EP3638244A1 - Formulations pharmaceutiques de xanthine ou de dérivés de xanthine, et leur utilisation - Google Patents

Formulations pharmaceutiques de xanthine ou de dérivés de xanthine, et leur utilisation

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Publication number
EP3638244A1
EP3638244A1 EP18735151.5A EP18735151A EP3638244A1 EP 3638244 A1 EP3638244 A1 EP 3638244A1 EP 18735151 A EP18735151 A EP 18735151A EP 3638244 A1 EP3638244 A1 EP 3638244A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
formulation
group
poly
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18735151.5A
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German (de)
English (en)
Inventor
Matthew J. Buderer
Dennis Saadeh
Andrew R. Boll
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Harrow IP LLC
Original Assignee
Harrow IP LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/620,430 external-priority patent/US10383875B2/en
Application filed by Harrow IP LLC filed Critical Harrow IP LLC
Publication of EP3638244A1 publication Critical patent/EP3638244A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • 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.
  • xanthine or a xanthine derivative such as pentoxifylline
  • Fibrotic diseases can be found in a variety of tissues.
  • Peyronie's disease 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.
  • TA tunica albuginea
  • 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.
  • 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).
  • a nonspecific PDEi e.g., pentoxifylline
  • 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).
  • oral pentoxifylline has been shown to have moderate to minimal improvement.
  • 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.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:
  • R 1 , R 2 and R 3 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • kits 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 R 1 , R 2 and R 3 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.
  • 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 R 1 , R 2 and R 3 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • a fibrotic disease e.g., Peyronie's disease
  • R 1 , R 2 and R 3 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • R 1 , R 2 and R 3 can be each, independently, H, or optionally substituted C1-C6 alkyl.
  • R 1 , R 2 and R 3 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).
  • PDEi phosphodiesterase inhibitor
  • the compound of formula I can also be selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
  • 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,.
  • kits 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.
  • 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).
  • 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.
  • the fibrotic disease is Peyronie's disease or keloid scar.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical formulation comprises a unit dosage of pentoxifylline.
  • the pharmaceutical formulation can be administered topically, transdermally, to the penis of the subject.
  • the pharmaceutical formulation is administered by intracavemosal injection.
  • the pharmaceutical formulation can comprise a sterile liquid composition so that the pharmaceutically acceptable excipient or carrier is suitable for intracavemosal injection.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®.
  • a collagenase such as collagenase Clostridium histolyticum, or Xiaflex®.
  • 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.
  • the formulation comprising the compound of formula I e.g, pentoxifylline
  • 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®.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:
  • each of R 1 , R 2 and R 3 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.
  • 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 R 1 , R 2 and R 3 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.
  • R 1 , R 2 and R 3 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).
  • PDEi nonspecific phosphodiesterase inhibitor
  • the nonspecific PDEi can be selected from the group consisting of pentoxifylline, caffeine, aminophylline, enprofylline, isbufylline, theophylline, theobromine, and 3-isobutyl-l- methylxanthine.
  • the fibrotic disease is Peyronie's disease.
  • the formulation leads to improvement of erectile dysfunction.
  • 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
  • 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.
  • 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.
  • anesthetic is selected from the group consisting of lidocaine, tetracaine, proparacaine, procaine, dyclonine and combinations thereof.
  • the polysaccharide is sodium hyaluronate.
  • the polysaccharide can be sodium hyaluronate.
  • 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).
  • the biodegradable polymer is poly(lactic acid-co-glycolic acid).
  • 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 R 1 , R 2 and R 3 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).
  • the biodegradable polymer is poly(lactic acid-co-glycolic acid).
  • 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.
  • a xanthine derivative e.g., pentoxifylline
  • intracavernosal injection of a composition comprising pentoxifylline has resulted remarkable improvement to symptoms of PD, such as erectile dysfunction.
  • intracavernosal injection of pentoxifylline has been found to produce fewer side effects.
  • xanthine or a xanthine derivative such as pentoxifylline
  • kits thereof and methods for treating a fibrotic disease by local administration.
  • Alkyl 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 refers to an alkyl group with at least one double bond.
  • Alkynyl refers to an alkyl groups with at least one triple bond.
  • Cycloalkyl refers to a monocyclic or bicyclic saturated hydrocarbon group, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexanyl.
  • Heterocyclyl refers to a cycloalkyl group with at least one heteroatom, such as N, O, S, and P.
  • heterocyclyl include aziridinyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl.
  • Aryl refers to a monocyclic or a bicyclic aromatic hydrocarbon group, including, but not limited to, phenyl and naphthyl.
  • Heteroaryl 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.
  • fibrotic disease 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.
  • fibrotic disease include Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, keloid scars, pulmonary fibrosis, liver fibrosis, renal fibrosis, and vascular fibrosis.
  • 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.
  • the erectile dysfunction referred to herein is vasculogenic erectile dysfunction, particularly vasculogenic impotence.
  • 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 thus encompasses both prevention of the disorder in a predisposed individual and treatment of the disorder in a clinically symptomatic individual.
  • 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.
  • active agent 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 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.
  • 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.
  • 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-
  • 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.
  • 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, protergur
  • Non-limiting examples of antihypertensive agents include diazoxide, hydralazine and minoxidil.
  • vasodilators include nimodipine, pinacidil, cyclandelate and isoxsuprine.
  • Non-limiting examples of naturally occurring prostaglandins include PGE 0 , PGEi, PGA1, PGBi, PGFi a , 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE 2 , PGA 2 , PGB 2 , 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.
  • 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).
  • anesthetic(s) i.e., substances or compounds that induce insensitivity to pain such as a temporary loss of sensation.
  • 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.
  • 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.
  • 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).
  • acid addition salts are prepared from the free base using conventional methodology, and involve reaction with a suitable acid.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • tracavernosal refers to an injection into one or both corpora of the corpora cavernosal tissues of the penis.
  • 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.
  • suitable skin contact adhesive materials include polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyure thanes, and the like.
  • 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.
  • topical administration is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa.
  • 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 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.
  • 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:
  • R 1 , R 2 and R 3 are each, independently, H, Ci-Ce alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • a method for treating Peyronie's disease in a subject in need thereof which comprises locally administering to the subject a
  • R 1 , R 2 and R 3 are each, independently, H, C 1 -C6 alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • R 1 , R 2 and R 3 are each, independently, H, or optionally substituted C 1 -C6 alkyl.
  • R 1 , R 2 and R 3 are each, independently, H, Ci-Ce alkyl, or Ci-Ce alkyl substituted with acyl.
  • the compound of formula I is a nonspecific
  • the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl- l-methylxanthine (IBMX).
  • the compound of formula I is selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
  • a method for treating a fibrotic disease in a subject in need thereof which comprises locally administering to the subject a
  • nonspecific PDEi pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3-isobutyl- l-methylxanthine (IBMX).
  • a method for treating Peyronie's disease in a subject in need thereof 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).
  • 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
  • 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.
  • the fibrotic disease is Peyronie's disease.
  • the fibrotic disease is keloid scar.
  • the treatment method leads to improvement of various fibrotic conditions, for example, reduction of fibrotic scars.
  • the treatment of Peyronie's disease results in reduction of PD plaques.
  • the treatment results in improvement of erectile dysfunction.
  • the erectile dysfunction is associated with PD.
  • the pharmaceutical formulation is administered locally to treat erectile dysfunction.
  • the erectile dysfunction is associated with Peyronie's disease.
  • the pharmaceutical formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and caffeine.
  • the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and EGCG (green tea catechin).
  • the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g., tranilast.
  • 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
  • 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.
  • 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
  • the preservative is benzyl alcohol.
  • 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.
  • 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.
  • the pharmaceutical formulation is filtered before local administration.
  • the pharmaceutical formulation is filtered through a 0.22 micron filter before local administration.
  • 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 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
  • the pharmaceutical formulation comprises a unit dosage of the compound of formula I.
  • 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.
  • the pharmaceutical formulation is administered topically.
  • the pharmaceutical formulation is administered transdermally.
  • the pharmaceutical formulation is administered locally to the penis of the subject.
  • the pharmaceutical formulation is administered locally to the penis of the subject.
  • composition is administered by intracavernosal injection.
  • 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.
  • the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the fibrotic disease.
  • the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the 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.
  • the pharmaceutical formulation further comprises a second active agent.
  • the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine.
  • 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).
  • 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.
  • the methods for treating Peyronie's disease the
  • the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®.
  • a collagenase such as collagenase Clostridium histolyticum, or Xiaflex®.
  • the pharmaceutical formulation comprises, consists essentially of or consists of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.
  • the formulation comprising the compound of formula I, e.g, pentoxifylline
  • 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.
  • the formulation comprising the compound of formula I is used as a part of a combo therapy.
  • the formulation consisting essentially of a nonspecific PDEi e.g., pentoxifylline
  • a fibrotic disease such as Peyronie's disease
  • a collagenase therapy e.g., collagenase Clostridium histolyticum or Xiaflex®.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I:
  • R 1 , R 2 and R 3 are each, independently, H, C 1 -C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
  • R 1 , R 2 and R 3 are each, independently, H, or optionally substituted C 1 -C6 alkyl.
  • R 1 is CH 3 -C(0)-(CH 2 )4 and each of R 2 and R 3 is CH 3 .
  • R 1 , R 2 and R 3 are each, independently, H, C 1 -C6 alkyl, or Ci- (, alkyl substituted with acyl.
  • the compound of formula I is a nonspecific
  • the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl-l-methylxanthine (IBMX).
  • the compound of formula I is selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
  • 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).
  • IBMX 3- isobutyl-l-methylxanthine
  • 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.
  • the formulation is useful in treating Peyronie's disease.
  • the formulation is useful in treating keloid scars.
  • the pharmaceutical formulation results in improvement of fibrotic conditions, for example, reduction of fibrotic scars.
  • 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.
  • the pharmaceutical formulation is administered locally to treat erectile dysfunction.
  • the erectile dysfunction is associated with Peyronie's disease.
  • the pharmaceutical formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline, and caffeine.
  • the formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline, and EGCG.
  • 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.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • cysteine cysteine hydrochloride
  • d- a-tocopherol natural
  • Non-limiting examples of the adjuvant or synergist are citric acid, EDTA
  • 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.
  • 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
  • the preservative is benzyl alcohol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical formulation comprises a unit dosage of the compound of formula I.
  • 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.
  • the pharmaceutical formulation comprises a sterile liquid composition, and the pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection.
  • the pharmaceutical formulation is suitable for topical or transdermal administration.
  • 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.
  • the pharmaceutical composition is an ointment, cream, gel or lotion.
  • the pharmaceutical formulation is not administered (e.g., intracavemosally injected) directly into the area of the fibrotic disease.
  • the pharmaceutical formulation is not administered (e.g., intracavemosally injected) directly into the area of the 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 further comprises a second active agent.
  • the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine.
  • 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).
  • 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.
  • the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum or Xiaflex®.
  • a collagenase such as collagenase Clostridium histolyticum or Xiaflex®.
  • 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.
  • the pharmaceutical formulation comprising the compound of formula I, e.g, pentoxifylline is used as a mono therapy.
  • 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.
  • the formulation comprising the compound of formula I e.g, pentoxifylline
  • the formulation consisting essentially of a nonspecific PDEi e.g., pentoxifylline
  • a fibrotic disease such as Peyronie's disease
  • a collagenase therapy e.g., collagenase Clostridium histolyticum or Xiaflex®.
  • a pharmaceutical formulation consisting essentially of a therapeutically effective amount of pentoxifylline or a
  • kits comprising: a pharmaceutical formulation containing a therapeutically effective amount of a compound of formula I:
  • R 1 , R 2 and R 3 are each, independently, H, Ci-Ce alkyl, C -Ce alkenyl, C -Ce alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
  • a container for housing the formulation and the drug delivery apparatus; and instructions for use.
  • R 1 , R 2 and R 3 are each, independently, H, or optionally substituted C1-C6 alkyl.
  • R 1 , R 2 and R 3 are each, independently, H, C1-C6 alkyl, or Ci-
  • the compound of formula I is a nonspecific
  • the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline, theobromine, or 3- isobutyl- l-methylxanthine (IBMX).
  • the compound of formula I is selected from the group consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
  • kits 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.
  • 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-
  • 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.
  • kits are used to treat a fibrotic disease.
  • fibrotic disease include Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid scars.
  • the fibrotic disease is Peyronie's disease.
  • the fibrotic disease is keloid scars.
  • the pharmaceutical formulation results in improvement of fibrotic conditions, for example, reduction of fibrotic plaques.
  • the formulation reduces PD plaques.
  • the formulation improves erectile dysfunction.
  • the erectile dysfunction is associated with PD.
  • the pharmaceutical formulation is administered locally to treat erectile dysfunction.
  • the erectile dysfunction is associated with Peyronie's disease.
  • the pharmaceutical formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and caffeine.
  • the formulation comprises, consists essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and EGCG.
  • 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.
  • 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.
  • 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.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • cysteine cysteine hydrochloride
  • d- a-tocopherol natural
  • Non-limiting examples of the adjuvant or synergist are citric acid, EDTA
  • the pharmaceutical formulation further comprises an
  • 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 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical formulation is filtered through a 0.22 micron filter.
  • the pharmaceutical formulation is to be filtered through a 0.22 micron filter before administration.
  • the pharmaceutical formulation has a pH of between 4 and 8.
  • 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
  • the pharmaceutical formulation is administered locally.
  • the pharmaceutical formulation comprises a sterile liquid composition and the pharmaceutically acceptable excipient or carrier is suitable for intracavernosal injection.
  • the pharmaceutical formulation comprises an ointment, cream, gel, or lotion, and the pharmaceutical acceptable excipient or carrier is suitable for topical or transdermal administration.
  • 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.
  • the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the fibrotic disease.
  • the pharmaceutical formulation is not administered (e.g., intracavernosally injected) directly into the area of the 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.
  • the pharmaceutical formulation further comprises a second active agent.
  • the second active agent is a vasodilator, e.g., alprostadil (Prostaglandin Ei), papaverine, and/or phentolamine.
  • 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).
  • 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.
  • the pharmaceutical composition comprises yet another component, a polysaccharide.
  • 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
  • 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.
  • the pharmaceutical formulation further comprises a collagenase, such as collagenase Clostridium histolyticum, or Xiaflex®.
  • a collagenase such as collagenase Clostridium histolyticum, or Xiaflex®.
  • the pharmaceutical formulation consists essentially of pentoxifylline and a collagenase, e.g., collagenase Clostridium histolyticum or Xiaflex®.
  • the pharmaceutical formulation comprising the compound of formula I e.g., pentoxifylline
  • the pharmaceutical formulation consisting essentially of a nonspecific PDEi e.g., pentoxifylline
  • a fibrotic disease such as Peyronie's disease.
  • the formulation comprising the compound of formula I e.g., pentoxifylline
  • the formulation consisting essentially of a nonspecific PDEi e.g., pentoxifylline
  • a fibrotic disease such as Peyronie's disease
  • a collagenase therapy e.g., collagenase Clostridium histolyticum or Xiaflex®.
  • 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
  • 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 ⁇ 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 poly(hydroxybutyrate) and blends thereof.
  • 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.
  • 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.
  • microparticles 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.
  • conventional methods such as intracavernosal injections.
  • USP pharmaceutical grade products were used in preparing the formulations described below.
  • Formulation 4 4. Benzyl Alcohol 0.9% or benzalkonium chloride 0.005-0.02% or
  • 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.
  • 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.
  • 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.
  • 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.
  • a pentoxifylline formulation (formulation 10) may be prepared using the following components in the amounts indicated:
  • 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.

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Abstract

La présente invention concerne des formulations pharmaceutiques comprenant de la xanthine ou des dérivés de xanthine, leurs kits, et des méthodes de traitement de maladies fibrotiques par administration locale.
EP18735151.5A 2017-06-12 2018-06-12 Formulations pharmaceutiques de xanthine ou de dérivés de xanthine, et leur utilisation Withdrawn EP3638244A1 (fr)

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US15/620,430 US10383875B2 (en) 2013-06-18 2017-06-12 Pharmaceutical formulations of xanthine or xanthine derivatives, and their use
PCT/US2018/036981 WO2018231739A1 (fr) 2017-06-12 2018-06-12 Formulations pharmaceutiques de xanthine ou de dérivés de xanthine, et leur utilisation

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US5242391A (en) 1990-04-25 1993-09-07 Alza Corporation Urethral insert for treatment of erectile dysfunction
US8133903B2 (en) 2003-10-21 2012-03-13 Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases
WO2014205081A1 (fr) * 2013-06-18 2014-12-24 Imprimis Pharmaceuticals Inc. Préparations pharmaceutiques de xanthine ou de dérivés de xanthine, et leur utilisation

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JP2020523300A (ja) 2020-08-06

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