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US005668133A United States Patent (19) 11 Patent Number: 5,668,133 Yanni et al. 45 Date of Patent: *Sep. 16, 1997

54. OPHTHALMEC COMPOSITIONS Vandewalker, M.L., et al., “Efficacy of Vasocon-A and its COMPRISINGEMEDASTENE AND components with conjunctival provaction testing (CPT).”J. METHODS FOR THER USE Allergy Clin. Immunol, 83:302 (1989). 75 Inventors: John M. Yanni, Burleson; Stella M. Abelson, M.B. et al., “Effects of topically applied ocular Robertson, Arlington, both of Tex.; and .” Am. J. Ophthalmol, Shigetoshi Okumura, Nara, Japan; 90:254-257 (1980). Hitoshi Tanaka, Nara-ken, Japan; Tadayuki Saito, Osaka, Japan DeChant, K.L. and K. L. Goa, "Levocabastine. A review of its pharmacological properties and therapeutic potential as a 73 Assignee: Alcon Laboratories, Inc., Fort Worth, topical antihistamine in allergic and , Tex. "Drugs, 41:202-224 (1991). * Notice: The term of this patent shall not extend Berdy et al., "Allergic conjunctivitis: A survey of new beyond the expiration date of Pat. No. .' J. Ocular Pharmacol, 7:313–324 (1991). 5.441,958. Yanni et al., "Effect of on in vitro and in vivo 21) Appl. No.: 445,850 conjunctival immediate hypersensitivity responses in rats.” Int, Arch. Allergy Immunol., 101:102-106 (1993). 22 Filed: May 22, 1995 Dunnett, C.W., “A multiple comparison procedure for com Related U.S. Application Data paring treatments with a control,” J. Am. Stat. Assoc., 50:1096-1121 (1955). 63 Continuation-in-part of Ser. No. 163,973, Dec. 8, 1993, Pat. No. 5,441,958. Bliss, C. and E. Giorgy, Vitamin Methods, vol. 2, pp. 445-610, Academic Press, Inc. New York (1951). (51] Int. Cl...... essessed to be sease eroses see possessrs A61K 3150 52 U.S. Cl...... 514/253: 514/912 58 Field of Search ...... 514/253, 912 Primary Examiner-Zohreh Fay Attorney, Agent, or Firm-Sally Yeager 56 References Cited U.S. PATENT DOCUMENTS [57] ABSTRACT 4,430,343 2/1984 Iemura et al. . Topical ophthalmic compositions comprising 1-(2- 5,192,780 3/1993 York et al., ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)- benzimidazole and its ophthalmically acceptable acid addi OTHER PUBLICATIONS tion salts have been found to be useful in treating ocular Miller, J. et al., " phosphate and allergies, especially allergic conjunctivitis, giant papillary hydrochloride, singly and in combination for the treatment conjunctivitis, and vernal conjunctivitis. of allergic conjunctivitis-a controlled, double-blind clinical trial.” Ann. Allergy, 35:81-86 (1975). 5 Claims, No Drawings 5,668,133 1 2 OPHTHALMC COMPOSITIONS treating ocular allergies, especially allergic conjunctivitis COMPRISINGEMEDASTINE AND (acute and chronic atopic conjunctivitis) and the pruritus METHODS FORTHER USE and/or edema associated with giant papillary conjunctivitis and vernal conjunctivitis. In particular, the components of This is a continuation-in-part of U.S. patent application the present invention have good local activity, with quick Ser. No. 08/163,973, filed Dec. 8, 1993 now U.S. Pat. No. onset of action and fairly long duration of action. 5.441958. DETALED DESCRIPTION OF THE BACKGROUND OF THE INVENTION INVENTION The present invention relates to the field of 10 ophthalmology, particularly the topical treatment of ocular allergies. Most particularly, the present invention relates to ophthalmic compositions comprising 1-(2-ethoxyethyl)-2- (4-methyl-1-homopiperazinyl)-benzimidazole, otherwise known as emediastine, and its ophthalmically acceptable acid 15 addition salts and methods for their use. Allergic conjunctivitis is frequently characterized by ocu lar pruritus (itching), erythema (inflammatory redness), edema and tearing. This condition is one of the most frequently treated by ophthalmologists, optometrists and 1-(2-Ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)- allergists. To date, treatment has been primarily through the benzimidazole, otherwise known as , is pictured use of topically applied H antagonists in com above and is disclosed and claimed in U.S. Pat. No. 4430, bination with O-. See, for example, the following 343 (Iemura et al.), along with numerous other benzimida articles: zole derivatives. Iemura et al. disclose the use of this class 1. Miller, J. and E. H. Wolf, "Antazoline phosphate and 25 of compounds as anti-allergics and antihistamines, but do naphazoline hydrochloride, singly and in combination not disclose the ophthalmic use of these types of com for the treatment of allergic conjunctivitis-a pounds. U.S. Pat. No. 5,192,780 (York et al.) discloses the controlled, double-blind clinical trial.” Ann. Allergy, use of combinations of antiallergics and antihistamines to 35:81-86 (1975). 30 prevent and treat ophthalmic allergic responses. To the 2. Vandewalker, M. L. et al., “Efficacy of Vasocon-A and extent that emura et al. disclose methods for preparation of its components with conjunctival provocation testing the compounds of the present invention, that patentis hereby (CPT)” J. Allergy Clin. Immunol, 83:302 (1989). incorporated by reference herein. 3. Abelson, M. B. et al., "Effects of topically applied The compounds useful in the present invention include ocular decongestant and antihistamine." Am. J. Oph 35 emedastine and its ophthalmically acceptable acid addition thalmol 90:254-257 (1980). salts. Ophthalmically acceptable acid addition salts include Recent studies indicate that the antihistamine levocabas salts of organic or inorganic acids, such as maleic acid, tine exhibits clinical activity in patients with allergic con fumaric acid, hydrochloric acid or sulfuric acid. These salts junctivitis without the addition of a vasoconstrictor. See, may be formed conventionally. It is preferred to use the Dechant, K. L. and K. L. Goa, "Levocabastine. A review of difumarate salt of emedastine. its pharmacological properties and therapeutic potential as a In forming compositions for topical administration, the topical antihistamine in and conjunctivitis.” compounds of the present invention are generally formu Drugs 41:202-224 (1991). In addition, it has recently been lated at between about 0.0001 and about 1.0 percent by demonstrated that H antagonists are effective in relieving weight (wt %) solutions in water at a pH between about 6 conjunctival injection (hyperemia) and erythema, as well as 45 and about 8. The compounds are preferably formulated at pruritus. See, Berdy, G. J. et al., "Allergic conjunctivitis: A between about 0.005 and about 0.2 wt % and, most Survey of new antihistamines.” J. Ocular Pharmacol. preferably, between about 0.05 and about 0.2 wt %. While 7:313-324 (1991). the precise regimen is left to the discretion of the clinician, Although there are many different antihistamines avail it is recommended that the resulting compositions be topi able for systemic treatment of allergies and related ailments, 50 cally applied by placing one or more drops in each eye one many such antihistamines are not suitable for topical oph or more times a day. thalmic use because of limited ocular bioavailability. For The compositions of the present invention may be pre example, (Seldane(s), made by Marion Merrell pared by combining one or more of the compounds of the Dow), (His manal(8), made by Janssen present invention with a suitable vehicle to form a solution, Pharmaceutica) and ioratadine (Clariting, made by 55 dispersion or gel. The compositions of the presentinvention Schering) all have good systemic activity; however, terfena may also include one or more ingredients conventionally dine has little or no local ocular activity, and astemizole and found in ophthalmic formulations, such as preservatives each have greatly reduced local ocular activity (as (e.g., or thimerosal), viscosity compared to their systemic activity). A need therefore exists imparting agents (e.g., polyvinyl alcohol or hydroxypropyl for an antihistamine having good local ocular activity and methylcellulose) and tonicity agents (e.g., sodium chloride having minimal side effects. or mannitol). The compositions will typically also include buffering agents to maintain the pH within physiological pH SUMMARY OF THE INVENTION (between 6 and 8); however, it has been found that citrate, It has now been unexpectedly discovered that topical acetate and phosphate buffers are not compatible with the ophthalmic compositions comprising 1-(2-ethoxyethyl)-2- 65 compounds of the present invention, as these buffering (4-methyl-1-homopiperazinyl)-benzimidazole and its oph agents, particularly phosphate buffers, compromise the sta thalmically acceptable acid addition salts are useful in bility and solubility of the compounds. It is therefore pre 5,668,133 3 4 ferred to use Tris (tri(hydroxymethyl)aminomethane) as a buffering agent in the compositions of the present invention. TABLE 1. Hydrochloric acid or sodium hydroxide will normally be used to adjust the pH of the resultant compositions. Effects of Emedastine Difumarate On Histamine-Induced 5 Vascular Permeability. In Guinea Pigs EXAMPLE 1. Pretreatment Concentration Percent EDso The following examples are typical compositions of the Compound Interval (wt %) Change (wt %) present invention. These formulations may be prepared in NaCl. 1 min 0.9 - - accordance with procedures known to those skilled in the Emedastine 1 min 0.0001 -44 0.0002 art. 10 Difumarate 0.001 -62 0.01 -81. NaCl 30 min 0.9 - Emedastine 30 min 0.000006 -28 0.000035 FORMULA- FORMULA- FORMULAT Difumarate 0,00006 -58* TONA TION B TION C 0.0006 -93 INGREDIENT (wt %) (wt %) (wt %) 15 NaCl 2 hr O.9 - - Emedastine 2.hr 0.001 -35* 0.0029 Emedastine 0.177 O.0884 0.884 Difumarate 0.005 -53* Difumarate O.01 -72* Benzalkonium 0.01 O.O1 0.01 NaCl. 4hr O.9 - ---- Chloride Emedastine 4 hr 0.001 -9 0.09 Disodium EDTA 0.01 O.O. 0.01 Difumarate 0.00 -39* Tris(hydroxymethyl)- 0.5 0.5 O.5 2O 0.1 -84 aminomethane 1.0 -95k Sodium Chloride 0.64 0.66 0.46 NaCl 8 hr 0.9 - --- Hydroxypropyl 0.25 0.25 0.25 Emedastine 8 hr 0.01 -5 0.19 Methylcellulose (2910) Difumarate 0.05 -33* (E4M) 0.1 -43* NaOH and/or HC qs. to pH 7.4 qs. to pH 7.4 qs. to pH 7.4 25 0.5 -66 Purified Water qs. to 100% qs. to 100% q.s. to 100% 1.0 -71 x *p < 0.01, Dunnett's t test EXAMPLE 2 The topical ocular antihistaminic effect of emedastine ' difumarate was assessed in a model of histamine induced vascular permeability in guinea pig conjunctiva. The As shown in Table 1, above, topical ocular administration potency of emediastine difumarate in this model was then of emediastine difumarate at 1 minute, 30 minutes, 2, 4 or 8 compared with those of reference antihistamines. hours prior to subconjunctival histamine challenge inhibited Male Dunkin Hartley Viral Antibody Free outbred guinea 35 in concentration-dependent fashion the vascular permeabil pigs (Charles River Labs, Portage, Mich.), weighing ity response. Calculated EDo values obtained from these approximately 250-350 grams (6/group) were injected intra data were 0.0002%, 0.000035%, 0.0029%, 0.019% and venously (i.v.) via the marginal ear vein with 1.0 mL of 0.19% respectively. These results indicate that emediastine Evans Blue dye (1.0 mg/mL). Forty-five (45) minutes post 40 difumarate possesses a rapid onset and an acceptable dura dye injection, 20 L of test compound or vehicle was tion of action following topical ocular administration. applied topically to one eye of each experimental animal. Thirty minutes following topical drug application, the guinea pigs were anesthetized and challenged subconjunc tivally with histamine (300 ng/10 L). Responses were quantitated as described by Yanni et al. in Int. Arch. Allergy 45 EXAMPLE 3 Immunol., 101:102-106 (1993). Response scores from the treated groups were then compared with scores obtained in the saline-treated group using Dunnett's t test (Dunnett C. W., “A multiple comparison procedure for comparing treat Comparisons of emediastine difumarate's potency with ments with a control.' J. Am. Stat. Assoc. 50:1096-1121 50 those of reference antihistamines utilizing topical ocular (1955)). Regression analysis was used to determine relative administration and treatment intervals of 1 minute or 30 potency (Bliss, C. and E. Gjorgy. In Vitamin Methods, Vol. minutes in the in vivo testing paradigm described above 2, pp. 445-610, Academic Press, Inc., New York, 1951). were completed.

TABLE 2 Effects of H. Antagonists Applied Topically Immediately Prior to Histamine Challenge Wheal Whea Concentration Area X Concentration Area X Compound (wt %) Intensity Potency Compound (wt %) Intensity Potency **

NaCl 0.9 308-20 ------Emedastine 0.0001 16614 1.0 Pyrilamine 0.0001 220 - 17 0.737a difumarate 0.001 104 - 20 0.001 94 - 23 0.01 57 - 16* 0.01 41 20* NaCl 0.9 276. 10 5,668,133

TABLE 2-continued Effects of H. Antagonists Applied Topically Immediately Prior to Histamine Challenge Wheal Wheal Concentration Area X Concentration Area X Compound (wt %) Intensity Potency Compound (wt %) Intensity Potency's Emediastine 0.0001 159 - 26: 10 0.0001 2101 0.288 Difumarate (0.147-0.565) 0.001 141 38% 0.001 138.21 0.01 45 - 18 0.01 89 22: 0.1 33 - 22. 0.001 1816 0.130 (0.054–0.326) 0.01 87 40k 0.1 59 + 23* NaCl 0.9 285 19 --- Emediastine 0.000 1593: 10 Antazoline 0.0001 244 it 4 0.060 Difumarate (0.023–0.132) OOO1 09: 14 0.001 T842: OO1 55 - 12. O.O1 1156. NaCl 0.9 336 78 w Emedastine 0.01 262s 10 Levocabastine O,05 23158 Difumarate *p < 0.05, Dunnett's t test *(95% Confidence Limits) Value represents approximate potency; confidence limits were not calculated because of lack of parallelism between the regression lines.

The results shown in Table 2, above, demonstrate that lenge. Levocabastine (0.05%) failed to attenuate signifi emedastine difumarate is 3, 8, and 17 times more potent than cantly the histamine-induced vascular permeability response ketotifen, pheniramine, and antazoline, respectively, and so in the conjunctiva when administered topically 1 minute approximately equipotent to pyrilamine when compounds before histamine injection. are administered topically 1 minute before histamine chal

TABLE 3 Relative Potencies of Topically Applied H. Antagonists in Histamine-Induced Vascular Permeability in Guinea Pigs Wheal Wheal Concent Area X Concen- Area X tration Intensity tration Intensity Compound (wt %) (Xt S.D.) Potency Compound (wt %) (xit S.D.) Potency"

NaCl 0.9 21441 m w --- Emedastine OOOOOO6 154 - 62 10 Ketotifen. 0.0000007 157 it 66 3.72 (0.973-11.892) Difumarate OOOOO6 91:26 OOOOOO 10852. 0.0006 1614 . OOOOO! 6 - 26: NaCl 0.9 219 - 20 o w - --- Emedastine 0.00001 19148 - 10 0.0001 167 it 26* 0.14 (0.078-0.263) Difumarate 0.0001 104.47 0.001 924.4 OOO1 89 OO 58-k NaCl 0.9 217 35 o Emecastine 0.00001. 16168 10 Chlorpheniramine 0.0001 161 + 57 0.13 (0.056-0.295) Difumarate OOOO1 11258 OOO1 76 22 O.OO1 1823: 0.O. 9 12 NaCl 0.9 350-31 o 1 Emediastine OOOOOO1. 26535 10 000001 283 it 37* 0.105 (OO63-0.176) Difumarate OOOOO1 16530 OOOO1 13136: 0.0001 7027. 0.001 65 28: OOO 67. OO 1884 NaC 0.9 1944 --- Emediastine 0.000006 136 it 42 1.0 Pyrilamine OOOOO1 202 it 46 0.099 (0.028-0.261) Difumarate 0.00006 75 - 22- OOOO1 124 - 49* OOOO6 67 OOO1 75 42. NaCl 0.9 252 30 o w Emedastine 0.00001 191 - 27: 10 Levocabastine 0.0005 189+ 66 0.01 (0.006-0.038) Difumarate OOOO1 137 24 OOOS 116 67 OOO 7. 9 0.05 56.41: Pheniramine OOO3 175 - 53* OOO28 0.03 12233k O.3 56.41: NaC 0.9 24-34 - o Emedastine 0.00001 163 - 32° 10 0.01 210 23 00003 5,668,133

TABLE 3-continued Relative Potencies of Topically Applied H. Antagonists in Histamine-induced Vascular Permeability in Guinea Pigs Wheal Wheal Concen Area X Concen- Area X tration Intensity tration Intensity Compound (wt %) CXE S.D.) Potency Compound (wt %) (xit S.D.) Potency'" Difumarate (0.00018-0.00051) OOOO1 98 - 22 0.1 12725 0.001 1219 O 53.31 NaC 0.9 287 - 20 o Emediastine OOOOO1 19757' 10 Antazoline O.O1 205 61st O.OOO17 Difumarate 0.0001 65.32 0.1 14526 0.001 44 10 91 + 2* *p < 0.05, Dunnett's t test Values are approximate potencies; confidence limits were not calculated because of lack of parellelism between the regression lines *(95% Confidence limits) 20 Results obtained using a 30 minute treatment interval are 0-None presented in Table 3. Emedastine difumarate is equipotent to 1-Glazed, glassy appearance ketotifen, and 7, 7, 10, 10, 100, and 3333 times more potent 2-Moist lids and surrounding hair than brompheniramine, chlorpheniramine, clemastine, 3-Moist lids and surrounding hair, thicker mucous pyrilamine, levocabastine and diphenhydramine, respec 25 like tively. In addition, these studies demonstrate that emedastine difumarate is approximately 357 and 5813 times more TABLE 4 potent than pheniramine and antazoline, respectively. Effect of Emediastine Difumarate on (Approximate potency has been calculated due to lack of Passive Anaphylaxis in Guinea Pig Coniunctiva parallelism.) 30 Antigen Conc. % EDso EXAMPLE 4 Challenge Compound (wt %) Change (wt %) Emedastine difumarate was evaluated for its ability to iv. NaCl 0.9 o inhibit a passive conjunctival immediate hypersensitivity Emediastine 0.000 -4 OOOO22 35 0.00 -66 response following topical ocular administration. 0.0 -96 Guinea pigs (5-8/group) were passively sensitized with topical NaCl O.9 anti-ovalbumin seruminjected Subconjunctivally in one eye. ocular Emediastine OOOO. -29* OOO46 Twenty-four hours after passive sensitization, ovalbumin 0.001 -45: (OA) was administered either i.v. or topically to the eye. 0.01 -5 The allergic response following i.v. antigen challenge was 40 0. -64 assessed as follows: thirty minutes prior to challenge, ani *p < 0.05, Dunnett's t test mals received 20 L of emediastine difumarate or saline As shown in Table 4, above, significant reductions of the applied topically to the eye. Guinea pigs were then chal allergic response were observed in animals treated with lenged i.v. via the marginal ear vein with 1.0 mL of a 45 0.001% and 0.01% solutions of emedastine difumarate 30 solution containing 100 g of OA and 1 mg of Evans Blue minutes before i.v. antigen challenge. The EDso value for dye. Responses were quantitated as previously described in emedastine difumarate obtained from this experiment was Example 2. 0.00022%. In an experiment in which the allergic response For assessment of the allergic response following topical was initiated by topical ocular antigen challenge and quan ocular antigen challenge, 20 L of ovalbumin (1.0 wt %) 50 tified by clinical scoring, emediastine difumarate adminis was administered to the sensitized eye 5 minutes after tration 5 minutes before antigen challenge produced topical ocular application of emediastine difumarate or saline concentration-dependent reductions in the severity of the (20 L). Thirty minutes later, the reaction was quantitated, hypersensitivity response (See Table 4, above). Significant using the following scoring scheme (maximum score per attenuation was observed with concentrations ranging from animal-10): 55 0.0001% to 0.1% (ED=0.0046%). Congestion (refers to palpebral and bulbar conjunctiva): The invention has been described by reference to certain 0-Normal preferred embodiments; however, it should be understood 1-Pink conjunctiva that it may be embodied in other specific forms or variations 2-Red conjunctiva thereof without departing from its spirit or essential char 3-Dark red conjunctiva; petechiae present acteristics. The embodiments described above are therefore Swelling: considered to be illustrative in all respects and not 0-None restrictive, the scope of the invention being indicated by the 1-Any swelling on lower lid only appended claims rather than by the foregoing description. 2-Swelling upper and lower lid, lids partially closed What is claimed: 3-Lids everted, very swollen, lids at least half closed 65 1. A method for treating the pruritus and/or edema asso 4-Swelling of both lids and side of face ciated with giant papillary conjunctivitis and Vernal Discharge: conjunctivitis, comprising topically administering to an 5,668,133 9 10 affected eye an antihistaminic effective amount of a com- 4. The method of claim 3, wherein said compound is pound selected from the group consisting of 1-(2- present at a concentration between about 0.05 and about 0.2 ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)- wt %. benzimidazole and its ophthalmically acceptable acid 5. The method of claim 1, wherein the compound com "A Goa of claim 1, wherein said compound is prises the difumarate salt of 1-(2-ethoxyethyl)-2-(4-methyl present at a concentration between about 0.0001 and about 1-homopiperazinyl)-benzimidazole. 1.0 wt %. 3. The method of claim 2, wherein said compound is present at a concentration between about 0.005 and about 10 0.2 wt %. ck :: * : :