Title:  Use of PARP inhibitors in the treatment of glaucoma

United States Patent:  6,444,676

Issued:  September 3, 2002

Inventors:  Pang; Iok-Hou (125 Starbridge La., Grand Prairie, TX 75052); Clark; Abbot F. (5603 Rachel Ct., Arlington, TX 76017)

Appl. No.:  723511

Filed:  November 28, 2000

The invention provides pharmaceutical compositions containing PARP inhibitors and methods of using these compositions to prevent, treat or ameliorate glaucomatous retinopathy and/or optic neuropathy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods of preventing, treating or ameliorating glaucomatous retinopathy and optic neuropathy. More specifically, the present invention is directed to compositions containing compounds that inhibit or retard the activity of PARP and methods of using these compositions to prevent or treat diseases and disorders of the retina and optic nerve resulting from glaucoma. As described above, PARP is an intracellular enzyme that uses NAD⁺ as a substrate to cause poly ADP-ribosylation of proteins important for the normal functioning of cells. Such protein modification leads to the subsequent apoptosis and cell death. While not intending to be bound by any theory, the inventors believe that, due to PARP involvement in cell death following cellular stress, PARP is involved in retinopathy and/or optic neuropathy related to glaucoma. The inventors of the present invention also believe that PARP inhibitors have therapeutic value in the prevention or treatment of glaucomatous retinopathy and optic neuropathy. As used herein, "PARP inhibitors" refer to those compounds or agents that inhibit or retard the activation of, or enzymatic activity of, PARP; and "inhibition of PARP" refers to the inhibition or retardation of the activation of PARP, or its activity. As stated above, PARP is believed to be a critical factor involved in ocular neuronal response to glaucoma.

The compositions and methods of the present invention employ one or more PARP inhibitors in an amount effective to prevent, treat or ameliorate glaucomatous retinopathy and/or optic neuropathy. PARP inhibitors are known in the art and may also be elucidated using various techniques. Examples of PARP inhibitors include benzamide, 3-aminobenzamide, 4-aminobenzamide, 3-aminophtalhydrazide and 1,5-dihydroxyisoquinoline. Preferred PARP inhibitors include benzamide, 3-aminophtalhydrazide and 1,5-dihydroxyisoquinoline.

Inhibition of PARP may be effected by a number of approaches. A preferred method of the present invention is to employ specific inhibitors of PARP. For example, specific inhibitors of PARP, such as benzamide, 3-aminobenzamide, 4-aminobenzamide, 3-aminophtalhydrazide and 1,5-dihydroxyisoquinoline, may be used to inhibit apoptosis induced by PARP activity. U.S. Pat. No. 5,756,510 (Griffin et al.) discloses benzamide analogs having PARP inhibitory efficacy and those compounds may be used in the present invention methods and compositions; the entire contents of which are incorporated herein by reference. U.S. Pat. No. Re. 36,397 (Zhang et al.) discloses PARP inhibitors useful for vascular stroke and neurodegenerative disorders and those compounds may be used in the present invention methods and compositions; the entire contents of which are incorporated herein by reference. The use of PARP-specific inhibitors would allow the activation of non-PARP-regulated pathways that are necessary for normal functioning of tissues, while inhibiting apoptosis of retina and optic nerve at risk.

The PARP inhibitors of the present invention may also be determined by various assays described in the literature. The following publications teach various methods which may be employed to elucidate PARP inhibitors:

1) U.S. Pat. No. 5,756,510 (Griffin et al.);

2) Banasik et al. Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribose) transferase., J Biol Chem, volume 267, pages 1569-1575 (1992); and

3) Schanraufstatter et al. Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide., J Clin Invest, volume 77, pages 1312-1320 (1986); the entire contents of the foregoing literature references are incorporated herein by reference.

The compositions of the present invention comprise one or more PARP inhibitors and a pharmaceutically acceptable vehicle. As used herein, the term "pharmaceutically acceptable vehicle" refers to any formulation which is acceptable, i.e., safe and provides the appropriate delivery for the desired route of administration, of an effective amount of one or more PARP inhibitors. The compositions of the present invention may be administered in a variety of different ways including systemically (e.g., oral administration, intramuscular injection, subcutaneous injection, intravenous injection, transdermal administration and transmucosal administration), topically and by intraocular injection, intraocular perfusion, periocular injection or retrobulbar (sub-tenon) injection.

The exact dosage of the PARP inhibitor(s) will vary, but will be determined by skilled clinicians in the art. Various factors affecting the dosage amount include the actual disease to be treated, the severity of condition, the health of the patient, the potency and specific efficacy of the PARP inhibitor, and so on. The amount dosed, however, will be sufficiently effective to prevent, treat or ameliorate glaucomatous retinopathy and/or optic neuropathy; such an amount is referred herein as an "effective amount." In general, the daily dosage of PARP inhibitors will range between about 0.001 and 100 milligrams per kilogram body weight per day (mg/kg/day), and preferably between about 0.01 and 5.0 mg/kg/day.

The PARP inhibitors of the present invention may be contained in various types of ophthalmic compositions, in accordance with formulation techniques known to those skilled in the art. For example, the compounds may be included in solutions, suspensions and other dosage forms adapted for topical, intravitreal or intracameral use.

Aqueous compositions are generally preferred, based on ease of formulation and physiological compatibility. However, the PARP inhibitors of the present invention may also be readily incorporated into other types of compositions, such as suspensions and viscous or semi-viscous gels or other types of solid or semi-solid compositions for topical or retrobulbar injection. The ophthalmic compositions of the present invention may also include various other ingredients, such as buffers, preservatives, co-solvents and viscosity building agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium borate) may be added to prevent pH drift under storage conditions.

Topical ophthalmic products are typically packaged in multi-dose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Some of these preservatives, however, may be unsuitable for particular applications, (e.g., benzalkonium chloride may be unsuitable for intraocular injection). Such preservatives are typically employed at a level of from 0.001 to 1.0% weight/volume ("% w/v").

While at the present time there are no effective methods to effect back of the eye treatment of chronic conditions via topical administration, it is contemplated that such methods will be developed. If topical administration of PARP inhibitors becomes feasible, the dosage generally will range between about 1-2 two drops administered to the eye 1-4 times per day of a composition comprising 0.001 and 5% weight/volume ("w/v"), and preferably between 0.1 and 1% (w/v) of one or more PARP inhibitors. Solutions, suspensions, ointments, gels, jellies and other dosage forms adapted for topical administration are preferred. Additionally, PARP inhibitors may be delivered slowly, over time, to the afflicted tissue of the eye through the use of contact lenses. This regimen is generally performed by first soaking the lenses in a PARP inhibitor solution, and then applying the contact lenses to the eye for normal wear.

Claim 1 of 4 Claims

We claim:

1. A method for treating retinal or optic nerve disease or damage related to glaucoma, which comprises administering to a mammal a composition containing an effective amount of one or more PARP inhibitors in a pharmaceutically acceptable vehicle.
 

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