EP0521009A1

EP0521009A1 - 5-trans-prostaglandin-2-alpha as an ocular hypotensive agent

Info

Publication number: EP0521009A1
Application number: EP91905501A
Authority: EP
Inventors: David Frederick Woodward
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 1990-03-19
Filing date: 1991-02-12
Publication date: 1993-01-07
Also published as: FI924205A; JPH05505605A; CA2076023A1; WO1991014428A1; HU9202572D0; EP0521009A4; IE910865A1; HUT61666A; FI924205A0

Abstract

Cette invention concerne un moyen de réduire ou de maintenir la pression intraoculaire, et, plus particulièremenet, une méthode et une composition pour réduire ou maintenir la pression intraoculaire consistant à administrer une composition contenant du 5-trans prostaglandine F2alpha dans un support pharmaceutiquement acceptable.This invention relates to a means of reducing or maintaining intraocular pressure, and, more particularly, a method and a composition for reducing or maintaining intraocular pressure comprising administering a composition containing 5-trans prostaglandin F2alpha in a pharmaceutically acceptable carrier.

Description

ϋSE OF 5-TRANS PROSTAGLANDIN F^ AS AN OCULAR HYPOTENSIVE AGENT Field of the Invention

The present invention relates to a means of reducing or maintaining intraocular pressure, and, more particularly, to a method .and composition for reducing or maintaining intraocula pressure involving the administration of a compositio containing 5-trans prostaglandin F_2β in a pharmaceuticall acceptable carrier.

Background of the Invention The compositions and method of the present invention ar particularly useful for the management of glaucoma, a diseas of the eye characterized by increased intraocular pressure.

On the basis of its etiology, glaucoma has been classifie as primary or secondary. For example, primary glaucoma ,i adults (congenital glaucoma) may be either open-bangle or acut or chronic angle-closure. Secondary glaucoma results from pre existing ocular diseases such as uveitis, intraocular tumor o an enlarged cataract.

The underlying causes of primary glaucoma are not ye known. The increased intraocular tension is due to th obstruction of aqueous humor outflow. In chronic open-angl glaucoma, the anterior chamber . and its anatomic structure appear normal, but drainage of the aqueous humor is impeded In acute or chronic angle-closure glaucoma, the anterio chamber is shallow, the filtration angle is narrowed, and th iris may obstruct the trabecular meshwork at the entrance o the canal of Schlemm. Dilation of the pupil may push the roo of iris forward against the angle, and may produce pupillar block and thus precipitate an acute attack. Eyes with narro anterior chamber angles are predisposed to acute angle-closu glaucoma attacks of various degrees of severity. Secondary glaucoma is caused by any interference with t flow of aqueous humor from the posterior chamber into t anterior chamber and subsequently, into the canal of Schlem Inflammatory disease of the anterior segment may preve aqueous escape by causing complete posterior synechia in ir bombe, and may plug the drainage channel with exudates. Oth common causes are intraocular tumors, enlarged cataract central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical β-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possess ocular hypotensive activity, and have been recommended for use in glaucoma management. Eicosanoids and derivative include numerous biologically important compounds such as Prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid which has the following structural formula:

Various types of Prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of Prostaglandin [e.g.,.Prostaglandin E-, (PGE-,) , Prostaglandin E₂ (PGE₂) ] , and on the configuration of the substituents on the alicyclic ring indicated by α or 5 [e.g. Prostaglandin F_2α (PGF_2α) ].

Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last decade shows that some prostaglandins are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection With Prostaσlandins Cohen, M. M. , ed., Boca Raton, Fla, CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds.. New York, Grune & Stratton, 1984, pp. 477-505). Such Prostaglandins include PGF_2β, PGF_1(r, PGE₂, and certain lipid-soluble esters/ such as C, to C₂ alkyl esters, e.g. 1-isopropyl ester, of such compounds. Although the precise mechanism is not yet known, recent experimental results indicate that the Prostaglandin-induced reduction in intraocular pressure results from increased oveoscleral outflow [Nilsson et al., Invest, ophthalmol. Vis. Sci. 28(suppl) . 284 (1987)]. The isopropyl ester of PGF_2β has been shown to have significantly greater hypotensive potency than the parent compound, presumably as a result of its more effective transfer through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105. 1036 (1987), and Siebold et al., Prodrug JL, 3 (1989)].

Whereas Prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistentl associated with the topical ocular use of such compounds, i particular PGF_2a and its prodrugs, e.g. its 1-isopropyl ester, in humans. The clinical potentials of Prostaglandins in th management of conditions associated with increased ocula pressure, e.g. glaucoma are greatly limited by these sid effects.

In a series of co-pending United States patent application assigned to Allergan, Inc. Prostaglandin esters with increase ocular hypotensive activity accompanied with no o substantially reduced side-effects are disclosed. The co pending USSN 386,835 (filed 27 July 1989), relates to certai 11-acyl-Prostaglandins, such as 11-pivaloyl, 11-acetyl, 11 isobutyryl, 11-valeryl, and 11-isovaleryl PGF^. Intraocula pressure reducing 15-acyl Prostaglandins are disclosed in th co-pending application USSN 357,394 (filed 25 May 1989) Similarly, 11,15- 9,15- and 9,11-diesters of Prostaglandins for example 11,15-dipivaloyl PGF_2β are known to have ocula hypotensive activity. See the co-pending patent application USSN Nos. 385,645, 386,312 and 386,834 (all filed 27 Jul 1989) . The disclosures of all of these patent applications ar hereby expressly incorporated by reference. Summary of the Invention The present invention relates to the use of 5-trans Prostaglandin F_2β, formulated in a pharmaceutically acceptable vehicle, for the treatment of glaucoma and ocular hypertension. Quite surprisingly, 5-trans Prostaglandin F_2β, where the 5-6 double bond is in the trans rather than the natural cis configuration, has pronounced ocular hypotensive activity with significantly reduced adverse side effects, notably ocular surface hyperemia. 5-trans Prostaglandin F_2β is, therefore, excellent candidate for therapeutic treatment of a variety of ocular hypertensive conditions such as open-angle glaucoma, closed-angle glaucoma, ocular hypertensive episodes, post- surgical and post-laser trabeculectomy, and as a presurgical adjuvant. In accordance with another aspect of the present invention, there is provided a topically applicable pharmaceutical composition for treating ocular hypertension which comprises 5- trans Prostaglandin F_2α of the formula (I) :

or a salt thereof present in a pharmaceutically acceptable excipient, in a therapeutically effective amount. The therapeutically effective amount usually is within the range of approximately 0.0001% to 5%. Optionally, the composition of the present invention may further comprise co-solvents, pH buffers, viscosity enhancers, antibiotics or other advantageous adjuvants.

In accordance with a further aspect of the present invention, there is provided a method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension a therapeutically effective amount of 5- trans Prostaglandin PGF_2α; or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention relates to an ophthalmic solution comprising a therapeutically effective amount of PGF_2α, or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable liquid vehicle, packaged in a container suitable for metered application.

In a still further aspect, the present invention relates,to a pharmaceutical product, comprising a container adapted to dispense its contents in metered form; and an ophthalmic solution therein, as hereinabove defined. Further features and advantages of the present invention will become apparent from the detailed description of preferred embodiments which follows, taken together with the examples and claims appended hereto.

Detailed Description of the Invention The present invention relates to the use of PGF_2β an pharmaceutically acceptable salts thereof as ocula hypotensives. PGF_2a has the following structural formula (I)

In the foregoing formula thickened solid line attachmen indicates the beta configuration. The broken line attachment of th hydroxyl groups indicate that these substituents are i alpha con iguration.

As hereinabove mentioned, it has been established that PGF lowers intraocular pressure in man and other mammals whe applied topically to the eye. However, topical application o Prostaglandin F_2β produces side effects such as conjunctiva hyperemia, smarting, and foreign body sensations which range i degree from undesirable to unacceptable, depending upon t particular patient and the dosage necessary to produce sufficient pressure regulating effect. In additio Prostaglandin F_2α may produce transient ocular hypertension. to 6 carbons, either the mono- or diacids. Quaternary ammonium compounds can be prepared from alkylating agents such as methyl iodide and the like.

Pharmaceutical compositions may be prepared by combining a therapeutically efficient amount of 5-trans PGF_2β or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional ophthalmically acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v) , preferably about 0.001 to about 0.1% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives and stabilizers.

Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol , thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water-_*

Tonicity adjusters may be added as needed or convenient. They- include, but are not limited to, salts, pazrticularl sodium chloride, potassium chloride, mannitol and glycerin, o any other suitable opthalmically acceptable tonicity adjuster.

Various buffers and means for adjusting pH may be used s long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may b used to adjust the pH of these formulations as needed.

In a similar vein, an ophthalmically acceptable antioxidan for use in the present invention includes, but is not limite In accordance with the present invention, there has been provided an ocular hypotensive which comprises 5-trans Prostaglandin F_2β. - 5-trans Prostaglandin F_2β, where the 5-6 double bond is in the trans configuration, has substantially the same ocular hypotensive activity as natural Prostaglandin F_2α with significantly reduced adverse side effects, notably ocular surface hyperemia. Moreover, on a dose-effect basis, 5-trans Prostaglandin F_2a is less potent in causing ocular hypertension, an undesirable side-effect in glaucoma therapy. The PGF_2tf compound illustrated in Formula (I) is in the free acid form. However, as will be appreciated by one of skill in the art, any of a variety of the corresponding salts may also be utilized in the ophthalmic formulations of the present invention. Thus, if the carboxylic acid group at C-l of the Formula (I) compound is designated:

A may be -OH to produce the free acid, or -OR where R may be either the anion component of any of a variety of pharmaceutically acceptable salts. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to which it is administered and in the context in which it is administered. Suitable pharmaceutically acceptable salts may be derived from either an organic or inorganic base. Such a salt may comprise a mono- or polyvalent ion. Of particular interest are inorganic cations such as sodium, potassium, calcium, magnesium and zinc. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where acid addition salts are formed from amines, any inorganic or organic acid may be used. Preferred salts are hydrogen chloride salts, sulfate salts, phosphate salts and salts of simple organic acids of 2 to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it. The ingredients are usually used in the following amounts: Ingredient Afflpymt f% w/y) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed purified water as needed to make 100%

The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate the application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non- toxic plastic material, and generally contain between about 0.5 and about 15 μl solution.

The invention can be more fully appreciated by the following example. ESΔHE E:

Experimental quantities of 5-trans Prostaglandin F_2β and Prostaglandin F^ were prepared by dissolution in 2% (w/v) Na₂Cθ₃ with the pH adjusted to 7.0 by 0.1N HC1. Experimental rabbits were treated by giving one drop to the ocular surface of either a 0.01%, 0.1% or 1% solution so that three treatmen groups, each comprising 6-8 animals, were obtained for both 5 trans Prostaglandin F_2α and Prostaglandin F^. Intraocula pressure was measured by applanation pneumatonometry at th time of administration and at 0.5, 1, 2, 3, 4, and 6 hour thereafter. Ocular surface hyperemia was visually assessed an described as either absent or present in some degree. Th following data were obtained.

Comparison of the data obtained with 5-tran Prostaglandin F_2β and Prostaglandin F_2β indicates that they ar essentially equipotent as an ocular hypotensive agents However, Prostaglandin F_2β induced ocular hypotension i achieved with a very high incidence of ocular surfac hyperemia, whereas for the low (0.01%) and intermediate (0.1% doses of 5-trans Prostaglandin F_2β similar ocular hypotensio is achieved with minimal or, in the case of the 0.1% dose, n ocular surface hyperemia. Moreover, on a dose-effect basis, 5 trans Prostaglandin F_2β is less potent in causing ocula hypertension, an effect which is considered undesirable i glaucoma therapy. Although this invention is described herein in term of certain preferred embodiments, these embodiments ar intended to illustrate the invention and not to impose limits

Other embodiments that are apparent to those of skill in th art are also within the scope of this invention. Accordingl the scope of this invention is intended to be defined only reference to the appended claims.

Claims

WHAT IS CLAIMED IS:

1. Pharmaceutical composition for reducing or maintaining intraocular pressure, comprising a therapeutically effective amount of 5-trans PGF_2α of formula (I)

5

<k

or a pharmaceutically acceptable salt thereof, in admixture with a non-toxic, ophthalmically acceptable vehicle, in unit 15 dosage form suitable for topical ocular use.

2. The composition of Claim 1 wherein said compound is 5-trans PGF_2β.

3. A method of treating ocular hypertension which comprises administering to a mammal having ocular hypertension

20 a therapeutically effective amount of 5-trans PGF_2β or a pharmaceutically acceptable salt thereof.

4. The method of Claim 3 wherein said compound is 5- trans PGF_2β.

5. An ophthalmic solution comprising 25 therapeutically effective amount of 5-trans PGF_2β or pharmaceutically acceptable salt thereof, in admixture with non-toxic, ophthalmically acceptable liquid vehicle, package in a container suitable for metered application.

6. A pharmaceutical product, comprising

30 a container adapted to dispense the contents of sai container in metered form; and an ophthalmic solution in said container comprising 5 trans FGF_2α, or a pharmaceutically acceptable salt thereof, i admixture with a non-toxic, ophthalmically acceptable liqui

35 vehicle.