|||||||||||||| USOO54O7926A United States Patent (19) 11 Patent Number: 5,407,926 Clark (45) Date of Patent: Apr. 18, 1995

54 OPHTHALMC COMPOSITION by ,' Am. Journal of Oph., 82:492-493 (1976). 75 Inventor: Abbot F. Clark, Arlington, Tex. Cantrill et al., “Comparison of In Vitro Potency of 73) Assignee: Alcon Laboratories, Inc., Ft. Worth, Corticosteroids with Ability to Raise Intraocular Pres Tex. sure, Am. Journal of Oph., 79:1012-1016 (1975). Notice: The portion of the term of this patent Mindel et al., “Comparative Ocular Pressure Elevation subsequent to Jul. 31, 2007 has been by , , and disclaimed. Phosphate.” Arch Ophthal, 98: 1577-1578 (1980). Southren et al., “Intraocular Hypotensive Effect of a 21 Appl. No.: 966,118 Topically Applied Metabolite: 3a, 56 Tetrahy 22 Fed: Oct. 23, 1992 drocortisol,' Investigative Ophthalmology & Visual Sci ence, 28:901-903 (1987). Treister et al., “Intraocular Pressure and Outflow Facil Related U.S. Application Data ity,” Arch. Ophthal, 83:311-318 (1970). 63 Continuation of Ser. No. 555,692, Jul. 23, 1990, aban Meyer et al., “Influence of Norethynodrel With Mestra doned, which is a continuation-in-part of Ser. No. nol on Intraocular Pressure in Glaucoma.” Arch Oph 399,351, Aug. 28, 1989, Pat. No. 4,945,089, which is a continuation of Ser. No. 139,222, Dec. 29, 1987, aban thal, 75:771-773 (1966). doned, and Ser. No. 419,226, Oct. 10, 1989, abandoned, Lamble et al., “Some Effects of Progestogens, Oestro which is a continuation of Ser. No. 264,918, Oct. 31, gens and Androgens on the Ocular Tension of Rabbits 1988, Pat. No. 4,876,250. and Owl Monkeys,” Exp. Eye Res. 26:599-610 (1978). (51) Int. CI.' ...... A61K 31/56; A61K 31/58 (i list continued on next page.) 52) U.S. Cl...... 514/179; 514/172; Primary Examiner-Zohreh Fay 514/173; 514/176; 514/180; 514/182 Attorney, Agent, or Firm-Julie J. L. Cheng; Gregg C. 58) Field of Search ...... 514/170, 183, 171, 180, Brown 514/72, 173, 179, 176 57 ABSTRACT (56. References Cited Pharmaceutical compositions useful in the treatment of U.S. PATENT DOCUMENTS ophthalmic inflammation and methods of treating oph thalmic inflammation with those compositions are dis 4,617,299 10/1986 Knepper ...... 514/178 4,686,214 8/1987 Boltralik ...... 514/179 closed. The compositions contain a combination of a 4,876,250 10/1989 Clark ...... 514/179 and an angiostatic . The angio FOREIGN PATENT DOCUMENTS static steroid substantially prevents any significant in creases in intraocular pressure which might otherwise O088462A3 9/1983 European Pat. Off. . be experienced by the patient as a side effect of the 0250.088 5/1987 European Pat. Off. . glucocorticoid component of the compositions. The PCT/US86/- therapeutic interaction of the two components there O2189 10/1986 WIPO . fore allows the potent anti-inflammatory properties of OTHER PUBLICATIONS the to be utilized without fear of elevat Gillman et al., "Goodman & Gillman's The Pharmacolog ing intraocular pressure. ical Basis of Therapeutics', 7th Ed. 1473-1474 (1985). McKerns, Steroid Hormones and Metabolism, Ap pleton-Century-Croffs, New York:1969, Chapter 8, pp. 93-103. Kitazawa, Y., “Increased Intraocular Pressure Induced . 10 Claims, No Drawings 5,407,926 Page 2

OTHER PUBLICATIONS Capillary Basement Membrane Dissolution,” Endocri nology, 119(4): 176-1775 (1986). of the Ocular Hypertension in Glaucoma, Invest. Folkman et al., "Angiostatic ,' Ann. Surg., Ophth. & Vis. Science, 26:393-395 (Mar., 1985). 206(3):374-382 (1987). Knepper et al., “Intraocular Pressure & Glycosaminog Knepper et al. "Glycosaminoglycans and Cutflow lycan Distribution in the Rabbit Eye: Effect of Age and Pathways of the Eye and Brain, Pediatric Neuroscience, Dexamethosone.” Exp. Eye Res., 27:567-575 (1978). 12:240-251 (1985-86). Hester et al., "Steroid-Induced Ocular Hypertension in Knepper et al. “Effect of Dexamethasone, Progester the Rabbit: A Model Using Subconjunctival Injec one, and Testosterone on IOP & GaGs in the Rabbit tions,” J. Ocular Pharmacology, 3(3):185-189 (1987). Eye,” Invest. Ophth. & Vis. Science, 26:1093-1100 (Aug., Crum et al., "A New Class of Steroids Inhibits Angio 1985). genesis in the Presence of Heparin or a Heparin Frag Rohen, Johanness W. “Why is Intraocular Pressure ment,” Science, 230:1375-1378 (Dec., 1985). Elevated in Chronic Simple Glaucoma?”, Ophthalmol Ingber et al., "A Possible Mechanism for Inhibition of ogy, 90(7):758–764 (1983). Angiogenesis by Angiostatic Steroids: Induction of Southren et al. “5{3-Dihydrocortisol: Possible Mediator 5,407,926 1. 2 elevating intraocular pressure. A further objective of OPHTHALMIC COMPOSITION the invention is the provision of methods of treatment and ophthalmic compositions useful in that therapy. This application is a continuation of application Ser. The foregoing objectives and other general objec No. 07/555,692, filed Jul. 23, 1990, abandoned, which is tives of the present invention are met by the provision a continuation-in-part of application Ser. No. 399,351, of a therapy for ophthalmic inflammation wherein the filed Aug. 28, 1989, (now U.S. Pat. No. 4,945,089), elevations in intraocular pressure caused by glucocorti which is a continuation of application Ser. No. 139,222, coids are substantially prevented. The therapy involves filed Dec. 29, 1987, now abandoned, and application the combination of a first component, comprising an Ser. No. 419,226, filed Oct. 10, 1989, now abandoned, 10 anti-inflammatory glucocorticoid and a second compo which is a continuation of application Ser. No. 264,918, nent, comprising one or more angiostatic steroids which filed Oct. 31, 1988, (now U.S. Pat. No. 4,876,250). prevent or antagonize the intraocular pressure elevating effect of the glucocorticoid. This combination allows BACKGROUND OF THE INVENTION the intraocular pressure (“IOP”) elevating effect of Field of the Invention 15 glucocorticoids to be eliminated without adversely af The present invention relates to the field of ophthal fecting the anti-inflammatory activity of the glucocorti mology. More particularly, this invention relates to the coids. Thus, the therapy of the present invention makes treatment of inflamed, ocular tissue. it possible to employ the potent anti-inflammatory prop Description of Related Art erties of the glucocorticoids without causing any signifi Many compounds classified as glucocorticoids, such 20 cant elevations in intraocular pressure. as dexamethasone and , are very effective in the treatment of inflamed tissues, but in certain pa DESCRIPTION OF THE INVENTION tients, these compounds cause elevations in intraocular The present invention is based on the combination of pressure. Patients who experience elevations in intraoc one or more potent glucocorticoids with one or more ular pressure when treated with glucocorticoids are 25 angiostatic steroids. For purposes of the present inven generally referred to as "steroid responders.” The ele tion, the term “angiostatic steroids' means steroids and vations in intraocular pressure are of particular concern steroid metabolites which inhibit angiogenesis. in patients who are already suffering from elevated The present invention is based on the finding that intraocular pressures, such as glaucoma patients. More angiostatic steroids somehow inhibit the IOP elevating over, there is always a risk that the use of glucocorti effect of glucocorticoids. The mechanism by which coids in patients who have normal intraocular pressures angiostatic steroids prevent or antagonize the IOP ele will cause elevations in pressure that may cause damage vating effect of glucocorticoids is not totally under to ocular tissue. Since therapy with glucocorticoids is stood at this point. While applicant does not wish to be frequently long term (i.e., several days or more), there is bound by any theory, one possible explanation is that potential for significant damage to ocular tissue as a 35 these compounds interfere with the action of glucocor result of prolonged elevations in intraocular pressure ticoids on trabecular meshwork cells, thereby blocking attributable to that therapy. or reversing the IOP elevating effect of the glucocorti The following articles may be referenced for further coids. background information concerning the well-recog The angiostatic steroids utilized in the present inven nized association between ophthalmic glucocorticoid tion include all pharmaceutically acceptable steroids therapy and elevations in intraocular pressure: and steroid metabolites which inhibit angiogenesis. The Kitazawa, “Increased Intraocular Pressure Induced preferred angiostatic steroids have been previously by Corticosteroids,' Am. J. Ophthal.., 82:492-493 (1976); disclosed in U.S. Pat. No. 86/02189, and have the foi Cantrill, et al., “Comparison of In Vitro Potency of lowing formula: Corticosteroids with Ability to Raise Intraocular Pres 45 sure, Am. J. Ophthal, 79:1012-1016 (1975); and Mindel, et al., “Comparative Ocular Pressure Eleva (I) tion by Medrysone, Fluorometholone, and Dexametha sone Phosphate.” Arch. Ophthal, 98: 1577-1578 (1980). One approach to solving the foregoing problems has 50 been to search for compounds which are capable of alleviating ophthalmic inflammation without elevating intraocular pressure. The inventions described in com monly assigned U.S. Pat. No. 4,686,214 (Boltralik) and U.S. Pat. No. 5,223,493 (Boltralik) represent two exam 55 ples of this approach. Notwithstanding the success of the therapies described in the above-cited inventions, there continues to be a need for still further improve wherein: ments in the treatment of ophthalmic inflammation, R1 is 3-CH3 or 6-C2; such as an improvement which would allow potent 60 R2 is H or -Cl; glucocorticoids to be utilized to treat inflamed ocular R3 is H, =O, -OH, -O-alkyl (C1-C12), OC(=O)al tissue without fear of elevating intraocular pressure. kyl (C1-C12), -OC(=O)ARYL, -OC(=O)N(R)2 or a-OC(=O)CR7, wherein aryl is furyl, thienyl, SUMMARY OF THE INVENTION pyrrolyl, or pyridyl and each of said moieties is A principal objective of the present invention is the 65 optionally substituted with one or two (C1-C4)al provision of a therapy for ophthalmic inflammation kyl groups, or aryl is -(CH2)Aphenyl wherein f is which allows the potent anti-inflammatory activity of an integer from 0 to 2 and the phenyl ring is option the glucocorticoids to be employed without fear of ally substituted with 1 to 3 groups selected from 5,407,926 3 4. chlorine, fluorine, bromine, alkyl (C1-C3), alkoxy (C1-C3), thioalkoxy-(C1-C3), Cl3C-, F3C-, )COOH taken together is -NHCH2CONHCH -NH2 and -NHCOCH3 and R is hydrogen, alkyl 2COOH, (C1-C4), or phenyl and each R can be the same or with the proviso that except for the compound wherein different, and R7 is aryl as herein defined, or alkyl R1 is -CH3, R2 and R3 taken together form a double (C1-C12); or bond between positions 9 and 11, R4 and R6 are hydro R2 and R3 taken together are oxygen (-O-) bridg ing positions C-9 and C-11; or gen, R12 and R14 taken together form a double bond R2 and R3 taken together form a double bond be between positions 4 and 5, R5 is 3-F, R9 is 3-CH3, tween positions C-9 and C-11; or R10 is (3-OH, R13 and R15 are -O and R23 is -OP R2 is ol-F and R3 is (3-OH; or (o)-(OH)2, R13 is =O only when R23 with R10 forms R2 is o-Cl and R3 is G-Cl; and the above described cyclic phosphate, and pharmaceuti R4 is H, CH3, Clor F; cally acceptable salts thereof. R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; Excepted from the compounds of Formula (I) is the Reis H or CH3; 15 R9 is H, OH, CH3, F or =CH2; compound 3,11g, 17a, 21-tetrahydroxy-5 pregnane R10 is H, OH, CH3 or R10 forms a second bond be 20-one (the 3-alpha, 5-beta; 3-alpha, 5-alpha; 3-beta, tween positions C-16 and C-17; 5-alpha; and 3-beta, 5-beta isomers of tetrahydrocor R12 is -H or forms a double bond with R14; tisol) wherein; R13 is H, -OH, =O, -O-P(O)(OH)2 or -O-C(- 20 =O)-(CH2)COOH where t is an integer from 2 R-15 is -O; R10 is aOH: to 6: R1 is CH3; R3 is 6OH; R2 is H; R4 is H; R13 is m or R14 is H or forms a double bond with R12; -OH R14 is H; R15 is =O or -OH; and R12 is dor GH; R5 is H; R6is H; R9 is Hand R23 is OH. R23 with Rio forms a cyclic phosphate as depicted by 25 Unless specified otherwise, all substituent groups the following formula: attached to the cyclopenta phenanthrene moiety of Formula (I) may be in either the alpha or beta position. CH2 - O (II) W Additionally, the above structures include all pharma C-R15 30 ceutically acceptable salts of the angiostatic steroids. O The use of the above-described angiostatic steroids to control intraocular pressure is described in applicant's commonly assigned U.S. Pat. No. 4,876,250 issued Oct. 35 24, 1989; the entire contents of that patent are hereby wherein R1, R9 and R15 have the meaning defined incorporated in the present specification by reference. above; or R23 is -OH, O-C(=O)-R11, -OP Preferred angiostatic steroids of the above formula (O)-(OH)2, or -O-C(=O)-(CH2)COOH wherein include: t is an integer from 2 to 6; and R11 is -Y-(CH2)n-X- -(CH2)n-SO3H, -Y'- (CH2)p-X'-(CH2 )-NR16R17 or -Z(CH2)Q, wherein Y is a bond or -O-; Y is a bond, -O-, or -S-; each of X and X" is a bond, -CONOR 18)-, -N(R18)CO-, -O-, -S-, -SO)-, or -SO2)-; R18 is hydrogen or alkyl (C1-C4); each of R16 and R17 is a lower alkyl group of 45 from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R16 and R17 taken together with the nitrogen atom to which each is attached forms a mono cyclic heterocyclic selected from pyrrolidino, piperi dino, morpholino, thiomorpholino, piperazino or 50 N(lower)alkyl-piperazino wherein alkyl has 1 to 4 car bon atoms; n is an integer from 4 to 9; n is an integer 5g-pregnan-3ol,17a,21-triol-20-one, which is also from 1 to 5; p is an integer from 2 to 9: q is an integer known as tetrahydrocortexolone, and its pharmaceuti from 1 to 5; wherein Z is a bond or -O-; ris an integer cally acceptable salts; of from 2 to 9; and Q is one of the following: 55 (1) -R19-CH2COOH wherein R19 is -S-, -S- OH (O)-, -S(O)2-, -SO2NCR20)-, Ot W N(R20)SO2-; and R20 is hydrogen or lower alkyl (C1-C4); with the proviso that the total number of in OH carbon atoms in R20 and (CH2) is not greater than 60 10; or (2)-CO-COOH, or (3) CONOR21)CH(R22)COOH wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, -CH2CH2SCH3, or -CH2 65 O Ph-OH wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R22 taken to 4,9011)-pregnadien 17a,21-diol-3,20-dione, and its gether are -CH2CH2CH2-; or -NCR21)CH(R22 pharmaceutically acceptable salts; and 5,407,926 6 more glucocorticoids and one or more angiostatic ste OH roids are provided. The compositions will contain one W or more glucocorticoids in an anti-inflammatory effec tive amount and will contain one or more angiostatic iii OH Steroids in an amount effective to inhibit the IOP elevat ing effect of the glucocorticoids. The amount of each component will depend on various factors, such as the relative tendency of certain glucocorticoids to cause IOP elevations, the severity and type of ocular inflam 10 mation being treated, the estimated duration of the treatment, and so on. In general, the ratio of the amount F of glucocorticoid to the amount of angiostatic steroid 6-fluoro-17a,21-dihydroxy-166-methyl-pregna on a weight to weight basis will be in the range of 10:1 4,9011)-diene-3,20-dione, and its pharmaceutically ac to 1:20. The concentration of the glucocorticoid com ceptable salts. 15 ponent will typically be in the range of about 0.01% to Tetrahydrocortexolone is a particularly preferred about 2.0% by weight. The concentration of the angio angiostatic steroid. It is a known compound. It has a static steroid component will typically be in the range molecular weight of 350.5 and an empirical formula of of about 0.05% to about 5.0% by weight. C2H34O4. The compound is commercially available The above-described active ingredients may be incor and may, for example, be obtained from Sigma Chemi porated into various types of ophthalmic formulations cal Company, P.O. Box 14508, St. Louis, Mo. 63178 or for delivery to the eye. For example, the active ingredi Steraloids, Inc., P.O. Box. 310, Wilton, N.H. 03086. ents may be combined with ophthalmologically accept The above-described compounds may exist in several able preservatives, surfactants, viscosity enhancers, stereoisomeric forms. Specifically, with regard to buffers, toxicity agents and water to form an aqueous, stereoisometry, for tetrahydrocortexolone it refers to 25 sterile ophthalmic suspension. In order to prepare ster relative positions of the hydroxyi and hydrogen groups ile ophthalmic ointment formulations, the active ingre at the 3,5 positions, as to whether or not they are above dients are combined with a preservative in an appropri or below the plane of the ring structure. Alpha position ate vehicle, such as mineral oil, liquid ianolin, or white refers to below the plane of the ring structure, and beta petrolatum. Sterile ophthalmic gel formulations may be refers to above the ring structure. Thus, tetrahydrocor prepared by suspending the active ingredient in a hy texolone may exist as 3-alpha, 5-beta; 3-alpha, 5-alpha; 3-beta, 5-alpha; and 3-beta, 5-beta. The preferred isomer drophilic base prepared from the combination of Car for use in this invention is 3-alpha, 5-beta-tetrahy bopol-940 (a carboxy vinyl polymer available from the drocortexolone. The ring containing the 1–5 positions is B.F. Goodrich Company) according to published for referred to as the “A-ring'. 35 mulations for analogous ophthalmic preparations; pre The glucocorticoids which may be employed in the servatives and tonicity agents can also be incorporated. present invention include all pharmaceutically accept The specific type of formulation selected will depend able compounds which are effective in the treatment of on various factors, such as the severity and type of inflamed ocular tissue. The preferred glucocorticoids ophthalmic inflamnation being treated, and dosage include dexamethasone, fluorometholone, medrysone, 40 frequency. Ophthalmic solutions, suspensions, oint betanethasone, triancinolone, , predniso ments and gels are the preferred dosage forms, and lone, , and pharmaceutically acceptable topical application to the inflamed ocular tissue is the salts thereof. Further examples of glucocorticoids in preferred route of administration. clude , , halomethasone, tix The following Example is presented to illustrate fur ocortol, (21-diethylaminoacetate), predni 45 ther the compositions of the present invention. val, , , mepredni sone, , , acetate, EXAMPLE , , flurandrenolide, flupredniso The following formulation is representative of the lone, fluprednidine acetate, acetate, fluo antiinflammatory compositions of the present invention. cortolone, butyl, , 50 acetonide, , flumethasone, fluidrocortisone, fluclorinide, , , , diacetate, (desoxymetha Ingredient Annount (wt.%) sone), , , cortivazo, corticoster Tetrahydrocortexolone 1.0 55 Dexamethasore 3.1 one, , , , , Tyloxapol 0.01 to 0.05 , , cafestol, , be HPMC 0.5 clomethasone, ancinonide, allopregnane acetonide, Benzalkoniura chloride O,O1 aiclonetasone, 21-acetoxypregnenolone, , di Sodium chloride 0.8 florasone acetate, deacylcortivazol, RU-26988, budeso Edetate isodiurn 0.01 nide, and deacylcortivazol oxetanone. All of the above 60 NaOHAHC q.S. pit 7.4 cited glucocorticoids are known compounds. Further Purified water qs. 100 mL information about the compounds may be found, for example, in The Merck Index, Eleventh Edition (1989), The above formulation is prepared by first placing a and the publications cited therein, the entire contents of portion of the purified water into a beaker and heating which are hereby incorporated in the present specifica 65 to 90° C. The hydroxypropylmethylcellulose (HPMC) tion by reference. is then added to the heated water and mixed by means In accordance with the present invention, antiinflam of vigorous vortex stirring until all of the HPMC is matory, ophthalmic compositions containing one or dispersed. The resulting mixture is then allowed to cool

w 5,407,926 7 while undergoing mixing in order to hydrate the

HPMC. The resulting solution is then sterilized by (I) means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter. The sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HCl. The solution is then sterilized O by means of filtration. The tetrahydrocortexolone and dexamethasone are sterilized by either dry heat or ethylene oxide. If ethyl ene oxide sterilization is selected, aeration for at least 72 wherein: hours at 50 C. is necessary. The sterilized THS and 15 R1 is 3-CH3 or (3-C2H5; R2 is H or Cl; dexamethasone are weighed aseptically and placed into R3 is H, =O or OH; a pressurized balmill container. The tyloxapol, insteril R2 and R3 taken together are oxygen (-O-) bridg ized aqueous solution form, is then added to the balmill ing positions C-9 and C-11; or container. Sterilized glass balls are then added to the 20 R2 and R3 taken together form a double bond be container and the contents of the container are milled tween positions C-9 and C-11; or aseptically at 225 rpm for 16 hours, or until all particles R2 is a-F and R3 is 6-OH; or are in the range of approximately 5 microns. R2 is a-Cl and R3 is g-Cl; and Under aseptic conditions, the micronized drug sus R4 is H, CH3, Cl or F; pension formed by means of the preceding step is then 25 R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; poured into the HPMC solution with mixing. The ball R6 is H or CH3; mill container and balls contained therein are then R9 is H, OH, CH3, F or =CH2; R10 is H, OH, CH3 or forms a second bond between rinsed with a portion of the solution containing the positions C-16 and C-17; sodium chloride, the edietate disodium and benzalko 30 R12 is H or forms a double bond with R14; nium chloride. The rinse is then added aseptically to the R13 is H, OH, -O, -O-P(O)-(OH)2 or -O-C(- HPMC solution. The final volume of the solution is then =O)-(CH2)COOH, where t is an integer from 2 adjusted with purified water and, if necessary, the pH of to 6; the solution is adjusted to pH 7.4 with NaOH/HCl. R14 is H or forms a double bond with R12; The treatment method of the present invention com 35 R15 is =O or OH; and prises application of an effective amount of the above R23 with R10 forms a cyclic phosphate as depicted by described compositions to the eye. The dosage regimen the following formula: utilized will depend on the severity and type of inflam mation being treated, as well as various clinical factors, CH2 - O (II) such as, the patient's age, sex, weight and medical his / V tory. In general, the above-described compositions may C-R15 PEO be topically applied, for example, as drops to the upper R1 aii ilii iiii O / Yo, H globe, or as a 0.5-1 cm strip of ointment or gel to the lower conjunctival sac of the eye. Suspensions will 45 generally be applied 1 to 4 times daily, while ointments or gels will generally be applied once or twice daily. The application of sustained release formulations (e.g., wherein R1, R9 and R15 have the meanings defined polymer based gels) once daily at bedtime will be pre above; or 50 R23 is OH, -O-P(O)-(OH)2 or -O-C(- ferred in some conditions. Intraocular routes of admin =O)-(CH2)COOH whereint is an integer from 2 istration, such as injections or instillations in conjunc to 6; tion with intraocular surgery, are also contemplated. with the proviso that, except for the compound wherein What is claimed is: R1 is CH3, R2 and R3 taken together form a double bond 1. A method of treating ophthalmic inflammation 55 between positions 9 and 11, R4 and Ré, are hydrogen, which comprises topical application of a therapeutically R12 and R14taken together form a double bond between effective amount of a pharmaceutical composition to an positions 4 and 5, R5 is a-F, R9 is 3-CH3, R10 is affected eye, wherein the topical application of said a-OH, R13 and R16 are -O and R23 is -O-P- composition does not significantly increase the intraoc (O)-(OH)2, R13 is =O only when R23 with R10 forms ular pressure of the affected eye, said composition con the above-described cyclic phosphate; and excluding the compounds wherein R16 is =O, R10 is a-OH, R1 is prising an anti-inflammatory effective amount of a glu CH3, R3 is g-OH or H, R2 is H, R4 is H, R13 is a- or cocorticoid, an amount of an angiostatic steroid effec As-OH, R14 is H, R12 is a- or 8-H, R5 is H, R6 is H, R9 tive to inhibit the glucocorticoid from elevating the is H and R23 is OH. intraocular pressure of asteroid responder and a phar 65 2. The method of claim 1, wherein the angiostatic maceutically acceptable carrier therefore; wherein the steroid is selected from the group consisting of: 4,9(11)- angiostatic steroid has the following formula or is a pregnadien-17a,21-diol-3,20-dione; . 4-pregnen pharmaceutically acceptable salt thereof: 11 (3,17a,20p8,21-tetrol-3-one; 5,3-pregnan-3ol,17a-diol 5,407,926 9 10 20-one; 4-pregnen-17a-ol-3,20-dione; 4-pregnen methyl-pregna-4,9011)-diene-3,20-dione, or a pharma -1 if3,17a,20a,21-tetrol-3-one; 5p3-pregnan-3d, 17d.,21 ceutically acceptable salt thereof. 6. The method of claim 3, wherein the angiostatic triol-20-one; 1,4,9(11)-pregnatrien-17a,21-diol-3,20 steroid comprises 4,9(11)-pregnadien 17a,21-diol-3,20 dione; 6a-fluoro-17a,21-dihydroxy-16?3-methyl-pregna dione, or a pharmaceutically acceptable salt thereof. -4,9011)-diene-3,20-dione; or pharmaceutically accept 7. The method of claim 1, wherein the glucocorticoid abie salts thereof. is selected from dexamethasone, fluorometholone, med 3. The method of claim 2, wherein the angiostatic rysone, , triancinolone, prednisone, steroid is selected from the group consisting of 4,9011)- prednisolone, hydrocortisone, and pharmaceutically pregnadien-17a,21-diol-3,20-dione; 5p3-pregnan-3a,17a 1O acceptable salts thereof. 8. The method of claim 1, wherein the ratio of the diol-20-one, 4-pregnen-17a-ol-3,20-dione; 5,3-pregnan amount of the glucocorticoid to the amount of an angio 3d, 17a,21-triol-20-one; 6a-fluoro-17a,21-dihydroxy static steroid on a weight to weight basis in the range of -1619-methyl-pregna-4,9011)-diene-3,20-dione; or phar i0:1 to 1:20. maceutically acceptable salts thereof. 15 9. The method of claim 1, wherein the glucocorticoid 4. The method of claim 3, wherein the angiostatic is contained in the composition in an amount in the steroid comprises tetrahydrocortexolone or a pharma range of about 0.01% to about 2.0% by weight. 10. The method of claim 1, wherein the angiostatic ceutically acceptable salt thereof. Steroid is contained in the composition in an amount in 5. The method of claim 3, wherein the angiostatic 20 the range of about 0.05% to about 5.0% by weight. steroid comprises 6a-fluoro- 17a,21-dihydroxy-166

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