Brinzolamide and brimonidine for treating glaucoma

Details Brinzolamide and brimonidine for treating glaucoma Brinzolamide and brimonidine for treating glaucoma

2001-04-11

2001-11-13

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S363000, C514S913000

Reexamination Certificate

active

06316441

ABSTRACT:

This invention relates to the treatment of ocular diseases and conditions which find their etiology in compromised blood flow with novel formulations of brinzolamide combined with brimonidine tartrate and the use of brinzolamide and brimonidine tartrate administered separately.
BACKGROUND OF THE INVENTION
Brinzolamide R-(+)-4ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H thieno[3,2,e]1,2 thiazene-6 sulfonamide-1,1 dioxide) is a carbonic anhydrase inhibitor disclosed in U.S. Pat. No. 5,378,703 and sold in a topical ophthalmic formulation (Azopt™) for lowering elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT) (Alcon Laboratories, Inc., Fort Worth, Tex.).
Brimonidine tartrate ((5-bromo-6-2-imidzolidisnylideneamino) quinozoline L-tartrate) hereinafter “brimonidine” is a relatively selective alpha-2-adrenergic agonist sold in a topical ophthalmic formulation (Alphagan™) for lowering elevated IOP in patients with open angle-glaucoma or ocular hyp e r tension (Allergan, Inc., Irvine, Calif.).
U.S. Pat. No. 3,890,319 discloses a class of compounds, including brimonidine, and their usefulness as antihypertensive agents. Certain co mpounds in the group have also been disclosed for treating physical pain, anaesthetizing~ the central nervous system, to constrict blood vessels, treat ischemia, decongest nasal passages, effect reduction of one or more effects of an inflammatory disorder to increase retinal blood flow, and effect an altration in the rate of fluid transport in the gastrointestinal tract, see U.S. Pat. No. 5,756,503 (Column 1, lines 16-22). WO 97/01339 discloses the use of brimonidine to protect the optic nerve and the retina from “noxious provocations,” see page 1, first paragraph.
Oral and i.v. administration of the CAIs, acetazolamide and methazolamide, are known to increase both ocular and cerebral blood flow. The dosages used to achieve meaningful results are relatively high and is due to a number of factors. These compounds have relatively low affinity for carbonic anhydrase in as measured by their Ki (disassociation constant) values and are only modest inhibitors of the enzyme as measured by their IC
50
values. They have low distribution coefficients (octanol/water determined at pH 7.4) which is a measure of their lipophilicity. This low lipophilicity limits their ability to cross the blood retinal barrier. Finally, these compounds have relatively short half-lives in whole blood. This relatively rapid elimination rate limits their ability to redistribute into the back of the eye and maintain adequate drug concentrations.
The preclinical and clinical data for the effect of topically dosed CAIs, in particular dorzolamide, on ocular blood flow are conflicting. Gruenwald, et al., Acta Ophthalmologica, 75:236-238 (1997) disclosed that the use of dorzolamide has no effect on retinal vein blood flow in normal volunteers. Pillunat, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) showed that topical dorzolamide did not alter optic nerve head blood flow in healthy subjects. Shipman, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) found that dorzolamide did not alter the choroidal pressure flow relationships. Koller, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No.4 (Mar. 15, 1997) showed that topical dorzolamide did not change peripapillary blood flow. A study by Harris, et al., Acta Ophthalmologica, 74:4896 (1996) said dorzolamide accelerated blood velocity in the retina and superficial optic nerve head; and another study by Sugrue, et al. J. Ocular Pharm., 12 (3) 363-376 (1996) teaches that topical dorzolamide does not decrease blood flow to the iris, ciliary processes, optic nerve, or retina in rabbits. Sponsel has presented a few studies which suggest that topical dorzolamide has a positive effect on ocular blood flow. See ARVO abstracts, Investigative Ophthalmology & Visual Sciences, Vol. 37, No. 3 (Feb. 15, 1996) and Vol. 38, No. 4 (Mar. 15, 1997). Healthy subjects treated with dorzolamide exhibited accelerated artereovenous passage time and an increase in optic nerve head velocity is described in WO 96/37203. The publication further discloses the use of topical carbonic anhydrase inhibitors (CAIs) to increase retinal and optic nerve head blood velocity. Brinzolamide is not disclosed in any of these references.
SUMMARY OF THE INVENTION
This invention is directed to the use of brinzolamide in combination with brimonidine to treat ocular diseases which have their etiology in compromised blood flow. These diseases include, but are not limited to glaucoma, occlusion conditions, diabetic retinopathy, and ocular neovascularization. These agents can be used either alone, in separate compositions dosed within 5 to 10 min of each other, or together in a single formulation.
DESCRIPTION OF PREFERRED EMBODIMENTS
Brimonidine is a potent and relatively selective &agr;
2
agonist which has been shown to effectively lower IOP in rabbits, monkeys and man. Upon topical ocular administration brimonidine causes vasoconstriction in scleral vessels. However, brimonidine does not appear to be a vasoconstrictor in vessels in the back of the eye. While brimonidine is a relatively safe compound it has been shown to cause the side effects of sedation and ocular hyperemia in an allergic like reaction in some patients. These side effects are thought to be due to the relatively high concentration of the drug administered topically. The sedation like side effects are believed to be caused by the drug crossing the blood brain barrier and triggering the sedative effects. The mechanism by which brimonidine causes hyperemia is not well understood. It is likely that the frequent instillation of relatively high drug concentrations causes this side effect. Thus, lowering the overall dose of brimonidine while maintaining IOP control would be advantageous.
Combinations of brimonidine and brinzolamide represent a novel approach to producing potent and long lasting IOP lowering medications with fewer side-effects than observed when these are administered alone.
When two separate formulations of brinzolamide and brimonidine are used, the preferred administration sequence is brimonidine first and brinzolamide second. In this case, brimonidine serves to constrict ocular vessels and thereby reducing the flux of blood through the anterior portion of the eye. When brinzolamide is administered the reduced circulation in the eye should result in an increase in the bioavailability of the CAI. Overall this sequence is expected to result in an increase in efficacy and duration of actions thereby reducing the frequency of administration (i.e., from tid to bid). This would also result in improved patient compliance.
When a single formulation of both agents is used the above advantages are believed to apply. In addition, the novel compositions contemplated have relatively high viscosity and are expected to increase the retention of brimonidine in the cul-de-sac of the eye. The net impact allows for lowering the dose of brimonidine.
It is well established that blood flow is impaired in glaucoma; many researchers think there is a direct relationship between insufficient blood flow and neural damage. Thus, improving blood flow should decrease the rate of damage. Clearly, any vascular occlusive event in the eye leads to damage to the region with restricted blood flow; improving blood flow in this region or in close-by tissue should minimize the severity of this damage. The standard treatment for advanced diabetic retinopathy is retinal photocoagulation; this is thought to be effective by decreasing oxygen demand and thus decreasing the hypoxic signal released by the oxygen-starved tissue that leads to angiogenesis. Treatment that improves oxygen supply by improving ocular blood flow as proposed here would be preferable to this tissue destruction and should lead to the same benefit. Neovascularization of the retinal, choroidal,

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