|||||||||||||| US005358943A United States Patent (19) 11 Patent Number: 5,358,943 Clark et al. (45) Date of Patent: Oct. 25, 1994 54 USE OF TETRAHYDROCORTISOL TO The Merck Index, Tenth Edition (1983). PREVENTELEVATIONS IN INTRAOCULAR Meyer, et al., “Influence of Norethynodrel with Mes PRESSURE CAUSED BY tranol on Intraocular Pressure in Glaucoma', Arch Oph CORT COSTERODS thal, vol. 75, pp. 771-773 (1966). 76 Inventors: Abbot F. Clark, 5708 Stage Line Dr., Mindel, et al., “Comparative Ocular Pressure Elevation Arlington, Tex. 76017; Aaron L. by Medrysone, Flourometholone, and Dexamethasone Southren, 107 Grandview Ave., Phosphate', Archives of Ophthalmology, vol. 98, pp. Monsey, N.Y. 10952 1577-1578 (1980). Southren, A. Louis, et al., “Intraocular Hypotensive 21 Appl. No.: 12,181 Effect of a Topically Applied Cortisol Metabolite: 3a, 22 Filed: Feb. 2, 1993 5p3-Tetrahydrocortisol”, Investigative Ophthalmology & Visual Science, vol. 28, pp. 901-903 (May 1987). Related U.S. Application Data Treister, et al., “Intraocular Pressure and Outflow Fa cility”, Arch Ophthal, vol. 83, pp. 311-318 (1970). 63 Continuation of Ser. No. 399,349, Aug. 28, 1989, aban Medline Abstract 87193644 (1987), Southren, et al. doned, which is a continuation of Ser. No. 139,227, Danhaive, et al., "Binding of Glucocorticoid Antago Dec. 29, 1987, abandoned. nists to Androgen and Glucocorticoild Hormone Re 51 Int. Cl. ...................... A61K31/56; A61K 31/33 ceptors in Rat Skeletal Muscle', J. steroid Biochem., vol. 52 U.S. C. .................................... 514/170; 514/171; 24, No. 2, pp. 481-487, 1986. 514/182, 514/914: 514/922 Primary Examiner-Zohreh Fay 58 Field of Search ............... 514/170, 171, 182,914, Attorney, Agent, or Firm-James A. Arno; Gregg C. 514/922 Brown 56 References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS Pharmaceutical compositions useful in the treatment of 3,449,494 6/1969 Lerner ................................. 424/240 ophthalmic inflammation and methods of treating oph 3,474,168 10/1969 Schayer. ... 424/240 4,383,992 5/1983 Lipari........ ... 424/238 thalmic inflammation with those compositions are dis 4,617,299 10/1986 Knepper ... ... 514/1.78 closed. The compositions contain a combination of a 4,686,214 8/1987 Boltradik ... ... 514/179 glucocorticoid and tetrahydrocortisol. The tetrahy 4,863,912 9/1989 Southren ... ... 514/177 drocortisol serves to substantially prevent any signifi 4,945,089 7/1990 Clark ................................... 514/171 cant increases in intraocular pressure which might oth erwise be experienced by the patient as a side effect of FOREIGN PATENT DOCUMENTS the glucocorticoid component of the compositions. The 0250088 12/1987 European Pat. Off. therapeutic interaction of the two components there WO86/02554 5/1986 PCT Int'l Appl. fore allows the potent antiinflammatory properties of the glucocorticoids to be utilized without fear of elevat OTHER PUBLICATIONS ing intraocular pressure. A method of preventing in Cantrill, et al., “Comparison of In Vitro Potency of creases in intraocular pressure attributable to systemic Corticosteroids with Ability to Raise Intraocular Pres or topical corticosteroid therapy is also disclosed. That sure', American Journal of Ophthalmology, vol. 79, pp. method involves the administration of a pharmaceutical 1012-1016 (1975). composition containing tetrahydrocortisol to a patient Kitazawa, “Increased Intraocular Pressure Induced by receiving such therapy. Corticosteroids', American Journal of Ophthalmology, vol. 82, pp. 492-495 (1976). 12 Claims, No Drawings 5,358,943 1. 2 the invention is the provision of methods of treatment USE OF TETRAHYDROCORTESOL TO PREVENT and ophthalmic compositions useful in that therapy. ELEVATIONS IN INTRAOCULAR PRESSURE Another objective of the present invention is the CAUSED BY CORT COSTEROIDS provision of a prophylactic method of treatment 5 wherein the elevations in intraocular pressure some This is a continuation of application Ser. No. times associated with corticosteroid therapy are sub 07/399,349, filed Aug. 28, 1989 now abandoned, which stantially prevented. is a continuation of Ser. No. 07/139,227, filed Dec. 29, The foregoing objectives and other general objec 1987 now abandoned. tives of the present invention are met by the provision O of a therapy for ophthalmic inflammation wherein the BACKGROUND OF THE INVENTION elevations in intraocular pressure caused by glucocorti The present invention relates to the field of ophthal coids are substantially prevented. The therapy involves mology. More particularly, this invention relates to the the combination of a glucocorticoid with a second com treatment of inflamed ocular tissue. pound which prevents or antagonizes the intraocular Many compounds classified as glucocorticoids, such 15 pressure elevating effect of the glucocorticoid. The as dexamethasone and prednisolone, are very effective second compound is tetrahydrocortisol. It has been in the treatment of inflamed tissues, but in certain pa discovered that the intraocular pressure ("IOP”) elevat tients, these compounds cause elevations in intraocular ing effect of glucocorticoids can be eliminated without pressure. Patients who experience elevations in intraoc adversely affecting the antiinflammatory activity of the ular pressure when treated with glucocorticoids are 20 glucocorticoids. Thus, the therapy of the present inven generally referred to as "steroid responders'. The ele tion makes it possible to employ the potent topical anti vations in intraocular pressure are of particular concern inflammatory properties of the glucocorticoids without in patients who are already suffering from elevated causing any significant elevations in intraocular pres intraocular pressures, such as glaucoma patients. More Sle. 25 over, there is always a risk that the use of glucocorti DESCRIPTION OF PREFERRED coids in patients who have normal intraocular pressures EMBODIMENTS will cause elevations in pressure that result in damage to ocular tissue. Since therapy with glucocorticoids is The present invention is based on the combination of frequently long term (i.e., several days or more), there is one or more potent glucocorticoids with tetrahydrocor 30 tisol. It has been discovered that tetrahydrocortisol potential for significant damage to ocular tissue as a antagonizes the IOP elevating effect of glucocorticoids. result of prolonged elevations in intraocular pressure It was previously discovered that tetrahydrocortisol is attributable to that therapy. effective in controlling intraocular pressure; that dis The following articles may be referred to for further covery is the subject of U.S. patent application Ser. No. background information concerning the well recog 35 864,610, filed May 19, 1986, the entire contents of which nized association between ophthalmic glucocorticoid are hereby incorporated in the present specification by therapy and elevations in intraocular pressure: reference. The intraocular hypotensive effect of tet Kitazawa, “Increased Intraocular Pressure Induced by rahydrocortisol is reported by A. Louis Southren et al. Corticosteroids', American Journal of Ophthalmology, in Investigative Ophthalmology & Visual Science, Vol. 28, Vol. 82, pages 492-495 (1976); Cantrill et al., “Compari 40 pages 901-903 (May 1987); the entire contents of that son of In Vitro Potentcy of Corticosteroids with Ability report are also incorporated herein by reference. to Raise Intraocular Pressure', American Journal of It has been postulated that tetrahydrocortisol con Ophthalmology, Vol. 79, pages 1012-1016 (1975); and trols intraocular pressure by antagonizing the action of Mindel et al., “Comparative Ocular Pressure Elevation 5-alpha and/or 5-beta-dihydrocortisol, which are two by Medrysone, Fluorometholone, and Dexamethasone 45 substances that are believed to play a significant role in Phosphate', Archives of Ophthalmology, Vol. 98, pages a metabolic imbalance involving the trabecular mesh 1577-1578 (1980). work cells of the eye and, ultimately, elevations in intra One approach to solving the foregoing problems has ocular pressure. The present invention is based on the been to search for compounds which are capable of finding that tetrahydrocortisol somehow antagonizes alleviating ophthalmic inflammation without elevating 50 the IOP elevating effect of glucocorticoids. The mecha intraocular pressure. The inventions described in U.S. nism by which tetrahydrocortisol prevents or antago Pat. No. 4,686,214 and in copending U.S. patent appli nizes the IOP elevating effect of glucocorticoids is not cation Ser. No. 864,610, filed May 19, 1986, represent totally understood at this point. While applicants do not two examples of this approach. Notwithstanding the wish to be bound by any theory, one possible explana success of the therapies described in the above-cited 55 tion is that tetrahydrocortisol interferes with the action patent and patent application, there continues to be a of glucocorticoids on trabecular meshwork cells, need for still further improvements in the treatment of thereby blocking or reversing the IOP elevating effect ophthalmic inflammation, such as an improvement of the glucocorticoids. which would allow potent glucocorticoids to be uti Tetrahydrocortisol is a known compound. It has a lized to treat inflamed ocular tissue without fear of 60 molecular weight of 366.5, and an empirical formula of elevating intraocular pressure. C2H34O5. The compound is commercially available SUMMARY OF THE INVENTION and may, for example, be obtained