EP0480996A1 - Benzophenanthridin-alkaloide zur topischen aknetherapie - Google Patents

Benzophenanthridin-alkaloide zur topischen aknetherapie

Info

Publication number
EP0480996A1
EP0480996A1 EP19900910994 EP90910994A EP0480996A1 EP 0480996 A1 EP0480996 A1 EP 0480996A1 EP 19900910994 EP19900910994 EP 19900910994 EP 90910994 A EP90910994 A EP 90910994A EP 0480996 A1 EP0480996 A1 EP 0480996A1
Authority
EP
European Patent Office
Prior art keywords
acid
alkaloid
composition according
group
composition
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.)
Ceased
Application number
EP19900910994
Other languages
English (en)
French (fr)
Inventor
Kenneth C. Godowski
Elyse D. Wolff
Ronald J. Harkrader
Richard L. Dunn
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.)
Tolmar Therapeutics Inc
Original Assignee
Atrix Laboratories Inc
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
Application filed by Atrix Laboratories Inc filed Critical Atrix Laboratories Inc
Publication of EP0480996A1 publication Critical patent/EP0480996A1/de
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • the invention relates to the preparation and composition of a benzophenanthridine alkaloid with a skin penetration enhancer such that the benzo ⁇ phenanthridine alkaloid will be delivered topically to an acne lesion.
  • the topical delivery of the alkaloid will provide an effective treatment against Proprionibacterium acnes.
  • Acne is a chronic inflammatory disease of the pilosebaceous follicles typically with the onset at puberty.
  • the sebaceous glands enlarge due to androgenic stimulation and colonization of the gland with primarily Proprionibacterium acnes (P. acnes) ensues.
  • Acne affects approximately 80% of the population during adolescence.
  • Topical acne treatments include: benzoyl peroxide, salicylic acid, povidone-iodine, sulfur- resorcinol, sulfur, vitamin A derivatives and antibiotics such as tetracycline.
  • Systemic treatments include the oral administration of estrogen, tetracycline, minocycline and erythromycin.
  • Effective treatments for acne must have several characteristics. First low minimum inhibitory concentration values and low minimum bactericidal concentration values of the an imicrobic are needed against P_ ⁇ acnes. Dosage levels which are effective and safe must be tolerated by both males and females. The treatment must be effective for all age groups affected by the disease. The treatment must penetrate the epidermal layer to effectively treat the P ⁇ acnes in the sebaceous gland.
  • Sources of benzophenanthridine alkaloids include five plant families: Papaveraceae, Fumariaccae, Rutaceae Capifoliaceace and Meliaceae. Two of the most important sources of benzophenanthridine alkaloid are found in the Papaveraceae plant family. These plant species are San ⁇ uinaria canadensis L. (bloodroot) and Maclea a spp. Sanquinaria canadensis L. contains the benzophenanthridine alkaloid sanguinarine, chelery ⁇ thrine, sanguilutine, chelilutine, sanguirubine, and chelirubine. These alkaloids are known as sanguinaria extract.
  • the benzophenanthridine alkaloids can be isolated and purified on a commercial basis using the techniques and processes described in U.S. Patents 4,767,861; 4,769,452 and 4,878,533, for example. Macleaya spp. major alkaloid components are sanguinarine and chelerythrine. Patents describing an extract of these alkaloids include USSR Pat. No. 495,311 and German Pat. No. 2,856,577.
  • Plants containing the mixture of benzo ⁇ phenanthridine alkaloids have been used in a variety of medical ailments. These treatments include antiplaque and treating gingivitis using benzophenanthridine alkaloid in combination with zinc chloride in U.S. Patent No. 4,145,412 and as an antimicrobial agent with zinc chloride U.S. in Patent No. 4,406,081.
  • the following patents describe the use of benzo- phenanthridine alkaloid extracts in medical ailments: U.S. Patent No. 4,376,115; U.K. Pat. No. 2,042,336; German Pat. No. 2,901,406; Belgian Pat. No. 888,843.
  • Vichkanova has described the antifungal and antimicrobial effects of sanguirythrine sulfate (Farmakal Toksikol.Moscow 32, 1969), a 1:1 combination of sanguinarine and chelerythrine.
  • USSR Patent No. 230,387 describes the use of sanguirythrine as a topical antimicrobial treatment.
  • the present invention is directed toward a safe and effective topical treatment of acne using the benzo- phenanthridine alkaloids in combination with skin penetration enhancers in ointments or lotions.
  • This combination will improve the penetration of the epidermal layer by the benzophenanthridine alkaloid transdermally into the follicles containing the P ⁇ _ acnes.
  • the benzophenanthridine alkaloid will be either in the iminium ion form as a mineral acid salt, organic salt or in the alkanolamine or base form ( Figure 1) .
  • the alkanolamine forms can be as the pseudohydroxylate or pseudoalcoholate. These forms have limited water and alcohol solubility in comparison to the iminium ion form (Table 1) . These compounds are ideal for transdermal drug delivery.
  • This invention incorporates the benzophenanthridine alkaloid in a form compatible with the skin penetration enhancer to facilitate delivery of the alkaloid transdermally.
  • compositions used in this invention maybe in the form of liquids, lotions, gels, etc.
  • the benzophenanthridine alkaloids include: sanguinarine, chelerythrine, sanguilutine, sanguirubine, chelirubine, and chelilutine, or combinations of any of these.
  • the most effective formulation containing benzophenanthridine alkaloid against ⁇ _ acnes requires the active agent to penetrate the epidermal layer. Skin penetration enhancers will assist the transdermal delivery of the benzophenanthridine alkaloid or mixture. These types of compounds act by penetrating the skin and decreasing the skin's resistance to drug passage. Thus, in the present invention, large quantities of benzo ⁇ phenanthridine alkaloid can be delivered to the acne lesion site.
  • Typical skin penetration enhancers useful in the present invention include: pyrrolidones, pyrroles. ethanol, propylene glycol, oleic acids, isopropyl myristate, l-dodecylazacycloheptan-2-one, hexamethylene palmitamide, hexamethylene laurimide, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-diethyl toluamide, eaprolactam and other aliphatic alcohols and esters.
  • the effectiveness of a skin penetration enhancer must be able to solubilize the alkaloid and have a low water or body fluid solubility.
  • the benzophenanthridine alkaloids as acid salts are soluble in water at one percent or less.
  • Organic acid salt derivatives of the benzophenanthridine alkaloids such as the palmitate and benzoate can be used to increase alkaloid retention in the skin.
  • P. acnes is approximately 78 ⁇ g/ml. (Topical Acne Drug Product for Over-the-Counter Human Use; 21 CFR Part 333, March 23, 1982; using MIC as the basis for comparison.) Sanguinarine and chelerythrine are 78 times more effective than benzoyl peroxide against P. acnes.
  • the antibiotics tetracycline and doxycycline are 3 and 6 times more effective than sanguinarine and chelerythrine.
  • Sanguinarine has been shown to effective than benzoyl peroxide against P_;_ acnes.
  • the antibiotics tetracycline and doxycycline are 3 and 6 times more effective than sanguinarine and chelerythrine.
  • Sanguinarine has been shown to have antiinflammatory properties (U.S. Patent No. 4,737,503) and the toxicity studies on sanguinarine and benzophenanthridine alkaloids have demonstrated no animal or human tissue irritancy, sensitization, anaphylactic, mutagenic, cardiovascular
  • the pure compounds sanguinarine, chelerythrine or other benzophenanthridine alkaloids as the acid or organic acid salt may be dissolved in water, glycerin, propylene glycol or C ! -C 6 alcohol at a temperature of 20- 60°C. Higher temperatures will cause N-demethylation of the alkaloid salts.
  • the preparations may contain 0.001 to 10% by weight benzophenanthridine alkaloid salt. The preferred concentration range is 0.01 to 5% by weight.
  • the alkanolamine form or base form of the benzophenanthridine alkaloid can be dissolved in isopropyl myristate, N-methyl-2- pyrrolidone, 2-pyrrole, acetone or ethyl acetate at a concentration of 0.001 to 3% by weight.
  • the alkanolamine form usually used will be the hydroxylate or alcoholate.
  • These forms readily convert to the iminium ion at pH less than 7.0.
  • these forms can be incorporated into an ointment or lotion which is applied to the skin where the active form of the drug is generated at pH 5-6, the pH normally encountered in the epidermis.
  • These preparations usually contain between 0.01 and 5% by weight benzophenanthridine alkaloid. These preparations are all free from metal salts such as zinc or tin.
  • the base forms of the benzophenanthridine alkaloids can be prepared in the following example for treatment of acne:
  • a typical lotion with the benzophenanthridine alkaloid is shown below: 10

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP19900910994 1989-07-07 1990-06-22 Benzophenanthridin-alkaloide zur topischen aknetherapie Ceased EP0480996A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37718489A 1989-07-07 1989-07-07
US377184 1989-07-07

Publications (1)

Publication Number Publication Date
EP0480996A1 true EP0480996A1 (de) 1992-04-22

Family

ID=23488102

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900910994 Ceased EP0480996A1 (de) 1989-07-07 1990-06-22 Benzophenanthridin-alkaloide zur topischen aknetherapie

Country Status (4)

Country Link
EP (1) EP0480996A1 (de)
AU (1) AU6034690A (de)
CA (1) CA2062970A1 (de)
WO (1) WO1991000728A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175000A (en) * 1987-06-30 1992-12-29 Vipont Pharmaceutical, Inc. Free amine benzophenanthridine alkaloid compositions
IT1254321B (it) * 1992-04-10 1995-09-14 Kemiprogress S R L Composizione farmaceutica per il trattamento e la prevenzione delle infiammazioni cutanee e della mucosa orale.
KR100356697B1 (ko) * 1998-03-07 2002-12-18 주식회사 태평양 여드름에효과가있는피부용조성물
JP2002519366A (ja) * 1998-07-07 2002-07-02 トランスダーマル・テクノロジーズ・インコーポレーテツド 医薬的に活性な作用物質を迅速かつ非刺激的に経皮送達するための組成物、およびそのような組成物の調剤法およびそれらの送達
US9616127B2 (en) * 2008-03-11 2017-04-11 Livionex Inc. Method and topical formulation for treating localized edema

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4406881A (en) * 1980-05-20 1983-09-27 Vipont Laboratories Antimicrobial agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9100728A1 *

Also Published As

Publication number Publication date
AU6034690A (en) 1991-02-06
WO1991000728A1 (en) 1991-01-24
CA2062970A1 (en) 1991-01-08

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Inventor name: DUNN, RICHARD, L.

Inventor name: GODOWSKI, KENNETH, C.

Inventor name: WOLFF, ELYSE, D.

Inventor name: HARKRADER, RONALD, J.

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Effective date: 19921218

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