NZ733132A - Pharmaceutical formulations of xanthine or xanthine derivatives - Google Patents

Abstract

Pharmaceutical compositions and methods for treating various diseases and pathologies, such as Dupuytren contracture, are described, the compositions comprising pentoxifylline and a pharmaceutically acceptable carrier. Methods for fabricating the compositions and using them are also described.

Description

CEUTICAL FORMULATIONS OF XANTHINE OR XANTHINE DERIVATIVES CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to US. Provisional Application No. ,368 filed on January 6, 2015, entitled “Pharmaceutical Formulations of Xanthine or Xanthine tives,” the entire content of which is hereby incorporated by reference.

FIELD OF THE INVENTION The present invention relates generally to the field of pharmacology and more specifically to compositions and methods designed to treat, mitigate or prevent various diseases and pathologies, such as Dupuytren’s contracture, and to methods of ing and using such compositions.

BACKGROUND The present disclosure relates to ceutical formulations comprising xanthine or a xanthine derivative, such as pentoxifylline, and methods for treating various diseases and pathologies (eg, Dupuytren’s contracture) by local administration.

Fibrotic diseases can be found in a variety of tissues. For example, Dupuytren’s contracture, also described as ren’s disease or morbus Dupuytren, is believed to be caused by fibromatosis of the palm. Clinically, this usually leads to fleXion contracture and manifests itself as involuntary “clawing” of the hand, i.e., a l situation when the fingers tend to bend inwardly towards the center of the palm and cannot be easily and ssly htened, Painful nodules and cords are often formed in the hand as the e progresses.

Various methods and ies have been suggested for the treatment of Dupuytren’s disease and related disorders that are mentioned below. In particular, oral administration of a nonspecific phosphodiesterase inhibitors (PDEi) has been suggested and tried, but no more than l to moderate improvement has been achieved by such methods. Therefore, there remains a need for better treatments of such diseases.

This patent specification discloses such pharmaceutical compositions suitable for treatment and alleviation of various diseases and pathologies, including Dupuytren’s 2015/067835 disease, which can achieve positive patient outcomes while free of cks and ncies of existing formulations, and methods of fabricating and administering the same.

SUMMARY According to one embodiment of the invention, there is provided a method for ng a e, disorder or pathological condition, such as Dupuytren’s contracture, frozen shoulder, lipoma, cellulite, uterine fibroids, glaucoma, hyperthrophic scars, scarred tendons, keloids, herniated intervertebral disks or vitrectomy, in a mammalian subject in a need of the treatment. The method includes locally administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I: o R3 R1 / \NIIN o N N or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein each of R1, R2 and R3 is independently any of H, a C1-C6 alkyl, a C2—C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, an aryl or a heteroaryl, each of which is further optionally substituted.

According to another embodiment of the invention, the compound of formula I is pentoxifylline: 3,7-dimethy1-1—(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione or 1-(5- oxohexyl)-3,7-dimethylxantine.

DETAILED DESCRIPTION A. Terms and Definitions Unless c definitions are ed, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of ical chemistry, synthetic organic and inorganic chemistry bed herein, are those known in the art. Standard chemical symbols are used interchangeably with the full names ented by such symbols. Thus, for example, the terms “hydrogen” and “H” are understood to have identical meaning. rd techniques may be used for chemical syntheses, chemical analyses, formulating compositions and g them. The foregoing techniques and procedures can be generally med according to conventional methods well known in the art.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

As used herein, “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “includes,” and “included,” is not limiting.

“About” as used herein means that a number referred to as “about” comprises the d number plus or minus 1-10% of that recited . For example, “about” 100 degrees can mean 95-105 degrees or as few as 99-101 degrees depending on the context.

Whenever it appears herein, a cal range such as “1 to 20” refers to each integer in the given range; l'.e., meaning only 1, only 2, only 3, etc., up to and including only 20.

The term “pharmaceutical ition” is defined as a chemical or biological compound or substance, or a mixture or ation oftwo or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment, or prevention of disease or pathology.

The terms “Dupuytren’s contracture” and “Dupuytren’s e,” used herein interchangeably, are defined as one or several conditions associated with, or caused by, a proliferative connective tissue er in the hand’s palmar fascia and which manifests itself as a flexion contracture of the hand, lly due to a palmar fibromatosis. As the disease progresses, the fingers tend to bend inwardly towards the palm and cannot be fully and/or painlessly extended.

The term n shoulder” is defined as one or several conditions associated with, or caused by, the inflammation of shoulder capsule, which is the connective tissue surrounding the glenohurneral joint of the shoulder.

The term “lipoma” is defined as a benign tumor formed by a fatty tissue on various parts of a body. 2015/067835 The term “cellulite” is defined as formation of protrusions of subcutaneous fat within fibrous tive tissue typically on the buttocks or abdomen of a patient.

The term “uterine fibroids” is defined as benign tumors that develop in the uterus of a female patient.

The term “glaucoma” is defined as one or several conditions associated with, or caused by, damage to the optic nerve due to increased intraocular pressure.

The term “hyperthrophic scars” is defined as a skin condition typically developing after a thermal or traumatic injury and characterized by the ing scar to be raised above the surrounding skin.

The term ds” is defined as benign scars sed of fibrous nodules which are formed by excessive deposits of collagen on a patient’s skin.

The term “herniated intervertebral disks” refers to a medical condition in which a tear in the fibrous ring of an intervertebral disc causes the cushion that sits between the spinal vertebra to be pushed outside its normal position.

The term “vitrectomy” is defined a surgical procedure to remove some or all of the vitreous humor from the eye of a t.

The terms “solvate” and “hydrate” are used herein to indicate that a compound or substance is physically or chemically associated with a solvent for “solvates” such as water (for “hydrates”) .

The term “carrier” refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition.

The term ient” refers to a cologically inactive substance that is formulated in combination with the pharmacologically active ingredient of pharmaceutical ition and is inclusive of bulking agents, , diluents and ts used for facilitating drug absorption or solubility or for other pharmacokinetic considerations.

The term “mono therapy” as used herein refers to a method of treatment where only one therapeutic or pharmacologically active agent is utilized; the “combo therapy” involves the use of at least two such agents.

The term “therapeutically effective amount” is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician.

The term aceutically acceptable” is defined as a carrier, r t or excipient, that is compatible with the other ingredients of the formulation and not deleterious to the recipient f.

The terms “administration of a composition” or “administering a composition” is defined to include an act of providing a compound of the ion or pharmaceutical composition to the subject in need of treatment.

The terms “local administration” and “locally administering” as used herein refer to treatment of a f1brotic disease by administering at sites approximate to local symptoms (eg, Dupuytren cords) of the f1brotic disease. It is distinguished from systemic administrations, such as oral administration or intravenous injection, wherein dosage of a pharmaceutical composition is relatively similar throughout the body of a subject. Non-limiting examples of local administration include injection injection into a palpable cord, topical administration, and transdermal administration.

B. Embodiments of the Invention According to embodiments of the present invention, there are provided methods for treating several es, disorders or pathological conditions such as Dupuytren’s contracture, frozen er, lipoma, cellulite, uterine ds, glaucoma, hyperthrophic scars, scarred tendons, keloids, herniated intervertebral disks or vitrectomy, in a mammalian subject in a need of the treatment. The methods include stering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of a tumor necrosis factor (TNF) antagonist or inhibitor such as a nd of formula I: o R3 R1 / \XEN o I?! N or a pharmaceutically acceptable salt, solvate or hydrate thereof, n each of R1, R2 and R3 is independently any of H, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, an aryl or a heteroaryl, each of which may be further optionally substituted. The composition may include a single compound of a I or a combination of several such compounds each of which is described by formula I. In some embodiments, each of R1, R2 and R3 is ndently any of H, or a C1-C6 alkyl optionally substituted with a hydroxyl or acyl group (carbonyl or aldehyde).

The quantity of compound of formula I in the ceutical formulation expressed as molar concentration can be between about 0.03 mM and about 3 mM of nd of formula I per 1 uL of the entire formulation. In some embodiments, the eutic effective amount of compound of a I in the pharmaceutical formulation is between about 0.1 mg and about 20 mg such as between about 0.3 mg and about 10 mg, for example, about 0.5 mg, or about 4 to about 20 mg.

In one embodiment the compound of formula I is a nonspecific phosphodiesterase inhibitor (PDEi) such as pentoxifylline, l'.e., 1-(5-oxohexy1)-3, 7-dimethylxanthine, Le, a compound formula I where each of R2 and R3 is methyl and R1 is 5-oxohexyl, i.€., a functional group having the structure —(CH2)4—C(O)—CH3. Lisofylline, an active metabolite of pentoxifylline, i.e., 1-(5-hydroxyhexy1) -3,7-dimethylxanthine can be also used if desired.

The structure of lisofylline is basically the same as that of pentoxifylline except its functional group R1 includes a primary alcohol moiety —C(OH)— instead of the acyl moiety —C(O)— that is present in the R1 group in pentoxifylline. Other non-limiting examples of compounds encompassed by formula I that can be used include ne, aminophylline hylline with nediamine), enprofylline (3-propylxantine), isbufylline imethyl isobutylxantine), theophylline, theobromine, 3-isobuty1methylxanthine, oxitriphylline (choline theophyllinate), dyphylline (diprophylline or 7-(2,3-dihydroxypropy1)-l,3-dimethyl- 3,7-dihydro- 1H-purine-2,6-dione), 1-(5-hydroxymethylhexyl)methylxanthine (albifylline); 7-ethoxymethyl(5-hydroxy-5 -methylhexyl)methylxanthine fylline); and 7-propyl- l -(5 -hydroxymethylhexyl)-3 lxanthine.

In some embodiments, provided herein is a method for treating a fibrotic disease in a subject in need thereof, which comprises locally administering to the subject a pharmaceutical formulation comprising, consisting essentially of, or consisting of, a therapeutic effective amount of a nonspecific PDEi or a ceutically acceptable salt thereof, wherein the nonspecific PDEi is pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, theobromine or 3-isobutylmethylxanthine.

In some embodiments, the pharmaceutical ation further comprises a pharmaceutically able excipient or carrier, including, but not d to, an idant, an adjuvant or synergist, and a preservative. miting examples of the antioxidant that can be used include (x-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, yl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteine hydrochloride, d-oc—tocopherol natural, d-or—tocopherol tic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl e, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, and tocopherols.

Non-limiting examples of the adjuvant or synergist include citric acid, EDTA (ethylenediaminetetra acetic acid), its conjugate base, and salts, hydroxyquinoline sulfate, phosphoric acid, and tartaric acid.

In those embodiments where the formulation includes an EDTA sodium salt as an adjuvant, the EDTA sodium salt can be 0-0. 15% by weight of the formulation, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or 0.15% by weight of the formulation. If an EDTA magnesium salt is used as an adjuvant, the EDTA magnesium salt can be 0-0.15% by weight of the formulation, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0,07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or 0.15% by weight 0fthe formulation.

Non-limiting examples of the preservative are benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol, chorhexidine gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric e/nitrate, propylparaben, sodium te, sorbic acids and salts, ylethyl alcohol, and thimerosal. In particular embodiments, the preservative is benzyl alcohol.

In those embodiments where the formulation includes ethanol as a preservative, ethanol can be 190 proof The ethanol can be 0—15% by volume of the formulation, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% by volume of the formulation.

In those embodiments where the ation includes benzyl alcohol as a preservative, the benzyl l can be 0-1.5% by weight of the formulation, for example, 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 09,10, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume ofthe formulation.

In some embodiments, the pharmaceutical ation is filtered before local administration. In particular embodiments, the ceutical formulation is filtered through a 0.22 micron filter before local administration. In other embodiments, the pharmaceutical formulation has a pH of between 4 and 8. In particular embodiments, the ceutical formulation has a pH of between 5.5 and 6. The pH can be adjusted by adding acids or bases, e.g., HCl or NaOH.

The pharmaceutical formulation can be stered to a subject in need thereof by various local administrations, e. g. , by injection one to four times in a twenty-four hour period. In particular embodiments, the pharmaceutical formulation is administered daily until desired effects are ed.

In certain embodiments, the pharmaceutical formulation is administered topically.

In other embodiments, the pharmaceutical ation is administered transdermally. In still other embodiment, the pharmaceutical formulation is administered locally by injection directly into the area of the fibrotic disease. In particular embodiments, in case of treatment of the Dupuytren contracture, for example, the pharmaceutical formulation is injected directly into Dupuytren cord(s).

In certain embodiments, the pharmaceutical formulation further comprises one or more additional active agent(s). In particular embodiments, the second active agent is a vasodilator, e.g., alprostadil (prostaglandin E1), papaverine, phentolamine, or-receptor ng agents, ergot alkaloids, antihypertensive agents, vasodilators, nitrovasodilators, naturally occurring, nthetic and synthetic prostaglandins, and/or vasoactive intestinal peptide. In other embodiments, the pharmaceutical formulation further ses a collagenase, such as collagenase clostrz‘dz'um histolyticum.

The methods provided herein can be used as a mono therapy or a part of a combo y. In certain embodiments, the formulation comprising the compound of formula I, e.g., pentoxifylline, is used as a mono therapy. In certain ular embodiments, the formulation consisting ially of anonspecific PDEi, e.g., pentoxifylline, is used as a mono therapy to treat a fibrotic disease, such as Dupuytren’s contracture.

In other embodiments, the formulation comprising the compound of formula I, e.g., pentoxifylline, is used as a part of a combo therapy, for example, when the formulation 2015/067835 consisting essentially of a cific PDEi, e. g. is used to treat a fibrotic , pentoxifylline, disease, such as Dupuytren’s disease, in combination with a collagenase y, e.g., collagenase clostrz'dz'um histolyz‘z‘cum or Xiaflex® (collagenase closz‘rz'dz'um histolyiicum) from Auxilium Pharmaceuticals, Inc. of Chesterbrook, lvania.

The pharmaceutical formulations that are described herein may, in addition, optionally contain other pharmacologically active compounds, such as at least one anti- bacterial agent(s), or at least one antiviral medicament(s) and ations thereof. Those having ordinary skill in the art can ine what specific anti-bacterial and/or antiviral medicament(s) are to be used, if any.

The tration of the anti—bacterial agent(s) in the compositions of the present application may be between about 0.01mg/mL and about 50.0 mg/mL, such as between about 0.5 mg/mL and about 10.0 mg/mL, for example, about 1.0 mg/mL. Non-limiting examples of the anti-bacterial agents that may be used include fluoroquinolones such as moxifloxacin, gatifloxacin, nalidixic acid, ic acid, piromidic acid, pipemidic acid, cin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, levofloxacin, norfloxacin, ciprofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, prulifloxacin and combinations thereof.

Non-limiting examples of anti-bacterial agents other than fluoroquinolones that may be used include vancomycin, teicoplanin, telavancin, decaplanin, ramoplanin, azitromycin, gentamicin, ycin, amikacin, cefuroxime, mitomycin, neomycin, neosporin, amoebicides (e.g., metronidazole, tinidazole, secnidazole, ole, polyhexamethylene biguanide or chlorohexidine), polymyxin, clindamy cin, acin, chloramphenicol, erythromycin, natamycin, blephamide, sulfacetamide, sodium bicarbonate, povidone-iodine and combinations thereof The concentration of the ral medicament(s) in the compositions of the present application may be between about 0.01 mg/mL and about 75.0 mg/mL, such as between about 1mg/mL and about 50.0 mg/mL, for example, about 20.0 mg/mL. Non-limiting examples of the antiviral medicaments that may be used include idine, vidarabine and combinations thereof.

As mentioned above, the pharmaceutical composition that is the subject matter of the instant application may further ally include one or several pharmaceutically acceptable excipient(s). In some embodiments, an excipient that can be used may be a non- ionic polyoxyethylene-polyoxypropylene block copolymer having the following general structure: HO—(CH2-CH2—0)x—(C3H6—O)y—(CH2—CH2—O)x—H, wherein X is an integer having the value of at least 8 and y is an integer having the value of at least 38.

If a non-ionic yethylene-polyoxypropylene block copolymer is used as an excipient, its contents in the overall composition may be between about 001 mass % and about 20.0 mass % such as n about 1.0 mass % and about 15 mass %, for example, about 10.0 mass %.

One non-limiting example of a specific non-ionic polyoxyethylene- polyoxypropylene block copolymer that can be used as a solubilizing and stabilizing agent in the pharmaceutical compositions of the instant invention is the product known under the trade name Poloxamer 407® (poly(ethylene )—block-poly(propylene glycol)-block- poly(ethylene glycol)) available from Aldrich Corp. of St. Louis, Missouri, with the molecular weight of the polyoxypropylene portion of about 4,000 Daltons, about a 70% polyoxyethylene content, the overall molecular weight of between about 9,840 Daltons and about 14,600 Daltons, and having the following chemical structure: wherein x=z and each is between about 78 and about 116; y is about 69.

According to further embodiments, the excipient portion of the pharmaceutical formulation may contain other products, instead of, or in combination with, non-ionic polyoxyethylene-polyoxypropylene block copolymer(s). One miting example of such additional excipient is poly(acrylic acid) in its various cross-linked or non-cross—linked ns, such as Carbomer 940® having a weight-average molecular weight of about 940 and available from ol Corp. of Wickliffe, Ohio. Another type of products that can be used in the excipient portion of the pharmaceutical formulation may be soluble methylcellulose and hydroxypropyl cellulose polymers, such as Methocel® family of WO 11885 products available from Dow Chemical Co. of Midland, Michigan, for e, a hydroxypropyl methylcellulose product Methocel® E4M.

According to further embodiments, methods for fabricating the above-described pharmaceutical compositions are provided. A one-batch formulation method may be used, where the components of the pharmaceutical formulation can be combined in single container; the components may be added to the container simultaneously or consecutively.

Alternatively, a two- or multiple-batch method(s) may be used if desired, where each component of the pharmaceutical formulation can be combined in separate ner followed by combining the ts of each container.

In one exemplary, non-limiting procedure, a quantity of a tumor necrosis factor inhibitor such as pentoxifylline may be placed into a mixing container ed by adding a quantity of sterile water and a polymeric gel (e. g. , a Poloxamer 407®-based gel), the mixture is d until a clear stable on is obtained, allowing the formulation to remain closed system thus preventing contamination and the loss of sterility.

The resulting product may then be transferred into single dose vials, capped, sealed, autoclaved and shaken until cool. Finally, te sterility and endotoxin removal may be performed on the product according to commonly used methods known to those having ordinary skill in the art. As mentioned above, in some embodiments, the ceutical compositions can be used for topical administration such as compositions formulated and delivered to a patient as injections. The compositions may also n some quantity of vative(s) such as benzalkonium de, if desired.

In one exemplary, non-limiting embodiment, illustrating in general the method for treating Dupuytren contracture, the process of administering pharmaceutical compositions described herein may be as follows. The pharmaceutical composition can be injected into a palpable cord with a contracture of a metacarpophalangeal or a proximal interphalangeal joint, the dose of the active pharmaceutical agent in the composition being typically between about 0.4 and about 0.7 mg per injection. The injection can be followed by the finger extension procedure, and then the inj ection/finger ion cycle may be repeated after approximately 24 to 72 hours. Injections and finger ion ures may be administered up to 3 times per cord at approximately 4-week intervals. A reasonably skilled practitioner can select the equipment to be used for injections. For example, a 27-gauge 1/2— inch needle may be used.

It will be understood by those having ordinary skill in the art that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, gender, diet, and the ty of the particular condition being treated.

In onal ments, pharmaceutical kits are provided. The kit includes a sealed container approved for the e of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions and a device for locally administering the formulation (6. g. , a syringe and a needle). An instruction for the use of the composition and the information about the composition are to be affixed to the container or otherwise enclosed with it.

The following examples are provided to r elucidate the advantages and es of the present invention, but are not intended to limit the scope of the invention. The examples are for the rative purposes only. USP pharmaceutical grade products were used in preparing the formulations described below.

Example 1. Preparing a Pharmaceutical Composition No.1 A pharmaceutical composition may be prepared as described below. The following products can be used in the amounts and concentrations specified: (a) about 20.0 g of aqueous solution of Poloxamer 407®, at a concentration of Poloxamer 407® of about 20.0 mass %; (b) about 0.11 g of Carbomer 940® (a powder), and (0) about 100.0 mL of sterile water for injection.

Poloxamer 407® and Carbomer 940® can be thoroughly mixed with water, until fully ved, the pH may be adjusted to about 5.5 using sodium hydroxide. The product can then be refrigerated overnight, placed into a vial and autoclaved followed by adding the preservative benzalkonium chloride (at about 1:10,000 mass ratio) to form a stock Poloxamer/Carbomer gel to be used in further steps. Next, the following products may be used in the amounts and trations specified: ((1) about 1.0 g of pentoxifylline, at a concentration of about 1.0%; (e) about 90 mL of the Poloxamer/Carbomer gel ed as described above, and 2015/067835 (f) about 9.0 mL of e water for injection.

Pentoxifylline may be combined with the gel and water and the final product can be transferred into dropper bottles (10 mL size), capped and sealed. The product should have an estimated shelf life of about 90 days when kept refrigerated.

Example 2. ing a Pharmaceutical Composition No. 2 A pharmaceutical composition may be prepared as described below. The following products can be used in the s and concentrations specified: (a) about 0.4 g of Methocel® E4M (a powder); (b) about 0.2 g of Carbomer 940® (a powder); and (c) about 100.0 mL of e water for injection.

The Methocel® E4M and Carbomer 940® powders can be combined in a beaker, then water can be added to allow hydrating overnight to form a solution, the pH may be adjusted to about 5.0 using sodium hydroxide. The gel can be autoclaved and cooled followed by adding vative benzalkonium chloride (at about 1:10,000 mass ratio) to form a stock Methocel® E4M /Carbomer solution to be used in further steps. Next, the following products may be used in the amounts and concentrations specified: (d) about 1.0 g of pentoxifylline, at a concentration of about 1.0%, (e) about 90 mL of the Methocel® E4M /Carbomer solution obtained as described above; and (f) about 9.0 mL of sterile water for injection.

Pentoxifylline may be combined with the gel and water and the final product can be erred into dropper s (10 mL size), capped and sealed. The product should have an estimated shelf life of about 90 days when kept refrigerated.

Although the invention has been described with reference to the above examples, it will be understood that ations and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

WO 11885

Claims (18)

WHAT IS CLAIMED IS:

1. A method for treating a disease, disorder or pathological condition in a mammalian subject in need thereof, comprising locally administering to the subject a ceutical formulation comprising a therapeutic effective amount of a compound of formula I: o R3 R1 / \N N A | /> o I?! N or a ceutically acceptable salt thereof, wherein: each of R1, R2 and R3 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is further optionally substituted, with the further proviso that the disease, disorder or pathological condition is selected from the group consisting of Dupuytren’s contracture, frozen er, lipoma, cellulite, uterine fibroids, glaucoma, hrophic scars, scarred tendons, s, herniated intervertebral disks and Vitrectomy.

2. The method of claim 1, wherein each of R1, R2 and R3 is ndently selected from the group consisting of H and an optionally substituted C1-C6 alkyl.

3. The method of claims 1, wherein each of R1, R2 and R3 is independently ed from the group consisting of H, a C1-C6 alkyl and an acyl-substituted C1-C6 alkyl,

4. The method of claim 1, wherein the nd of formula I is a nonspecific phosphodiesterase inhibitor.

5. The method of claim 4, wherein the nonspecific phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, theobromine and 3-isobutyl- l -methylxanthine.

The method of claim 4, wherein the nonspecific odiesterase tor is pentoxifylline.

A method for treating a disease, disorder or pathological condition in a mammalian subject in need thereof, comprising locally administering to the subject a pharmaceutical formulation consisting essentially of a eutic effective amount of a compound of formula I: o R3 R1 / \NXiN o I?! N or a pharmaceutically acceptable salt thereof, wherein: each of R1, R2 and R3 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is further ally substituted, with the further proviso that the disease, disorder or pathological condition is selected from the group consisting of Dupuytren’s contracture, frozen shoulder, lipoma, cellulite, uterine ds, glaucoma, hyperthrophic scars, scarred tendons, keloids, herniated intervertebral disks and Vitrectomy.

The method of claim ?, wherein each of R1, R2 and R3 is independently selected from the group consisting of H and an optionally substituted C1-C6 alkyl.

The method of claims 7, wherein each of R1, R2 and R3 is independently selected from the group consisting of H, a C1-C6 alkyl and an acyl-substituted C1-C6 alkyl.

10. The method of claim 7, wherein the compound of formula I is a nonspecific odiesterase inhibitor.

11. The method of claim 10, wherein the nonspecific phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, omine and 3 -isobutyl- l -methylxanthine.

12. The method of claim 11, wherein the nonspecific odiesterase inhibitor is ifylline.

13. The method of claim 1, wherein the disease, er or pathological condition is Dupuytren’ s contracture.

14. The method of claim 13, wherein the pharmaceutical formulation is injected into the hand or paw of the mammalian subject.

15. The method of claim 7, wherein the disease, disorder or pathological condition is Dupuytren’ s contracture.

16. The method of claim 15, wherein the pharmaceutical formulation is injected into the hand or paw of the ian subject.

17. The method of claiml, wherein the therapeutic effective amount is between 4 mg and 20 mg.

18. The method of claim 1, wherein the pharmaceutical formulation further comprises at least one second active agent selected from the group ting of alprostadil, papaverine, phentolamine nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertensive agents, vasodilators, nthetic and synthetic prostaglandins, vasoactive intestinal peptides and a collagenase.