POLY(ADP-RIBOSE) POLYMERASES INHIBITOR FOR TREATING OPHTHALMIC CONDITION

The present invention is directed to a method for the treatment of ophthalmic condition, preferably diabetic retinopathy. The method involves the administration of an inhibitor of poly(ADP-ribose) polymerase (PARP) to an animal, such as a mammal, in particular a human, in an amount sufficient to treat the retina for diabetic retinopathy. The inhibitor _λ of poly(ADP-ribose) polymerase (PARP) is preferably 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one or a pharmaceutically acceptable salt thereof.

Background of the Invention

Poly(ADP-ribose) polymerase (PARP) inhibitors have been known for their use to treat ophthalmic conditions. (See: Invest Ophthalmol Vis Sci. 2007 Jan;48(1 ):361-7; Microvasc Res. 2007 Jan;73(1 ):1-6. Epub 2006 Sep 18.; Diabetes. 2006 Jun;55(6):1686-94.; Diabetes. 2005 Dec;54(12):3435-41. ;Diabetes. 2005 May;54(5):1514-22.; Diabetes. 2004 Nov;53(11 ):2960-7.; Curr Eye Res. 2004 Jul;29(1 ):11-6.; Diabetologia. 2004 Apr;47(4):710-7).

The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one represented by formula 1 :

1 is a small molecule inhibitor of PARP. The compound of formula 1 and salts thereof, can be prepared as described in U.S. Patent No. 6,495,541 ; PCT Application No. PCT/IB2004/000915, International Publication No. WO 2004/087713; U.S. Provisional Patent Application Nos. 60/612,457, 60/612,459 and 60/679,296, the disclosures of which are incorporated herein by reference in their entireties.

Hyperproliferative disorders and several diseases and conditions of the posterior segment of the eye threaten vision. Age related macular degeneration (ARMD or AMD),

choroidal neovascularization (CNV), retinopathies (e.g., diabetic retinopathy, vitreoretinopathy, retinopathy of prematurity), retinitis (e.g., cytomegalovirus (CMV) retinitis), uveitis, macular edema, and glaucoma are several examples.

Age related macular degeneration (ARMD or AMD) is the leading cause of blindness in the elderly. ARMD attacks the center of vision and blurs it, making reading, driving, and other detailed tasks difficult or impossible. About 200,000 new cases of ARMD occur each year in the United States alone. Current estimates reveal that approximately forty percent of the population over age 75, and approximately twenty percent of the population over age 60, suffer from some degree of macular degeneration. "Wet" ARMD is the type of ARMD that most often causes blindness. In wet ARMD, newly formed choroidal blood vessels (choroidal neovascularization (CNV)) leak fluid and cause progressive damage to the retina. In the particular case of CNV in ARMD, two main methods of treatment are currently being developed, (a) photocoagulation and (b) the use of angiogenesis inhibitors. However, photocoagulation can be harmful to the retina and is impractical when the CNV is in proximity of the fovea. Furthermore, photocoagulation often results in recurrent CNV over time.

Angiogenesis is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. See Merenmies et al., Cell Growth & Differentiation, 8, 3-10 (1997). On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors). Folkman, Nature Med., 1 , 27-31 (1995). Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK-1 ); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).

Oral administration of anti-angiogenic compounds is also being tested as a systemic treatment for ARMD. However, due to drug-specific metabolic restrictions, systemic administration usually provides sub-therapeutic drug levels to the eye.

Therefore, to achieve effective intraocular drug concentrations, either an unacceptably high dose or repetitive conventional doses are required. Various implants have also been developed for delivery of anti-angiogenic compounds locally to the eye. Examples of such implants are disclosed in U.S. Pat. Nos. 5,824,072 to Wong, U.S. Pat. No. 5,476,511 to Gwon et al., and U.S. Pat. No. 5,773,019 to Ashton et al., each of which is herein incorporated by reference in their entireties for all purposes.

More than 14 million people in the United States have diabetes. People with diabetes are at risk of retinal complications. However, people with type I, i.e., insulin- dependent, diabetes, face a greater risk of severe vision loss than people with type II, i.e., non-insulin dependent, diabetes. Initially, the high blood glucose level in diabetic people causes an increase in growth factors in their eyes. This condition is known as the "pre-diabetic retinopathy stage" and can lead to retinopathy, if not prophylactically treated. Retinopathy will affect the majority of diabetic people to some extent during their lifetimes (Anonymous, MMWR 42(10): 191-195 (1993)). It is the leading cause of blindness in Americans of age 20 to 74 today and is expected to impair vision in approximately one-third of diabetic people in the United States. Each year in the United States, as many as 40,000 new cases of blindness occur among diabetic people (CDC, unpublished data, 1993). Diabetic people are 25 times more likely than the general population to become blind due to retinopathy. Diabetic retinopathy has two stages-a nonproliferative stage, which typically occurs first, and a proliferative stage. The nonproliferative stage, which is also referred to as "background diabetic retinopathy," is characterized by thickening of the basement membrane, loss of retinal pericytes, microvascular abnormalities, intraretinal microaneurysms, retinal hemorrhages (also known as "dot blot" hemorrhages), retinal edema, in particular diabetic macular edema, capillary closure associated with retinal ischemia or poor retinal perfusion (i.e., poor vessel development) and soft and hard exudates. The proliferative stage, which affects an estimated 700,000 Americans (Chen et al., J. Miss. State Med. Assoc. 36(7): 201- 208 (1995)), is characterized by neovascularization and fibrovascular growth (i.e., scarring involving glial and fibrous elements) from the retina or optic nerve over the inner surface of the retina or disc or into the vitreous cavity. The proliferative stage can lead to rubeotic or neovascular glaucoma. Macular edema can occur in either stage and it, along with complications from retinal neovascularization, are the two major retinal

- A - problems that cause the diabetes-related vision loss.

While the pathological stages of diabetic retinopathy are well-described, the molecular events underlying diabetic retinopathy are poorly understood. This is due, in part, to the fact that the disease progresses over ten to thirty years, depending on a given individual. Tight control of glycemia and hypertension and ophthalmic screening of diabetics appears beneficial in preventing the disease. Current treatment consists of regular observation by an ophthalmologist, laser photocoagulation and vitrectomy. Macular edema threatening or involving the macular center is treated with focal macular photocoagulation. Small (50. mu. in diameter), mild-intensity laser burns are targeted at areas of leakage in the macula (Murphy, Amer. Family Physician 51 (4): 785-796 (1995)). If the macular edema persists, retreatment may be necessary. Patients with severe to very severe nonproliferative retinopathy and patients, who are at high risk for proliferative retinopathy or who already have early or advanced proliferative retinopathy, are treated with scatter or panretinal photocoagulation. Panretinal photocoagulation involves 1 ,500-2,000 laser burns, which are 500. mu. in diameter, in the midperipheral and peripheral portion of the retina (Murphy (1995), supra). The best documented biochemical mechanism for the development of microvascular complications of diabetes is the sorbitol pathway. In the sorbitol pathway, the enzyme aldose reductase catalyzes the conversion of glucose to sorbitol and galactose to galactitol. Aldose reductase has a low substrate affinity for glucose. Accordingly, when glucose concentrations are normal, the pathway is inactive. During hyperglycemia, the sorbitol pathway becomes active. Activation of the sorbitol pathway is important for retinal pericytes, for example, which do not require insulin for glucose penetration. Similarly, retinal capillary cells appear to contain substantial amounts of aldose reductase (Ferris, Hospital Practice: 79-89 (May 15, 1993)). Given the prevalence of diabetic retinopathy, there remains a need for an effective prophylactic and therapeutic treatment of diabetic retinopathy. Accordingly, it is a principal object of the present invention to provide a method of prophylactically and therapeutically treating diabetic retinopathy, including treatment at the pre-diabetic retinopathy stage, the nonproliferative diabetic retinopathy stage, and the proliferative diabetic retinopathy stage. This and other objects of the present invention will become apparent from the detailed description provided herein.

Summary of the Invention

The present invention is directed to a method of prophylactically or therapeutically treating an animal suffering an ophthalmic condition, which method comprises administering to said animal a therapeutically effective amount of poly(ADP-ribose) polymerase (PARP) inhibitor of formula 1 :

1, or pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt is a phosphate salt having formula 1a:

1a.

In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered systemically.

In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered orally or by injection.

In another embodiment, said ophthalmic condition is selected from the group consisting of glaucoma, diabetic macular edema, uveitis, retinitis, retinopathies, choroidal neovascularization, ocular angiogenesis, and age related macular degeneration.

In another embodiment, said ophthalmic condition is diabetic macular edema.

In another embodiment, said retinopathies comprise diabetic retinopathy, vitreoretinopathy, and retinopathy of prematurity.

In another embodiment, said retinitis comprises cytomegalovirus retinitis.

In another embodiment, said retinopathies is diabetic retinopathy.

In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered at the pre-diabetic retinopathy stage.

In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered at the nonproliferative diabetic retinopathy stage. In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered topically, subconjunctival^, retrobulbarly, periocular^, subretinally, suprachoroidally, or intraocularly.

In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered at the proliferative diabetic stage. In another embodiment, said compound of formula 1 or a pharmaceutically acceptable salt thereof is administered before, during or after surgical removal from an eye of scar tissue generated during neovascularization during the proliferative diabetic stage.

Detailed Description of the Invention The present invention provides a method for the prophylactic and therapeutic treatment of diabetic retinopathy, including treatment at the pre-diabetic retinopathy stage, the nonproliferative diabetic retinopathy stage, and the proliferative diabetic retinopathy stage. By "prophylactic" is meant the protection, in whole or in part, against diabetic retinopathy, in particular diabetic macular edema. By "therapeutic" is meant the amelioration of diabetic retinopathy, itself, and the protection, in whole or in part, against further diabetic retinopathy, in particular diabetic macular edema.

The method comprises the administration of a PARP inhibitor in an amount sufficient to treat the retina for retinopathy prophylactically or therapeutically. Any PARP inhibitor can be used in the method of the present invention as long as it is safe and efficacious.

Preferably, the PARP inhibitor is compound of formula 1 or a pharmaceutically acceptable salt thereof, such as compound 1a.

The PARP inhibitor, which is preferably compound of formula 1 , or a pharmaceutically acceptable salt thereof, can be administered in accordance with the present inventive method by any suitable route. Suitable routes of administration include systemic, such as orally or by injection, topical, intraocular, periocular (e.g., subTenon's), subconjunctival, subretinal, suprachoroidal and retrobulbar. The manner in which the PARP inhibitor is administered is dependent, in part, upon whether the

treatment of retinopathy is prophylactic or therapeutic. The manner in which the PARP inhibitor is administered for therapeutic treatment of retinopathy is dependent, in part, upon the cause of the retinopathy.

The term "compound of formula 1" refers to 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, free base.

The term "compound of formula 1a" refers to the phosphate salt of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.

The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in a compound. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. Particularly preferred salts include phosphate and gluconate salts. The invention also includes isotopically-labeled compounds, which are identical to this recited in Formula 1 , but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into

compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds, which contain the aforementioned isotopes and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H, ¹⁴ C, ¹¹ C or ¹⁸ F are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability and ¹¹ C or ¹⁸ F for use in positron emission tomography. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. An isotopically labeled compound of Formula 1 of this invention can generally be prepared by carrying out the procedures described for the non-labeled compound, substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

For example, given that diabetes is the leading cause of retinopathy, the PARP inhibitor can be administered prophylactically as soon as the pre-diabetic retinopathy state is detected. For the prophylactic treatment of retinopathy that can result from diabetes, the PARP inhibitor is preferably administered systemically, e.g., orally or by injection. For the therapeutic treatment of nonproliferative diabetic retinopathy, the PARP inhibitor can be administered systemically, e.g., orally or by injection, or intraocularly. Proliferative diabetic retinopathy can be therapeutically treated by the administration of the PARP inhibitor intraocularly, topically, subconjunctival^ or periocularly (e.g., subTenon's), for example. The PARP inhibitor is preferably administered intraocularly, topically, subconjunctival^ or periocularly (e.g., subTenon's) for the prophylactic or therapeutic treatment of retinopathy before, during or after surgical removal from an eye of scar tissue generated during neovascularization during the proliferative diabetic stage.

The PARP inhibitor is preferably administered as soon as possible after it has been determined that an animal, such as a mammal, specifically a human, is at risk for retinopathy (prophylactic treatment) or has begun to develop retinopathy (therapeutic

treatment). Treatment will depend, in part, upon the particular PARP inhibitor used, the amount of the PARP inhibitor administered, the route of administration, and the cause and extent, if any, of retinopathy realized.

Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract. The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open- angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity. Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage. The dose administered to an animal, particularly a human, in accordance with the present invention should be sufficient to effect the desired response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the strength of the particular PARP inhibitor employed, the age, species, condition or disease state, and body weight of the animal, as well as the amount of the retina about to be affected or actually affected by retinopathy. The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular PARP inhibitor and

the desired physiological effect. It will be appreciated by one of ordinary skill in the art that various conditions or disease states, in particular, chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. The present inventive method will typically involve the administration of 1 mg/m ² to 100 mg/m ² of the compound of formula 1, preferably 12 mg/m ² of the compound of formula 1 , if administered systemically (intravenously). The dosing regiment is 12mg/m ² of the compound of formula 1 to patients every three days for 5 cycles (12 treatment days). Other dosing regiment is 12 mg/m ² of the compound of formula 1 every 5 days for 5 cycles (20 treatment days).

Compositions for use in the present inventive method preferably comprise a pharmaceutically acceptable carrier and an amount of a PARP inhibitor sufficient to treat retinopathy prophylactically or therapeutically. The carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration.

The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the PARP inhibitor and one which has no detrimental side effects or toxicity under the conditions of use.

The choice of excipient will be determined in part by the particular PARP inhibitor, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations are merely exemplary and are in no way limiting.

Injectable formulations are among those that are preferred in accordance with the present inventive method. The requirements for effective pharmaceutically carriers for injectable compositions are well-known to those of ordinary skill in the art (see Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). It is preferred that such injectable compositions be administered intramuscularly, intravenously, or intraperitoneal^.

Topical formulations are well-known to those of skill in the art. Such formulations are suitable in the context of the present invention for application to the skin. The use of patches, corneal shields (see, e.g., U.S. Pat. No. 5,185,152), and ophthalmic solutions

(see, e.g., U.S. Pat. No. 5,710,182) and ointments, e.g., eye drops, is also within the skill in the art.

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The inhibitor can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or

hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-1 ,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants. Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral.

Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

Suitable soaps for use in parenteral formulations include fatty alkali metals, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-p-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.

The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.

The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried

(lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. All of the references cited herein, including patents, patent applications, literature publications, and the like, are hereby incorporated in their entireties by reference.

While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred compounds and methods may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.