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USOO5932572A United States Patent (19) 11 Patent Number: 5,932,572 Dean et al. (45) Date of Patent: *Aug. 3, 1999

54 TOPICAL ANTI- O 452 151 A1 10/1991 European Pat. Off.. COMPOSITIONS O 495 421 A1 7/1992 European Pat. Off.. 0.507 224 A2 10/1992 European Pat. Off.. 75 Inventors: Thomas R. Dean, Weatherford; Louis sof 18.1. Span Pat. Off. Desantis, Jr., Forth Worth, both of Tex. WO91/02262 10/1991 WIPO 73) ASSignee: Alcon Laboratories, Inc., Fort Worth, OTHER PUBLICATIONS CX. J. Med. Chem., 15:651–655 (1972). * Notice: This patent issued on a continued pros Gunning, F. P., “Medical treatment of glaucoma: develop ecution application filed under 37 CFR ments in research on topical carbonic anhydrase inhibitors,” 1.53(d), and is subject to the twenty year International Ophthalmology, 15:11-12 (1991). F.55 rm provisions of 35 U.S.C. Pfeiffer, “Additive Wirkung von und dem lokalen Karboanhydrasehemmer MK-417 (Sezolamid).” Fortschr Ophthalmol., 88(6):846-847 (1991). 21 Appl. No.: 08/920,314 Annual Reports in Medicinal Chemistry, 14:81–87 (1979). 22 Filed: Aug. 27, 1997 J. Med. Chem., 27:503–509 (1984). J. Med. Chem., 26:7-11 (1983). Related U.S. Application Data J. Med. Chem., 26:1561–1569 (1983). 63 Continuation of application No. 08/526,240, Sep. 11, 1995, J. Med. Chem., 26:1109–1112 (1983). abandoned, which is a continuation of application No. J. Med. Chem., 26:950–957 (1983). 08/115,970,tion-in-part ofSep. application 1, 1993, abandoned,No. 07/839,869 which Feb. is a 21,continua- 1992, J. Med. Chem,s 649–657 (1983). abandoned. J. Med. Chem., 26:352–357 (1983). 51) Int. Cl...... A61K 3.1/54; A61K 31/535 Physicians' Desk Reference for Ophthalmology, 16 Ed., 52 U.S. Cl...... 514/226.5; 514/235.8; 1988, p. 11. 514/913 58 Field of Search ...... 514/226.5,514/913 235s, Attorney,Primary ExaminerAgent, or Firm-SallyZohreh Fay Yeager 56) References Cited 57 ABSTRACT Ophthalmic pharmaceutical compositions useful in control U.S. PATENT DOCUMENTS ling elevated associated with glaucoma 3,655,663 4/1972 Wasson ...... 260/247.1 and ocular are described. The compositions 3,729,469 4/1973 Wasson ...... 260/247.1 comprise a combination of a beta-blocker and a carbonic 4,731,368 3/1988 Hoffman, Jr. et al. . ... 514/301 anhydrase inhibitor to reduce the production of aqueous 4,797413 1/1989 Baldwin et al...... 514/432 humor, preferably formulated as a Suspension having a pH 4,847.289 7/1989 Baldwin et al. . ... 514.f445 4,863,922 9/1989 Baldwin ...... 514/232.5 between about 6.8 and about 7.8. These compositions may 4,911,920 3/1990 Jani 424/81 additionally contain a mucomimetic anionic polymer and/or 5153,192 10/1992 Deanet al... .514,2265 a finely-divided drug carrier Substrate to provide Sustained 5,240,923 8/1993 Dean et al...... 514/226.5 release. A method of controlling elevated intraocular pres Sure with these compositions is also described. FOREIGN PATENT DOCUMENTS O 429 732 A1 6/1991 European Pat. Off.. 23 Claims, No Drawings 5,932,572 1 2 TOPCAL ANTI-GLAUCOMA two of the above-mentioned four classes of drugs has the COMPOSITIONS advantage of reducing intraocular pressure via two different mechanisms. In particular, although both beta-blockers and This application is a Continuation; application under 37 carbonic anhydrase inhibitors are believed to lower IOP by CFR 1.62 of prior application Ser. No. 08/526,240, filed on decreasing the formation of aqueous humor, each of these Sep. 11, 1995 now abandoned, which is a continuation of classes of drugs operates by different mechanisms; Ser. No. 08/115,970, filed Sep. 1, 1993 now abandoned, therefore, a combination of at least one beta-blocker and at which is a continuation-in-part of Ser. No. 07/839,869, filed least one carbonic anhydrase inhibitor (“CAI”), when for Feb. 21, 1992 now abandoned. mulated in a composition also including anionic mucomi metic polymers and finely-divided drug carrier Substrates BACKGROUND OF THE INVENTION (“DCS'-defined below) provides reduction of IOP and The present invention relates to the field of ophthalmol additionally provides comfortable, Sustained-released com ogy. In particular, the invention relates to the treatment of positions. glaucoma and associated elevations of intraocular pressure It has also been found, quite unexpectedly, that certain and to the treatment of associated with 15 CAI's which have exceptionally low inherent aqueous Solu other diseases or conditions. bility are effective in lowering and controlling IOP when Although the underlying causes of glaucoma are not dosed topically to the eye as Suspensions, preferably having understood, its Symptoms often include elevated intraocular neutral pH. These formulations have been found to be very preSSure, which may be caused either by over-production or well tolerated, and appear to be significantly more comfort inadequate outflow of aqueous humor. If left untreated, or if able and have fewer side effects than Solutions of CAI's inadequately treated, glaucoma can lead to blindness or which have higher inherent aqueous Solubility (these Solu Significant loSS of vision. There is therefore a continuing tions are typically formulated at a pH between about 5.0 and need for therapies which control the elevated intraocular 6.0). As such, combinations of beta-blockers with these low preSSure associated with glaucoma. aqueous Solubility CAI's formulated as Suspensions will There are currently a number of drugs utilized in the 25 provide comfortable and effective medicaments for treatment of glaucoma, including: miotics (e.g., , lowering and controlling IOP. The additional inclusion of and acetylcholinesterase inhibitors); Sympathomi anionic mucomimetic polymers and/or DCS will provide metics (e.g., epinephrine, dipivalylepinephrine and parn Sustained release formulations. amino ); beta-blockers (e.g., , Thus, the present invention is directed to Such anti and timolol); and carbonic anhydrase inhibitors (e.g., glaucoma compositions, as well as methods of controlling , and ethoXZolamide). Miotics IOP utilizing these compositions. and Sympathomimetics are believed to lower intraocular pressure (“IOP”) by increasing the outflow of aqueous DETAILED DESCRIPTION OF THE INVENTION humor, while beta-blockers and carbonic anhydrase inhibi 35 tors are believed to lower IOP by decreasing the formation The anti-glaucoma compositions of the present invention of aqueous humor. All four types of drugs have potentially comprise a combination of one or more beta-blockers and Serious Side effects. MioticS Such as pilocarpine can cause one or more carbonic anhydrase inhibitors, formulated as blurring of vision and other visual side effects, which may suspensions having a pH between about 5.0 and about 7.8, lead either to decreased patient compliance or to termination 40 preferably formulated as Suspensions having a pH between of therapy. Carbonic anhydrase inhibitors can also cause about 6.8 and about 7.8. The anti-glaucoma compositions of Serious Side effects which affect patient compliance and/or the present invention may additionally contain anionic necessitate the withdrawal of treatment. Moreover, at least mucomimetic polymers and/or DCS to provide Sustained one beta-blocker, timolol, has increasingly become associ release. ated with serious pulmonary side effects attributable to its 45 The beta-blockers which are useful in the compositions of effect on beta-2 receptors in pulmonary tissue. the present invention include all beta-blockers which dem A significant number of glaucoma patients require the onstrate the requisite cation charge and intraocular preSSure administration of more than one type of drug in order to effect. Such beta-blockers are typically represented by the achieve therapeutic control over their IOP. That is, a single following generic Structure: drug does not provide adequate control of IOP in these 50 patients. Treatment which includes the use of two or more of the above-cited classes of drugs requires the patient to apply the compositions to the affected eye(s) in Separate, Spaced wherein: dosages Several times a day. Patient compliance with Such R", is a Substituted or unsubstituted cyclic or aliphatic complicated dosage regimens can be very poor, particularly 55 moiety; cyclic moieties include mono- and polycyclic with elderly patients. Since the majority of glaucoma Structures which may contain one or more heteroatoms patients are elderly, this is a significant problem. Selected from C, N, and O; and In light of the foregoing circumstances, it is clear that a R" and R's are independently selected from H and Sub need exists for new, more potent anti-glaucoma composi Stituted and unsubstituted alkyl. tions which avoid or reduce the above-cited side effects, 60 With regard to Structure (I), above, the following refer while increasing patient compliance. The present invention ences are hereby incorporated by reference herein: Annual is directed to Such compositions. Reports in Medicinal Chemistry. 14:81–87 (1979); J. Med. Chem., 26:1570–1576 (1983); ibid., 27:503–509 (1984); SUMMARY OF THE INVENTION ibid. 26:7-11 to (1983); ibid., 26:1561–1569 (1983); ibid., AS mentioned above, two or more different types of drugs 65 26:1109–1112 (1983); ibid., 26:950–957 (1983); ibid., are Sometimes required to achieve therapeutic control of 26:649–657; and ibid., 26:352–357 (1983). Representative intraocular pressure. The use of a combination of drugs from beta-blockers include the racemic and enantiomeric forms 5,932,572 3 4 of betaxolol, timolol, , , fallintolol, thiazolidinyl, p-thiainyl, piperazinyl and the like group levobunolol, , , , , optionally substituted by C. lower alkyl; or (12) R addi , , , , , tionally can be a 5 or 6 membered heterocyclic ring having , , , ICI 118,551, , oxygen, nitrogen or Sulfur as the hetero atom and preferably , , , , , the 2-furyl, 2- or 3-thienyl, 2-pyrryl and the o-, m- or , , , , , p-pyridyl. These thiadiazoles may be prepared by the meth , , IPS 339, labetolol, dilevalol, ods disclosed in U.S. Pat. No. 3,655,663 and U.S. Pat. No. , , bunolol, , , 3,729,469 whose entire contents are incorporated by refer hydroxylevobunolol, and the like. The preferred ence herein. Especially preferred thiadiazoles are those of beta-blocker is betaxolol, especially S-betaxolol. Structure (II), above, wherein R" is chloro, ethyl, allyl, Other preferred beta-blockers are certain 4-(3-substituted cyclopropyl, ethoxy, phenyl, phenyl-chloromethyl, or amino-2-hydroxypropoxy)-1,2,5-thiadiazoles which were 2-(cyclopropylmethoxy)ethyl. originally disclosed in German Patent No. 1,925,956 (issued The CAIs which are useful in the compositions of the in 1969 to B. K Wasson), equivalent to U.S. Pat. No. present invention include all thiophene Sulfonamides and thienothiazines which lower and control IOP by inhibiting 3,655,663 (issued in 1972) and U.S. Pat. No. 3,729,469 15 carbonic anhydrase when administered topically. Represen (issued in 1973). These thiadiazoles have the following tative CAIs are disclosed in: U.S. Pat. Nos. 4,797.413 general Structure: (Baldwin et al.), 4,847,289 (Baldwin et al.) and 4,731,368 (Hoffman Jr., et al.); U.S. Pat. No. 5,153,192 (Dean et al.) (II) and U.S. patent application Ser. No. 07/775,313 (filed Oct. N R" 9, 1991); PCT/US91/02262 (filed Apr. 9, 1990); and EP452 / N CH, CH3 S 151 (published Oct. 16, 1991). The entire contents of each OH of the above-mentioned patents and patent applications are CC N hereby incorporated by reference herein. Preferred CAIs of the present invention are those dis HO 25 closed in U.S. patent application Ser. No. 07/775,313. Such CAIS have the following generic Structure: and optically active isomers and pharmacologically accept able salts thereof, wherein R" represents: (1) hydrogen; (2) (III) halogen, preferably chloro or bromo; (3) Cls lower alkyl having either a Straight or branched chain Such as methyl, ethyl, propyl, isopropyl, butyl iso-, Secondary- or tert-butyl and amyl, including all of its branched chain configurations, (4) C slower alkenyl, Such as vinyl, allyl, methallyl and the R1 a. 5 1. 2. like; (5) a group having the structure Y-X-Z-, wherein Y is 1. N-G1 Ys SONH2 either a Straight or branched chain C alkyl optionally 35 Substituted with a phenyl group or a phenyl optionally Substituted with one or more halogen atoms (especially or a pharmaceutically acceptable Salt thereof, wherein: chloro, bromo, fluoro), hydroxy, C. lower alkyl or alkoxy, R is: H, C alkyl, C. alkyl Substituted optionally with X is oxygen or Sulfur and Z is a C- alkyl, (6) a carbamoyl OH, halogen, Calkoxy or C(=O)R7; group having the structure R"HNCO, wherein R" is a Cs 40 R is: H, C alkyl, C. s. alkyl Substituted with OH, lower alkyl, (7) C. s. cycloalkyl, Such as cyclopropyl, NRSR, halogen, C , alkoxy, C alkoxyC alkoxy, cyclobutyl, cyclopentyl, cyclohexyl and the like; (8) C OC(=O)R, or C(=O)R., C , alkenyl unsubstituted lower alkoxy, either a Straight or branched chain and includ or substituted optionally with OH, NRSR or C, ing methoxy, ethoxy, propoxy, isopropoxy, butoxy, and alkoxy, C , alkynyl unsubstituted or Substituted optionally with OH, NRR, or C alkoxy, C alkyl pentoxy (the latter groups existing in either straight or 45 Substituted with phenyl or Ro either of which can be branched configuration); (9) phenyl or Substituted phenyl, unsubstituted or Substituted optionally with C alkyl, wherein the Substitutes are Selected from one or more C haloalkyl, OH, (CH),NRR, halogen, C halogen atoms (preferably chloro or fluoro) and a C is alkoxy, C haloalkoxy, C(=O)R7, S(=O),Rs or lower alkyl or alkoxy; (10) phenyl-lower alkyl, wherein the SONRR, wherein m is 0–2 and n is 0-2; C alkoxy lower alkyl moiety is either a Straight or branched chain and 50 Substituted optionally with NRSR, halogen, C has from 1 to 4 carbons and the phenyl moiety can be alkoxy, or C(=O)R7; phenyl or Rio either of which can unsubstituted or Substituted with one or more halogen atoms be unsubstituted or substituted optionally with C, (preferably chloro, fluoro, or bromo) or C lower alkyl or alkyl, C. haloalkyl, OH, (CH), NRSR, halogen, alkoxy; (11) an amino having the structure-NR"R", C alkoxy, C haloalkoxy, C(=O)R7, S(=O),Rs wherein R" represents hydrogen, C lower alkyl and C. 55 or SONRR, wherein m is 0–2 and n is 0-2, provided hydroxy-substitited substituted lower alkyl, R" represents that R and R cannot both be H; or R and R can be joined to form a Saturated ring of 5 or 6 atoms Selected hydrogen, C lower alkyl, a hydroxy-Substituted lower from O, S, C or N, Such as, pyrrolidine, oxazolidine, alkyl and phenyl, or R" and R" can be joined together thiomorpholine, thiomorpholine 1, 1 dioxide, either directly to give a 3 to 7 membered ring with the morpholine, , thiazolidine 1,1 dioxide, or nitrogen to which they are attached thereby forming 60 tetrahydrooxazine, which can be unsubstituted or Sub aZiridinyl, azetidinyl, pyrrolidyl, piperidyl, or a hexahy stituted optionally on carbon with OH, NRs Rs. droazepinyl group, Said 3 to 7 membered rings being either halogen, Calkoxy, C(=O)R7, Ce alkyl, Ce alkyl unsubstituted or substituted, preferably with one or more Substituted optionally with OH, NRR, halogen, C Cs lower alkyl and C hydroxy-lower alkyl, or alterna alkoxy, C(=O)R, or on nitrogen with NRSR, C tively R" and R" can be joined through an oxygen, 65 alkoxy, C(=O)R7, C alkyl or C. alkyl Substituted nitrogen or Sulfur atom to form a 5 or 6 membered ring, optionally with OH, NRSR, halogen, C, alkoxy or advantageously a morpholino, hexahydropyrimidyl, C(=O)R; 5,932,572 S 6 Ra is: H, halogen; C alkyl, Cs alkoxy, Cs alky optionally with OH, halogen, C alkoxy, C(=O)R, lthiol, C. s. alkoxy substituted optionally with OH, or on nitrogen with C alkoxy, C(=O)R 7, NRSR, halogen, C, alkoxy or C(=O)R7; C, alkyl S(=O).Rs, Calkyl or Ce alkyl Substituted option Substituted optionally with R, or R and R can be ally with OH, halogen, Calkoxy, C(=O)R, or on joined together with carbon atoms to form a ring of 5 Sulfur by (=O), wherein m is 0–2; from 5 to 7 members in which said carbon atoms can R7 is: Cs alkyl, C , alkyl Substituted optionally with be unsubstituted or substituted optionally with R: OH NRs.R., halogen, C, alkoxy or C(=O)Ro: C, R is: OH, C alkyl unsubstituted or substituted option alkoxy, C. alkoxy Substituted optionally with OH, ally with OH, NRSR, halogen, Calkoxy or C(=O) NRR, halogen or C alkoxy; NRR, or phenyl or R7, C alkoxy, Calkoxy Substituted optionally Ro either of which can be unsubstituted or substituted with OH, NRR, halogen, Calkoxy or C(=O)R7; optionally with OH, halogen, C alkyl, C. NRR, phenyl or Ro either of which can be unsub haloalkoxy, (CH), NRSR, S(=O).Rs or SONRR, stituted or substituted optionally with OH, (CH), wherein n is 0 or 1 and m is 0-2, NRSR, halogen, Calkoxy, Chaloalkoxy, C(=O) Rs is: C alkyl, C. alkyl Substituted optionally with R7, S(=O).Rs or SO2NRR, wherein m is 0–2 and in 15 OH, NRR, halogen, Calkoxy or C(=O)R7; is 0-2, Ro is: C alkyl, C , alkoxy, amino, C , alkylamino, or Provided that when G is SO and R is in the 4 position di-C alkylamino; and is H or halogen then R and R are not H. C. alkyl Substituted optionally with OH, Calkoxy, C Ro is: a monocyclic ring System of 5 or 6 atoms com alkoxycarbonyl, C. alkenyl, phenyl, phenoxy, posed of C, N, O, and/or S, Such as furan, thiophene, pyridyl, tetrahydrofuryl, C alkanoyl, C. alkenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, nor are they joined to form a 5, 6 or 7 member ring, Oxazole, isoxazole, isothiazole, thiazole, thiadiazole, Saturated or unsaturated, comprised of atoms Selected pyridine, pyrimidine, pyridazine, and pyrazine, and optionally from C, O, S, Nin which said nitrogen, when G is: C(=O) or SO. Saturated, is Substituted optionally with H or C alkyl 25 In the above definitions, the total number of carbon atoms or in which said carbon is substituted optionally with in a Substituent group is indicated by the C, prefix where C alkyl, C alkoxy or OH, and when R is in the i and j are numbers from 1 to 8 for example. This C, , 5 position and is H, Cl, Br, or C, alkyl then neither definition includes both the straight and branched chain R nor R can be H or C alkyl, and when G is isomers. For example, C , alkyl would designate methyl C(=O) and in the 5-position and R is H, then R and through the butyl isomers, and C alkoxy would designate R cannot both be CH; methoxy through the butoxy isomers. Rs R are the same or different and are: H, C alkyl, C., The term "halogen,” either alone or in compound words alkyl Substituted optionally with OH, halogen, C Such as "haloalkyl, means fluorine, chlorine, bromine or alkoxy or C(=O)R7; C alkoxy; C alkoxy substi iodine. Further, when used in compound words Such as tuted optionally with OH, halogen, C alkoxy or “haloalkyl,” said alkyl may be partially or fully substituted C(=O)R7; C 7alkenyl unsubstituted or substituted 35 optionally with OH, NRSR, or C, alkoxy; C 7 with halogen atoms, which may be the same or different. alkynyl unsubstituted or substituted optionally with Structure (III) includes isomers, wherein R and GNRR OH, NRSR, or C alkoxy, Calkyl-C scycloakl; are attached to the 4 and 5 position respectively or R is C(=O)R, or Rs and R6 can be joined to form a ring of attached to the 5 position and GNRR is attached to the 4 5 or 6 atoms selected from O, S, C or N, Such as, 40 position. Many of the novel compounds of Structure (III) pyrrolidine, oxazolidine, thiomorpholine, thiomorpho possess one or more chiral centers and this invention line 1,1 dioxide, morpholine, piperazine or thiazolidine includes all enantiomers, diastereomers and mixtures 1,1-dioxide, which can be unsubstituted or Substituted thereof. optionally on carbon with OH, (=O), halogen, C. Especially preferred CAIS of the present invention are alkoxy, C(=O)R7, C alkyl, Ce alkyl Substituted those listed in Table 1, below.

TABLE 1.

Y 2N. O O

W Y CHEMICALNAME 1. CHCH (CH)OCHCH, (R)-3,4-Dihydro-2-(2-ethoxy)ethyl-4-ethylamino-2H thieno3,2-e-1,2-thiazine-6- 1,1-dioxide hydrochloride 2 (CH)2CH (CH)OCHCH, (R)-3,4-Dihydro-2-(2-ethoxy)ethyl-4-propylamino-2H thieno3,2-e-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride 3 CHCH (CH)OCH (R)-3,4-Dihydro-4-ethylamino-2-(3-methoxy)propyl-2H thieno3,2-e-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride

5,932,572 10 In general, an amount of a beta-blocker less than or equal The size of the DCS can be important, both with respect to about 2.0% by weight (wt %) and amount of a CAI less to mode of action and comfort. The average particle size of than or equal to about 5 wt % are used. It is preferred that the typical commercially available form of the DCS material an amount of beta-blocker between about 0.01 and about 1.0 of choice, an ion eXchange resin, is about 40 to about 150 wt % is used and it is especially preferred to use an amount microns. Such particles are most conveniently reduced to a between about 0.05 to about 0.5. An amount of a CAI particle size range of about 1.0 to about 25.0 microns, between about 0.25 and about 3 wt % is preferred and an preferably between about 1.0 and 10.0 microns, by ball wt %. amount between about 0.5 and about 2 wt % is milling, according to known techniques. In the alternative, especially preferred. The ratio by weight of beta-blocker to Small particles may be Synthesized in the optimal size range CAI is generally between about 4:1 to about 1:300, prefer 1O of 3–7 microns. Although this procedure can be more ably between about 1:1 to about 1:40. expensive, it is Superior in providing a more uniform and The high molecular weight, anionic mucomimetic poly narrow distribution of sizes in the preferred range. mers useful in the present invention have a molecular weight These anionic mucomimetic polymers and DCS are dis between about 50,000 and 6 million daltons. The polymers cussed in greater detail in U.S. Pat. No. 4,911,920 issued are characterized as having carboxylic acid functional 15 Mar. 27, 1990 and EP 507 224 (published Oct. 7, 1992). groupS and preferably contain between 2 and 7 carbon atoms The entire contents of the patent and patent application per functional group. The gels which form during prepara are hereby incorporated by reference herein. tion of the ophthalmic polymer dispersion have a Viscosity In addition to the above-described principal ingredients, between about 1,000 to about 300,000 centipoise (cps). the anti-glaucoma compositions of the present invention Suitable polymers are carboxy vinyl polymers, preferably may further comprise various formulatory ingredients, Such those called Carbomers, e.g., CarbopolR) (B. F. Goodrich as antimicrobial preservatives and tonicity agents. Examples Co., Cleveland, Ohio). Specifically preferred are Carbopol(R) of Suitable antimicrobial preservatives include: benzalko 934 and 940. Such polymers will typically be employed in nium chloride, thimerosal, chlorobutanol, methyl paraben, an amount between about 0.05 and about 8.0 wt %, depend propyl paraben, phenylethyl , edetate disodium, Sor ing on the desired Viscosity of the composition. Pourable 25 bic acid, Onamer ME) and other agents equally well-known liquid compositions generally comprise an amount of the to those skilled in the art. Such preservatives, if utilized, will polymer between about 0.05 and about 2.0 wt %. typically be employed in an amount between about 0.001 to The DCS component of the present compositions is added 1.0 wt %. Examples of suitable agents which may be utilized to provide an additional means of controlling release, as well to adjust the tonicity or OSmolality of the formulations as to prevent the Stinging which often occurs with the topical include: Sodium chloride, potassium chloride, mannitol, administration of certain drugs, Such as betaxolol. AS used dextrose, glycerin and propylene glycol. Such agents, if herein, the term “finely-divided drug carrier substrate” (or utilized, will typically be employed in an amount between “DCS”) means finely-divided Solids, colloidal particles, or about 0.1 to 10.0 wt %. Soluble polymers and/or polyelectrolytes which are capable As will be appreciated by those skilled in the art, the of Selective adsorption or binding with drug molecules. 35 compositions may be formulated in various dosage forms Examples of DCS include, but are not limited to: finely Suitable for topical ophthalmic delivery, including Solutions, divided Silica, Such as fumed Silica, Silicates and bentonites, Suspensions, emulsions, gels and erodible Solid ocular ion exchange resins, which can be anionic, cationic or inserts. The compositions preferably are acqueous, have a pH non-ionic in nature, and Soluble polymers, Such as, alginic between 5.0 to 7.8 and an osmolality between 280 to 320 acid, pectin, Soluble carrageenans, Carbopolf), and polySty 40 milliOSmoles per kilogram (mCSm/kg). rene sulfonic acid. Preferred DCS are the ion exchange The following example further illustrates the anti resins. Some resins which are used in chromatography make glaucoma compositions of the present invention. ideal DCS for binding drugs in the compositions of the present invention. The DCS component is present in the EXAMPLE 1. compositions of the present invention at a concentration 45 The following formulations are typical of aqueous oph between about 0.05 and about 10.0% by weight. thalmic Suspensions of the present invention.

AMOUNT (wt %

INGREDIENT A. B C D E F

Betaxolol HC O.28 O.28 O.28 Compound 3 1.78: 1.78: Compound 12* 1.5 1.5 Compound 13* 1.5 1.5 Timolol maleate O.68 O.68 O.68 BAC O.O1 O.O1 O.O1 O.O1 O.O1 O.O1 EDTA O.05 O.OS O.05 O.OS O.05 O.OS Carbopol (R) 934P 0.4 0.4 0.4 0.4 0.4 0.4 Polysorbate 80 O.05 O.OS O.05 O.OS O.05 O.OS Mannitol qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 mOsm/kg mC)sm/kg mCosm/kg mOsm/kg mosm/kg mC)sm/kg pH qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 Water qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 *See Table 1. **Roughly equivalent to 1.5 wt % of the free base. 5,932,572 11 12 Preparation blocker and a carbonic anhydrase inhibitor in an ophthalmi cally acceptable vehicle, wherein the final composition pH Compound 3, 12 or 13, and betaxolol or timolol are mixed in 50% of the total water volume component to form an is between about 5.0 and 7.8 and wherein the carbonic uniform dispersion. Carbopol 934P is slowly added as an anhydrase inhibitor is (R)-3,4-dihydro-4-ethylamino-2-(3- aqueous dispersion. The mixture is then homogenized at mathoxy) propyl-2H-thieno-1,2 thiazine-6-sulfonamide 1,1- high Speed. The other ingredients are added as aqueous dioxide. Solutions and then water is added to make the final Volume. 2. The composition of claim 1, wherein the final compo The resultant products, A-F, will be white uniform suspen Sition concentration of beta-blocker is less than or equal to SOS. about 2.0 wt %, and the final composition concentration of 1O carbonic anhydrase inhibitor is less than or equal to about 5 wt %. EXAMPLE 2 3. The composition of claim 2, wherein the final compo The following formulations are typical of aqueous oph sition concentration of the beta-blocker is between about 0.1 thalmic Suspensions of the present invention. and about 1.0 wt %.

AMOUNT (wt %

INGREDIENT G H J K L M N O Betaxolol HC O.28 O.56 O.28 O.56 O.28 O.56 O.28 O.56 Compound 3 1.78: 1.78: Compound 9* 167* * 167* * 167* * 167* * 167* * 167* * Compound 12* 1.5 1.5 Compound 13* 1.5 1.5 BAC O.O1 O.O1 O.O1 O.O1 O.O1 O.O1 O.O1 O.O1 EDTA O.OS O.OS O.05 O.OS O.05 O.OS O.05 O.OS Amberlite (R) O.25 O.SO O.25 O.SO O.25 O.SO O.25 O.SO IRP-69 Carbopol (R) 0.4 2.O 0.4 2.O 0.4 2.O 0.4 2.0 934P Polysorbate 80 O.OS O.OS O.05 O.OS O.05 O.OS O.05 O.OS Mannitol qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 qs to 300 mOsm/kg mC)sm/kg mCosm/kg mC)sm/kg mCsm?kg mCsm/kg mosm/kg mC)sm/kg pH qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 qs to 7.5 Water qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 qs to 100 *See Table 1. **Roughly equivalent to 1.5 wt % of the free base.

Preparation 4. The composition of claim 3, wherein the final compo Amberlite, betaxolol and Compound 3, 9, 12 or 13 are sition concentration of the beta-blocker is between about mnixed in 50% of the total water volume component to form 0.25 and about 0.5 wt %. an uniform dispersion. Carbopol 934P is slowly added as an 40 5. The composition of claim 4, wherein the final compo aqueous dispersion. The mixture is then homogenized at sition concentration of the beta-blocker is 0.25 wt %. high Speed. The other ingredients are added as aqueous 6. The composition of claim 2, wherein the final compo Solutions and then water is added to make the final Volume. Sition concentration of the carbonic anhydrase inhibitor is The resultant products, G-O, will be white uniform suspen between about 0.25 and about 3 wt %. Sions. 45 7. The composition of claim 6, wherein the final compo The present invention is also directed to methods of Sition concentration of the carbonic anhydrase inhibitor is treating and controlling ocular hypertension associated with about 1.5 wt %. glaucoma and other ophthalmic diseases and abnormalities. 8. The composition of claim 1, wherein the beta-blocker The methods comprise topically applying to the affected is Selected from the racemic and enantiomeric forms of: eye(s) of the patient a therapeutically effective amount of a 50 betaxolol, timolol, metoprolol, befunolol, fallintolol, composition according to the present invention. The fre levobunolol, carteolol, mepindolol, pindolol, bisoprolol, quency and amount of dosage will be determined by the bopindolol, atenolol, arotinolol, acebutolol, nadolol, clinician based on various clinical factors. The methods will celiprolol, metipranolol, bevantolol, ICI 118,551, pamatolol, typically comprise topical application of one or two drops penbutolol, toliprolol, tiprenolol, practolol, procinolol, exaprolol, cicloprolol, carazolol, tazolol, tienoxolol, (or an equivalent amount of a Solid or semi-solid dosage 55 oxprenolol, propranolol, IPS 339, labetolol, dilevalol, form) to the affected eye one to two times per day. esmolol, bupranolol, bunolol, isoxaprolol, diacetolol, The invention has been described by reference to certain hydroxylevobunolol, carvedilol, and their pharmaceutically preferred embodiments; however, it should be understood acceptable Salts. that it may be embodied in other specific forms or variations 9. The composition of claim 8, wherein the beta-blocker thereof without departing from its Spirit or essential char 60 is Selected from the racemic and enantiomeric forms of: acteristics. The embodiments described above are therefore be taxolol, timolol, carteolol, le Vobunolol and considered to be illustrative in all respects and not hydroxylevobunolol, and their pharmaceutically acceptable restrictive, the Scope of the invention being indicated by the Salts. appended claims rather than by the foregoing description. 10. The composition of claim 9, wherein the beta-blocker What is claimed is: 65 is betaxolol or a pharmaceutically acceptable Salt thereof. 1. A topical ophthalmic Suspension for the treatment of 11. The composition of claim 9, wherein the beta-blocker glaucoma and ocular hypertension comprising a beta is S-timolol or a is pharmaceutically acceptable Salt thereof. 5,932,572 13 14 12. The composition of claim 1, wherein the beta-blocker consisting of, hydrogen, halogen, C. s. alkyl, C2 s mono is a thiadiazole of formula: alkenyl, Cs alkoxy, C. cycloalkyl, phenyl, phenalkyl, morpholino, furyl, thienyl and pyrryl. (II) 19. A method for the treatment of glaucoma and ocular CH CH hypertension, which comprises, applying to an affected eye a topical ophthalmic Suspension comprising a beta-blocker and a carbonic anhydrase inhibitor in an ophthalmically ~~X- acceptable vehicle, wherein the final composition pH is HO between about 5.0 and 7.8 and wherein the carbonic anhy drase inhibitor is (R)-3,4-dihydro-4-ethylamino-2-(3- and optically active isomers and pharmacologically accept methoxy) propyl-2H-thieno- 1,2 thiazine-6-sulfonamide able salts thereof, wherein R" is selected from the group 1,1-dioxide. consisting of hydrogen, halogen, C. s. alkyl, C2 s mono alkenyl, C2 s alkoxy, C. cycloalkyl, phenyl, phenalkyl, 15 20. The method of claim 19, wherein the beta-blocker is morpholino, furyl, thienyl and pyrryl. Selected from the racemic and enantiomeric forms of 13. The composition of claim 12, wherein R" is selected betaxolol, timolol, metoprolol, befunolol, fallintolol, from the group consisting of chlorine, ethyl, allyl, cyclopropyl, ethoxy, phenyl, phenyl-chloromethyl and levobunolol, carteolol, mepindolol, pindolol, bisoprolol, 2-(cyclopropylmethoxy) ethyl. bopindolol, atenolol, arotinolol, acebutolol, nadolol, 14. The composition of claim 1, further comprising an celiprolol, metipranolol, bevantolol, ICI 118,551, pamatolol, anionic mucomimetic polymer wherein the final composi penbutolol, toliprolol, tiprenolol, practolol, procinolol, tion concentration of the anionic mucomimetic polymer is exaprolol, to cicloprolol, carazolol, tazolol, tienoXolol, between about 0.05 and about 8.0 wt %. oxprenolol, propranolol, IPS 339, labetolol, dilevalol, 15. The composition of claim 14, wherein the final eSmolol, bupranolol, bunolol, isoxaprolol, diacetolol and composition concentration of beta-blocker is less than or 25 hydroxylevobunolol, and their pharmaceutically acceptable equal to about 2.0 wt %, and the final composition concen Salts. tration of carbonic anhydrase inhibitor is less than or equal to about 5 wt %. 21. The method of claim 20, wherein the beta-blocker is 16. The composition of claim 15, further comprising a Selected from the group consisting of betaxolol, timolol, finely-divided drug carrier Substrate, wherein the final com position concentration of the finely-divided drug carrier carteolol, levobunolol and hydroxylevobunolol, and is their Substrate is between about 0.05 and about 10.0 wt %. pharmaceutically acceptable Salts. 17. The composition of claim 14, wherein the beta 22. The method of claim 19, wherein the beta-blocker is blocker is Selected from the racemic and enantiomeric forms a thiadiazole of formula: of betaxolol, timolol, metoprolol, befunolol, fallintolol, 35 levobunolol, carteolol, mepindolol, pindolol, bisoprolol, bopindolol, atenolol, arotinolol, acebutolol, nadolol, (II) celiprolol, metipranolol, bevantolol, ICI 118,551, pamatolol, penbutolol, toliprolol, tiprenolol, practolol, procinolol, exaprolol, cicloprolol, carazolol, tazolol, tienoxolol, 40 oxprenolol, propranolol, IPS 339, labetolol, dilevalol, esmolol, bupranolol, bunolol, isoxaprolol, diacetolol, hydroxylevobunolol, carvedilol, and their pharmaceutically acceptable Salts. 18. The composition of claim 14, wherein the beta 45 blocker is a thiadiazole of formula: and optically active isomers and pharmacologically accept able salts thereof, wherein R" is selected from the group consisting of hydrogen, halogen, Cs alkyl, C. s. mono (II) alkenyl, C2 s alkoxy, C.s 6 cycloalkyl, phenyl, phenalkyl, 50 morpholino, furyl, thienyl and pyrryl. 23. The method of claim 22, wherein R" is selected from the group consisting of chlorine, ethyl, allyl, cyclopropyl, ethoxy, phenyl, phenyl- chloromethyl and 55 2-(cyclopropylmethoxy)ethyl. and optically active isomers and pharmacologically accept able salts thereof, wherein R" is selected from the group