JP2020523300A - Pharmaceutical preparation of xanthine or xanthine derivative and use thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation containing xanthine or a xanthine derivative, a kit thereof, and a method for treating fibrotic diseases by local administration.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under US Patent Application No. 15/620,430, filed June 12, 2017. U.S. Patent Application No. 15/620,430 is a continuation-in-part application of U.S. Patent Application No. 14/307,773, filed June 18, 2014, and U.S. Provisional Application No. filed June 18, 2013. Claims priority in accordance with 35 USC § 119(e) under 61/836,535. The entire contents of these applications are incorporated herein by reference.

The present disclosure relates to pharmaceutical formulations containing xanthine or xanthine derivatives such as pentoxifylline, and methods of treating fibrotic disorders such as Peyronie's disease by topical administration.

Fibrotic disorders are found in various tissues. For example, Peyronie's disease (PD) is a specialized intimal membrane of the corpus cavernosum (TA) fibromatosis (Hellstrom and Bivalacqua, 2000; Schwarzer et al., 2001; Jarowra, 1997; Devine et al., 1997. ). This usually results in penile deformity (curvature of the penis during erection), pain, and very frequent erectile dysfunction. Fibrotic disorders are also found in other tissues, such as lung fibrosis, liver fibrosis, renal fibrosis, vascular fibrosis and the like.

By reducing collagen synthesis and inducing myofibroblast apoptosis, it is possible to pharmacologically arrest or reduce the size of PD plaques and/or other fibrotic conditions. (Gonzalez-Cadavid et al., US Pat. No. 8,133,903).

Oral administration of non-specific PDEi's such as pentoxifylline has been suggested to help reduce collagen levels in Peyronie's disease plaques (Brant et al., Nature Clinical Practice Urology 2006, Vol 3, p. 111; 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 mild improvement.

Therefore, there is a need for a treatment for fibrotic disorders such as Peyronie's disease.

U.S. Pat. No. 8,133,903

Nature Clinical Practice Urology 2006, Vol 3, p.111 BJU International 2010, Vol 106, p.240

The present specification describes a pharmaceutical preparation containing xanthine or a xanthine derivative such as pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine), a kit thereof, and a method for treating fibrotic diseases by local administration. I will provide a.

（式中、Ｒ^１、Ｒ^２、及びＲ^３のそれぞれは独立に、Ｈ、それぞれ任意に置換されていてもよい、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、シクロアルキル、ヘテロシクリル、アリール、及びヘテロアリールからなる群から選択される。）
の化合物、又はその薬学的に許容される塩、エステル、アミド、もしくはプロドラッグ；及び
薬学的に許容される、局所投与に適した賦形剤又は担体
を含む、医薬製剤が提供される。 In one aspect, as used herein,
A therapeutically effective amount of Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ which may be optionally substituted, respectively. Selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.)
Or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof; and a pharmaceutically acceptable excipient or carrier suitable for topical administration.

In another aspect, herein,
A therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein each of R ¹ , R ² , and R ³ is independently H, Each selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.) A pharmaceutical formulation comprising:
A device for topical administration of the pharmaceutical formulation;
A kit is provided that includes a container containing the pharmaceutical formulation and a drug delivery device thereof; and instructions for use.

In yet another aspect, as used herein, a method of treating a fibrotic disorder, such as Peyronie's disease, wherein a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Each of R ¹ , R ² , and R ³ is independently H, each optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, cycloalkyl. , A heterocyclyl, an aryl, and a heteroaryl.) in a therapeutically effective amount topically to a subject in need of treatment for a fibrotic disease. Will be provided.

Each of R ¹ , R ² , and R ³ can be independently H, or optionally substituted C ₁ -C ₆ alkyl. R ^{1, R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, or acyl with can be a _C 1 -C ₆ alkyl substituted.

The compound of formula I can be a non-specific phosphodiesterase inhibitor (PDEi). The compound of formula I can also be selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.

As used herein, it consists essentially of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier suitable for topical administration. Pharmaceutical formulations, which consist of or consist of them, are also provided.

In another aspect, herein is provided a pharmaceutical formulation consisting essentially of or consisting of a non-specific PDEi or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof; A kit is provided, comprising: a device for carrying out; a container containing the pharmaceutical formulation and its drug delivery device; and instructions for use.

In yet another aspect, as used herein, a method of treating a fibrotic disorder, eg, Peyronie's disease, wherein a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable salt, ester, amide thereof, Alternatively, a method is provided that comprises topically administering to a patient in need of treatment of a fibrotic disease a therapeutic agent that consists essentially of, or consists of, a prodrug in a therapeutically effective amount.

The non-specific PDEi mentioned can be pentoxifylline, aminophylline, enprophylline, isobufylline, theophylline, theobromine, and 3-isobutyl-1-methylxanthine (IBMX).

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

Fibrotic disorders include Peyronie's disease, Raynaud's syndrome, psoriatic plaques, eczema, keloid scars. In certain embodiments, the fibrotic disease is Peyronie's disease or keloid scar.

In certain embodiments, the pharmaceutical formulations, kits, and methods described above relate to the treatment of Peyronie's disease or erectile dysfunction. Erectile dysfunction may be associated with Peyronie's disease.

In another embodiment, the pharmaceutical formulations, kits thereof, and methods described above relate to the treatment of keloid scars in a patient in need thereof. It can include, consist essentially of, or consist of non-specific PDEi (eg pentoxifylline) and caffeine. The pharmaceutical formulation can also include, consist essentially of, or consist of non-specific PDEi (eg pentoxifylline) and EGCG (green tea catechin). Furthermore, the pharmaceutical formulation can comprise, consist essentially of, or consist of a non-specific PDEi (eg pentoxifylline) and a mast cell stabilizer (tranilast). These formulations can be injected into keloid scars.

The pharmaceutical formulation can further include a pharmaceutically acceptable excipient or carrier. Excipients or carriers include, but are not limited to, antioxidants, adjuvants or synergists, and preservatives.

The pharmaceutical formulation can include EDTA sodium salt. EDTA sodium salt is 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. obtain.

The pharmaceutical formulation can also include EDTA magnesium salt. EDTA magnesium salt is 0-0.15% by weight of the formulation, such as 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. obtain.

The pharmaceutical formulation can further include ethanol. Ethanol can be 190 proof. Ethanol is 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. possible.

The pharmaceutical formulation can include benzyl alcohol. Benzyl alcohol is 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 weight of the formulation. Can be

The pharmaceutical formulation can be filtered prior to topical administration, for example through a 0.22μ filter.

The pharmaceutical formulation has a pH of 4-8. In certain embodiments, the pharmaceutical formulation has a pH of 5.5-6. The pH can be adjusted by adding acids or bases, such as HCl or NaOH.

A therapeutically effective amount can be between 4 mg and 20 mg. In certain embodiments, the therapeutically effective amount is 6 mg-10 mg.

The pharmaceutical formulation can be administered 1 to 4 times within a 24 hour period. In certain embodiments, pharmaceutical formulations are administered daily until the desired effect is achieved.

The pharmaceutical formulation may include a unit dose of a compound of Formula I. In certain embodiments, the pharmaceutical formulation comprises a unit dose of pentoxifylline.

The pharmaceutical formulation can be administered topically and transdermally to the patient's penis. In a particular embodiment, the pharmaceutical formulation is administered by intracavernosal injection. Accordingly, pharmaceutical formulations can include sterile liquid compositions such that a pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection. In another embodiment, the pharmaceutically acceptable excipient or carrier is suitable for topical or transdermal administration, and the formulation is a composition applied to a body surface, such as an ointment, cream, gel, or lotion. including.

In certain embodiments, the pharmaceutical formulation is not directly administered (eg, injected intracavernosally) to the area of fibrotic disease, eg, Peyronie's disease. In one particular embodiment for treating Peyronie's disease, the pharmaceutical formulation is administered (eg, intracavernosal injection) to the base of the penis approximately 2 cm from where the penis attaches to the abdomen.

The pharmaceutical formulation comprises a nitrovasodilator, an alpha receptor blocker, an ergot alkaloid, an antihypertensive, a vasodilator, a natural, semi-synthetic and synthetic prostaglandin, and a second active agent including a vasoactive intestinal peptide be able to. Vasodilators can be alprostadil (prostaglandin E ₁ ), papaverine, and phentolamine.

In certain embodiments of the pharmaceutical formulation, kit thereof, and method of treating Peyronie's disease, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®. Including. In certain embodiments, the pharmaceutical formulation comprises, consists essentially of, or consists of pentoxifylline and a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®. Consists of.

The formulations, kits, and methods provided herein can be used as monotherapy or as part of a combination therapy to treat fibrotic disorders such as Peyronie's disease. For example, a formulation containing a compound of Formula I, such as pentoxifylline, can be used as a monotherapy or as part of a combination therapy. Formulations consisting essentially of or consisting of non-specific PDEi's, such as pentoxifylline, may be used alone in combination with collagenase therapies such as collagenase Clostridium histolyticum or Xiaflex®. It can also be used as a therapy or as part of a combination therapy.

（式中、Ｒ^１、Ｒ^２、及びＲ^３のそれぞれは独立に、Ｈ、それぞれ任意に置換されていてもよい、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、シクロアルキル、ヘテロシクリル、アリール、及びヘテロアリールからなる群から選択される。）
の化合物又はその薬学的に許容される塩、エステル、アミド、もしくはプロドラッグ；
ある量の、ヒアルロン酸、ヘパリン、ヘパラン、コンドロイチン、デルマタン、ケラチン、及びその薬学的に許容される水溶性塩からなる群から選択される多糖類；及び
薬学的に許容される、局所投与に適した賦形剤又は担体
を含む、医薬製剤が提供される。 In this specification,
A therapeutically effective amount of Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ which may be optionally substituted, respectively. Selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.)
Or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof;
An amount of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof; and pharmaceutically acceptable, suitable for topical administration Pharmaceutical formulations are provided that include other excipients or carriers.

In one aspect, provided herein is a method of treating a fibrotic disorder in a patient in need thereof.
A pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and an amount of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof. There is provided a method comprising topically administering to a patient a therapeutically effective amount of a pharmaceutical formulation comprising a polysaccharide selected from the group.

In the formula, each of R ¹ , R ² , and R ³ is independently H, each optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl. , Cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The compound of formula I can be a non-specific phosphodiesterase inhibitor (PDEi). The non-specific PDEi can also be selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, and 3-isobutyl-1-methylxanthine. ..

In one embodiment, the fibrotic disease is Peyronie's disease. In one embodiment, the pharmaceutical formulation results in amelioration of erectile dysfunction.

In one embodiment, the pharmaceutical formulation has a pH between 5.5 and 6. In one embodiment, the therapeutically effective amount is between 4 mg and 20 mg.

In one embodiment, the pharmaceutical formulation further comprises a sterile liquid composition and the excipient or carrier is suitable for intracavernosal injection. In one embodiment, the pharmaceutical formulation is topically administered to the patient's penis. In one embodiment, the pharmaceutical formulation is administered by intracavernosal injection.

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

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

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

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

In another aspect, there is provided herein 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 suitable for topical administration. There is provided a pharmaceutical composition comprising essentially spherical particles incorporated with an agent or carrier. In formula I, each of R ¹ , R ² , and R ³ is independently H, optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, the particles are poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and It is made of a water-soluble biodegradable polymer selected from the group consisting of poly(hydroxybutyrate).

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

The present disclosure relates to the discovery that topical administration of xanthine derivatives, such as pentoxifylline, resulted in an unexpected improvement in the treatment of fibrotic disorders. For example, intracavernosal injection of a composition containing pentoxifylline resulted in a significant improvement in symptoms of PD such as erectile dysfunction. Furthermore, intracavernosal injection of pentoxifylline has been found to have fewer side effects.

Accordingly, provided herein are pharmaceutical formulations of xanthine or xanthine derivatives (eg, pentoxifylline, etc.), kits thereof, and methods of treating fibrotic disorders by topical administration.

[Definition]
Before describing the present invention in detail, it should be understood that the present invention is not limited to a particular drug or drug delivery system and 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.

As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural indicating patients unless the context clearly dictates otherwise. Must be kept in mind. Thus, for example, reference to "non-specific phosphodiesterase inhibitor" includes mixtures of two or more non-specific phosphodiesterase inhibitors, and reference to "excipient or carrier" includes two or more Mixtures of such excipients or carriers.

（式中、Ｒは、それぞれ任意に置換されていてよい、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロシクリル、又はヘテロアリールである。）の基を指す。 In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Non-limiting examples of C ₁ -C ₆ alkyl, methyl, ethyl, n-, and iso- propyl, n-, iso-, sec-, and t- butyl, n- pentyl, n- hexyl, 1 Includes 3,3-dimethylbutyl and 3,3-dimethylbutyl.
As used herein, “alkenyl” refers to an alkyl group that has at least one double bond.
As used herein, “alkynyl” refers to an alkyl group that has at least one triple bond.
As used herein, "cycloalkyl" 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 having at least two heteroatoms such as N, O, S, and P. Non-limiting examples of heterocyclyl include aziridinyl, azetidinyl, pyrrolidinyl, and tetrahydrofuranyl.
As used herein, "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group including, but not limited to, phenyl and naphthyl.
As used herein, “heteroaryl” refers to an aryl group having at least one heteroatom such as N, O, S, and P. Non-limiting examples of heteroaryl include pyrrolyl, imidazolyl, furanyl, pyridinyl, and pyrazinyl.
As used herein, "acyl" has the formula:

Wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted.

The term "fibrotic disease" as used herein refers to a condition in which a fibroproliferative response causes an abnormal accumulation of fibrotic scar tissue that impairs the normal structure and function of the affected tissue. Non-limiting examples of fibrotic disorders include Peyronie's disease, Raynaud's syndrome, psoriatic plaques, eczema, keloid scars, pulmonary fibrosis, liver fibrosis, renal fibrosis, and vascular fibrosis.

The term "erectile dysfunction" refers to angiogenic, neurogenic, endocrine, and psychogenic impotence ("impotence", in its broadest sense, achieving sufficient erection rigidity for intercourse or Inability to maintain, or exhibit periodic or consistent disability; see US Pat. No. 5,242,391); Peyronie's syndrome; priapism; premature ejaculation; and of human sexual response regardless of cause or origin. Includes three stages: desire, agitation, and other conditions, illnesses, or disorders that interfere with at least one of orgasms (see Kaplan, Disorders of Sexual Desire (New York, NY: Brunner Mazel Book Inc., 1979). It is intended to include all types of erectile dysfunction, but in general the erectile dysfunction referred to herein is angiogenic erectile dysfunction, in particular angiogenic impotence.

The terms "treat" and "treatment" as used herein, reduce the severity and/or frequency of symptoms, elimination of symptoms and/or underlying causes, symptoms and/or their underlying causes. Prevention of damage and improvement or repair of damage. Thus, the present method of "treating" a fibrotic disease, as used herein, includes 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 capable of inhibiting or selectively reducing the activity of any one or more phosphodiesterases.

The term "active agent" as used herein refers to a chemical compound or compound that induces a desired effect, such as a reduction in fibrotic scarring and/or amelioration of other conditions.

As used herein, "excipient or carrier" refers to an excipient or carrier material suitable for topical drug administration. Excipients or carriers useful herein include such materials known in the art that are non-toxic and do not interact with other components of the composition in a deleterious manner.

An "effective" amount of a drug or pharmacologically active agent is a nontoxic but sufficient amount of the drug or agent to provide a desired effect, such as reduction of fibrotic scarring and/or amelioration of other symptoms. means.

The additional pharmacologically active agent may optionally be delivered with the primary active agent, a non-specific phosphodiesterase inhibitor. Non-limiting examples of active agents include nitro vasodilators, alpha receptor blockers, ergot alkaloids, antihypertensives, vasodilators, natural, semisynthetic and synthetic prostaglandins, and vasoactive intestinal peptides. Is included.

Non-limiting examples of nitro vasodilators include nitroglycerin, linsidomine, such as linsidomine chloride hydrate (“SIN-1”), molsidomine, organic nitrates, isosorbide nitrate, erythrityl tetranitrate and amyl nitrate, nitroprusside. Sodium, S-nitrosothiols such as S-nitroso-N-acetyl-d,1-penicillamine (“SNAP”), S-nitroso-N-cysteine, and S-nitroso-N-glutathione (“SNO-GLU”) ), etc., and diazeniumdiolates (“NONOates”), for example (Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium. -1,2-diolate, (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate, (Z)-1 -{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate, and sodium (Z)-1-(N ,N-diethylamino)-diazen-1-ium-1,2-diolate and the like are included.

Non-limiting examples of alpha receptor blockers include phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, trazoline, prazosin, trimazosin, alfizosine, tamsulosin, and indoramin.

Non-limiting examples of ergot alkaloids include ergotamine and ergotamines themselves, such as acetoergamine, brazelgoline, bromelgrid, cyanergoline, delorgotril, disleggin, ergonovine maleate, ergotamine tartrate, ethithrugine, lergotril, lisergide, mesulergine, Includes goline, metergotamine, nicergoline, pergolide, properidine, proterguride, and terguride.

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

Non-limiting examples of vasodilators include nimodipine, pinacidil, cyclandrate, and isoxuprine.

Non-limiting examples of natural prostaglandins include PGE ₀ , PGE ₁ , PGA ₁ , PGB ₁ , PGF _1α , 19-hydroxy-PGA ₁ , 19-hydroxy-PGB ₁ , PGE ₂ , PGA ₂ , PGB. ₂ , 19-hydroxy-PGA ₂ , 19-hydroxy-PGB ₂ , PGE ₃ , PGF _3α are included. Non-limiting examples of semi-synthetic or synthetic derivatives of natural prostaglandins include carboprosttromethamine, dinoprosttromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone, and thiaprost.

Non-limiting examples of non-specific phosphodiesterase inhibitors include theophylline, theobromine, 3-isobutyl-1-methylxanthine (IBMX), and pentoxifylline.

In some embodiments, additional agents that may optionally be delivered with the primary active agent include anesthetics (ie, substances or compounds that induce pain insensitivity, such as temporary sensory loss). Be done. Those skilled in the art will select such anesthetics and their concentrations, if desired. As a non-binding guideline only, the concentration of anesthetic in the composition may be between about 0.1% and about 0.5% by weight.

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

In addition, if desired, other pharmacological agents, such as, but not limited to, antibacterial agents (ie, antibiotics), antiviral or antifungal agents, optionally for delivery with the primary active agent. May be additionally included in. Those of ordinary skill in the art will select such additional agents and their concentrations as needed.

The active agent is optionally in the form of a salt, ester, amide, prodrug, derivative or the like, and the salt, ester, amide, prodrug or derivative is pharmacologically suitable, that is, effective in the present method. Can be administered, provided that it is targeted. Activator salts, esters, amides, prodrugs and other derivatives are known to those skilled in synthetic organic chemistry and are described, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Edition (New York: Wiley -Can be prepared using standard procedures described in Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methodology and involve reaction with the appropriate 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 to it. The salt obtained can be precipitated or taken out of solution by adding a less polar solvent. Suitable acids for the preparation of acid addition salts include organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Includes both benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., as well as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Be done. The acid addition salt can be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the activators herein are the halide salts which can be prepared using hydrochloric acid or hydrobromic acid. Conversely, the preparation of basic salts of acid moieties that may be present on the phosphodiesterase inhibitor molecule may be carried out using pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine and the like. Prepared in a similar manner using. Particularly preferred basic salts herein are alkali metal salts, such as sodium salts and copper salts. Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug. Esters are typically acyl-substituted derivatives of free alcohol groups, ie, moieties derived from carboxylic acids of the formula RCOOH, where R is alkyl, preferably lower alkyl. The ester can be reconverted to the free acid, if desired, using conventional hydrogenolysis or hydrolysis procedures. Amides and prodrugs can also be prepared using techniques known to those of ordinary skill in the art or described in the relevant literature. For example, the amide can be prepared from the ester using a suitable amine reagent, or the amide can be prepared from the anhydride or acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs are typically prepared by covalent attachment to a moiety that results in a therapeutically inactive compound until modified by the metabolic system of the individual.

As used herein, the terms "local administration" and "locally administrating" refer to fibers by administration at a site close to the local symptoms of fibrotic disease (eg, PD plaque). Refers to the treatment of sexual disorders. It is distinguished from systemic administration, such as oral administration or intravenous injection, in which the dosage of the pharmaceutical composition is relatively similar throughout the body of the patient. Non-limiting examples of topical administration include intracavernosal injection, topical administration, and transdermal administration.

The term “intracavernosal” injection as used herein refers to an injection into one or both of the cavernous tissue of the penis.

The term “transdermal” delivery includes both transdermal and transmucosal administration, that is, delivery by passage of the drug across the body surface (ie skin or mucosal tissue). "Transdermal" delivery is also intended to include delivery of the drug by passing through the scrotum tissue. Examples of conventional transdermal drug delivery systems include transdermal "patches", where the drug is typically contained within a laminated structure that functions as a drug delivery device that is applied to the skin. In such a structure, the drug composition is typically contained in a layer, or "reservoir," underlying the upper backing layer. The stacking device may include a single reservoir or multiple reservoirs. The reservoir can include a polymer matrix of pharmaceutically acceptable contact adhesive material that helps secure the system to the skin during drug delivery. Non-limiting examples of suitable skin contact adhesive materials include polyethylene, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes and the like. Alternatively, the drug-containing reservoir and the skin-contacting adhesive are present as separate and distinct layers, the adhesive being below the reservoir, where the reservoir is the lower polymer matrix described above, or a liquid or hydrogel reservoir. There may be, or other forms.

The term "topical administration" is used in its conventional sense and refers to the delivery of a topical drug or pharmacologically active agent to the skin or mucous membranes. Examples of formulations for topical drug delivery include ointments and creams. Ointments are semisolid formulations that are typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents include viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. The cream base is washable with water and contains an oil phase, an emulsifier and an aqueous phase. The oil phase, also referred to as the "internal" phase, is generally, but not necessarily, composed of petrolatum and a fatty alcohol (such as cetyl alcohol or stearyl alcohol), but usually the volume of the aqueous phase exceeds that of the oil phase and is generally moisturizing. Including agents. Emulsifiers for cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. The particular ointment or cream base used is one that provides optimal drug delivery, as will be appreciated by those in the art. The ointment base, like other carriers or vehicles, must be inert, stable, non-irritating, and non-sensitizing.

[Method of treatment]
In one aspect, a method of treating a fibrotic disorder in a patient in need thereof for treating the fibrotic disorder, wherein the patient is treated with a therapeutically effective amount of Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ (Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.)
There is provided a method comprising topically administering a pharmaceutical formulation comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

(式中、Ｒ^１、Ｒ^２、及びＲ^３のそれぞれは独立に、Ｈ、それぞれ任意に置換されていてもよい、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、シクロアルキル、ヘテロシクリル、アリール、又はヘテロアリールである。)
の化合物又はその薬学的に許容される塩を含む医薬製剤を局所投与することを含む方法を提供する。 In another aspect, a method of treating Peyronie's disease in a patient in need thereof for treating Peyronie's disease, wherein a therapeutically effective amount of formula I is provided for the patient.

(In the formula, each of R ¹ , R ² , and R ³ is independently H, optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ (Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.)
There is provided a method comprising topically administering a pharmaceutical formulation comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

In a particular embodiment of the method, each of R ¹ , R ² , and R ³ is independently H, or optionally substituted C ₁ -C ₆ alkyl.

In another ^embodiment, R 1, ^{R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, or _C 1 -C ₆ alkyl substituted with acyl.

In yet another embodiment, the compound of formula I is a non-specific phosphodiesterase inhibitor (PDEi). In a particular embodiment, the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX).

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

In another aspect, a method for treating a fibrotic disorder in a patient in need thereof, comprising a therapeutically effective amount of a non-specific PDEi or a pharmaceutically acceptable salt thereof, A pharmaceutical formulation consisting essentially of a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable salt thereof, or consisting of a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable salt thereof. Administering locally to a patient, wherein the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobufylline, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX). provide.

In yet another aspect, in yet another aspect, a method for treating Peyronie's disease in a patient in need thereof for treating Peyronie's disease, comprising a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable thereof. Comprising a salt, consisting essentially of a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable salt thereof, or consisting of a therapeutically effective amount of a non-specific PDEi or pharmaceutically acceptable salt thereof, Injecting the pharmaceutical formulation into at least one of the corpus cavernosum of the patient's penis, wherein the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, or 3-isobutyl. A method is provided that is -1-methylxanthine (IBMX).

In certain embodiments of the above-described method, the pharmaceutical formulation consists essentially of pentoxifylline or a pharmaceutically acceptable salt thereof.

Fibrotic disorders include Peyronie's disease, Raynaud's syndrome, psoriatic plaques, eczema, keloid scars. In certain embodiments, the fibrotic disease is Peyronie's disease. In another embodiment, the fibrotic disorder is keloid scar.

The method of treatment results in amelioration of various fibrotic conditions such as reduction of fibrotic scarring. In certain embodiments, treating Peyronie's disease results in a reduction in PD plaques. In another embodiment, the treatment results in amelioration of erectile dysfunction. In certain embodiments, the erectile dysfunction is associated with PD.

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

In certain embodiments of the method of treating keloid scar in a patient in need of treatment of keloid scar, the pharmaceutical formulation comprises or consists essentially of non-specific PDEi (eg, pentoxifylline) and caffeine. , Or consist of it. In other embodiments, the formulation comprises, consists essentially of, or consists of non-specific PDEi (eg, pentoxifylline) and EGCG (green tea catechin). In yet another embodiment, the formulation comprises, consists essentially of, or consists of a non-specific PDEi (eg, pentoxifylline) and a mast cell stabilizer (eg, tranilast). These formulations can be injected into keloid scars. In certain embodiments, the pharmaceutical formulation further comprises a pharmaceutically acceptable excipient or carrier including, but not limited to, antioxidants, adjuvants or synergists, and preservatives.

Non-limiting examples of antioxidants include alpha-tocopherol acetate, sodium bisulfite acetone, acetyl cysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine. Hydrochloride, natural d-α-tocopherol, synthetic d-α-tocopherol, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite , Sodium sulfite, sodium thiosulfate, thiourea, tocopherol.

Non-limiting examples of adjuvants or synergists are citric acid, EDTA (ethylenediaminetetraacetic acid) and salts, hydroxyquinoline sulfate, phosphoric acid, and tartaric acid.

In certain embodiments, the pharmaceutical formulation further comprises EDTA sodium salt. The EDTA sodium salt may be 0-0.15% by weight of the formulation, such as 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% of the formulation. ..

In certain embodiments, the pharmaceutical formulation further comprises EDTA magnesium salt. The EDTA magnesium salt may be 0-0.15% by weight of the formulation, such as 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% of the formulation. ..

Non-limiting examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethylammonium bromide, chlorobutanol, chlorocresol, chlorhexidine gluconate. Or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenylphenol, paraben, phenol, acetic acid/phenylmercuric nitrate, propylparaben, sodium benzoate, sorbic acid and salt, β-phenylethyl alcohol , Thimerosal. In a particular embodiment, the preservative is benzyl alcohol.

In certain embodiments, the pharmaceutical formulation further comprises ethanol. Ethanol may be 190 proof. Ethanol is 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. is there.

In another embodiment, the pharmaceutical formulation further comprises benzyl alcohol. Benzyl alcohol is 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. May be

In another embodiment, the pharmaceutical formulation is filtered prior to topical administration. In certain embodiments, the pharmaceutical formulation is filtered through a 0.22 micron filter prior to topical administration.

In another embodiment, the pH of the pharmaceutical formulation is 4-8. In a particular embodiment, the pH of the pharmaceutical formulation is 5.5-6. The pH can be adjusted by adding acids or bases, such as HCl or NaOH.

In another embodiment of this method the therapeutically effective amount is 4 mg to 20 mg. In certain embodiments, the therapeutically effective amount is 6 mg-10 mg.

In another embodiment of this method, the pharmaceutical formulation is administered 1 to 4 times within a 24 hour period. In certain embodiments, pharmaceutical formulations are administered daily until the desired effect is achieved.

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

The pharmaceutical formulation can be administered to a patient in need thereof by a variety of topical administrations. In a particular embodiment, the pharmaceutical formulation is administered topically. In another embodiment, the pharmaceutical formulation is administered transdermally. In yet another embodiment, the pharmaceutical formulation is topically administered to the patient's penis. In certain embodiments, the pharmaceutical formulation is administered by intracavernosal injection.

In certain embodiments, a method of treating Peyronie's disease in a patient in need thereof for treating Peyronie's disease, wherein at least one of the corpus cavernosum of the patient has a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable amount. And injecting a pharmaceutical formulation consisting essentially of the salt thereof.

In certain embodiments of the method the pharmaceutical formulation is not administered directly (eg, intracavernosal injection) to the area of fibrotic disease. In certain embodiments of the method for treating Peyronie's disease, the pharmaceutical formulation is not administered directly (eg, intracavernosal injection) to the area of Peyronie's disease. In another embodiment of the method for treating Peyronie's disease, the pharmaceutical formulation is administered (eg, intracavernosal injection) to the base of the penis approximately 2 cm from where the penis attaches to the abdomen.

In certain embodiments of this method, the pharmaceutical formulation further comprises a second active agent. In a particular embodiment, the second active agent is a vasodilator, such as alprostadil (prostaglandin E ₁ ), papaverine, and/or phentolamine. In another embodiment, the second active agent is a non-specific phosphodiesterase inhibitor as defined above, such as pentoxifylline, aminophylline, enprophylline, isobufylline, theophylline, theobromine, and/or 3-isobutyl-1-. It is methylxanthine (IBMX). In yet another embodiment, the second active agent is a nitrovasodilator, an alpha receptor blocker, an ergot alkaloid, an antihypertensive, a vasodilator, natural, semi-synthetic and synthetic prostaglandins, and/or It is selected from the group consisting of vasoactive intestinal peptides.

In another embodiment of the method for treating Peyronie's disease, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®. In certain embodiments, the pharmaceutical formulation comprises, consists essentially of, or consists of pentoxifylline and collagenase (eg, collagenase Clostridium histolyticum or Xiaflex®).

The methods provided herein can be used as monotherapy or as part of a combination therapy. In a particular embodiment, a formulation comprising a compound of formula I, eg pentoxifylline, is used as a monotherapy. In certain embodiments, the formulation consisting essentially of non-specific PDEi, such as pentoxifylline, is used as a monotherapy to treat fibrotic disorders such as Peyronie's disease.

In another embodiment, a formulation comprising a compound of formula I, eg pentoxifylline, is used as part of a combination therapy. In certain embodiments, the formulation consisting essentially of the non-specific PDEi, eg, pentoxifylline, is combined with a collagenase therapy, eg, collagenase Clostridium histolyticum or Xiaflex®, to produce a fibrotic disorder, eg, Peyronie's disease. Used to treat such as.

(式中、Ｒ^１、Ｒ^２、及びＲ^３のそれぞれは独立に、Ｈ、それぞれ任意に置換されていてもよい、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、シクロアルキル、ヘテロシクリル、アリール、又はヘテロアリールである。)
の化合物又はその薬学的に許容される塩、エステル、アミド、もしくはプロドラッグと、薬学的に許容される、局所投与に適した賦形剤又は担体と、を含む医薬製剤を提供する。 [Pharmaceutical formulation]
In one aspect, Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ (Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.)
And a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for topical administration.

In one embodiment, each of R ¹ , R ² , and R ³ is independently H, or optionally substituted C ₁ -C ₆ alkyl.

In another embodiment, ^{R 1} is _{CH 3 -C (O) - (} CH 2) _4, and each of ^{R 2} and ^{R 3} is CH _3.

In another ^embodiment, R 1, ^{R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, or _C 1 -C ₆ alkyl substituted with acyl.

In yet another embodiment, the compound of formula I is a non-specific phosphodiesterase inhibitor (PDEi). In one embodiment, the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX).

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

As used herein, a therapeutically effective amount of a non-specific PDEi, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for topical administration, Also provided is a pharmaceutical formulation comprising, consisting essentially of, or consisting of. Here, the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX).

In certain embodiments, the pharmaceutical formulation comprises a therapeutically effective amount of pentoxifylline or a pharmaceutically acceptable salt, ester, amide or prodrug thereof and a pharmaceutically acceptable excipient suitable for topical administration. And/or consist essentially of, or consist of, a form or carrier.

The pharmaceutical formulation is useful for treating fibrotic disorders. Fibrotic disorders include Peyronie's disease, Raynaud's syndrome, psoriatic plaques, eczema, and keloid scars. In certain embodiments, the pharmaceutical formulations are useful in treating Peyronie's disease. In another embodiment, the pharmaceutical formulation is useful for treating keloid scars.

In certain embodiments, the pharmaceutical formulation results in improvement of the fibrotic condition, eg, reduction of fibrotic scarring. In certain embodiments, the pharmaceutical formulation reduces PD plaque. In another embodiment, the pharmaceutical formulation results in amelioration 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 certain embodiments, erectile dysfunction is associated with Peyronie's disease.

In a particular embodiment of the formulation for treating keloid scars in a patient in need thereof, the pharmaceutical formulation consists essentially of non-specific PDEi (eg pentoxifylline) and caffeine. In another embodiment, the formulation consists essentially of non-specific PDEi (eg pentoxifylline) and EGCG. In yet another embodiment, the formulation consists essentially of a non-specific PDEi (eg pentoxifylline) and a mast cell stabilizer (eg tranilast). The formulation can be injected into keloid scars.

Pharmaceutically acceptable excipients or carriers include, but are not limited to, antioxidants, adjuvants or synergists, and/or preservatives.

Non-limiting examples of antioxidants include α-tocopherol acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine. Hydrochloride, natural d-α-tocopherol, synthetic d-α-tocopherol, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite , Sodium sulfite, sodium thiosulfate, thiourea, and tocopherol.

Non-limiting examples of adjuvants or synergists are citric acid, EDTA (ethylenediaminetetraacetic acid) and salts, hydroxyquinoline sulfate, phosphoric acid, and tartaric acid.

In certain embodiments, the pharmaceutical formulation further comprises EDTA sodium salt. EDTA sodium salt is 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. obtain.

In certain embodiments, the pharmaceutical formulation further comprises EDTA magnesium salt. EDTA magnesium salt is 0-0.15% by weight of the formulation, such as 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. obtain.

Non-limiting examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethylammonium bromide, chlorobutanol, chlorocresol, chlorhexidine gluconate. Or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenylphenol, paraben, phenol, acetic acid/phenylmercuric nitrate, propylparaben, sodium benzoate, sorbic acid and salt, β-phenylethyl alcohol , Thimerosal. In a particular embodiment, the preservative is benzyl alcohol.

In certain embodiments, the pharmaceutical formulation further comprises ethanol. Ethanol may be 190 proof. Ethanol is 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. is there.

In another embodiment, the pharmaceutical formulation further comprises benzyl alcohol. Benzyl alcohol is 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. May be

In another embodiment, the pharmaceutical formulation is filtered prior to topical administration. In certain embodiments, the pharmaceutical formulation is filtered through a 0.22 micron filter prior to topical administration.

In another embodiment, the pharmaceutical formulation has a pH of 4-8. In certain embodiments, the pharmaceutical formulation has a pH of 5.5-6. The pH is adjusted to 5.5 by adding an acid or base such as HCl or NaOH.
Can be adjusted to ~6.

In another embodiment of the pharmaceutical formulation, the therapeutically effective amount is 4 mg to 20 mg. In certain embodiments, the therapeutically effective amount is 6 mg-10 mg.

In another embodiment, the pharmaceutical formulation is administered 1 to 4 times over a 24 hour period. In certain embodiments, pharmaceutical formulations are administered daily until the desired effect is achieved.
In certain embodiments, the pharmaceutical formulation comprises a unit dose of a compound of formula I. In certain embodiments, the pharmaceutical formulation comprises a unit dose of pentoxifylline.

The pharmaceutical formulation can be administered to a patient in need thereof by a variety of topical administrations, such as intracavernosal injection, topical administration, and transdermal administration. In certain embodiments, the pharmaceutical formulation comprises a sterile liquid composition and the pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection. In another embodiment, the pharmaceutical formulation is suitable for topical or transdermal administration. In certain embodiments, the pharmaceutical formulation comprises the composition applied to a body surface, and the pharmaceutically acceptable excipient or carrier is suitable for topical or transdermal administration. In a particular embodiment, the pharmaceutical composition is an ointment, cream, gel or lotion.

In certain embodiments, the pharmaceutical formulation is not directly administered (eg, intracavernosal) to the area of fibrotic disease. In certain embodiments of pharmaceutical formulations, the pharmaceutical formulation is not directly administered (eg, injected intracavernosally) to the area of Peyronie's disease. In another embodiment of the pharmaceutical formulation, the pharmaceutical formulation is administered (eg, injected intracavernosally) into the base of the penis approximately 2 cm from where the penis attaches to the abdomen.

In certain embodiments, the pharmaceutical formulation further comprises a second active agent. In a particular embodiment, the second active agent is a vasodilator, such as alprostadil (prostaglandin E ₁ ), papaverine, and/or phentolamine. In another embodiment, the second active agent is a non-specific phosphodiesterase inhibitor as defined above, for example pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, and/or 3-isobutyl-1-. It is methylxanthine (IBMX). In yet another embodiment, the second active agent is a nitrovasodilator, an alpha receptor blocker, an ergot alkaloid, an antihypertensive, a vasodilator, a natural, semi-synthetic and synthetic prostaglandin, and/or It is selected from the group consisting of vasoactive intestinal peptides.

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

The pharmaceutical formulations provided herein can be used as a monotherapy or as part of a combination therapy. In a particular embodiment, a pharmaceutical formulation comprising a compound of formula I, eg pentoxifylline, is used as a monotherapy. In certain embodiments, pharmaceutical formulations consisting essentially of non-specific PDEi, such as pentoxifylline, are used as monotherapy for treating fibrotic disorders such as PD.

In another embodiment, a pharmaceutical formulation comprising a compound of formula I, eg pentoxifylline, is used as part of a combination therapy. In certain embodiments, a pharmaceutical formulation consisting essentially of a non-specific PDEi, eg, pentoxifylline, is combined with a collagenase therapy (eg, collagenase Clostridium histolyticum or Xiaflex®) to produce a fibrotic disorder such as Peyronie. It is used to treat diseases.

In a particular embodiment, a medicament 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. Provide a formulation.

(式中、Ｒ^１、Ｒ^２、及びＲ^３のそれぞれは独立に、Ｈ、それぞれ任意に置換されていてもよい、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、シクロアルキル、ヘテロシクリル、アリール、又はヘテロアリールである。)
の化合物又はその薬学的に許容される塩、エステル、アミド、もしくはプロドラッグと、薬学的に許容される、局所投与に適した賦形剤又は担体と、を含む医薬製剤；
− 前記医薬製剤を局所投与するための装置；
− 前記医薬製剤を収容する容器及び薬物送達装置；
− 使用説明書
を含むキットを提供する。 [kit]
In one aspect,
-Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, optionally substituted, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ (Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.)
A pharmaceutical preparation comprising the compound of claim 1 or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier suitable for topical administration;
-A device for the topical administration of said pharmaceutical formulation;
-A container containing said pharmaceutical formulation and a drug delivery device;
-Provide a kit containing instructions for use.

In one embodiment, each of R ¹ , R ² , and R ³ is independently H, or optionally substituted C ₁ -C ₆ alkyl.

In another ^embodiment, R 1, ^{R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, or _C 1 -C ₆ alkyl substituted with acyl.

In yet another embodiment, the compound of formula I is a non-specific phosphodiesterase inhibitor (PDEi). In one embodiment, the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX).

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

In another aspect, provided herein is a kit, which comprises, or consists essentially of, a therapeutically effective amount of a non-specific PDEi or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Or a pharmaceutical preparation comprising the same (wherein the non-specific PDEi is pentoxifylline, aminophylline, enprophylline, isobufilin, theophylline, theobromine, or 3-isobutyl-1-methylxanthine (IBMX)); A kit is provided that includes a device for topical administration of a drug; a container containing a pharmaceutical formulation and a drug delivery device; and instructions for use.

In certain 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 a particular embodiment, the kit is used to treat fibrotic disorders. Non-limiting examples of fibrotic disorders include Peyronie's disease, Raynaud's syndrome, psoriatic plaques, eczema, and keloid scars. In a particular embodiment, the fibrotic disease is Peyronie's disease. In another embodiment, the fibrotic disorder is keloid scar.

In other embodiments of the kit, the pharmaceutical formulation provides an improvement in the fibrotic condition, eg, reduction of fibrotic plaque. In certain embodiments, the pharmaceutical formulation reduces PD plaque. In another embodiment, the formulation improves erectile dysfunction. In certain embodiments, the erectile dysfunction is associated with PD.

In another embodiment of the kit, the pharmaceutical formulation is administered topically to treat erectile dysfunction. In certain embodiments, erectile dysfunction is associated with Peyronie's disease.

In certain embodiments of a formulation for treating keloid scars in a patient in need thereof, the pharmaceutical formulation comprises, consists essentially of, or consists of non-specific PDEi (eg, pentoxifylline) and caffeine. Or consist of it. In other embodiments, the formulation comprises, consists essentially of, or consists of non-specific PDEi (eg, pentoxifylline) and EGCG. In yet another embodiment, the pharmaceutical formulation comprises, consists essentially of, or consists of a non-specific PDEi (eg, pentoxifylline) and a mast cell stabilizer (eg, tranilast). The formulation can be injected into a keloid scar.

In certain embodiments, the pharmaceutical formulation further comprises a pharmaceutically acceptable excipient or carrier including, but not limited to, antioxidants, adjuvants or synergists, and preservatives.

Non-limiting examples of antioxidants include α-tocopherol acetate, sodium bisulfite acetone, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteine. Hydrochloride, natural d-α-tocopherol, synthetic d-α-tocopherol, dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite , Sodium sulfite, sodium thiosulfate, thiourea, tocopherol.

Non-limiting examples of adjuvants or synergists are citric acid, EDTA (ethylenediaminetetraacetic acid) and salts, hydroxyquinoline sulfate, phosphoric acid, and tartaric acid.

In certain embodiments, the pharmaceutical formulation further comprises EDTA sodium salt. EDTA sodium salt is 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. obtain.

In certain embodiments, the pharmaceutical formulation further comprises EDTA magnesium salt. EDTA magnesium salt is 0-0.15% by weight of the formulation, such as 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. obtain.

Non-limiting examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts, cetylpyridinium chloride, cetyltrimethylammonium bromide, chlorobutanol, chlorocresol, chlorhexidine gluconate. Or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol, methylparaben, nitromersol, o-phenylphenol, paraben, phenol, acetic acid/phenylmercuric nitrate, propylparaben, sodium benzoate, sorbic acid and salt, β-phenylethyl alcohol , And thimerosal. In a particular embodiment, the preservative is benzyl alcohol. Benzyl alcohol is 0-1.5 wt% 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 wt% of the formulation. May be

In certain embodiments, the pharmaceutical formulation further comprises ethanol. Ethanol may be 190 proof. Ethanol is 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. Good.

In yet another embodiment of the kit, the therapeutically effective amount is 4 mg-20 mg. In certain embodiments, the therapeutically effective amount may be 6 mg-10 mg.

In certain embodiments, the pharmaceutical formulation is administered 1-4 times over a 24-hour period. In another embodiment, the pharmaceutical formulation is administered daily until the desired effect is achieved.

In yet another embodiment, the pharmaceutical formulation is filtered through a 0.22 micron filter. In a particular embodiment, the pharmaceutical formulation is filtered through a 0.22 micron filter prior to administration.

In another embodiment, the pH of the pharmaceutical formulation is 4-8. In a particular embodiment, the pH of the pharmaceutical formulation is 5.5-6. The pH can be adjusted to 5.5-6 by adding acid or base, such as HCl or NaOH, before administration.

Furthermore, the pharmaceutical formulation is administered topically. 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 pharmaceutically acceptable excipient or carrier is suitable for topical or transdermal administration.

In certain 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. Be correct.

In certain embodiments, the pharmaceutical formulation is not administered directly to the area of fibrotic disease (eg, intracavernosal injection). In certain embodiments, the pharmaceutical formulation is not administered directly (eg, intracavernosal injection) to the area of Peyronie's disease. In another embodiment, the pharmaceutical formulation is administered (eg, intracavernosal injection) to the base of the penis approximately 2 cm from where the penis attaches to the abdomen.

In certain embodiments of the kit, the pharmaceutical formulation further comprises a second active agent. In a particular embodiment, the second active agent is a vasodilator, such as alprostadil (prostaglandin E ₁ ), papaverine, and/or phentolamine. In another embodiment, the second active agent is a non-specific phosphodiesterase inhibitor as defined above, such as pentoxifylline, aminophylline, enprophylline, isobufylline, theophylline, theobromine, and/or 3-isobutyl-1-. It is methylxanthine (IBMX). In yet another embodiment, the second active agent is a nitrovasodilator, an alpha receptor blocker, an ergot alkaloid, an antihypertensive, a vasodilator, a natural, semisynthetic and synthetic prostaglandin, and/or Or selected from the group consisting of vasoactive intestinal peptides.

In some additional embodiments, the pharmaceutical composition further comprises another component, a polysaccharide. Some exemplary polysaccharides that may be used include hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof, as well as one or more of such polysaccharides. Combinations are included, but are not limited to. The polysaccharides can be used both in compositions containing only compound I as active agent as well as in compositions containing both compound I and the second active compound described above.

In another embodiment, the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®. In certain embodiments, the pharmaceutical formulation consists essentially of pentoxifylline and collagenase (eg, collagenase Clostridium histolyticum or Xiaflex®).

In certain embodiments, pharmaceutical formulations containing a compound of Formula I (eg, pentoxifylline) are used as monotherapy. In certain embodiments, pharmaceutical formulations consisting essentially of non-specific PDEi (eg, pentoxifylline) are used as monotherapy for treating fibrotic disorders such as Peyronie's disease.

In another embodiment, formulations containing a compound of formula I (eg pentoxifylline) are used as part of a combination therapy. In certain embodiments, the formulation consisting essentially of the non-specific PDEi (eg, pentoxifylline) is combined with a collagenase therapy (eg, collagenase Clostridium histolyticum or Xiaflex®) to produce a fibrotic disorder (eg, Peyronie). Disease, etc.).

In additional embodiments, the pharmaceutical formulations described above (with or without polysaccharides) can be incorporated into microparticles. Microparticles are essentially spherical particles (shells) made of a water-soluble biodegradable polymer that define a space therein, the space being filled with a pharmaceutical formulation. Therefore, the microparticles constitute a structure in which the water-soluble biodegradable polymer wraps the drug product to securely enclose the drug product and does not leak or release the drug product.

Microparticles loaded with formulation can be manufactured according to methods and techniques known to those skilled in the art. The size of the microparticles is typically less than about 100 μm in diameter, and exemplary water-soluble polymers used to make the shell include, but are not limited to, poly(lactic-co-glycolic acid), poly(lactic acid). , Poly(glycolic acid), poly(caprolactone), poly(hydroxybutyrate) and blends thereof. In one typical example, poly(lactic-co-glycolic acid) can be used to form the shell and the ratio of units derived from lactic acid and glycolic acid is a 50:50 (mass) ratio. .. Other acceptable ratios between the lactic acid and glycolic acid moieties can be 65:35, 75:25, and 85:15. Those skilled in the art of using poly(lactic-co-glycolic acid) may select various ratios as needed. The intrinsic viscosity of the polymer solution used to form the shell (i.e., the ratio of the natural log of the relative viscosity to the mass concentration of polymer) is about 0.15 dL/g to about 1.20 dL/g, for example about 0.15 dL/g to 0.25. It may be dL/g, or the following ranges: 0.26 to 0.54, 0.55 to 0.75, 0.62 to 0.65, 0.65 to 0.85, 0.76 to 0.94, and 0.95 to 1.20 dL/g.

After the microparticles described above have been prepared, they can be administered to a patient in need of the drug by conventional methods (eg, intracavernosal implantation).

The following examples are provided to further demonstrate the advantages and features of the present invention, but are not intended to limit the scope of the invention. These examples are for illustrative purposes only. USP pharmaceutical grade products were used to prepare the formulations described below.

Example 1. Preparation of Pentoxifylline Formulations Several pentoxifylline formulations were prepared using the compounds described in Table 1 in the amounts shown.

Example 2. Preparation of Caffeine Formulation Formulations were prepared using the compounds described in Table 2 in the amounts shown.

Example 3. Preparation of Aminophylline and Theophylline Formulations The following formulations were prepared using the compounds described in Table 3 in the amounts shown.

Examples 4-6. Intracavernosal Penile Injection of Pentoxifylline Preparation In Example 4, in a 63-year-old man with erectile dysfunction, a combination of three vasoactive agents: phentolamine, alprostadil, and papaverine did not affect erectile dysfunction. confirmed. A new injection containing additional pentoxifylline along with the three vasoactive agents described above was re-formulated and administered to this patient.

Various combinations of strengths of phentolamine, alptostadil, papaverine, and pentoxifylline were used in an attempt to improve erectile dysfunction with no demonstrable effects. However, the patient did realize a significant improvement at the 4 mg pentoxifylline dose per injection. This improvement was more pronounced at the 6 mg dose.

In Examples 5 and 6, patients suffering from Peyronie's disease were treated. The treatment cycle included an injection of sterile pentoxifylline. More specifically, 6 separate injections were performed every 2 weeks. The dose was 5 mg pentoxifylline in a volume of 1 ml. Disposable vials were dispensed. A 21 gauge cannula was used to directly inject into Peyronie's plaques. A nerve block was placed around the injection site to relieve pain. Manual procedures and extensions were used to massage the injection site. The patient returned 2 weeks later for the next injection and procedural session of the procedure.

Baseline measurements were collected before each treatment to characterize the degree of illness in the patient. The degree of curvature was recorded and any current pain/discomfort of the patient and current sexual performance were also recorded. We also observed psychosocial effects related to patient illness.

In Example 5, a patient suffering from Peyronie's disease was taken to an operating room prepared and cloth covered in the usual sterile fashion. The baseline characteristics of the patient's illness were 40 degrees dorsal and the position of the Peyronie's plaque was dorsal and medial.

Topical blocks were performed using a total of 1 mL of 1% lidocaine. Once the patient was anesthetized, the plaque was isolated between two fingers and 1 mL of 5 mg pentoxifylline was fan-shaped injected into the plaque. The patient tolerated this procedure well. The patient was pressed and a light compression bandage was applied. The patient was instructed to hold it in place for 3 hours and then remove it. Patients were further instructed not to have 24-hour intercourse or masturbation.

In Example 6, another patient with Peyronie's disease was treated in the same manner as the patient in Example 5. The baseline characteristics of the disease state are that the patient is 40 degrees dorsal and the position of the Peyronie plaque is dorsal, distal 2x1.

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

Example 7. Preparation of Pentoxifylline Formulations Containing Polysaccharides Pentoxifylline formulation (Formulation 10) can be prepared using the following compounds in the amounts shown:
(1) about 2.0 g of pentoxifylline in the form of a dry powder;
(2) About 1.0 g of dry powder sodium hyaluronate;
(3) About 0.515 g of granular sodium chloride;
(4) About 100 L of sterile water for injection.

All dry ingredients can be mixed, weighed and mixed with about 90% water. The pH is then adjusted to 6.0-7.0 with 1% sodium hydroxide solution, the remaining amount of water is added, filtered in a pre-sterilized amber vial and sealed therein. be able to.

Equivalents One of ordinary skill in the art will understand that there are many equivalents of the particular embodiments and methods described herein, or can be ascertained within routine experimentation. Such equivalents are intended to be included within the scope of the following claims.

INCORPORATION BY REFERENCE All of the published patent applications and other references cited herein are expressly incorporated herein in their entirety.

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

Claims (31)

A pharmaceutical formulation for use in the treatment of fibrotic disorders, comprising topically administering to a patient in need of treatment of the fibrotic disorder a therapeutically effective amount of the pharmaceutical formulation,
(A) A certain amount of Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ which may be optionally substituted, respectively. Selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.)
A compound or a pharmaceutically acceptable salt thereof,
(B) A pharmaceutical formulation comprising an amount of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and a polysaccharide selected from the group consisting of pharmaceutically acceptable water-soluble salts thereof. The pharmaceutical formulation according to claim 1, wherein each of R ¹ , R ² , and R ³ is independently selected from the group consisting of H and optionally substituted C ₁ -C ₆ alkyl. R ^{1, R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, and is selected from the group consisting of _C 1 -C ₆ alkyl substituted with acyl, according to claim 1 Pharmaceutical formulation. The pharmaceutical preparation according to claim 1, wherein the compound of formula I is a non-specific phosphodiesterase inhibitor (PDEi). The pharmaceutical preparation according to claim 4, wherein the non-specific PDEi is selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, and 3-isobutyl-1-methylxanthine. The pharmaceutical preparation according to claim 1, wherein the fibrotic disease is Peyronie's disease. The pharmaceutical preparation according to claim 1, wherein administration of the pharmaceutical preparation results in improvement of erectile dysfunction. The pharmaceutical formulation according to claim 1, having a pH of 5.5-6. The pharmaceutical preparation according to claim 1, wherein the therapeutically effective amount is 4 mg to 20 mg. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is topically administered to the penis of a patient. 11. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is administered by intracavernosal injection. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation further comprises a second active agent selected from the group consisting of alprostadil, papaverine, phentolamine. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation further comprises collagenase. A therapeutically effective amount of Formula I:

(In the formula, each of R ¹ , R ² , and R ³ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ which may be optionally substituted, respectively. Selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.)
Or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof;
An amount of a polysaccharide selected from the group consisting of hyaluronic acid, heparin, heparan, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble salts thereof; and pharmaceutically acceptable, suitable for topical administration A pharmaceutical formulation comprising a different excipient or carrier. R ^{1, R 2,} and independently each ^{R 3,} H, and is selected from the group consisting of optionally _C 1 -C ₆ alkyl substituted optionally, pharmaceutical formulation according to claim 14. R ^{1, R 2,} and independently each ^{R 3,} _H, C 1 -C ₆ alkyl, and is selected from the group consisting of _C 1 -C ₆ alkyl substituted with acyl, according to claim 14 Pharmaceutical formulation. The pharmaceutical formulation according to claim 14, wherein the compound of formula I is a non-specific PDEi. 18. The pharmaceutical preparation according to claim 17, wherein the non-specific PDEi is selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprophylline, isobuphylline, theophylline, theobromine, and 3-isobutyl-1-methylxanthine. The pharmaceutical formulation according to claim 14, having a pH of 5.5-6. 15. The pharmaceutical formulation according to claim 14, wherein the therapeutically effective amount is 4 mg to 20 mg. 15. The pharmaceutical formulation of claim 14, further comprising a sterile liquid composition, the excipient or carrier of which is suitable for intracavernosal injection. 15. The pharmaceutical formulation of claim 14, further comprising an additional additive selected from the group consisting of alprostadil, papaverine, and phentolamine. 15. The pharmaceutical formulation of claim 14, further comprising collagenase. 15. The medicament of claim 14, further comprising an active agent selected from the group consisting of at least one anesthetic, at least one antimicrobial agent, at least one antiviral agent, at least one antifungal agent, and combinations thereof. Formulation. 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. The pharmaceutical preparation according to claim 1, wherein the polysaccharide is sodium hyaluronate. The pharmaceutical preparation according to claim 14, wherein the polysaccharide is sodium hyaluronate. The pharmaceutical formulation is water-soluble biodegradable selected from the group consisting of poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and poly(hydroxybutyrate). 15. A pharmaceutical formulation according to claim 14 encapsulated within essentially spherical particles made of a polymer. 29. The pharmaceutical formulation of claim 28, wherein the water soluble biodegradable polymer is poly(lactic-co-glycolic acid). A therapeutically effective amount of Formula I

(In the formula, each of R1, R2, and R3 is independently H, each optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl. , And heteroaryl.)
Or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,
A pharmaceutical formulation comprising essentially spherical particles incorporated with a pharmaceutically acceptable excipient or carrier suitable for topical administration, comprising:
The particles are water-soluble biodegradable selected from the group consisting of poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and poly(hydroxybutyrate). A pharmaceutical formulation made of a polymer. 31. The pharmaceutical formulation of claim 30, wherein the water soluble biodegradable polymer is poly(lactic acid-co-glycolic acid).