GB2077102A - Ophthalmic compositions - Google Patents

Abstract

Ophthalmic compositions and inserts of 4'-[1-hydroxy-2-(isopropylamino)- ethyl]methanesulfonanilide (sotalol) and process for treating glaucoma by reducing intraocular pressure are disclosed.

Description

SPECIFICATION Opthalmic compositions and process for treating glaucoma Field of the Invention This invention is concerned with process and compositions of the drug, bio-affecting, and bodytreating type. More specifically, this invention deals with a process for treatment of ocular hypertension by ocular installation of 4'1 -hydroxy-2-(isoprnpylamino)-ethylmethanesulfonanal- ide.

Description of the Prior Art Ocular hypertension is associated with glaucoma, a disease of the eye characterized by a progressive time related increase in intraocular pressure ultimately resulting in injury to the optic nerve. Thus, the primary goal in the treatment of glaucoma is to prevent damage to optic nerve fibers by lowering elevated intraocular pressure. Among drugs currently used for treating glaucoma are myotics such as pilocarpine and cholinesterase inhibitors such as physostigmine.

While these drugs are useful, they are known to cause a variety of untoward reactions as a result of local and in some instances systemic effects. For instance, local side effects such as extreme miosis, accommodative myopia, night blindness and transient blurred vision are sometimes seen. Other common local effects include twitching of the eyelids, browache, headache, ocular pain, ciliary and conjunctival congestion, lacrimation, localized allergy manifested by conjunctivitis and contact dermatitis. As a result of absorption, cholinesterase inhibitors produce such undesirable systemic effects as salivation, sweating, nausea, vomiting, bradycardia, and hypotension. Certain adrenergic drugs such as the alphaagonist epinephrine and the betaagonists isoproterenol and salbutamol have also been used to reduce intraocular pressure.However, when topically applied, these compounds can produce systemic side effects resulting from absorption such as tachycardia, hypertension, headaches, sweating, tremors, palpitations, and tachyphylaxis.

A more recent approach to treating glaucoma involves use of certain betadrenergic blocking drugs to decrease production of aqueous humor thereby reducing intraocular pressure. The underlying mechanism of betaadrenergic blocking agents in reducing intraocular pressure is not known and is considered a paradox in that beta-adrenergic agonists (stimulants) also produce ocular hypotensive effects by decreasing production of aqueous humor.

According to AMA Drug Evaluations, Page 360, Fourth Ed. (American Medical Association, Chicago), topical preprations of the betaadrenergic blocking agents propanolol, practolol, atenolol, pindolol, and timolol have been used to treat chronic glaucoma. The latter agent is described in British Patent 1,524,405 published September.13, 1978 and U.S. Patent 4,195,085.

The active ingredient of the ophthalmic compositions and process of the instant invention is the substance 4'-[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide. This compound, described in U.S. Patent 3,341,584 to Larsen, et al., is considered a betaadrnnergic blocking agent and is referred to as sotalol or MJ 1 999 in the following publications dealing with intraocular pressure reduction.

A. Musini, et al., American Journal of Ophthalmology, 72(4), 773-781 (1971) conducted a comparative study of the effect of propanolol, MJ 1 999 HCI (sotaloi hydrochloride) and INPEA (nifenolol) on intraocular pressure in man and concluded that of the three betaadrenergic blocking agents, only propanolol decreased intraocular pressure.

J. W. Lamble, et a., Invest. Ophthalmol. Visual Sci., 16, (7), 628-633 (1977) in a study entitled "Effects of catacholamines on the intraocular pressure of conscious monkeys" concluded that sotalol is without intrinsic activity on intraocular pressure of owl monkeys.

L. Bonomi, et al., Albrecht. Graefes. Arch. Klim. Exp. Ophthal., 210(1), 1-8 (1979) compared the effects of nine betaadrenergic blocking agents on intraocular pressure in rabbits and found that sotalol instilled in the eye at a 1% concentration reduced intraocular pressure in experimentally induced ocular hypertension in rabbits.

Thus, with respect to use of sotalol as an intraocular pressure lowering agent, the prior art indicates that it is ineffective in man and species dependent in lower mammals.

Summary of the Invention This invention is specifically concerned with a process for treating human glaucoma by lowering intraocular pressure which comprises topical application to the glaucomatous eye an effective ophthamologically acceptable amount of 411-hydrnxy-2-(isopropylamino)-ethyl]methan- esulfonanilide. This compound is referred to herein as sotalol and characterized by the formula:

Other aspects of the invention ophthalmic compositions adapted for practicing the process for lowering intraocular pressure comprising sotalol as the active ingredient or ophthalmologically acceptable salts thereof such as the hydrochloride in combination with an ophthalmic carrier in the form of a buffered isotonic liquid, a solid, or a vegetable oil as well as methods of administration by polymeric insert or soft contact lens.

In accord with the present invention, sotalol is topically applied to the eye in an effective ophthalmologically acceptable amount to provide a therapeutically useful reduction in intraocular pressure having a duration of 5 to 9 hours. It is to be understood that the term "effective ophthalmologically acceptable amount" as used herein refers to the quantity of sotalol necessary to lower intraocular pressure without causing any toxic, harmful or deliterous effects such as irritation, pain, allergic reaction, or systemic side effects related to blockade of cardiac and noncardiac betaseceptors such as bradycardia, hypotension, and bronchospasm.

In practicing the process of the invention, sotalol is preferably topically applied as an ophthalmic composition formulated to contain from 2% to 10% and especially 4% to 6% of sotalol in an amount sufficient to deliver an effective dose of from 1 mg. to 8 mg. per eye in a non-toxic pharmaceutically acceptable ophthalmological carrier therefor. One to four drops of such compositions are sufficient to produce the desired reduction of intraocular pressure.

The instant ophthalmological preparations may be conveniently prepared by admixture of sotalol hydrochloride or ophthalmologically acceptable salts thereof with typical pharmaceutically acceptable carriers such as water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils polyalkylene glycols, petroleum based jelly, methylcellulose, ethylcellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The ophthalmological preparations of the instant invention may also contain non-toxic auxillary substances such as emulsifying, preserving, wetting agents, and the like, as well as bacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use.Suitable buffering ingredients such as sodium chloride, sodium borate, sodium acetate, gluconate buffers and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate may also be employed. Additionally, suitable ophthalmic vehicles can be used as carrier media for sotalol (and salts thereof such as the hydrochloride) including conventional phosphate buffered vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. Solid water soluble polymeric inserts are also employed as carriers for sotalol and its salts.The polymer used to form the insert may be of any water soluble non-toxic polymer including cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyacrylamides; natural products such as gelatin, alginates, pectins, tragacanth, acacia; starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, in addition to other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methylether and polyethylene oxide.

This invention is illustrated by the following specific examples which are not intended to be limiting in any manner.

Description of Specific Embodiments EXAMPLE 1 Effects of Sotalol Hydrochloride Eyedrops On Intraocular Pressure In Normal Subjects The objective of the study was to assess effects and tolerance of sotalol hydrochloride eyedrops on intraocular pressure compared with placebo eyedrops in normal test subjects. The study design was double-blind, randomized within patient crossover. It was performed on two consecutive days followed' by a 5-day wash-out period, followed by a final two consecutive days of testing.

Sotalol hydrochloride was administered dropwise to the eye at 4.2% concentration with the placebo eyedrops being isotonic saline. Both drug and placebo were dispensed from matched containers using a dropper with a delivery volume of 28.6 microliters.

Eight subjects were enrolled in the study and were divided into two equal groups randomly allocated as follows: Day 1: No treatment Day 2: 10 a.m. Installation of two drops in both eyes of either sotalol hydrochloride eyedrops or placebo saline eyedrops; immediately after the first 10 a.m. set of tests.

Following a wash-out period of 5 days, the study groups were crossed-over, so that subjects who previously received placebo eyedrops received sotalol hydrochloride eyedrops, and the subjects who had previously received sotalol hydrochloride eyedrops received placebo eyedrops.

During the study, tests were performed according to the following schedule: Time of day 10.00: Visual acquity, pupil size, pulse and blood pressure with intraocular pressure (IOP) measured using a Goldmann Applanation Tonometer.

11.30: lOP and pupil size.

13.30: IOP and pupil size.

15.30: IOP and pupil size.

17.00: IOP and pupil size, pulse and blood pressure.

The following table sets forth data collected while on pretherapy and post-administration.

TABLE I MEAN INTRAOCULAR PRESSURE (mmHg) PLACEBO vs. SOTALOL HYDROCHLORIDE Percent Sotalol Percent Time Eye n Placebo Drop HCI Drop Pre- Right 8 12.38 12.25 Treatment Left 8 12.00 12.63 Both 16 12.19 - 12.44 1.5 hours Right 8 11.25 10.25 later Left 8 11.38 11.13 Both 16 11.31 7.2 10.69 14.1 3.5 hours Right 8 11.13 9.38 later Left 8 11.13 9.88 Both 16 11.13 8.7 9.63 22.6 5.5 hours Right 8 10.63 10.63 later Left 8 10.50 11.13 Both 16 10.56 13.4 10.88 12.5 7 hours Right 8 11.13 10.25 later Left 8 10.88 11.00 Both 16 11.00 9.8 10.63 14.6 Last 4 Right 32 11.03 10.13 Readings Left 32 10.97 10.78 Both 64 11.00 9.8 10.45 16.0 Conventional statistical analysis of the above results indicates no significant (P > .05) differences between placebo and sotalol for either right or left eyes at any particular time.However, when both the right and left eyes were used as multiple responses per subject, reduction of intraocular pressure was significantly (P < .002) lower with sotalol hydrochloride compared to placebo at 3.5 hours post-treatment. Analysis of combined values for the four post-treatment observation times (1.5, 3.5, 5.5 and 7 hours after treatment) gave the following results: Sotalol hydrochloride values were significantly (P < .007) lower than placebo in the right eye. When both eye values were combined as multiple responses per subject; sotalol hydrochloride values were again found to be significantly (P < .02) lower.

No adverse effects were observed during the study with no significant (P > .05) differences apparent between mean pupil sizes, heart rate and blood pressure measurements for sotalol hydrochloride and placebo.

EXAMPLE 2 Effects of Sotalol Hydrochloride Eyedrops on Intraocular Pressure in Patients with Simple Chronic Glaucoma or With Raised Intraocular Pressure The objective of this study was to assess effects and tolerance of sotalol hydrochloride eyedrops on intraocular pressure compared with placebo eyedrops in a group of patients with simple chronic glaucoma or with raised intraocular pressure. Five females and three males participated in the study with a median age of 73 in a range of 44 to 80 years old. The study design was double-blind cross-over with a 5-day wash-out period between the two phases of the study. Sotalol hydrochloride was administered dropwise to the eye at 4.2% concentration with placebo eyedrops being isotonic saline. Both drug and placebo were dispensed from matched containers using a dropper with a delivery volume of 28.6 microiiters.

The eight patients were divided into two equal groups randomly allocated as follows: Day 1. No treatment Day 2: 9:00 a.m. Installation of drops in both eyes of either sotalol hydrochloride eyedrops or placebo saline eyedrops; immediately after the first 9:00 a.m. set of tests.

Following a wash-out period of 5 days, the groups were crossed-over, so that subjects who had previously received placebo eyedrops received sotalol hydrochloride eyedrops, and the subjects who had previously received sotaloi hydrochloride eyedrops received placebo eyedrops.

During the study, tests were performed according to the following schedule: Time of day 09.00: Visual acquity, pupil size, pulse and blood pressure with intraocular pressure (IOP) measured using Goldman Applanation Tonometer.

10.30: IOP and pupil size 12.30: IOP and pupil size.

14.30: IOP and pupil size.

16.30: IOP and pupil size, pulse and blood pressure.

TABLE II below sets forth-data collected while on pretherapy and post-administration.

TABLE II MEAN INTRAOCULAR PRESSURE (mmHg) PLACEBO vs.

SOTALOL HYDROCHLORIDE Time Placebo Percent drop Sotalol.HCI Percent drop 9:00 22.56 - 22.00 10:30 21.50 4.7 19.81 10.0 12:30 19.88 11.9 18.56 15.6 14:30 21.13 6.3 19.63 10.8 16:30 21.50 4.7 20.63 6.2 Conventional statistical analysis of the above results indicates no significant (P > .05) differences between placebo and sotalol for either right or left eyes, at any particular time. However, when both the right and left eyes were used as multiple responses per subject, intraocular pressure was lower on sotalol than on placebo at 1.5, 3.5, 5.5, and 7.5 hours with the following P-values: 0.07, 0.29, 0.03, and 0.27.

Average values for the pupil size, pulse and blood pressure are set forth in TABLE Ill below with the observed differences calculated to be statistically insignificant.

TABLE Ill MEAN PUPIL SIZE; PULSE, SYSTOLIC AND Dl ASTOLIC BLOOD PRESSURE OF PLACEBO vs.

SOTALOL HYDROCHLORIDE Mean Pupil Size (min) Time Placebo - Sotalol. HCI 09.00 3.11 3.08 10.30 3.04 3.49 12.30 3.03 3.42 14.30 2.99 3.21 16.30 3.14 3.23 Pulse (beats per minute) Time Placebo Sotalol. HCI 09.00 75.25 76.88 16.30 76.25 76.88 Blood Pressure (mmHg) Systolic/Diastolic Time Placebo Sotalol. HCI 09.00 141.0/78.5 135.0/77.5 16.30 143.3/83.0 142.9/86.6 No adverse effects were observed during the study.

EXAMPLE 3 Ophthalmic Compositions Containing Sotalol Ophthalmic compositions including solutions, ointments and ocular medicinal inserts comprised of sotalol hydrochloride and a non-toxic pharmaceutically acceptable ophthalmological -carrier therefor suitable for ocular installation are preferred for practice of the present invention.

Ophthalmic solutions of sotalol employed in the instant process can be formulated in accord with good pharmaceutical practice as set forth in Chapter 83 of Remington's Pharmaceutical Sciences, 1 4th Edition, Mack Publishing Company. Such solutions are preferably sterile with sterility maintained during use by conventional quaternary ammonium bacteriostats such as benzalkonium chloride. Inasmuch as sotalol or ophthalmologically acceptable salts thereof such as the hydrochloride are not appreciably susceptible to oxidative decomposition, an antioxidant is not required but can be employed if desired. Suitable antioxidants, by way of example, include sodium bisulfite, N-acetylcystine salts, sodium ascorbate, and other water soluble ophthalmologically acceptable antioxidants known to the pharmaceutical art.Ophthalmic solutions of sotalol hydrochloride may be adjusted with inert ingredients such as sodium chloride or boric acid to provide a solution which is comfortable for application to the eye. For example, a composition containing about 4.2% sotalol hydrochloride (equivalent to 3.7% sotalol base) with 0.9% sodium chloride, or a vehicle of equivalent tonicity such as 1.9% boric acid are satisfactory. Ointments are prepared with conventional petrolatum vehicles employing liquid petrolatum and white petrolatum in such proportions as to provide an ointment of desirable fluidity.

Ophthalmic Solution Sotalol hydrochloride 4.2 g.

Excipient q.s. 100.0 g.

Excipient Composition: Benzalkonium chloride 0.02 g.

Sodium dihydrogen phosphate dihydrate 0.00586 9.

Disodium hydrogen phosphate, anhydrous 0.0536 g.

Water, q.s. 100.00 g.

If desired, 0.9% by weight aqueous sodium chloride may replace water as a solvent. The solution is sterilized by filtration and aseptically packaged.

Ophthalmic Ointment Sotalol hydrochloride, micronized 4.76 g.

White petrolatum, q.s.) Liquid petrolatum, q.s.) 100.0 g.

The product is prepared an packaged under aseptic conditions to yield a sterile ointment.

Sotalol hydrochloride may also be applied to the eye through the vehicle of a polymeric insert or soft contact lens. For the latter purpose, the polymeric hydrophilic hydrogels prepared from polymers of acrylic and methyacrylic esters, modified collagens, cross-linked polyether gels, cross-linked polyvinyl alcohol, or cross-linked partially hydrolyzed polyvinyl acetate as disclosed in U.S. Patent Nos. 2,976,576, 3,220,960, and 3,419,006 may be employed and are included herein by reference. Ocular inserts prepared from these or other polymeric materials which are insoluble in tear liquid but which may absorb tear liquid to form a swollen hydrogel as disclosed in U.S. Patent Nos. 3,416,530 and 3,618,604 may also be employed and are included herein by reference.All such means of applying sotalol hydrochloride to the eye are included within the present invention as are compositions adapted for such use.

In practicing the process of the present invention for lowering intraocular pressure by topical administration of sotalol hydrochloride, an ophthalmologically acceptable polymeric ocular insert placed and retained in contact with an eyeball is preferred wherein the compound diffuses from the insert at a rate sufficient to provide an effective intraocular pressure lowering dose of from 1.0 g. to 5.5 mg. over a period of 5 to 9 hours.

Ocular inserts particularly preferred in the practice of the process of the present invention are conventionally prepared, for example, by soaking a polymeric insert or soft lens in a 1% to 5% solution of sotalol hydrochloride until equilibrium is established, which is generally within a period of 1 to 5 minutes.

Ocular Insert Sotalol hydrochloride r 1 mg.

Hydroxypropyl cellulose, q.s. 12 mg.

Ophthalmic inserts are also manufactured from compression molded films which are,prepared by subjecting the above powdered mixture to a compressional force of 12,000 Ibs. (gauge) at 300"F. for a period of 1-4 minutes on a suitable press. The film is cooled under pressure by having cold water circulate in the platen. Ophthalmic inserts are individually cut from the film with a rod-shaped punch. Each insert is placed into a vial, which is then placed in a 88% humidity cabinet and held at 30on. for 2-4 days. After removal from the humidity cabinet, the vials are stoppered and then capped. The vials containing the hydrated insert are then autoclaved at 200-250"F. for one-half hour.

Ophthalmic inserts in the form of solvent cast film can be prepared by making a viscous solution of sotalol hydrochloride and hydroxypropyl methylcellulose in the above proportions using methanol as a solvent. T,he solution is placed on a Teflon plate and allowed to dry at ambient conditions. After drying, the film is placed in an 88% humidity cabinet until it is pliable. Appropriately-sized inserts are cut from the film.

Claims (10)

1. A process for treating glaucoma by lowering intraocular pressure which comprises topical application to the glaucomatous eye of an effective ophthalmologically acceptable amount of 4' -[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide or ophthalmologically acceptable salts thereof.

2. The process of Claim 1 wherein 4'-(1-hydroxy-2-(isopropylamino)ethyl)methanesulfonani- lide hydrochloride is administered.

3. The process of Claim 1 wherein 4'-[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonani- lide hydrochloride is administered in a water soluble polymeric insert.

4. The process of Claim 1 wherein 4'-[1 -hydroxy-2-(isopropylamino)ethyl]methanesulfonani- lide hydrochloride is applied topically with an ophthalmic carrier in the form of a solid, a buffered isotonic liquid or a vegetable oil.

5. The process of any one of Claims 1, 2 and 4 wherein 4'(1-hydroxy-2-(isopropylamino)e- thyl)methanesulfonanilide hydrochloride is applied topically as a 4,2% by weight aqueous solution.

6. An ophthalmic composition for topical treatment of glaucoma comprising in solution an intraocular pressure lowering effective amount of 4'-[1 -hydroxy-2-(isoprnpylaminoethyl]methan- esulfonanilide hydrnchldride with an ophthalmic carrier in the form of a solid, a vegetable oil, or a buffered isotonic liquid.

7. A composition according to Claim 6 wherein the buffered isotonic liquid contains 4.2% by weight of 4'-[1 -hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride.

8. An opthalmic composition substantially as hereinbefore described in any one of the examples.

9. A water-soluble opthalmic insert comprising 4'-( 1Thydrnxy-2-(isoprnpylamino)ethyl)meth- anesulfonanilide hydrochloride.

10. 4'-(1 -hydroxy-2-(isopropylamino)ethyl) methanesulfonanilide or an opthalmologically acceptable salt thereof for use in lowering intraocular pressure.