EP3638244A1

EP3638244A1 - Pharmaceutical formulations of xanthine or xanthine derivatives, and their use

Info

Publication number: EP3638244A1
Application number: EP18735151.5A
Authority: EP
Inventors: Matthew J. Buderer; Dennis Saadeh; Andrew R. Boll
Original assignee: Harrow IP LLC
Current assignee: Harrow IP LLC
Priority date: 2017-06-12
Filing date: 2018-06-12
Publication date: 2020-04-22
Also published as: CA3060079A1; WO2018231739A1; KR20200042458A; AU2018282741A1; JP2020523300A

Abstract

The present invention relates to pharmaceutical formulations comprising xanthine or xanthine derivatives, kits thereof, and methods for treating fibrotic diseases by local administration.

Description

PHARMACEUTICAL FORMULATIONS OF XANTHINE OR XANTHINE

DERIVATIVES, AND THEIR USE

Cross-Reference To Related Applications

This application claims priority to U.S. Patent application No. 15/620,430, filed on June 12, 2017, which is a continuation-in-part of U.S. Patent application No. 14/307,773 filed on filed on June 18, 2014, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 61/836,535 filed on June 18, 2013, the contents of which are incorporated herein by reference in their entireties.

Field of Use

The present disclosure relates to pharmaceutical formulations comprising xanthine or a xanthine derivative, such as pentoxifylline, and methods for treating a fibrotic disease, such as Peyronie's disease by local administration.

Background of the Invention

Fibrotic diseases can be found in a variety of tissues. For example, Peyronie's disease (PD) is a fibromatosis (Hellstrom and Bivalacqua, 2000; Schwarzer et al, 2001; Jarow et al, 1997; Devine et al., 1997) of the tunica albuginea (TA), the specialized lining of the corpora cavernosa of the penis. Clinically, this usually leads to penile deformation (curved penis during erection), pain, and quite frequent erectile dysfunction. Fibrotic disease can also be found in other tissues, for example, pulmonary fibrosis, liver fibrosis, renal fibrosis, and vascular fibrosis.

It has been indicated that PD plaques and/or other fibrotic conditions can be pharmacologically arrested or reduced in size, by decreasing collagen synthesis and inducing myofibroblast apoptosis (Gonzalez-Cadavid et al., US Patent No. 8, 133,903).

Oral administration of a nonspecific PDEi, e.g., pentoxifylline, has been suggested to be useful in reducing collagen levels in Peyronie's Disease plaques (Brant et al, Nature Clinical Practice Urology 2006, Vol 3, p. I l l; Smith et al., Asian Journal of Andrology 2011, Vol 13, p. 322; Safarinejad et al, BJU International 2010, Vol 106, p. 240). However, oral pentoxifylline has been shown to have moderate to minimal improvement.

Therefore, there remains a need for treatment of fibrotic diseases, e.g., Peyronie's disease. Summary of the Invention

Provided herein are pharmaceutical formulations comprising xanthine or a xanthine derivative, such as pentoxifylline (l-(5-oxohexyl)-3, 7-dimethylxanthine), kits thereof, and methods for treating a fibrotic disease by local administration.

In one aspect, provided herein is a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein R¹, R² and R³ are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.

In another aspect, provided herein is a kit comprising:

a pharmaceutical formulation containing a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein R¹, R² and R³ are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; an apparatus for locally administering the formulation;

a container for housing the formulation and the drug delivery apparatus; and instructions for use.

In still another aspect, provided herein is a method for treating a fibrotic disease, e.g., Peyronie's disease, in a subject in need thereof, comprising locally administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R¹, R² and R³ are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.

R¹, R² and R³ can be each, independently, H, or optionally substituted C1-C6 alkyl. In particular, R¹, R² and R³ are each, independently, H, C1-C6 alkyl, or C1-C6 alkyl substituted with acyl. The compound of formula I can be a nonspecific phosphodiesterase inhibitor (PDEi). The compound of formula I can also be selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.

Also provided herein is a pharmaceutical formulation comprising, consisting essentially of, or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration,.

In another aspect, provided herein is a kit comprising: a pharmaceutical formulation comprising, consisting essentially of, or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or prodrug thereof; an apparatus for locally administering the formulation; a container for housing the formulation and the drug delivery apparatus; and instructions for use.

In yet another aspect, provided herein is a method for treating a fibrotic disease, e.g., Peyronie's disease, in a subject in need thereof, comprising locally administering to the subject a pharmaceutical formulation comprising, consisting essentially of, or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt thereof.

The nonspecific PDEi mentioned can be pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3-isobutyl-l-methylxanthine (IBMX).

In certain particular embodiments, the pharmaceutical formulation consists essentially of or consists of the therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt thereof.

The fibrotic disease includes Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid scars. In certain particular embodiments, the fibrotic disease is Peyronie's disease or keloid scar.

In particular embodiments, the pharmaceutical formulations, kits thereof, and methods described above relate to treatment of Peyronie's disease or erectile dysfunction. The erectile dysfunction can be associated with Peyronie's disease.

In other embodiments, the pharmaceutical formulations, kits thereof, and methods described above relate to treatment of keloid scars in a subject in need thereof. The pharmaceutical formulation can comprise, consist essentially of, or consist of a nonspecific PDEi, e.g., pentoxifylline, and caffeine. The formulation can also comprise, consist essentially of, or consist of a nonspecific PDEi, e.g., pentoxifylline, and EGCG (green tea catechin). Furthermore, the formulation can comprise, consist essentially of, or consist of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g., tranilast. These formulations can be injected into the keloid scars.

The pharmaceutical formulation can further comprise a pharmaceutically acceptable excipient or carrier, including, but not limited to, an antioxidant, an adjuvant or synergist, and a preservative.

The pharmaceutical formulation can comprise an EDTA sodium salt. 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.

The pharmaceutical formulation can also comprise an EDTA magnesium salt. 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 of the formulation.

The pharmaceutical formulation can further comprise ethanol. The 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.

The pharmaceutical formulation can comprise benzyl alcohol. The benzyl alcohol 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, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the formulation.

The pharmaceutical formulation can be filtered before local administration, such as filtering through a 0.22 micron filter.

The pharmaceutical formulation has a pH of between 4 and 8. In particular embodiments, the pharmaceutical formulation has a pH of between 5.5 and 6. The pH can be adjusted by adding acids or bases, e.g., HC1 or NaOH.

The therapeutically effective amount can be between 4 mg and 20 mg. In particular embodiments, the therapeutically effective amount is between 6 mg and 10 mg.

The pharmaceutical formulation can be administered one to four times in a twenty- four hour period. In particular embodiments, the pharmaceutical formulation is administered daily until desired effects are achieved.

The pharmaceutical formulation can comprise a unit dosage of the compound of formula I. In particular embodiments, the pharmaceutical formulation comprises a unit dosage of pentoxifylline.

The pharmaceutical formulation can be administered topically, transdermally, to the penis of the subject. In particular embodiments, the pharmaceutical formulation is administered by intracavemosal injection. Accordingly, the pharmaceutical formulation can comprise a sterile liquid composition so that the pharmaceutically acceptable excipient or carrier is suitable for intracavemosal injection. In other embodiments, the pharmaceutically acceptable excipient or carrier is suitable for topical or transdermal administration, and the formulation comprises a composition to be applied to a body surface, such as an ointment, cream, gel or lotion.

In certain embodiments, the pharmaceutical formulation is not administered (e.g., intracavemosally injected) directly into the area of the fibrotic disease, e.g., the area of the Peyronie's disease. In certain particular embodiments for treating Peyronie's disease, the pharmaceutical formulation is administered (e.g., intracavemosally injected) at the base of the penis about 2 cm from where the penis attaches to the abdomen.

The pharmaceutical formulation can comprise a second active agent, including nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertensive agents, vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins, and vasoactive intestinal peptides. The vasodilators can be alprostadil (Prostaglandin Ei), papaverine, and phentolamine.

In certain embodiments of the formulations, kits thereof, and methods for treating Peyronie's disease, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®. In certain particular embodiments, the pharmaceutical formulation comprises, consists essentially of, or consists of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.

The formulations, kits thereof, and methods provided herein can be used as a mono therapy or a part of a combo therapy to treat a fibrotic disease, such as Peyronie's disease. For example, the formulation comprising the compound of formula I, e.g, pentoxifylline, can be used as a mono therapy or a part of a combo therapy. The formulation consisting essentially of or consisting of a nonspecific PDEi, e.g., pentoxifylline, can also be used as a mono therapy, or a part of a combo therapy, e.g., in combination with a collagenase therapy, such as collagenase Clostridium histolyticum or Xiaflex®. Also provided herein is a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, a quantity of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparin, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein each of R¹, R² and R³ is independently selected from the group consisting of H, a Ci- (, alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, a aryl, and a heteroaryl, each of which is optionally substituted.

In an aspect, provided herein are methods for treating a fibrotic disease in a subject in need thereof, comprising locally administering to the subject a therapeutically effective amount of a pharmaceutical formulation, comprising a quantity of a compound of formula I, 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, i-Ce alkenyl, i-Ce alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted; and a quantity of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparin, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof.

R , R and R^J can each be independently selected from the group consisting of H and an optionally substituted C1-C6 alkyl. In particular, R¹, R² and R³ can be independently selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 alkyl substituted with acyl.

The compound of formula I can be a nonspecific phosphodiesterase inhibitor (PDEi). The nonspecific PDEi can be selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and 3-isobutyl-l- methylxanthine.

In an embodiment, the fibrotic disease is Peyronie's disease. In an embodiment the formulation leads to improvement of erectile dysfunction.

In an embodiment, the pharmaceutical formulation has a pH of between 5.5 and 6. In an embodiment, the therapeutically effective amount is between 4 mg and 20 mg. In an embodiment, the pharmaceutical formulation further comprises a sterile liquid composition, wherein the excipient or carrier is suitable for intracavernosal injection. In an embodiment, the pharmaceutical formulation is administered locally to the penis of the subject. In an embodiment, the pharmaceutical formulation is administered by

intracavernosal injection.

In an embodiment, the pharmaceutical formulation further comprises a second active agent selected from the group consisting of alprostadil, papaverine, and phentolamine. In an embodiment, the pharmaceutical formulation further comprises a collagenase.

In an embodiment, the pharmaceutical formulation further comprises an active agent selected from the group consisting of at least one anesthetic, at least one anti -bacterial agent, at least one antiviral medicament, at least one antifungal medicament, and combinations thereof. In an embodiment, the anesthetic is selected from the group consisting of lidocaine, tetracaine, proparacaine, procaine, dyclonine and combinations thereof.

In an embodiment, the polysaccharide is sodium hyaluronate. The polysaccharide can be sodium hyaluronate.

In an embodiment, the pharmaceutical formulation is ensconced within essentially spherical particles fabricated of a water soluble biodegradable polymer selected from the group consisting of poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(gly colic acid), poly(caprolactone), and poly(hydroxybutyrate). In an embodiment, the biodegradable polymer is poly(lactic acid-co-glycolic acid).

In another aspect, provided herein is a pharmaceutical composition comprising essentially spherical particles incorporating a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein each of R¹, R² and R³ is independently selected from the group consisting of H, a C1-C6 alkyl, a C -Ce alkenyl, a C -Ce alkynyl, a cycloalkyl, a heterocyclyl, a aryl, and a heteroaryl, each of which is optionally substituted, wherein the particles are fabricated of a water soluble biodegradable polymer selected from the group consisting of poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and poly(hydroxybutyrate).

In an embodiment, the biodegradable polymer is poly(lactic acid-co-glycolic acid).

Detailed Description

This disclosure relates to the finding that local administration of a xanthine derivative, e.g., pentoxifylline, has produced unexpected improvement in treating a fibrotic disease. For example, intracavernosal injection of a composition comprising pentoxifylline has resulted remarkable improvement to symptoms of PD, such as erectile dysfunction. Furthermore, intracavernosal injection of pentoxifylline has been found to produce fewer side effects.

Accordingly, provided herein are pharmaceutical formulations of xanthine or a xanthine derivative, such as pentoxifylline, kits thereof, and methods for treating a fibrotic disease by local administration.

Definitions

Before describing the present invention in detail, it is to be understood that this invention is not limited to particular drugs or drug delivery systems, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a nonspecific phosphodiesterase inhibitor" includes a mixture of two or more nonspecific phosphodiesterase inhibitors, and reference to "an excipient or carrier" includes mixtures of two or more excipients or carriers, and the like.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

"Alkyl" as used herein refers to a linear or branched saturated hydrocarbon group.

Non-limiting examples of C1-C6 alkyl include methyl, ethyl, n-, and iso-propyl, n-, iso-, sec-, and t-butyl, n-pentyl, n-hexyl, 1,3 - dimethylbutyl, 3,3-dimethylbutyl.

"Alkenyl" as used herein refers to an alkyl group with at least one double bond.

"Alkynyl" as used herein refers to an alkyl groups with at least one triple bond.

"Cycloalkyl" as used herein refers to a monocyclic or bicyclic saturated hydrocarbon group, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexanyl.

"Heterocyclyl" as used herein refers to a cycloalkyl group with at least one heteroatom, such as N, O, S, and P. Non-limiting examples of heterocyclyl include aziridinyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl.

"Aryl" as used herein refers to a monocyclic or a bicyclic aromatic hydrocarbon group, including, but not limited to, phenyl and naphthyl.

"Heteroaryl" as used herein refers to an aryl group with at least one heteroatom, such as, N, O, S, and P. Non-limiting examples of heteroaryl include pyrrolyl, imidazolyl, furanyl, pyridinyl, and pyrazinyl. "Acyl" as used herein refers to a group of formula ^ ^R , wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which can be optionally substituted.

The term "fibrotic disease" as used herein refers to conditions where the

fibroproliferative response produces an abnormal accumulation of fibrocellular scar tissue that compromises the normal architecture and function of the affected tissue. Non- limiting examples of fibrotic disease include Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, keloid scars, pulmonary fibrosis, liver fibrosis, renal fibrosis, and vascular fibrosis.

The term "erectile dysfunction" is intended to include any and all types of erectile dysfunction, including: vasculogenic, neurogenic, endocrinologic and psychogenic impotence ("impotence" is used herein its broadest sense to indicate an inability, or a periodic or consistent inability, to achieve or sustain an erection of sufficient rigidity for sexual intercourse; see U.S. Pat. No. 5,242,391); Peyronie's syndrome; priapism; premature ejaculation; and any other condition, disease or disorder, regardless of cause or origin, which interferes with at least one of the three phases of human sexual response, i.e., desire, excitement and orgasm (see Kaplan, Disorders of Sexual Desire (New York, N.Y.: Brunner Mazel Book Inc., 1979)). Generally, however, the erectile dysfunction referred to herein is vasculogenic erectile dysfunction, particularly vasculogenic impotence.

The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. The present method of "treating" a fibrotic disease, as the term is used herein, thus encompasses both prevention of the disorder in a predisposed individual and treatment of the disorder in a clinically symptomatic individual.

The term "phosphodiesterase inhibitor" as used herein is intended to mean an agent that is capable of inhibiting or selectively reducing the activity of any one or more phosphodiesterases.

The term "active agent" used herein refers to a chemical material or compound that induces a desired effect, e.g., reduction of fibrosis scars and/or improvement of other symptoms.

"Excipient or carrier" as used herein refers to excipients or carrier materials suitable for local drug administration. Excipient or carriers useful herein include any such material known in the art which is nontoxic and does not interact with other components of the composition in a deleterious manner.

By an "effective" amount of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, e.g., reduction of fibrosis scars and/or improvement of other symptoms.

Additional pharmacologically active agents may be optionally delivered along with the primary active agent, i.e., the nonspecific phosphodiesterase inhibitor. Non- limiting examples of the active agent include nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertensive agents, vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins, and vasoactive intestinal peptide.

Non-limiting examples of nitrovasodilators include nitroglycerin, linsidomine such as insidomine chlorhydrate ("SIN-1"), molsidomine, organic nitrates such as isosorbide dinitrate, erythrityl tetranitrate and amyl nitrate, sodium nitroprusside, S-nitrosothiols such as S-nitroso-N-acetyl-d,l-penicillamine ("SNAP"), S-nitroso-N -cysteine and S-nitroso- N-glutathione ("SNO-GLU"), and diazenium diolates ("NONOates") such as (Z)-1-{N- methyl-

N-[6-(N-methyl-ammoniohexyl)amino]}diazen-l-ium- l,2-diolate, (Z)-l-[N-(3- ammoniopropy l)-N-(n-propyl)amino] diazen- 1 -ium- 1 ,2-diolate, (Z)- 1 - {N- [3 -aminopropyl] -N- [4-(3-aminopropylammonio)butyl]amino}diazen- l-ium- l,2-diolate and sodium (Ζ)- Ι-(Ν,Ν- diethylamino)-diazen-l-ium-l,2-diolate.

Non-limiting examples of alpha receptor blocking agents include phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trimazosin, alffizosin, tamsulosin and indoramin.

Non-limiting examples of ergot alkaloids include ergotamine and ergotamine analogs, such as acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride.

Non-limiting examples of antihypertensive agents include diazoxide, hydralazine and minoxidil.

Non-limiting examples of vasodilators include nimodipine, pinacidil, cyclandelate and isoxsuprine.

Non-limiting examples of naturally occurring prostaglandins include PGE₀, PGEi, PGA1, PGBi, PGFi_a, 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE₂, PGA₂, PGB₂, 19- hydroxy-PGA2, 19-hydroxy-PGB2, PGE3, PGF3_a. Non-limiting examples of semisynthetic or synthetic derivatives of natural prostaglandins include carboprost tromethamine, dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and tiaprost.

Non-limiting examples of nonspecific phosphodiesterase inhibitors include theophylline, theobromine, 3-isobutyl-l-methylxanthine (IBMX), and pentoxifylline.

In some embodiments, additional pharmacological agents that may be optionally delivered along with the primary active agent include anesthetic(s) (i.e., substances or compounds that induce insensitivity to pain such as a temporary loss of sensation). Those having ordinary skill in the art will select such anesthetic(s) and their concentrations, if desired. As a non-binding guideline only, the concentration of an anesthetic in the composition may be between about 0.1 mass % and about 0.5 mass %.

Non-limiting examples of acceptable anesthetics that may be so used include lidocaine, tetracaine, proparacaine, procaine or dyclonine.

Furthermore, if desired, other pharmacological agents, for example, without limitations, anti-bacterial agent(s) (i.e., antibiotics), antiviral medicament(s) or antifungal medicament(s), may be optionally additionally included for delivery along with the primary active agent. Those having ordinary skill in the art will select such additional agents and their concentration, if desired.

The active agents may be administered, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology, and involve reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of acid moieties which may be present on a phosphodiesterase inhibitor molecule are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Particularly preferred basic salts herein are alkali metal salts, e.g., the sodium salt, and copper salts. Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug. The esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Amides and prodrugs may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs are typically prepared by covalent attachment of a moiety which results in a compound that is therapeutically inactive until modified by an individual's metabolic system.

The terms "local administration" and "locally administering" as used herein refer to treatment of a fibrotic disease by administering at sites approximate to local symptoms (e.g., PD plaques) of the fibrotic 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 intracavernosal injection, topical administration, and transdermal administration.

The term "intracavernosal" as used herein refers to an injection into one or both corpora of the corpora cavernosal tissues of the penis.

The term "transdermal" delivery includes both transdermal (or "percutaneous") and transmucosal administration, i.e., delivery by passage of a drug through the body surface, i.e., the skin or mucosal tissue. "Transdermal" delivery is also intended to encompass delivery of a drug by passage across scrotal tissue. Examples of conventional transdermal drug delivery systems include transdermal "patches" wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is typically contained in a layer, or "reservoir," underlying an upper backing layer. The laminated device may contain a single reservoir, or it can contain multiple reservoirs. The reservoir can comprise a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Non-limiting examples of suitable skin contact adhesive materials include polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyure thanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or a liquid or hydrogel reservoir, or some other form.

The term "topical administration" is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa. Examples of formulations for topical drug delivery include ointments and creams. Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent include viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

Methods of Treatment

In one aspect, provided herein is a method for treating a fibrotic disease in a subject i need thereof, which comprises locally administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:

(I),

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and R³ are each, independently, H, Ci-Ce alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.

In another aspect, provided herein is a method for treating Peyronie's disease in a subject in need thereof, which comprises locally administering to the subject a

pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:

(I),

or a pharmaceutically acceptable salt thereof, wherein

R¹, R² and R³ are each, independently, H, C₁-C6 alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.

In certain embodiments of the methods, R¹, R² and R³ are each, independently, H, or optionally substituted C₁-C6 alkyl.

In other embodiments, R¹, R² and R³ are each, independently, H, Ci-Ce alkyl, or Ci-Ce alkyl substituted with acyl.

In still other embodiments, the compound of formula I is a nonspecific

phosphodiesterase inhibitor (PDEi). In certain embodiments, the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl- l-methylxanthine (IBMX).

In yet other embodiments, the compound of formula I is selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.

In another aspect, 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 therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt thereof, wherein the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3-isobutyl- l-methylxanthine (IBMX).

In yet another aspect, provided herein is a method for treating Peyronie's disease in a subject in need thereof, which comprises injecting into at least one of the corpus cavernosa of the penis of the subject a pharmaceutical formulation comprising, consisting essentially of or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt thereof, wherein the nonspecific PDEi is pentoxifylline, aminophylline, enproiylline, isbufylline, theophylline, theobromine, or 3-isobutyl-l-methylxanthine (IBMX).

In particular embodiments of the methods provided above, the pharmaceutical formulation consists essentially of pentoxifylline or a pharmaceutically acceptable salt thereof.

The fibrotic disease includes Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid scars. In certain particular embodiments, the fibrotic disease is Peyronie's disease. In other embodiments, the fibrotic disease is keloid scar.

The treatment method leads to improvement of various fibrotic conditions, for example, reduction of fibrotic scars. In certain particular embodiments, the treatment of Peyronie's disease results in reduction of PD plaques. In other embodiments, the treatment results in improvement of erectile dysfunction. In certain embodiments, the erectile dysfunction is associated with PD.

In certain embodiments, the pharmaceutical formulation is administered locally to treat erectile dysfunction. In particular embodiments, the erectile dysfunction is associated with Peyronie's disease.

In certain embodiments of the methods for treating keloid scars in a subject in need thereof, the pharmaceutical formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and caffeine. In other embodiments, the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and EGCG (green tea catechin). In still other embodiments, the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g., tranilast. These formulations can be injected into the keloid scars. In certain embodiments, the pharmaceutical formulation further comprises a pharmaceutically acceptable excipient or carrier, including, but not limited to, an antioxidant, an adjuvant or synergist, and a preservative.

Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-tocopherol natural, d- a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, tocopherols. Non-limiting examples of the adjuvant or synergist are citric acid, EDTA

(ethylenediaminetetraacetate) and salts, hydroxy quinoline sulfate, phosphoric acid, and tartaric acid.

In particular embodiments, the pharmaceutical formulation further comprises an EDTA sodium salt. 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.

In particular embodiments, the pharmaceutical formulation further comprises an EDTA magnesium salt. 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 of the 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

acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, β-Phenylethyl alcohol, thimerosal. In particular embodiments, the preservative is benzyl alcohol.

In particular embodiments, the pharmaceutical formulation further comprises ethanol. The 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 other embodiments, the pharmaceutical formulation further comprises benzyl alcohol. The benzyl alcohol 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, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the formulation.

In other embodiments, the pharmaceutical formulation is filtered before local administration. In particular embodiments, the pharmaceutical 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 pharmaceutical formulation has a pH of between 5.5 and 6. The pH can be adjusted by adding acids or bases, e.g., HC1 or NaOH.

In other embodiments of the methods, the therapeutically effective amount is between 4 mg and 20 mg. In particular embodiments, the therapeutically effective amount is between 6 mg and 10 mg. In other embodiments of the methods, the pharmaceutical formulation is administered one to four times in a twenty-four hour period. In particular embodiments, the

pharmaceutical formulation is administered daily until desired effects are achieved.

In certain embodiments of the methods, the pharmaceutical formulation comprises a unit dosage of the compound of formula I. In particular embodiments, the pharmaceutical formulation comprises a unit dosage of pentoxifylline.

The pharmaceutical formulation can be administered to a subject in need thereof by various local administrations. In certain embodiments, the pharmaceutical formulation is administered topically. In other embodiments, the pharmaceutical formulation is administered transdermally. In still other embodiment, the pharmaceutical formulation is administered locally to the penis of the subject. In particular embodiments, the

pharmaceutical formulation is administered by intracavernosal injection.

In certain particular embodiment, provided herein is a method for treating Peyronie's disease in a subject in need thereof, comprising injecting into at least one of the corpus cavernosa of the penis of the subject a pharmaceutical formulation consisting essentially of a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt thereof.

In certain embodiments of the methods, the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the fibrotic disease. In particular embodiments of the methods for treating Peyronie's disease, the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the Peyronie's disease. In other embodiments of the methods for treating Peyronie's disease, the pharmaceutical formulation is administered (e.g., intracavernosally injected) at the base of the penis about 2 cm from where the penis attaches to the abdomen.

In certain embodiments of the methods, the pharmaceutical formulation further comprises a second active agent. In particular embodiments, the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine. In other embodiments, the second active agent is a nonspecific phosphodiesterase inhibitor as defined above, e.g., pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and/or 3-isobutyl- l-methylxanthine (IBMX). In still other embodiments, the second active agent is selected from the group consisting of nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertensive agents, vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins, and/or vasoactive intestinal peptide. In other embodiments of the methods for treating Peyronie's disease, the

pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®. In certain particular embodiments, the pharmaceutical formulation comprises, consists essentially of or consists of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.

The methods provided herein can be used as a mono therapy or a part of a combo therapy. In certain embodiments, the formulation comprising the compound of formula I, e.g, pentoxifylline, is used as a mono therapy. In certain particular embodiments, the formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used as a mono therapy to treat a fibrotic disease, such as Peyronie's disease.

In other embodiments, the formulation comprising the compound of formula I, e.g, pentoxifylline, is used as a part of a combo therapy. In certain particular embodiments, the formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used to treat a fibrotic disease, such as Peyronie's disease, in combination with a collagenase therapy, e.g., collagenase Clostridium histolyticum or Xiaflex®.

Pharmaceutical Formulation

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein R¹, R² and R³ are each, independently, H, C₁-C6 alkyl, C₂-C6 alkenyl, C₂-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.

In one embodiment, R¹, R² and R³ are each, independently, H, or optionally substituted C₁-C6 alkyl.

In another embodiment, R¹ is CH₃-C(0)-(CH₂)4 and each of R² and R³ is CH₃.

In another embodiment, R¹, R² and R³ are each, independently, H, C₁-C6 alkyl, or Ci- (, alkyl substituted with acyl. In still another embodiment, the compound of formula I is a nonspecific

phosphodiesterase inhibitor (PDEi). In one embodiment, the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl-l-methylxanthine (IBMX).

In yet another embodiment, the compound of formula I is selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.

Also provided herein is a pharmaceutical formulation comprising, consisting essentially of or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl-l-methylxanthine (IBMX).

In certain particular embodiments, the pharmaceutical formulation comprises, consists essentially of or consists of a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration.

The formulations are useful in treating fibrotic diseases. The fibrotic diseases include Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid scars. In certain particular embodiments, the formulation is useful in treating Peyronie's disease. In other embodiments, the formulation is useful in treating keloid scars.

In certain embodiments, the pharmaceutical formulation results in improvement of fibrotic conditions, for example, reduction of fibrotic scars. In certain particular

embodiments, the formulation reduces PD plaques. In other embodiments, the formulation results in improvement of erectile dysfunction. In certain embodiments, the erectile dysfunction is associated with PD.

In certain embodiments of the formulations for treating keloid scars in a subject in need thereof, the pharmaceutical formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline, and caffeine. In other embodiments, the formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline, and EGCG. In still other embodiments, the formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g., tranilast. The formulations can be injected into the keloid scars. The pharmaceutically acceptable excipient or carrier includes, but is not limited to, an antioxidant, an adjuvant or synergist, and/or a preservative.

Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-tocopherol natural, d- a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, and tocopherols.

Non-limiting examples of the adjuvant or synergist are citric acid, EDTA

In other embodiments, the pharmaceutical formulation further comprises benzyl alcohol. The benzyl alcohol 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, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the formulation. In other embodiments, the pharmaceutical formulation is filtered before local administration. In particular embodiments, the pharmaceutical formulation is filtered through a 0.22 micron filter before local administration.

In other embodiments, the pharmaceutical formulation has a pH of between 4 to 8. In particular embodiments, the pharmaceutical formulation has a pH of between 5.5 and 6. The pH can be adjusted to 5.5-6 by adding acids or bases, e.g., HC1 or NaOH.

In other embodiments of the pharmaceutical formulations, the therapeutically effective amount is between 4 mg and 20 mg. In particular embodiments, the therapeutically effective amount is between 6 mg and 10 mg.

In other embodiments, the pharmaceutical formulation is administered one to four times in a twenty-four hour period. In particular embodiments, the pharmaceutical formulation is administered daily until desired effects are achieved.

In certain embodiments, the pharmaceutical formulation comprises a unit dosage of the compound of formula I. In particular embodiments, the pharmaceutical formulation comprises a unit dosage of pentoxifylline.

The pharmaceutical formulation can be administered to a subject in need thereof by various local administration, e.g., intravacernosal injection, topical administration, and transdermal administration. In particular embodiments, the pharmaceutical formulation comprises a sterile liquid composition, and the pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection. In other embodiments, the pharmaceutical formulation is suitable for topical or transdermal administration. In certain particular embodiments, the pharmaceutical formulation comprises a composition to be applied to a body surface, and the pharmaceutically acceptable excipient or carrier is suitable for topical or transdermal administration. In certain embodiments, the pharmaceutical composition is an ointment, cream, gel or lotion.

In certain embodiments, the pharmaceutical formulation is not administered (e.g., intracavemosally injected) directly into the area of the fibrotic disease. In particular embodiments of the pharmaceutical formulations, the pharmaceutical formulation is not administered (e.g., intracavemosally injected) directly into the area of the Peyronie's disease. In other embodiments of the pharmaceutical formulations, the pharmaceutical formulation is administered (e.g., intracavemosally injected) at the base of the penis about 2 cm from where the penis attaches to the abdomen.

In certain embodiments, the pharmaceutical formulation further comprises a second active agent. In particular embodiments, the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine. In other embodiments, the second active agent is a nonspecific phosphodiesterase inhibitor as defined above, e.g., pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and/or 3- isobutyl-l-methylxanthine (IBMX). In still other embodiments, the second active agent is selected from the group consisting of nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertenseive agents, vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins, and/or vasoactive intestinal peptide.

In other embodiments, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®. In certain particular embodiments, the pharmaceutical formulation comprises, consists essentially of or consists of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.

The pharmaceutical formulations provided herein can be used as a mono therapy or a part of a combo therapy. In certain embodiments, the pharmaceutical formulation comprising the compound of formula I, e.g, pentoxifylline, is used as a mono therapy. In certain particular embodiments, the pharmaceutical formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used as a mono therapy to treat a fibrotic disease, such as PD.

In other embodiments, the formulation comprising the compound of formula I, e.g, pentoxifylline, is used as a part of a combo therapy. In certain embodiments, the formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used to treat a fibrotic disease, such as Peyronie's disease, in combination with a collagenase therapy, e.g., collagenase Clostridium histolyticum or Xiaflex®.

In one particular embodiment, provided herein is a pharmaceutical formulation consisting essentially of a therapeutically effective amount of pentoxifylline or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier suitable for intracavernosal administration.

Kit

In one aspect, provided herein is a kit comprising: a pharmaceutical formulation containing a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein

R¹, R² and R³ are each, independently, H, Ci-Ce alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;

an apparatus for locally administering the formulation;

In one embodiment, R¹, R² and R³ are each, independently, H, or optionally substituted C1-C6 alkyl.

In another embodiment, R¹, R² and R³ are each, independently, H, C1-C6 alkyl, or Ci-

Ce alkyl substituted with acyl.

In still another embodiment, the compound of formula I is a nonspecific

phosphodiesterase inhibitor (PDEi). In one embodiment, the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl- l-methylxanthine (IBMX).

In another aspect, provided herein is a kit comprising: a pharmaceutical formulation comprising, consisting essentially of or consisting of a therapeutically effective amount of a nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3-isobutyl- l-methylxanthine (IBMX); an apparatus for locally administering the formulation; a container for housing the formulation and the drug delivery apparatus; and instructions for use.

In certain particular embodiments, the pharmaceutical formulation comprises, consists essentially of or consists of a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

In certain embodiments, the kits are used to treat a fibrotic disease. Non-limiting examples of the fibrotic disease include Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid scars. In particular embodiments, the fibrotic disease is Peyronie's disease. In other embodiments, the fibrotic disease is keloid scars.

In other embodiments of the kits, the pharmaceutical formulation results in improvement of fibrotic conditions, for example, reduction of fibrotic plaques. In particular embodiments, the formulation reduces PD plaques. In other embodiments, the formulation improves erectile dysfunction. In certain embodiments, the erectile dysfunction is associated with PD.

In other embodiments of the kits, the pharmaceutical formulation is administered locally to treat erectile dysfunction. In particular embodiments, the erectile dysfunction is associated with Peyronie's disease.

In certain embodiments of the formulations for treating keloid scars in a subject in need thereof, the pharmaceutical formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and caffeine. In other embodiments, the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and EGCG. In still other embodiments, the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g., tranilast. The formulations can be injected into the keloid scars.

In certain embodiments, the pharmaceutical formulation further comprises a pharmaceutically acceptable excipient or carrier, including, but not limited to, an antioxidant, an adjuvant or synergist, and a preservative.

Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-tocopherol natural, d- a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, tocopherols.

Non-limiting examples of the adjuvant or synergist are citric acid, EDTA

In particular embodiments, the pharmaceutical formulation further comprises an

EDTA sodium salt. 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. In particular embodiments, the pharmaceutical formulation further comprises an EDTA magnesium salt. 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 of the formulation.

acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, β-Phenylethyl alcohol, and thimerosal. In particular embodiments, the preservative is benzyl alcohol. The benzyl alcohol 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, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the formulation.

In still other embodiments of the kits, the therapeutically effective amount is between 4 mg and 20 mg. In particular embodiments, the therapeutically effective amount is between 6 mg and 10 mg.

In certain embodiments, the pharmaceutical formulation is administered one to four times in a twenty-four hour period. In other embodiments, the pharmaceutical formulation is administered daily until desired effects are achieved.

In still other embodiments, the pharmaceutical formulation is filtered through a 0.22 micron filter. In particular embodiments, the pharmaceutical formulation is to be filtered through a 0.22 micron filter before administration.

In other embodiments, the pharmaceutical formulation has a pH of between 4 and 8.

In particular embodiments, the pharmaceutical formulation has a pH of between 5.5 and 6.

The pH can be adjusted to 5.5-6 before administration by adding acids or bases, e.g., HC1 or

NaOH.

Furthermore, the pharmaceutical formulation is administered locally. In certain embodiments, the pharmaceutical formulation comprises a sterile liquid composition and the pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection. In other embodiments, the pharmaceutical formulation comprises an ointment, cream, gel, or lotion, and the pharmaceutical acceptable excipient or carrier is suitable for topical or transdermal administration.

In certain particular embodiments, the pharmaceutical formulation consists essentially of a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier suitable for intracavernosal administration.

In certain embodiments, the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the fibrotic disease. In particular embodiments, the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the Peyronie's disease. In other embodiments, the pharmaceutical formulation is administered (e.g., intracavernosally injected) at the base of the penis about 2 cm from where the penis attaches to the abdomen.

In certain embodiments of the kits, the pharmaceutical formulation further comprises a second active agent. In particular embodiments, the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine. In other embodiments, the second active agent is a nonspecific phosphodiesterase inhibitor as defined above, e.g., pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and/or 3- isobutyl-l-methylxanthine (IBMX). In still other embodiments, the second active agent is selected from the group consisting of nitrovasodilators, alpha receptor blocking agents, ergot alkaloids, antihypertenseive agents, vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins, and/or vasoactive intestinal peptide.

In some additional embodiments, the pharmaceutical composition comprises yet another component, a polysaccharide. Some exemplary polysaccharides that may be used include, without limitations, any of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, keratin, and pharmaceutically acceptable water-soluble salts thereof, and

combinations of more than one of such polysaccharides. Polysaccharides may be used both in compositions comprising solely compound I as an active agent and in compositions containing both compound I and the above-described second active compound.

In other embodiments, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®. In certain particular embodiments, the pharmaceutical formulation consists essentially of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.

In certain embodiments, the pharmaceutical formulation comprising the compound of formula I, e.g., pentoxifylline, is used as a mono therapy. In certain particular embodiments, the pharmaceutical formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used as a mono therapy to treat a fibrotic disease, such as Peyronie's disease.

In other embodiments, the formulation comprising the compound of formula I, e.g., pentoxifylline, is used as a part of a combo therapy. In certain embodiments, the formulation consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used to treat a fibrotic disease, such as Peyronie's disease, in combination with a collagenase therapy, e.g., collagenase Clostridium histolyticum or Xiaflex®.

In additional embodiments, the above described pharmaceutical formulations (both with and without the polysaccharide) may be incorporated within microparticles. The microparticles may be essentially spherical particles (shells) fabricated of a water soluble biodegradable polymer defining a space therein, which space is to be filled with

pharmaceutical formulation. Thus, the microparticles represent the structures where the water soluble biodegradable polymer envelops the formulation securely ensconcing the latter and not allowing the formulation to escape or to leak out.

The formulation filled microparticles can be manufactured according to methods and techniques known to those having ordinary skill in the art. The size of microparticles may be typically less than about 100 μιη in diameter, and the exemplary water soluble polymer to be used to manufacture the shells may be, without limitations, any of poly(lactic acid-co- glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone),

poly(hydroxybutyrate) and blends thereof. In one typical example, poly(lactic acid-co- glycolic acid) can be used to form the shells, with the 50:50 (mass) ratio between the units derived of lactic and glycolic acids. Other acceptable ratios between the lactic and glycolic acid portions may be 65:35, 75:25 and 85: 15. Those having ordinary skill in the art using poly (lactic acid-co-gly colic acid) may select a different ratio, if desired. The inherent viscosities (i.e., the ratio of the natural logarithm of the relative viscosity to the mass concentration of the polymer) of the polymer solutions used to form the shells may be between about 0.15 dL/g and about 1.20 dL/g, such as between about 0.15 dL/g and 0.25 dL/g, or the following ranges: 0.26-0.54, 0.55-0.75, 0.62-0.65, 0.65-0.85, 0.76- 0.94 and 0.95-1.20 dL/g.

When the above described microparticles have been fabricated, they can then be administered to a patient in need of the medication by conventional methods, such as intracavernosal injections. The following examples are provided to further elucidate the advantages and features of the present invention, but are not intended to limit the scope of the invention. The examples are for illustrative purposes only. USP pharmaceutical grade products were used in preparing the formulations described below.

Examples

Example 1. Preparing Pentoxifylline Formulations

Several pentoxifylline formulations were prepared using the compounds described in Table 1 in the quantities shown:

Table 1.

1. Pentoxifylline 2% (active)

2. Ethanol 10% (cosolvent)

3. Edetate Disodium 0.1% (antioxidant/preservative)

Formulation 1 4. Benzyl Alcohol 0.9% (preservative)

5. Hydrochloric Acid qs (pH adjustment/buffer)

6. Sodium Hydroxide qs (pH adjustment/buffer)

7. Water for injection qs ad

1. Pentoxifylline 0.1%-2.5%

2. Ethanol 0.1%-10%

3. Edetate Disodium 0.02%-0.1%

Formulation 2 4. Benzyl Alcohol 0.9%

5. Hydrochloric Acid qs or citric acid qs

6. Sodium Hydroxide qs or sodium citrate qs

7. Water for injection qs ad

1. Pentoxifylline 2%

2. Propylene glycol 0.5%-5%

3. Edetate Disodium 0.1%

Formulation 3 4. Benzyl Alcohol 0.9%

5. Hydrochloric Acid qs

6. Sodium Hydroxide qs

7. Water for injection qs ad

1. Pentoxifylline 2%

2. Ethanol 10%

3. Edetate Disodium 0.1%

Formulation 4 4. Benzyl Alcohol 0.9% or benzalkonium chloride 0.005-0.02% or

hydroxy quinoline sulfate 0.005%- 0.01%

5. Hydrochloric Acid qs

6. Sodium Hydroxide qs

7. Water for injection qs ad

1. Pentoxifylline 2%

Formulation 5 2. No cosolvent

3. No Antioxidant

4. Benzyl Alcohol 0.9% or any preservative 5. Hydrochloric Acid or citric acid qs

6. Sodium Hydroxide or sodium citrate qs

7. Water for injection qs ad

1. Alprostadil 0.005%

2. Papaverine 3%

3. Phentolamine 0.3%

4. Pentoxifylline 0.6%

Formulation 9 5. Ethanol 10%

3. Edetate Disodium 0.1%

4. Benzyl Alcohol 0.9%

5. Hydrochloric Acid qs or citric acid qs

6. Sodium Hydroxide qs or sodium citrate qs

7. Water for injection qs ad

Example 2. Preparing A Caffeine Formulation

A formulation was prepared using the compounds described in Table 2 in the quantities shown:

Table 2.

1. Caffeine 0.1-2.5% (as caffeine base or caffeine citrate) (active)

2. Ethanol 10% (cosolvent)

3. Edetate Disodium 0.1% (antioxidant/preservative)

Formulation 6 4. Benzyl Alcohol 0.9% (preservative)

5. Hydrochloric Acid qs or citric acid (pH adjustment/buffer)

6. Sodium Hydroxide qs or sodium citrate (pH adjustment/buffer)

7. Water for injection qs ad

Example 3. Preparing Aminophylline and Theophylline Formulations

The following formulations were prepared using the compounds described in Table 3 in the quantities shown:

Table 3.

Examples 4-6. Intracavernosal Injections of a Pentoxifylline Formulation

In Example 4, a 63 year old male with erectile dysfunction found that a combination of three vasoactive drugs: phentolamine, alprostadil, and papaverine, had no effect on his erectile dysfunction. A new injection was reformulated to contain the 3 vasoactive drugs mentioned above along with the addition of pentoxifylline, and was administered to the patient.

Various combined strengths of phentolamine, alprtostadil, papaverine and pentoxifylline were used in an attempt to improve his erectile dysfunction without demonstrable effects. However, the patient did notice remarkable improvement at a pentoxifylline dose of 4 mg per injection. The improvement was more remarkable at a 6 mg dose.

In Examples 5 and 6, patients suffering from Peyronie's disease were treated. A therapy cycle included injections of sterile pentoxifylline. More specifically, 6 separate injections were to be conducted over every two weeks. The dosage was 5 mg of pentoxifylline in a 1 ml volume. Single use vials were dispensed. The injections were made using a 21 gauge cannula directly into the Peyronie's plaque. A nerve block was done around the injection site to lessen the pain. Manual manipulation and traction techniques were employed to massage the area of the injection. Patients returned after two weeks for another injection and manual manipulation session.

Baseline measurements were collected before any treatment occurred to characterize the extent of the patient's disease. The degree of curvature was noted, as well as any pain/discomfort that the patient presently had and current sexual ability. Psychosocial effects related to the patient's disease were observed as well.

In Example 5, the patient suffering from Peyronie's disease was brought to the procedure room, prepared and draped in the usual sterile fashion. As a baseline characteristic of the disease state, the patient had 40 degrees dorsal and the location of the Peyronie's plaque was at dorsal and mid-shaft.

A total of 1 mL of 1% lidocaine was used to perform a local block. Once the patient was anesthetized, the plaque was isolated between two fingers and 1 mL of 5 mg pentoxyfilline was injected into the plaque in a fan-like fashion. The patient tolerated the procedure well. The patient held pressure, and a light compressive dressing was applied. The patient was instructed to keep this in place for three hours and then remove it. He was further instructed not to have sexual intercourse or masturbate for 24 hours. In Example 6, another the patient suffering from Peyronie's disease was treated in the same fashion as the patient in Example 5. As a baseline characteristic of the disease state, the patient had 40 degrees dorsal and the location of the Peyronie's plaque was at dorsal and distal 2x1.

The patient tolerated the procedure well and received the same instructions as the patient in Example 5.

Example 7. Preparing Pentoxifylline Formulations Containing a Polysaccharide

A pentoxifylline formulation (formulation 10) may be prepared using the following components in the amounts indicated:

(1) about 2.0 g of pentoxifylline in the form of dry powder;

(2) about 1.0 of sodium hyaluronate in the form of dry powder;

(3) about 0.515 g of sodium chloride, granulated;

(4) about 100 L of sterile water for injections.

All dry components can be mixed, weighed and mixed with about 90% of water. The pH can then be adjusted to be within 6.0 to 7.0 range using 1% solution of sodium hydroxide, followed by adding the balance of water, filtering and sealing in pre-sterilized amber vials.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Incorporation by Reference

The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference.

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

Claims

1. A pharmaceutical formulation for use in treating a fibrotic disease in a subject in need thereof, comprising locally administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical formulation, the formulation comprising:

(a) a quantity of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

each of R¹, R² and R³ is independently selected from the group consisting of H, a Ci- Ce alkyl, a C -Ce alkenyl, a C -Ce alkynyl, a cycloalkyl, a heterocyclyl, an aryl, and heteroaryl, each of which is optionally substituted; and

(b) a quantity of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof.

2. The pharmaceutical formulation of claim 1, wherein each of R¹, R² and R³ is independently selected from the group consisting of H and an optionally substituted C 1-C6 alkyl.

3. The pharmaceutical formulation of claim 1, wherein each of R¹, R² and R³ is independently selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 alkyl substituted with acyl.

4. The pharmaceutical formulation of claim 1, wherein the compound of formula I is a nonspecific phosphodiesterase inhibitor (PDEi).

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

6. The pharmaceutical formulation of claim 1, wherein the fibrotic disease is Peyronie's disease.

7. The pharmaceutical formulation of claim 1, wherein administration of the formulation leads to improvement of erectile dysfunction.

8. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation has a pH of between 5.5 and 6.

9. The pharmaceutical formulation of claim 1, wherein the therapeutically effective amount is between 4 mg and 20 mg.

10. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is administered locally to the penis of the subject.

11. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is administered by intracavernosal injection.

12. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation further comprises a second active agent selected from the group consisting of alprostadil, papaverine, and phentolamine.

13. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation further comprises a collagenase.

14. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, a quantity of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof, and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein

each of R¹, R² and R³ is independently selected from the group consisting of H, a Ci- (, alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, an aryl, and heteroaryl, each of which is optionally substituted.

15. The formulation of claim 14, wherein each of R¹, R² and R³ is independently selected from the group consisting of H and an optionally substituted C1-C6 alkyl.

16. The formulation of claim 14, wherein each of R¹, R² and R³ is independently selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 alkyl substituted with acyl.

17. The formulation of claim 14, wherein the compound of formula I is a nonspecific PDEi.

18. The formulation of claim 17, wherein the nonspecific PDEi is selected from the group consisting pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and 3-isobutyl-l-methylxanthine.

19. The formulation of claim 14, having a pH of between 5.5 and 6.

20. The formulation of claim 14, wherein the therapeutically effective amount is between 4 mg and 20 mg.

21. The formulation of claim 14, further comprising a sterile liquid composition and wherein the excipient or carrier is suitable for intracavernosal injection.

22. The pharmaceutical formulation of claim 14, further comprising an additional active agent selected from the group consisting of alprostadil, papaverine, and phentolamine.

23. The pharmaceutical formulation of claim 14, further comprising a collagenase.

24. The pharmaceutical formulation of claim 14, further comprising an active agent selected from the group consisting of at least one anesthetic, at least one anti-bacterial agent, at least one antiviral medicament, at least one antifungal medicament and combinations thereof.

25. The pharmaceutical formulation of claim 24, wherein the anesthetic is selected from the group consisting of lidocaine, tetracaine, proparacaine, procaine, dyclonine and combinations thereof.

26. The method of claim 1, wherein the polysaccharide is sodium hyaluronate.

27. The formulation of claim 14, wherein the polysaccharide is sodium hyaluronate.

28. The formulation of claim 14, wherein the formulation is ensconced within essentially spherical particles fabricated of a water soluble biodegradable polymer selected from the group consisting of poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(gly colic acid), poly(caprolactone), and poly(hydroxybutyrate).

29. The formulation of claim 28, wherein the biodegradable polymer is poly(lactic acid-co- glycolic acid).

30. A pharmaceutical composition comprising essentially spherical particles incorporating a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof and a pharmaceutically acceptable excipient or carrier suitable for local administration, wherein

each of R¹, R² and R³ is independently selected from the group consisting of H, a Ci- (, alkyl, a C₂-C6 alkenyl, a C₂-C6 alkynyl, a cycloalkyl, a heterocyclyl, an aryl, and heteroaryl, each of which is optionally substituted,

wherein the particles are fabricated of a water soluble biodegradable polymer selected from the group consisting of poly (lactic acid-co-glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and poly(hydroxybutyrate)

31. The formulation of claim 30, wherein the biodegradable polymer is poly(lactic acid-co- glycolic acid).