least partially solubilize said therapeutic agent, said amount being from about 1% to about 50% by weight, based on the total weight of the composition.

3. The composition of claim 2, wherein the cyclodextrin is present in an amount from about 1% to about 25% by weight, based on the total weight of the composition.

4. The composition of claim 2, wherein the polymer is about 0.1%
to about 10% of the composition.

5. A composition of claim 2 wherein the polymer is lightly cross-linked and is about 0.1% to about 6.5% by weight of the composition.

6. The composition of claim 3, wherein the polymer is about 0.5 %
to about 2% of the composition.

7. The composition of claim 4, wherein the cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

8. The composition of claim 4, wherein the therapeutic agent is selected from the group consisting of [4(N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)-succinyl]-L-phenylalanine-N-methylamide,((5)-4-methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-C]pyridin-1-ylmethyl)-benzene sulphonyl]-amino}pentanoic acid ethyl ether, fluoromethalone, prednisolone acetate, dexamethasone, erythromycin, hydrocortisone, CBT-101 and levobunolol HCl.

9. The composition of claim 7, wherein the therapeutic agent is selected from the group consisting of [4(N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)-succinyl]-L-phenylalanine-N-methylamide,((5)-4-methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-C]pyridin-1-ylmethyl)-benzene sulphonyl]-amino}pentanoic acid ethyl ether, fluoromethalone, prednisolone acetate, deyamethasone, erythromycin, hydrocortisone, CBT-101 and levobunolol.

10. The composition of claim 9, wherein the polymer is polycarbophil.

11. The composition of claim 8, wherein the polymer is CARBOPOL 974 P.

12. The composition of claim 7, further comprising one or more additives selected from the group consisting of sodium edetate, methyl paraben, propyl paraben, flavoring agents and colorants.

13. The composition of claim 4 wherein the composition in formulated for topical applications.

14. The composition of claim 13 formulated for topical ophthalmic application and having a viscosity of about 1,000 centipoises to about 100,000 centipoises and wherein said cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

15. The composition of claim 14 and having a viscosity of about 1,000 centipoises to about 30,000 centipoises.

16. A composition of claim 14 having a pH between 3 and about 9 and an osmolality of about 10 mOsM to about 400 mOsM.

17. A pharmaceutical composition comprising an amino-substituted steroid therapeutic agent selected from the group consisting of the C20 through C26 aminosteroids of the formula XI

(XI) where:
(A-I) R6 is .alpha.-R61:.beta.-R62, R10 is .alpha.-R101:.beta.-R102 and R7 is .alpha.-H:.beta.-H, where one of R61 and R62 is -H, and the other is -H, -F, or C1-C3 alkyl, R102 is -CH3, R101 and R5 taken together are -(CH2)2-C(-R33)-CH ? or -CH-CH-CO-CH ?, where R33 is ? O or .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -P( ? O)(OH)2, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5;

(A-II) R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64, R10 is .alpha.-R103:.beta.-R104 and R7 is .alpha.-H:.beta.-H, where one of R63 and R64 is -H, and the other taken together with one of R53 and R54 forms a second bond between C5 and C6, R104 is -CH3, R103 and the other of R53 and R54 taken together are -(CH2)2-C(H)(OH)-CH2- or -(CH2)2-C[H][OP(=O)-(OH)2]-CH2-;
(A-III) R10 and R5 taken together are =CH-CH=
C(OR3)-CH= where R3 is -H, -P(=O)(OH)2, C1-C3 alkyl, -CO-H, C2-C4 alkanoyl or benzyl, R6 is .alpha.-R65:.beta.-R66 where one of R65 and R66 is -H, and the other is -H, -F, or C1-C3 alkyl and R7 is .alpha.-H:.beta.-H;
(A-IV) R5 is .alpha.-R57:.beta.-R58, R6 is .alpha.-R67:.beta.-R68, R7 is .alpha.-H:.beta.-H and R10 is .alpha.-R107:.beta.-R108, where one of R57 and R58 is -H, R107 and the other of R57 and R58 taken together are -(CH2)2-C(=R33)-CH2, where R33 is as defined above, R108 is -CH3, where one of R67 and R68 is -H and the other is -H, -F, or C1-C3 alkyl;
(A-V) R6 is R69:R610, R7 is R79:R710, R10 is .alpha.-R109:R1010, where one of R69 and R610 is -H and the other taken together with one of R79 and R710 forms a second bond between C6 and C7, and the other of R79 and R710 is -H, R1010 is -CH3, R109 and R5 taken together are -(CH2)2-C(=R33)-CH= or -CH=CH-CO-CH=, where R33 is as defined above; where:
(C-I) R11 is .alpha.-R111:.beta.-R112, where one of R111 and R112 is taken together with R9 to form a second bond between C9 and C11 and the other of R111 and R112 is -H;
(C-II) R9 is -Cl and R11 is =O or .alpha.-H:.beta.-R114 where R114 is -Cl or -OH;

(C-III) R9 is -H or -F and R11 is =O or .alpha.-R115:.beta.-R116, where one of R115 and R116 is -H, and the other of R115 and R116 is -H, -OH or C1-C12 alkoxy;
(C-IV) R9 is -H or -F and R11 is .alpha.-O-CO-R117:.beta.-H, where R117 is (A) C1-C3 alkyl, (B) C1-C12 alkoxy, (C) furanyl, (D) -NR122R123, where one of R122 and R123 is -H, methyl or ethyl and the other is -H, C1-C4 alkyl or phenyl, (E) -X3-X1, where X3 is -O- or a valence bond, where X, is phenyl optionally substituted with 1 through 2 -Cl, -Br, C1-C3 alkoxy, -COOH, -NH2, C1-C3 alkylamino, di(C1-C3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3;
where:
(D-I) R16 is R161:R162 and R17 is R171:R172, where one of R16l and R162 is -H or -CH3 and the other taken together with one of R171 and R172 forms a second bond between C16 and C17, and the other of R171 and R172 is -C(=Z)-(CH2)n-NR21R210, where Z is =O, =CH2 or R179:-H where R179 is -H
or-CH3, where n is 0 through 6, where (A) R21 is (1) -(CH2)m-NR211-X2, where m is 2,3 or 4, where R211 is -H or C1-C3 alkyl, where X2 is: [A]
(a) pyridin-2-,3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R212, being the same or different, where R212 is (i) -F, (ii) -Cl, (iii) -Br, (iv) C1-C5 alkyl, (v) -CH2-CH=CH2, (vi) -X1, where X, is as defined above, (vii) -NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CH2-CH = CH2, (viii.alpha.) *CH2-(CH2)q-CH2-N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5, (viii.beta.) *CH2-CH2-(CH2)c-G-(CH2)d-CH2-CH2-N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where G is -O-, -S-, -SO-, -SO2- or -NHR214, where R214 is -H, C1-C3 alkyl, or X1 as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, [a]
(ix) 3-pyrrolin-1-yl, [b]
(x) pyrrol-1-yl optionally substituted with C1-C3 alkyl, [c]
(xi) piperidin-1-yl optionally substituted with 1 or 2 C1-C3 alkyl, [d]
(xii) 1,2,3,6-tetrahydro-pyridin-1-yl, [e]
(xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5-double bonds, [f]
(xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C1-C3 alkyl being the same or different, [g]
(xv) -OH, (xvi) C1-C3 alkoxy, (xvii) -NR217-(CH2)e-Q where Q is 2-pyridinyl where R217 is -H or C1-C3 alkyl and e is 0 through 3 (1) (xviii) pyridin-2-, 3- or 4-yl, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 asis defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 asis defined above, (5)(d) pyrimidin-2-yl optionally substituted at the 4- and/or 6- position with 1 or 2 R212 as is defined above, (6) (e) pyrazin-2-yl optionally substituted with 1 or 2 R212 as is defined above, (7)(f) imidazol-2-yl optionally substituted in the 1 position with C1-c3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (8) (g) 1,3,4-triazol-2-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with R212 as defined above, (9) (h) imidazol-4- or5-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (10) (i) benzo[b]thien-2-yl, (12a) (j) indol-2-yl, (12b) (k) benzo[b]thiazol-2-yl, (12c) (l) benzimidazol-2-yl, (12d) (m) 4-[2-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]ethyl]piperazinyl, (13) (n) 1,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with R212 as is defined above, (14) (2) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B](3) -X2, as defined above, [O]
(4) -(CH2)m-X4 where m is as defined above and where X4 is (a) -O-CH2CH2-Y, where Y is C1-C3 alkylamino, di(C1-C3)alkylamino where the alkyl groups are the same or different, C3-C6 alkyleneimino, optionally substituted with 1 or 2 C1-C3 alkyl, (b) -NR220CH2CH2-Y, where R220 is -H or C1-C3 alkyl and Y is as defined above, (c) -(CH2)g-N(R220)-X2, where g is 2, 3 or 4, and where R220 and X2 are as defined above, [H] (5) -(CH2)m-NR222R223, where R222 is -H or C1-C3 alkyl and R223 is -X1 or -X2 as defined above, or R222 and R223 are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C3-C6 heterocyclic ring and where m is as defined above, [I] (6) -(CHCH3)b-(CH2)f-R224, where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R224 is phenyl substituted with 1 through 3 -OH, C1-C3 alkoxy, -NR225R226 where R225 and R226 are the same or different and are -H, C1-C3 alkyl or are taken together with the attached nitrogen atom to form a C4-C7 cyclic amino ring, [J] (7) -(CH2)i-X2, where i is 1 through 4 and X2 is as defined above, [K] (8) (1-piperazinyl)acetyl substituted in the 4-position by X2 where X2 is as defined above, [L](9) (1-piperazinyl)carbonylmethyl substituted in the 4- position by -X2 where X2 is as defined above, and [M]

(B) R210 is (1) -H, (2) C1-C3 alkyl, (3) C5-C7 cycloalkyl, (4) -(CH2)m-NR211-X2, where m, R211 and X2 are as defined above, [A]
(5) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B]
(6) -(CH2)m-X4, where m and X4 are as defined above, [H]
(7) -(CH2)m-NR222R223, where m, R222 and R223 are as defined above, [I]
(8) -(CHCH3)b-(CH2)f-R224, where b, f and R224 are as defined above, [J]
(C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-1-pyrrolidinyl optionally as the C1-C3 alkyl ester or as a pharmatceutically acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperidinyl optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-2]
(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-3]
(4) 2-(carboxy)-1-heptamethylene-imino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-4]
(5) 1-piperazinyl substituted in the 4- position with R228-CO-(CH2)j- where R228 is -X1, -NR229X1 or 2-furanyl, where R229 is -H or C1-C3 alkyl, where j is 0 through 3 and X, is as defined above, [D]
(6) 1-piperazinyl substituted in the 4- position with X2-(CH2)j-, where X2 and j are as defined above, [E]
(7) 1-piperazinyl substituted in the 4- position with X1-(CH2)j-, where X1 and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4- position with X1 as defined above, [G]
(9) 1-piperazinyl substituted in the 4- position with X2-NR229-CO-(CH2)i-, where X2, R229 and i are as defined above; [N]
(D-II) R16 is .alpha.-R163:.beta.-R164 where one of R163 and R164 is -H and the other is -H, -F, -CH3 or -OH, and R17 is -CH-(CH2)p-NR21R210, where p is 1 or 2, where R21 and R210 are as defined above;
(D-III) R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-R176, where R165 is -H, -OH, -F or -CH3 and R166 is -H, -OH,-F, or -CH3, with the proviso that at least one of R165 and R166 is -H, where R175 is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, where X1 is as defined above, and where R176 is -C(=Z)-(CH2)n-NR21R210, where Z, n, R21 and R210 are as defined above;
(D-IV) the 16,17-acetonide of a compound where R165 is -OH, R166 is -H, R175 is -OH and R176 is -C(=Z)-(CH2)n-NR21R210, where Z, n, -R21 and R210 are as defined above;
and the pharmaceutically acceptable salts, hydrates and solvates thereof;
with the following overall provisos that:
(I) one of R161 or R162 is taken together with one of R171 or R172 to form a second bond between C16 and C17, only when R10 is .alpha.-R101:.beta.-R102, .alpha.-R103:.beta.-R104, .alpha.-R107:.beta.-R108 or .alpha.-R109:.beta.-R1010, (II) R17 is -CH-(CH2)p-NR21R210, only when R10 is .alpha.-R101:.beta.-R102, a-R103:.beta.-R104, .alpha.-R107:.beta.-R108 or .alpha.-R109:.beta.-R1010, (III) R5 and R10 taken together are =CH-CH=C(OR3)-CH=, only when R17 is .alpha.-R175:.beta.-R176 or the 16,17-acetonide of a compound where R16 is .alpha.-OH:.beta.-H and R17 is .alpha.-OH:.beta.-C(=Z)-(CH2)n-NR21R210, and (IV) R5 is .alpha.-R57:.beta.-R58, only when R,7 is .alpha.-R175:.beta.-R176 or .alpha.-OH:.beta.-C-(=Z)-(CH2)n-NR21R210, or the 16,17-acetonide thereof;
an effective stabilizing amount of lightly cross-linked carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, in an aqueous medium, said cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .alpha., .beta.- and .gamma.-cyclodextrin, modified or nonmodified.

18. The composition according to Claim 17, wherein the therapeutic agent is selected from the group consisting of the C21 aminosteroids of formula XI and the pharmaceutically acceptable salts, hydrates and solvates thereof.

19. The composition according to Claim 18, formulated for dermal administration.

20. The composition according to claim 18 formulated for topical ophthalmic administration.

21. The comoosition according to Claim 18, wherein the cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

22. The composition according to Claim 17, wherein the cyclodextrin is present in an amount of from about 1% to about 50% by weight, based on the total weight of the composition.

23. The composition of claim 22 wherein the polymer is lightly cross-linked and is about 0.1% to about 6.5% by weight of the composition.

24. The composition according to Claim 18, wherein the cyclodextrin is present in an amount of from about 1% to about 25% by weight, based on the total weight of the composition.

25. The composition according to Claim 24, wherein the polymer is about 0.1% to about 6.5% by weight of the composition.

26. The composition according to Claim 24, wherein the polymer is about 0.5% to about 5% by weight of the composition.

27. A method for stabilizing and solubilizing a therapeutic agent in a pharmaceutical composition, comprising combining said therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, said cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .alpha., .beta.-and .gamma.-cyclodextrin, modified or nonmodified.

28. The method of claim 27, wherein the cyclodextrin is present in an amount from about 1% to about 50% by weight, based on the total weight of the composition.

29. The method of claim 28, wherein the cyclodextrin is present in an amount from about 1% to about 25% by weight, based on the total weight of the composition.

30. The method of claim 28, wherein the cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

31. The method of claim 30, wherein the polymer is about 0.1%
to about 10% by weight of the composition.

32. The method of claim 28, wherein the polymer is lightly cross-linked and is about 0.1% to about 6.5% by weight of the composition.

33. The method of claim 31, wherein the polymer is about 0.5%
to about 5% by weight of the composition.

34. The method of claim 29, wherein the therapeutic agent is selected from the group consisting of [4(N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)-succinyl]-L-phenylalanine-N-methylamide,((5)-4-methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-C]pyridin-1-ylmethyl)-benzene sulphonyl]-amino}pentanoic acid ethyl ether, fluoromethalone, prednisolone acetate, dexamethasone, erythromycin and hydrocortisone, CBT 101 and levobunolol HCl.

35. The method of claim 31, wherein the therapeutic agent is selected from the group consisting of [4(N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)-succinyl]-L-phenylalanine-N-methylamide,((5)-4-methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-C]pyridin-1-ylmethyl)-benzene sulphonyl]-amino}pentanoic acid ethyl ether, fluoromethalone, prednisolone acetate, dexamethasone, erythromycin and hydrocortisone, CBT-101 and levobunolol HCl.

36. The method of claim 32, wherein the polymer is polycarbophil.

37. The method of claim 32, wherein the polymer is CARBOPOL 974 P.

38. The method of claim 29, further comprising one or more additives selected from the group consisting of sodium edetate, methyl paraben, propyl paraben, flavoring agents and colorants.

39. A method for stabilizing and solubilizing an amino-substituted steroid therapeutic agent in a pharmaceutical composition, said method comprising combining an amino-substituted steroid therapeutic agent selected from the group consisting of the C20 through C26 aminosteroids of the formula XI

(XI) where:
(A-I) R6 is .alpha.-R61:.beta.-R62, R10 is .alpha.-R101:.beta.-R102 and R7 is .alpha.-H:.beta.-H, where one of R61 and R62 is -H, and the other is -H, -F, or C1-C3 alkyl, R102 is -CH3,R101 and R5 taken together are -(CH2)2-C(-R33)-CH = or -CH-CH-CO-CH=, where R33 is =O or .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -P(=O)(OH)2, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or-CO-O-C2H5;
(A-II) R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64, R10 is .alpha.-R103:.beta.-R104 and R7 is .alpha.-H:.beta.-H, where one of R63 and R64 is -H, and the other taken together with one of R53 and R54 forms a second bond between C5 and C6, R104 is -CH3, R103 and the other of R53 and R54 taken together are -(CH2)2-C(H)(OH)-CH2- or -(CH2)2-C[H][OP(=O)-(OH)2]-CH2-;
(A-III) R10 and R5 taken together are =CH-CH=
C(OR3)-CH= where R3 is -H, -P(=O)(OH)2, C1-C3 alkyl, -CO-H, C2-C4 alkanoyl or benzyl, R6 is .alpha.-R65:.beta.-R66 where one of R65 and R66 is -H, and the other is -H, -F, or C1-C3 alkyl and R7 is .alpha.-H:.beta.-H;
(A-IV) R5 is .alpha.-R57:.beta.-R58, R6 is .alpha.-R67:.beta.-R68, R7 is .alpha.-H:.beta.-H and R10 is .alpha.-R107:.beta.-R108, where one of R57 and R58 is -H, R107 and the other of R57 and R58 taken together are -(CH2)2-C(=R33)-CH2, where R33 is as defined above, R108 is -CH3, where one of R67 and R68 is -H and the other is -H, -F, or C1-C3 alkyl;
(A-V) R6 is R69:R610, R7 is R79:R710, R10 is .alpha.-R109:R1010, where one of R69 and R610 is -H and the other taken together with one of R79 and R710 forms a second bond between C6 and C7, and the other of R79 and R710 is -H, R1010 is -CH3, R109 and R5 taken together are -(CH2)2-C(=R33)-CH= or -CH=CH-CO-CH=, where R33 is as defined above; where:
(C-I) R11 is .alpha.-R111:.beta.-R112, where one of R111 and R112 is taken together with R9 to form a second bond between C9 and C11 and the other of R111 and R112 is -H;
(C-II) R9 is -Cl and R11 is =0 or .alpha.-H:.beta.-R114 where R114 is -Cl or -OH;
(C-III) R9 is -H or -F and R11 is =O or .alpha.-R115:.beta.-R116, where one of R115 and R116 is -H, and the other of R115 and R116 is -H, -OH or C1-C12 alkoxy;
(C-IV) R9 is -H or -F and R11 is .alpha.-O-CO-R117:.beta.-H, where R117 is (A) C1-C3 alkyl, (B) C1-C12 alkoxy, (C) furanyl, (D) -NR122R123, where one of R122 and R123 is -H, methyl or ethyl and the other is -H, C1-C4 alkyl or phenyl, (E) -X3-X1, where X3 is -O- or a valence bond, where X1 is phenyl optionally substituted with 1 through 2 -Cl, -Br, C1-C3 alkoxy, -COOH, -NH2, C1-C3 alkylamino, di(C1-C3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3;
where:
(D-I) R16 is R161:R162 and R17 is R171:R172, where one of R16l and R162 is -H or -CH3 and the other taken together with one of R171 and R172 forms a second bond between C16 and C17, and the other of R171 and R172 is -C(=Z)-(CH2)n-NR21R210, where Z is =O, =CH2 or R179:-H where R179 is -H
or -CH3, where n is 0 through 6, where (A) R21 is (1) -(CH2)m-NR211-X2, where m is 2, 3 or 4, where R211 is -H or C1-C3 alkyl, where X2 is: [A]
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R212, being the same or different, where R212 is (i) -F, (ii) -Cl, (iii) -Br, (iv) C1-C5 alkyl, (v) -CH2-CH=CH2, (vi) -X1, where X1 is as defined above, (vii) -NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CH2-CH=CH2, (viii.alpha.) *CH2-(CH2)q-CH2-N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5, (viii.beta.) *CH2-CH2-(CH2)c-G-(CH2)d-CH2-CH2-N* - where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where G is -O-, -S-, -SO-, -SO2- or -NHR214, where R214 is -H, C1-C3 alkyl, or X1 as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, [a]
(ix) 3-pyrrolin-1-yl, [b]
(x) pyrrol-1-yl optionally substituted with C1-C3 alkyl, [c]
(xi) piperidin-1-yl optionally substituted with 1 or 2 C1-C3 alkyl, [d]
(xii) 1,2,3,6-tetrahydro-pyridin-1-yl, [e]
(xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5-double bonds, [f]
(xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C1-C3 alkyl being the same or different, [g]
(xv) -OH, (xvi) C1-C3 alkoxy, (xvii) -NR217-(CH2)e-Q where Q is 2-pyridinyl where R217 is -H or C1-C3 alkyl and e is 0 through 3 (1) (xviii) pyridin-2-, 3- or 4-yl, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 asis defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 asis defined above, (5) (d) pyrimidin-2-yl optionally substituted at the 4- and/or 6- position with 1 or 2 R212 as is defined above. (6) (e) pyrazin-2-yl optionally substituted with 1 or 2 R212 as is defined above, (7) (f) imidazol-2-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (8) (g) 1,3,4-triazol-2-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with R212 as defined above, (9) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (10) (i) benzo[b]thien-2-yl, (12a) (j) indol-2-yl, (12b) (k) benzo[b]thiazol-2-yl, (12c) (l) benzimidazol-2-yl, (12d) (m) 4-[2-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]ethyl]piperazinyl, (13) (n) 1,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with R212 as is defined above, (14) (2) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B]
(3) -X2, as defined above, [O]
(4) -(CH2)m-X4 where m is as defined above and where X4 is (a) -O-CH2CH2-Y, where Y is C1-C3 alkylamino, di(C1-C3)alkylamino where the alkyl groups are the same or different, C3-C6 alkyleneimino, optionally substituted with 1 or 2 C1-C3 alkyl, (b) -NR220CH2CH2-Y, where R220 is -H or C1-C3 alkyl and Y is as defined above, (c) -(CH2)g-N(R220)-X2, where g is 2, 3 or 4, and where R220 and X2 are as defined above, [H]
(5) -(CH2)m-NR222R223, where R222 is -H or C1-C3 alkyl and R223 is -X1 or -X2 as defined above, or R222 and R223 are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C3-C6 heterocyclic ring and where m is as defined above, [I]
(6) -(CHCH3)b-(CH2)f-R224, where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R224 is phenyl substituted with 1 through 3 -OH, C1-C3 alkoxy, -NR225R226 where R225 and R226 are the same or different and are -H, C1-C3 alkyl or are taken together with the attached nitrogen atom to form a C4-C7 cyclic amino ring, [J]

(7) -(CH2)i-X2, where i is 1 through 4 and X2 is as defined above, [K]
(8) (1-piperazinyl)acetyl substituted in the 4-position by X2 where X2 is as defined above, [L]
(9) (1-piperazinyl)carbonylmethyl substituted in the 4- position by -X2 where X2 is as defined above, and [M]
(B) R210 is (1) -H, (2) C1-C3 alkyl, (3) C5-C7 cycloalkyl, (4) -(CH2)m-NR211-X2, where m, R211 and X2 are as defined above. [A]
(5) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B]
(6) -(CH2)m-X4, where m and X4 are as defined above, [H]
(7) -(CH2)m-NR222R273, where m, R222 and R223 are as defined above, [I]
(8) -(CHCH3)b-(CH2)f-R224, where b.
f and R224 are as defined above. [J]
(C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-1-pyrrolidinyl optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperidinyl optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-2]
(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-3]
(4) 2-(carboxy)-1-heptamethylene-imino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-4]
(5) 1-piperazinyl substituted in the 4- position with R228-CO-(CH2)j- where R228 is -X1, -NR229X1 or 2-furanyl, where R229 is -H or C1-C3 alkyl, where j is 0 through 3 and X1 is as defined above, [D]
(6) 1-piperazinyl substituted in the 4- position with X2-(CH2)j-, where X2 and j are as defined above, [E]
(7) 1-piperazinyl substituted in the 4- position with X1-(CH2)j-, where X1 and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4- position with X1 as defined above, [G]
(9) 1-piperazinyl substituted in the 4- position with X2-NR229-CO-(CH2)i-, where X2, R229 and i are as defined above; [N]
(D-II) R16 is .alpha.-R163:.beta.-R164 where one of R163 and R164 is -H and the other is -H, -F, -CH3 or-OH, and R17 is -CH-(CH2)p-NR21R210, where p is 1 or 2, where R21 and R210 are as defined above;
(D-III) R16 is .beta.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-R176, where R165 is -H, -OH, -F or -CH3 and R166 is -H, -OH,-F, or -CH3, with the proviso that at least one of R165 and R166 is -H, where R175 is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1 where X1 is as defined above, and where R176 is -C(=Z)-(CH2)n-NR21R210, where Z, n, R21 and R210 are as defined above;
(D-IV) the 16,17-acetonide of a compound where R165 is -OH, R166 is -H, R175 is -OH and R176 is -C(=Z)-(CH2)n-NR21R210, where Z, n, -R21 and R210 are as defined above;

and the pharmaceutically acceptable salts, hydrates and solvates thereof;
with the following overall provisos that:
(I) one of R161 or R162 is taken together with one of R171 or R172 to form a second bond between C16 and C17, only when R10 is .alpha.-R101:.beta.-R102, .alpha.-R103:.beta.-R104, .alpha.-R107:.beta.-R108 or .alpha.-R109:.beta.-R1010, (II) R17 is -CH-(CH2)p-NR21R210, only when R10 is .alpha.-R101:.beta.-R102, a-R103:.beta.-R104,.alpha.-R107:.beta.-R108 or .alpha.-R109:.beta.-R1010, (III) R5 and R10 taken together are =CH-CH=C(OR3)-CH=. only when R17 is .alpha.-R175:.beta.-R176 or the 16,17-acetonide of a compound where R16 is .alpha.-OH:.beta.-H and R17 is .alpha.-OH:.beta.-C(=Z)-(CH2)n-NR21R210, and (IV) R5 is .alpha.-R57:.beta.-R58, only when R17 is .alpha.-R175:.beta.-R176 or .alpha.-OH:.beta.-C-(=Z)-(CH2)n-NR21R210, or the 16,17-acetonide thereof;
in an aqueous medium with an effective stabilizing amount of lightly cross-linked carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, said cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .alpha., .beta.- and .gamma.-cyclodextrin, modified or nonmodified.

40. The method according to claim 39, wherein the therapeutic agent is selected from the group consisting of the C21 aminosteroids of formula X1 and the pharmaceutically acceptable salts, hydrates and solvates thereof.

41. The method according to claim 34, wherein the therapeutic agent is selected from the group consisting of the C21 aminosteroids of the formula I

(I) where:
a' is selected from the group 1,2-dihydro (saturated) and 1,2-dehydro (1,2-double bond);
b' is selected from the group 6.alpha.-H, 6.alpha.-methyl and 6.alpha.-flouro;
c' is selected from the group 9,11-dihydro (saturated), 9(11)-dehydro (double bond), 9.alpha.-H-11.alpha.-OH-11.beta.-H,9.alpha.-H-11.beta.-OH-11.alpha.-H,9.alpha.-H-11-keto,9.alpha.-F-11.beta.-OH-11.alpha.-H and 9.alpha.-F-11-keto;
d' is selected from the group 16.alpha.-methyl-16.beta.-H-17.alpha.-H,16.beta.-methyl-16.alpha.-H-17.alpha.-H, 16-H2-17.alpha.-H, 16-H-16,17-dehydro (double bond), and 16-methyl-16,17-dehydro. Less preferably, a 17.alpha.-OH group can be present instead of 17.alpha.-H when d' is not 16-H-16,17-dehydro or 16-methyl-16,17-dehydro;
and where:
X'is selected from the complex 21-amino substituents X1' and X2' where X1' is and X2' is where e' and f' may be the same or different and are selected from the group: H,NHR1' and NR1'R2', where R1' and R2' are C1 to C3 lower alkyl or R1' and R2', taken together with N, constitute a heterocyclic ring;
and the pharmaceutically acceptable salts, hydrates and solvates thereof.

42. The method according to claim 41, wherein e' and f', which may be the same or different, are selected from the group consisting of H,NHR1' and NR1'R2', wherein R1' and R2' are C1 to C3 lower alkyl or R1' and R2', taken together with N, constitute a heterocyclic ring selected from the group consisting of 1-ethyleneimino, 1-trimethyleneimino, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl and 1-(4-methyl)piperazinyl.

43. The method according to claim 39, wherein the therapeutic agent is selected from the group consisting of 21-[4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione or a pharmaceutically acceptable slat, hydrate or solvate thereof; 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and 21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione,or a pharmaceutically acceptable salt, hydrate or solvate thereof.

44. The method according to claim 39, wherein the therapeutic agent is selected from the group consisting of the methanesulfonate salt of 21-[4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3.20-dione; the hydrochloride salt of 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione; and the hydrochloride or maleic acid salt of 21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione.

45. The method according to claim 39, wherein the cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

46. The method according to claim 39, wherein the cyclodextrin is used in an amount of from about 1 % to about 50% by weight, based on the total weight of the composition.

47. The method of claim 46 wherein the polymer is lightly cross-linked and is about 0.1 % to about 6.5% by weight of the composition.

48. The method according to claim 42, wherein the cyclodextrin is used in an amount of from about 1 % to about 25% by weight, based on the total weight of the composition.

49. A method as recited in claim 43, wherein the polymer is about .5% to about 2% by weight of the composition.