IE57028B1 - Composition for reducing intraocular pressure - Google Patents

Description

Compos it ion for reducing intraocular pressure Teehnicn I. FieldThis invention is directed to a composition for reducing Lnl. raocular pressure and reducing aqueous humor formal-ion by applying an effective amount of the composition topically to the cornea; the composition is an aqueous solution of a carbonic anhydrase inhibitor. background of the Invention GLaucorna is well known as a condition in which the Internal pressure in the eye increases to Lhe extent LhaL i.t causes damage to Lhe optic nerve and may eventual Ly cause blindness. This condition is primarily caused by Lhe failure ofajueous humor to properly drain from Lin» eye., resulting in a high internal, or intraocular pressure. IL has been recognized that the fonnaLj.on of aqueous humor is 1.5 i.n parL the result of Lhe activity of the enzyme carbonic anhydrase which is employed by the human body to reversibly catalyze the hydration of carbon dioxide. Compounds, principally heterocyclic sulfonamides, are known which inhibit the activity of carbonic anhydrase and thus control the production of aqueous humor and the intraocular pressure resulting therefrom. /Havener, Ocular Pharmacology, 4th Ed. (1978, C„V. Moseby); Maren, Investigative Ophthalmology, Vole 13 . pp. 479-484 (1974); Becker, Am. J. of Ophthalmology, Vol„ 32» P> 177 (1^5)7.

IL i.s necessary to «ί*Iminister Lhese materia Is e parenLeraLLy in order to achieve intraocular pressure reduction. Parenteral administration requires relatively λ. Large dosages and. very oEten results in the patient experiencing fatigue, depression, anorexia, numbness and tingling sensations.

It has now been discovered that certain carbonic anhydrase inhibitors can be administered topically, i.e., applied directLy to the cornea, and that these compounds 1.0 will penetrate the cornea and be immediately effective in inhibiting the activity of carbonic anhydrase and decreasing intraocular pressure and aqueous humor flow resulting from this activity.

The topical or Local applicability of intraocuLar pressure depressants offers several major advantages over drugs requiring parenteral administration. Topical applicability avoids the unpleasant side effects de.seribed above which result from systemic applications of carbonic anhydrase inhibitors. In addition, topical application enables a more rapid, localized concentration of the drug at the situs requiring the drug’s action.

Irish Patent Specification No. 52065 describes a composition for treating glaucoma which comprises an aqueous solution of a sulfonamide carbonic anhydrase inhibitor. However, according to that specification, the sulfonamide must have certain properties in order to be * effective against glaucoma. Amongst these properties, the sulfonamide must ”be sufficiently water soluble to J form a 1 to 57O, by weight, solution or it must have a pK.i of not, greater than 7.0’\ In that specification, example·’ are cited of known carbonic anhydrase inhibitors which do not work and this is ascribed, amongst other reasons, to the inhibitors having a pKa of greater Lhan j 7.0. We have now discovered that sulfonamide inhibitors having a pKa of greater than 7.0 and/or a solubility of t. less Lhan 1% are highly effective in treating glaucoma,, According to the present invention, there is provided a composition for topical application JO to the eye in unit dosage form comprising an aqueous solution of an amount of carbonic anhydrase inhibitor sufficient Lo reduce aqueous humor formation and to reduce intraocular pressure, said carbonic anhydrase inhibitor comprising a pharmaceutically acceptable snltonamide hav15 ing the following properties: a. either a pKa of greater than 7u0 but not greater than 7.3 or sufficiently soluble in water to form at least a 3mM (which for most of the sulfonamides under consideration amounts to approximately 0.1%, by weight) solution at pH 8.2 but not sufficiently soluble to form a solution of I7o by weight, l>. ether partition coefficient of at least 1.0 preferably at pH 7.2; c. chloroform partition coefficient of at least 0.01 preferably at pH 7.2; d. dissociation constant against carbonic anhydrase of not more than 3x10 molar; e. first order rate constant for penetration of said sulfonamide through a living rabbit cornea of at I east. ().0()5 hr1; . f. not injurious to the cornea; and g. stable in solution and in contact with the cornea, but subject to the constraint that the molecular weight of the sulphonamidc must not be greater than 3,333.

The sulfonamide is preferably a heterocyclic sulfonamide, e.g. a thiadiazole sulfonamide.

The applicants have found that, over and above the carbonic anhydrase inhibitors described in Irish Patent Specification 52065, other sulfonamides can be safely and advantageously applied directly to the cornea in the form of drops of aqueous solution. These further sulfonamides must have certain properties in order to effectively function in this fashion. First, the sulfonamide in its acid form must either have a pKa which is greater than 7.0 but not greater than 7.3, or the sulfonamide in the acid form must be sufficiently soluble in water to produce at least a 3mM (which for most sulfonamides under consideration amounts to approximately 0.1% by weight) solution at pH 8.2 but not sufficiently soluble to form a solution of 1% by weight.

This property is important in that it permits the compound to be used in an at least 3mM aqueous solution at a pH below 8.2 and therefore can be applied to the eye at a relatively neutral pH. The pKa may be measured by titrating the compound with NaOH and finding the point at which half of the compound is neutralized. The pH at this point is the pKa .

Another necessary property of these compounds is that they must possess an ether partition coefficient of at least 1.0. This property in conjunction with the chloroform coefficient is a measure of the lipid solubility of this compound. This is a critical feature since the compound must be readily absorbed by the lipid materials in the eye and be available for intimate contact with carbonic anhydrase so as to control its activity.

Ibis property is measured by preparing an aqueous solution of the compound at pH 7.2 and shaking the solution with an ί> equal volume of ether until equilibrium is achieved in the system. An ether layer and an aqueous layer are formed, separated, and each analyzed for its content of the compound. The coefficient is the ratio of the amount of the compound in the ether layer to the amount of the compound in the aqueous layer. See, e.g., Maren, .J.

Pharm. lixpt. Therap. Vol. 150, p. 26, ( 1960) for the method of analysis for the compound in each layer.

IS Another critical property necessary in the inhibitors employed in this invention is the chloroform partition coefficient which must be at least 0.01. This property also relates to the lipid solubility of the compound employed and it is measured as described above with respect to ether. The procedure is the same as that described above except that chloroform is employed in place of e the r.

Another necessary property in the inhibitors employed in this invention is that they must have a 25 dissociation constant against carbonic anhydrase of not more than 3x10 molar. This property denotes that the compound has a high activity against carbonic anhydrase in the ciliary process of the eye which is, at least in part, responsible for the secretion of aqueous humor. The 30 dissociation constant is the concentration of the compound that will inhibit one-half of the carbonic anhydrase in a test system wherein the conditions arc so arranged that the compound is present in excess of the carbonic anydrase. The test system is described in Maren, sujira , and in a subsequent article by Maren in the same volume at page 389. fa Still another critical property of the inhibitor compounds employed in this invention is that the compound must have a first order rate constant for penetration of the compound through a living rabbit cornea of at least 0.005 hr This property is important in that it sets a standard for a speed in which the inhibitor will pass through the cornea to the interior of the eye and be available to inhibit the activity of carbonic anhydrase in that location. This is measured by placing a solution of the compound (about 0.5 ml) on the cornea of the living, lightly anesthetized rabbit. The lids are held by light hemostats in such a way as to create a well to hold the solution so that a steady state concentration is achieved. At timed intervals, samples are withdrawn from the anterior chamber of the rabbit and the fluid analyzed for the concentration of drug. The analyses arc done by the method of Maren, supra. The data are treated to yield the first order rate constants which arc cited herein.

Still another critical property of the compounds employed in this invention is that they be pharmaceutically acceptable and not be injurious to the cornea being treated.

The final property which is necessary for a 2S compound used in this invention is that it be stable against decomposition in solution and in contact with the cornea. This property may be tested by dissolving the compound in aqueous solution and in solution containing corneal tissue to determine whether the compound has remained stable or has decomposed into other materials.

None of the carbonic anhydrase inhibitors previously employed by parenteral administration is uselul in the present invention because they do not meet all of the criteria mentioned above and therefore cannot be used topically. Perhaps the best known inhibitor in the prior art is acctazο 1 amtdc (2-,nctyldinino-l,3,4thiadiazole-5-sulfonamide) which cannot be made into a water solution below pH 8 at concentrations sufficiently high to enable its use effectively as a topically applied agent. Moreover, the pKa of acetazolamidc is 7.4; the ether partition coefficient is 0.14 and the chloroform coefficient is 0.001. This material has been tried and found to be completely unsuitable in lowering intraocular pressure by topical administration. [Foss, Am. J.

Ophthalmology, Vol. 39, p. 336 (1955)). Mcthazolainide ( 2 - ace t y 1 imino-3-methyl -Δ^ -1 , 3,4-thiadiazol i ne - 5 - su 1 fori a mide) is another known carbonic anhydrase inhibitor but it is unsuitable in the process of this invention. This compound has a pKa of 7.4 and cannot be made into a neutral solution with a sufficiently high concentration to enable topical application. In a series of tests employing met hazo 1 ainidc topically the intraocular pressure was not reduced except to a very slight extent in one of the series of tests. Still another prior art inhibitor is etboxzo1 amidc (6·ethoxy-benzothiazo1e-2·su1fon.unide) having properties somewhat similar to those of methazo1 amide.

This material has a pKa of 8,1 and cannot be made into an aqueous solution at a concentration above about 0.004’».

This drug is ineffective in topically treating the eye to reduce intraocular pressure.

One compound satisfying the above criteria is 2-oLhochlorophenylthiadiazole-5«sulfonamiden The compound has a pKa of 7rt3, an ether partition coefficient of 25, a chloroform partition coefficient of 10, a dissocation constant -9 of 1x1.0 M, an in vivo rabbit cornea penetration rate constant / - 8 of 0.3 hr , is stable in solution and is not injurious to the cornea.

The above-described compound, i.e. 2-orthochlorophenylthiadiazole-5-sulfonamjde as well as other compounds meeting the above-listed criteria^is useful and operable in lowering intraocular pressure and in reducing the formation of aqueous humor by topical treatment of the eye in accordance with the invention.

Sulfonamides which are sufficiently water soluble to form a solution having a concentration of between 3mM and 1% at a pH of 8.2 may be dissolved in the acid form. Those sulfonamides that are not sufficiently soluble to form a solution having a concentration of between 3mM and 1% at a pH of 8.2 but have a pKa of between 7.0 and 7.3 may be utilized in the form of their pharmaceutically acceptable water soluble salts, e.g. sodium, potassium, triethanolamine. The sulfonamide solutions are applied topically to the eye by exposing the entire cornea to the solution for a time sufficient for penetration into the eye of an amount of carbonic anhydrase inhibitor sufficient to effect a reduction in aqueous humor formation and intraocular pressure The composition of the invention is effective to reduce intraocular pressure at least 4 mm Hg and to reduce aqueous humor formation 30-80%. Generally, when employing solutions containing 3niM to 1% by weight of sulfonamide, exposure to the cornea for from 2 to 30 minutes is adequate to enable an effective penetration of sulfonamide. The exact time of exposure will vary depending on the nature of the sulfonamide.

Claims (2)

1. CLAIMS J. A composition for topical application to the eye in unit dosage form comprising an aqueous solution of an amount of carbonic anhydrase inhibitor sufficient to 5 reduce aqueous humor formation and to reduce intraocular pressure, said carbonic anhydrase inhibitor comprising a pharmaceutically acceptable sulfonamide having the following properties: a. either a pKa of greater than 7.0 but not 10 greater than 7.3 or sufficiently soluble .in water to form at least a 3mM solution at pH of 8.2 but not sufficiently soluble to form a 1%, by weight, solution; b. ether partition coefficient of at least 1.0; c. chloroform partition coefficient of at least 15 0.01; d. dissociation constant against carbonic anhydrase — 8 of not more than 3x10 molar; c. first order rate constant for penetration of said sulfonamide through a living rabbit, cornea of at 20 I east 0.005 hr ; f. non-injuriousness to the cornea; and g. stability in solution and in contact with the cornea, subject to the constraint that the molecular weight of the 25 sulfonamide must not be greater than 3,333.
2. 2. The composition of claim 1, wherein said sulfonamide is a heterocyclic sulfonamide. 3. , The composition of claim 2, wherein said sulfonamide is a thiadiazole sulfonamide. 4. The composition of claim 2, wherein said sulfonamide is 2-orthochlorophenyl-1,3,4-thiadiazole-5-sulfonamide. 55. Λ composition according to claim 1, substantially as herein described.