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United States Patent (19) 11 Patent Number: 5,811,443 Desantis, Jr

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United States Patent (19) 11 Patent Number: 5,811,443 Desantis, Jr USOO5811443A United States Patent (19) 11 Patent Number: 5,811,443 DeSantis, Jr. et al. (45) Date of Patent: *Sep. 22, 1998 54) COMBINATIONS OF PROSTAGLANDINS 4,540,408 9/1985 Loyd . AND CLONDINE DERVATIVES FOR THE 4,576,962 3/1986 Matthews. TREATMENT OF GLAUCOMA 4,587.257 5/1986 DeSantis et al.. 4,599,353 7/1986 Bito . 4,614,825 9/1986 Snitman et al.. 75 Inventors: Louis DeSantis, Jr., Fort Worth; 4,730,013 3/1988 Bondi et al.. Verney L. Sallee, Southlake, both of 4,911,920 3/1990 Jani et al.. TeX. 4,994,274 2/1991 Chan et al.. 5,093,329 3/1992 Woodward. 73 Assignee: Alcon Laboratories, Inc., Fort Worth, 5,212,162 5/1993 Missell et al.. TeX. FOREIGN PATENT DOCUMENTS * Notice: The term of this patent shall not extend 0 286903 A1 10/1988 European Pat. Off.. beyond the expiration date of Pat. Nos. 0 289 349 B1 11/1988 European Pat. Off.. 5,480,900 and 5,605,922. 0 299 914 A1 1/1989 European Pat. Off.. 0.364 417 B1 4/1990 European Pat. Off.. 21 Appl. No.: 803,667 O 366 279 A2 5/1990 European Pat. Off.. O 399839 A2 11/1990 European Pat. Off.. 22 Filed: Feb. 21, 1997 O 458 589 A1 11/1991 European Pat. Off.. 39 23 797 1/1991 Germany. Related U.S. Application Data 1 444971 8/1976 United Kingdom. WO 85/02841 7/1985 WIPO. 63 Continuation of Ser. No. 571,326, Dec. 12, 1995, Pat. No. WO 91/14428 10/1991 WIPO. 5,605,922, which is a continuation of Ser. No. 422,570, Apr. 10, 1995, Pat. No. 5,480,900, which is a continuation of E. OTHER PUBLICATIONS No. 213,380, Mar. 14, 1994, abandoned, which is a con tinuation of Ser. No. 960,065, Oct. 13, 1992, abandoned. Advances in ProStaglandin Thromboxane, and Leukotriene Research, 14:263-307 (1985). 51) Int. Cl. ...................... A61K 31/415; A61K 31/215; Advances in ProStaglandin, Thromboxane, and Leukotriene A61K 31/19 Research, 14:309-425 (1985). 52 U.S. Cl. .......................... 514/392; 514/530; 514/573; Bito et al. “The Ocular Effect of Prostaglandins and Other 514/913 Eicosanoids.” Alan R. Liss, Inc., 1-13 (1989). 58 Field of Search ..................................... 514/392,530, Crabbe, P. (ed), “Prostaglandin Research,” Academic Press, 514/573,913 New York: 1977. Kriegelstein, “Medikamentose Glaukomtherapie,” 56) References Cited Fortschritte Der Ophthalmologie, 87: 172–174 (1990). Rouot, et al., “Clonidine & Related Analogues. Quantitative U.S. PATENT DOCUMENTS Correlations” J. Med. Chem., 19:1049-54 (1976). 3,202,660 8/1965 Zeile et al.. Timmermans et al., Structure-Activity Relationships in 3,468,887 9/1969 Stahle et al.. Clonidine-Like Imidazolidines and Related Compounds, 3,755.426 8/1973 Strike et al.. Gustav Fischer Verlag, 1–97 (1980). 3,873,607 3/1975 Bernady et al.. 3.884969 5/1975 Schaub et al.. Primary Examiner Zohreh Fay 4,029,681 6/1977 Smith. Attorney, Agent, or Firm-Barry L. Copeland 4,097.489 6/1978 Bundy. 4,110,368 8/1978 Floyd, Jr. et al. 57 ABSTRACT 4,288,616 9/1981 Sih. Combinations of at least one clonidine derivative and at least 4,321,4054,291,175 3/19829/1981 WissnerWeiss et al.. one prostaglandin are used to treat glaucoma and ocular 4,343949 8/1982 Bernady et al.. hypertension without Some of the Side effects typically 4,461,904 7/1984 York, Jr. asSociated with topical administration of prostaglandins. 4,515,800 5/1985 Cavero et al.. 4,517,199 5/1985 York, Jr.. 13 Claims, No Drawings 5,811,443 1 2 COMBINATIONS OF PROSTAGLANDINS effects which affect patient compliance and/or necessitate AND CLONDINE DERVATIVES FOR THE the withdrawal of treatment; at least one beta-blocker, TREATMENT OF GLAUCOMA timolol, has increasingly become associated with Serious pulmonary side effects attributable to its effect on beta-2 CROSS REFERENCE TO RELATED receptors in pulmonary tissue; and prostaglandins often APPLICATIONS produce hyperemia and edema of the conjunctiva, resulting in redness and hyperesthesia of the eye, which may affect This application is a continuation of U.S. patent applica patient compliance. In addition to these side effects, a tion Ser. No. 08/571,326, filed Dec. 12, 1995, now U.S. Pat. therapy regimen which includes the use of two or more No. 5,605,922, which was a continuation of U.S. patent pharmaceutical compositions containing drugs. Selected application Ser. No. 08/422,570, filed Apr. 10, 1995, now from two or more of the above-cited classes requires the U.S. Pat. No. 5,480,900, which was a continuation of U.S. patient to apply the compositions to the affected eye(s) in patent application Ser. No. 08/213,380, filed Mar. 14, 1994, Separate, Spaced dosages, Several times per day. Patient now abandoned, which was a continuation of U.S. patent compliance with Such complicated dosage regimens can be application Ser. No. 07/960,065 filed Oct. 13, 1992, now 15 very poor, particularly in elderly patients. Since the majority abandoned. of glaucoma patients are elderly, this patient compliance BACKGROUND OF THE INVENTION problem is significant. In light of the foregoing circumstances, it is clear that a 1. Field of the Invention need exists for new, more potent anti-glaucoma composi The present invention relates generally to the field of tions which avoid or reduce the above-cited side effects, ophthalmology. In particular, the invention relates to the while increasing patient compliance. The present invention treatment of glaucoma and ocular hypertension using a is directed to Such compositions. combination of at least one clonidine derivative (e.g., para amino clonidine) and at least one prostaglandin. SUMMARY OF THE INVENTION 2. Discussion of Related Art 25 It has unexpectedly been found that administration of one Although the underlying causes of glaucoma are not or more prostaglandins in combination with one or more understood, its Symptoms often include elevated intraocular clonidine derivatives controls or lowers intraocular preSSure preSSure, which may be caused either by over-production of (IOP) without the accompanying inflammatory response aqueous humor or by inadequate outflow of aqueous humor. (including hyperemia) typically found with prostaglandins. If left untreated, or if inadequately treated, glaucoma can The present invention therefore provides compositions and lead to blindness or Significant loSS of vision. There is methods useful for the treatment of glaucoma and ocular therefore a continuing need for therapies which control the hypertension. The compositions contain a combination of at elevated intraocular pressure associated with glaucoma. least one clonidine derivative and at least one prostaglandin There are currently a number of drugs utilized in the which are effective in reducing or controlling IOP, and treatment of glaucoma, including: miotics (e.g., pilocarpine, 35 which have a reduction or elimination of the side effects carbachol and acetylcholinesterase inhibitors); Sympathomi normally associated with topical application of prostaglan metics (e.g., epinephrine and dipivalylepinephrine); alpha-2 dins. agonists (e.g., para-amino clonidine); beta-blockers (e.g., In a preferred formulatory embodiment of the composi betaxolol, levobunolol and timolol); and carbonic anhydrase 40 tions of the present invention, the above combinations may inhibitors (e.g., acetazolamide, methazolamide and further include an anionic mucomimetic polymer, a gelling ethoXZolamide). Miotics and Sympathomimetics are polysaccharide, a finely divided drug carrier Substrate believed to lower IOP by increasing the outflow of aqueous (defined below), or a combination of these components. humor through the trabecular meshwork, while beta These additional components provide compositions which blockers, alpha-2 agonists and carbonic anhydrase inhibitors 45 are comfortable and have Sustained release. are believed to lower IOP by decreasing the formation of aqueous humor. DETAILED DESCRIPTION OF THE In addition, although they have not yet been approved for INVENTION anti-glaucoma therapy, certain classes of prostaglandins and The present invention utilizes combinations of at least one prostaglandin analogues (hereinafter collectively referred to 50 clonidine derivative and at least one prostaglandin to treat as “prostaglandins”) have been shown in various animal glaucoma and ocular hypertension. models and in Some clinical Studies to reduce intraocular Clonidine is a known hypotensive compound, and is pressure (IOP) to a greater extent than most currently used described, for example, in U.S. Pat. No. 3,202,660 (Zeile et therapeutic agents. See, for example: U.S. Pat. No. 4,097, al.); the contents of this patent relating to the structure, 489 (Bundy), U.S. Pat. No. 4,599,353 (Bito), U.S. Pat. No. 55 preparation and physical properties of this compound are 4,994,274 (Chan et al.) and EP 289 349 (Ueno et al.). In incorporated herein by reference. It is also known that contrast to the case with miotics, prostaglandins are believed certain clonidine derivatives are effective in lowering to lower IOP by increasing the outflow of aqueous humor via intraocular pressure when applied topically to the eye; this the uVeo-Scleral route. In addition, prostaglandins may poS discovery is described in U.S. Pat. No. 4,461,904 (York, Jr.), sibly have other effects in the eye, Such as enhancing 60 the entire contents of which are incorporated herein by vascular Support of ocular tissues; however, there is no reference. The clonidine derivatives described in this patent understanding of that mechanism at this time. are 2-(tri-Substituted phenylimino)-imidazoline compounds, All Six types of therapeutic agents have potentially Serious which are also known as 2-(tri-Substituted anilino)-1,3- Side effects: miotics Such as pilocarpine can cause blurring diazacyclopentene-(2) compounds. Reference is made to of vision and other, Visual side effects, which may lead either 65 this patent for further details concerning the Structure, prepa to decreased patient compliance or to termination of therapy; ration and physical properties of these clonidine derivatives.
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