Classifications

• • 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
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/07—Retinol compounds, e.g. vitamin A
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/203—Retinoic acids ; Salts thereof
• • 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
• • 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
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders

Definitions

• the present invention pertains to the field of pharmacological therapy of disease.
• the invention pertains to the field of pharmacological therapy of granulomatous rosacea.
• Rosacea also called acne rosacea, is a chronic dermatitis of the skin of the face. It is characterized by persistent erythema and often by telangiectasia with acute episodes of edema, papules, and pustules. Rosacea is said to affect about 14 million people in the United States and is triggered or exacerbated, in susceptible individuals, by a number of factors including sun exposure, hot environments, alcohol and various other foods, and application to the skin of astringents.
• Treatment for rosacea includes the avoidance of triggering or exacerbating triggers and the application of topical and internal medications.
• Various types of medications are used in the treatment of rosacea, oftentimes in combinations.
• Acne products such as benzoyl peroxide, immunosuppressants such as tacrolimus, and retinoids such as isotretinoin have shown efficacy in the treatment of rosacea.
• a topical antibiotic medication that has been shown to be effective in the therapy of rosacea is metronidazole, i.e. METROGEL® (Galderma Laboratories, Fort Worth, TX, USA) .
• Systemic antibiotics that are used to treat rosacea include clindamycin, erythromycin, tetracycline, minocycline, doxycycline, clarithromycin, and azithromycin.
• Azithromycin is administered for treatment of rosacea for a period of about 5 days at a level of 250 mg/day, often with a loading dose of 500 mg on day 1.
• Granulomatous rosacea is a variant of rosacea in which discrete papules occur on the medial and lateral facial areas of the face and periorally. Histologically, the papules in granulomatous rosacea, which typically are hard and vary in color from yellowish brown to red, are non-caseating epithelioid cell granulomas. These granulomas are not found in other forms of rosacea. Because of the presence of granulomas, there has been some question as to whether granulomatous rosacea is truly a variant of rosacea or whether it is a separate disease or a variant of another granulomatous disorder of the skin.
• Granulomatous rosacea has proven to be a difficult disease to treat. Most treatments that are effective for other various subtypes of rosacea are ineffective in the treatment of granulomatous rosacea. A significant need exists for an effective therapy for granulomatous rosacea.
• azithromycin administered systemically for a period of several weeks or more, is effective in treating the signs and symptoms of granulomatous rosacea.
• the invention is a method for treating the signs and symptoms of granulomatous rosacea in an individual suffering from such signs and symptoms by systemically administering azithromycin to the individual at a dosage and for a period of time sufficient to ameliorate the signs and symptoms of granulomatous rosacea in the individual.
• the azithromycin used for the method of the invention may be any form of azithromycin. Such forms include noncrystalline and crystalline azithromycin. Crystalline forms of azithromycin include dihydrate and monohydrate forms.
• Administration of azithromycin for the treatment of granulomatous rosacea is systemic. Such systemic administration includes both enteral and parenteral routes of administration. Examples of systemic administration suitable for the method of the invention include injection, such as intravenous, intramuscular, and subcutaneous, and oral administration, such as by swallowing tablets or capsules, including immediate release and delayed release tablets and capsules .
• the dosage of azithromycin that is used in accordance with the method of the invention is a dose that is effective to ameliorate the signs and symptoms of granulomatous rosacea in a person suffering from this disorder.
• a daily dose of 100 to 1000 mg of azithromycin is administered.
• the daily dose is between 150 mg and 750 mg.
• Most preferred is a daily dose of up to about 500 mg, such as between 175 to 350 mg.
• An alternative dosing regimen is an every other day regimen in which a patient receives between 250 mg and 1000 mg on alternate days, preferably between 250 mg and 750 mg on alternate days, and most preferably about 500 mg on an alternating day basis.
• the every other day dose regimen may be utilized following an initial period of daily dosing of azithromycin, if desired.
• dosing regimens are also possible under this invention including once weekly dosage in which a total weekly dose is provided that equals the total weekly amounts that would be administered under the above described daily dosing above.
• a typical weekly dose of azithromycin could be between 700 mg and 7000 mg administered as a single weekly dose.
• Additional variations in dosing schedule are also possible, for example to provide the same weekly amount of azithromycin by administering 2 or 3 doses per week.
• An alternative dosing schedule is as a cycle therapy. Cycle therapy means dosing for a period of time, such as for one week, followed by a rest period (no administration of azithromycin) for a period of time typically the same as that for the dosing period, for example one week. The cycle of dosing and rest is then repeated.
• the total treatment duration could be as little as 2 cycles or as many as 13 cycles or even more if desired.
• An alternative preferred treatment cycle is a one-month treatment, with any of the described dosing schedules within each week such as described above, and a one-month rest period.
• azithromycin is administered for at least two weeks, preferably for four weeks or more, and more preferably for at least two months. Generally therapy should be continued until clinically significant clearance is observed. Treatment with azithromycin in accordance with the invention may last for as long as 6 months or even longer.
• the azithromycin may be administered to an individual suffering from signs and symptoms of granulomatous rosacea in combination with other auxiliary medications and therapies.
• auxiliary medications include hormones such as sex hormones like estrogens, retinoids such as isotretinoin, and other topical medications such as azaleic acid (FINACEA®, Intendis, Montville, NJ) , sodium sulfacetamide 10% with sulfur 5% (ROSAC® Cream with Sunscreens, Stiefel Laboratories, Coral Gables, FL), and/or metronidazole (METROGEL®, Galderma Laboratories, Fort Worth, TX) .
• Topical and or systemic medications known to be effective in the treatment of forms of rosacea other than granulomatous rosacea may be administered in combination with the azithromycin.
• the method of the invention is especially well suited for treating cases of granulomatous rosacea that have not responded favorably, or have responded less favorably than is desired, to other therapy.
• Such unsuccessful therapies include treatments with antibiotics other than azithromycin, including with antifungal medications such as naftifine hydrochloride (NAFTIN®, Merz, Pharmaceuticals, Greensboro, NC) , and treatment with azithromycin for a time shorter than 2 weeks .
• NAFTIN® naftifine hydrochloride
• the method of the invention is further illustrated in the following non-limiting examples. Example 1
• Oral azithromycin at a dosage of 500 mg daily was started, together with daily topical application of a sodium sulfacetamide 10% with sulfur 5% cream and a metronidazole cream.
• the azithromycin was discontinued.
• Treatment was initiated with a variety of topical medications, including metronidazole gel, Elidel ®
• Treatment was subsequently initiated with azithromycin as the sole therapy, administered orally at a dosage of 250 mg daily for three weeks.
• the patient's condition underwent a remarkable improvement as her face cleared and she has not had a recurrence of her granulomatous rosacea following cessation of azithromycin therapy.

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• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Molecular Biology (AREA)
• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dermatology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

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• 2006
  • 2006-11-08 BR BRPI0617693-3A patent/BRPI0617693A2/pt not_active IP Right Cessation
  • 2006-11-08 RU RU2008122964/14A patent/RU2008122964A/ru not_active Application Discontinuation
  • 2006-11-08 WO PCT/US2006/043339 patent/WO2007086978A2/en not_active Ceased
  • 2006-11-08 CA CA002626551A patent/CA2626551A1/en not_active Abandoned
  • 2006-11-08 JP JP2008540128A patent/JP2009514963A/ja active Pending
  • 2006-11-08 US US11/594,451 patent/US20070105788A1/en not_active Abandoned
  • 2006-11-08 CN CNA2006800418105A patent/CN101304750A/zh active Pending
  • 2006-11-08 EP EP06849873A patent/EP1945227A4/en not_active Withdrawn
  • 2006-11-08 AU AU2006336612A patent/AU2006336612A1/en not_active Abandoned
• 2008
  • 2008-06-05 ZA ZA200804896A patent/ZA200804896B/xx unknown

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