Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-11-22
1992-01-07
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514392, 514400, 514424, 514653, 514913, A61K 3152, A61K 31415, A61K 3140, A61K 31135
Patent
active
050792539
DESCRIPTION:
BRIEF SUMMARY
The invention provides a composition for topical treatment of glaucoma or ocular hypertension comprising an effective intraocular pressure reducing amount of a mixture of an adrenergic agonist and a phosphodiesterase inhibitor in an opthalmically compatible carrier. Especially ophthalmic compositions comprising a mixture of epinephrine or dipivaloyepinephrine and isobutylmethylxanthine (IBMX) are at present preferred for use in treating glaucoma or ocular hypertension.
Glaucoma is an eye disorder characterized by increased intraocular pressure, cupping of the optic disc, and visual field loss. Although the pathophysiological mechanism of open angle glaucoma is still unknown there is substantial evidence to suggest that increased intraocular pressure is detrimental to the eye, and that the increased intraocular pressure in glaucoma is the most important factor causing degenerative changes in the retina. In one particular form of glaucoma, low tension glaucoma, the actual situation may simply be that the eye is unusually sensitive to pressure and therefore damage may occur at intraocular pressure levels otherwise regarded as physiologically normal. On the other hand, some individuals may exhibit an abnormally high intraocular pressure substantially without any manifest defects in the visual field or optic disc. Such individuals are referred to as ocular hypertensives. If untreated, glaucoma almost invariably leads to blindness. The course of the disease typically is slow with progressive loss of vision. The basical principle of glaucoma treatment is to lower the intraocular pressure, either by drugs, laser treatment or surgery. The modality of treatment with drugs comprises typically instillation of pilocarpine, epinephrine, or topical beta-blocker treatment, e.g. with timolol, as well as systemically administered inhibitors of carbonic anhydrase, e.g. acetazolamide. Cholinesterase inhibitors such as physostigmine and echothiopate may also be employed and have an effect similar to that of pilocarpine.
Although with many of these drugs the positive effects obtained are at least appreciable, concomitant adverse side-effects are often encountered which tend to diminish the usefulness of the drugs and may negatively affect patient compliance. Improvements in these respects are desirable, as well as improvements in drug efficacy.
The intraocular pressure (IOP) can be defined as according to formula (1): being around 9 mmHg, F the flow of aqueous humor and R the resistance to outflow of aqueous humor through the trabecular meshwork and adjacent tissue into Schlemm's canal. Drugs that decrease either F or R thus also decrease intraocular pressure. Aqueous humor is produced continuously in the ciliary processes behind the iris, but it is not known whether there is a neural or hormonal regulation of this process.
Adrenergic agonists can be divided into two main groups: alpha adrenergic and beta adrenergic agonists. Each of these groups can further be subdivided into alpha 1 and 2 and beta 1 and 2 respectively. Generally, the alpha receptors of the vascular smooth muscle in the eye are of the alpha 1 or 2 type whereas the presynaptic receptors on the adrenergic nerves are of the alpha 2 type. The receptors of the ciliary epithelium are predominantly of the beta 2 type. The beta-adrenergic receptors in the outflow channels of the aqueous humor are probably also of the beta 2 type predominantly. The presence of alpha receptors in the outflow channels seems to be species dependent.
Norepinephrine is predominantly an alpha-adrenergic agonist, but it does have some beta-adrenergic activity in addition. Epinephrine is predominantly a beta-adrenergic agonist with some alpha-adrenergic activity. Dipivaloyl-epinephrine is an esterified prodrug of epinephrine with the same spectrum of activity as epinephrine. 3-isobutyl-1-methylxanthine (IBMX) is an inhibitor of intracellular phosphodiesterase.
Pharmaceutical preparations containing a combination of adrenergic agonists and phosphodiesterase inhibitors are known per se (see Swis
REFERENCES:
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Geutsche Ophtalmologische Gesellschaft in Heidelberg. Bericht Uber die Zudsmmrnkunft, vol. 71, issued 1972 (Munchen) E. Genee, "Wirkung vasoaktiver Pharmaca auf das Glaucomauge", pp. 354-357.
Albrecht von Graefes Archiv fur klinische und experimentelle Ophtalmoloigie vol. 195, issued 1975 (Berlin), E. Genee and T. Geissendorfer, "Blutdruckandernde Medikamente und Augeninnendruck im Tierversuch" pp. 187-194.
Chem. Abst. 83: 157866y(1975), Genee et al.
Hoyng Philip
Stjernschantz Johan W.
Fay Zohren A.
Pharmacia AB
Philpitt Fred
Waddell Frederick E.
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