WO1997047300A1 - Antimycotics with metronidazole for treatment of skin disorders - Google Patents

Antimycotics with metronidazole for treatment of skin disorders Download PDF

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Publication number
WO1997047300A1
WO1997047300A1 PCT/US1997/010301 US9710301W WO9747300A1 WO 1997047300 A1 WO1997047300 A1 WO 1997047300A1 US 9710301 W US9710301 W US 9710301W WO 9747300 A1 WO9747300 A1 WO 9747300A1
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Prior art keywords
metronidazole
treatment
antimycotic agents
topical composition
milligrams
Prior art date
Application number
PCT/US1997/010301
Other languages
French (fr)
Inventor
Karl F. Popp
Jon A. Jungquist
Original Assignee
Stiefel 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 Stiefel Laboratories, Inc. filed Critical Stiefel Laboratories, Inc.
Publication of WO1997047300A1 publication Critical patent/WO1997047300A1/en

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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
    • A61K31/33—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
    • A61K31/415—1,2-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
    • A61K31/33—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
    • A61K31/425—Thiazoles

Definitions

  • the present invention relates to a novel method of treatment of skin disorders using coupled antibiotic therapy, particularly the use of antimycotics coupled with metronidazole.
  • Metronidazole 2-Methyl-5-nitroimidazole-l-ethanol
  • Metronidazole has an extremely broad spectrum of protozoal and antimicrobial activity.
  • Metronidazole is clinically effective in trichomoniasis, amebiasis, and giardiasis, as well as in a variety of infections caused by obligate, anaerobic, bacteria, including Bacteroides fragilis.
  • Metronidazole is commonly administered both orally and intravenously. Metronidazole has also been reported to be effective via both oral and topically application in the treatment of skin disorders including acne, impetigo, and rosacea.
  • Antimycotics have been used systemically and topically for the treatment of skin disorders.
  • Many agents are available for the treatment of superficial mycosis, including imidazoles and triazoles such as, clotrimazole, miconazole, and thiabendazole, polyenes such as nystatin, amphotericin-B, and natamycin, and others such as griseofulvin, tolnaftate, and ciclopirox olamine.
  • Rosacea is an acneform condition primarily affecting the areas of the nose, cheeks, and forehead of adults. The condition is characterized by erythema, pustules, papules, rhinophyma, and telangiectses.
  • the cause of Rosacea is unknown; however, dietary influence, gastrointestinal disturbances, phychologic or hormonal imbalance, sebaceous gland abnormalities, and infection have been considered but not validated.
  • Other theories range from solar-induced dermal connective tissue damage, with resultant vascular distension to humorally mediated active vasodilatory changes.
  • a causative role has also been suggested for the hair follicle mite, Demodex. C.E. Bonnnar, et al., "The Demodex Mite Population", J. Amer. Acad. Dematology, Vol. 28, No. 3, pp. 443-447, March 1993.
  • the method of treatment of the present invention overcomes the failures of a single course therapy with a novel coupled treatment using metronidazole in combination with one or more antimycotic agents.
  • the treatment of Rosacea and other acneform skin conditions is accomplished with a coupled antibiotic therapy incorporating the use of metronidazole in combination with one or more antimycotic agents.
  • the antibiotics may be administered either orally or topically or any combination or mixture of both.
  • the choice of the route of administration is, in part, determined by patient intolerance, anticipated patient compliance, the nature of the condition, formulation considerations, or other problems.
  • One of the antibiotics may be administered orally with the second antibiotic being administered topically; or, a partial dose of one or both of the antibiotics may be administered orally with the remainder of the dose being administered topically.
  • metronidazole as used in this specification and claims is meant to include not only 2- methyl-5-nitroimidazole-l-ethanol, but also those analogs and derivatives of metronidazole which are pharmaceutically desirable and which have therapeutic activity when orally administered and/or topically applied. Metronidazole is employed in the treatment in a therapeutically effective amount. The actual dosage or concentration of metronidazole may vary, depending upon the nature and degree of the disorders being treated, and whether the drug is being administered for therapeutic or prophylactic purposes.
  • metronidazole For oral drug delivery, the daily dose of metronidazole ranges from about 10 milligrams to about
  • Topical compositions would comprise at least 0.1 wt-%, up to 5 wt-%, preferably from about 0.25 to 3 wt-%.
  • the antimycotic agent may be selected from any of the available compounds used for treating mycotic infections.
  • Preferred antimycotics include, imidazoles, triazoles, polyenes, and others such as griseofulvin; preferably thiabendazole.
  • Antimycotics for oral administration preferably have distribution concentrated in the stratum corneum, such as, griseofulvin and ketoconazole.
  • references to any antimycotic agent includes not only the agent itself, but also those analogs and derivatives which are pharmaceutically and which have therapeutic activity when administered orally and/or topically applied.
  • the oral daily dose of the anytimycotic agents ranges from about 10 milligrams to about 2 grams; preferably from about 25 milligrams to about 750 milligrams.
  • Levels of the antimycotic agents in topical compositions would typically range from about 0.1 to 20 wt-%; preferably from about
  • Oral administration of any antibiotic would encompass conventional and sustained release oral dosage forms, including tablets and capsules, with or without surface active coatings, (in intimate contact with either active drug,) in combination with a pharmaceutically acceptable carrier. Additional excipients would include, but are not limited to, binders, diluents, disintegrants, surfactants, film formers, polymers, and lubricants, to enhance the processability or therapeutic effectives of the therapeutic compound. Topical drug delivery systems include, but are not limited to, creams, lotions, gels, ointments, aerosols, solutions, pastes, plasters, ophthalmic solutions, ointments, etc.
  • Topical drug delivery systems may be either aqueous or non-aqueous in composition, and may also include polymers, liposomes, surfactants, thickeners, stabilizers, buffers, and other pharmaceutically acceptable ingredients which enhance the products physical or chemical presentation or therapeutic effectiveness.
  • Preferred topical delivery systems are emulsion based, but other topical pharmaceutical dosage forms will also be operative.
  • the active agent or agents may be dissolved, dispersed, suspended, solubilized, coated, entrapped, or encapsulated within the formulation matrix.
  • compositions which do not adversely affect the effectiveness of the antibiotics will be evident to one skilled in the art, and or within the scope of this invention.
  • additional ingredients such as coloring agents, sunscreens, and the like, may be included in the compositions, as long as the resulting composition retains the desirable properties, e.g., non-comedogenicity, high specific activity, and the like, described above.
  • Subtotal 677.0 Individual powders are weighed and screened. The screened powders are then blended and combined and granulated with water. The wetted material is then dried. The dried combination is then screened to size the particles. The final blend ingredients are then combined with the primary granulation and compressed into tablets. The film coating is applied using a suitable spray coating apparatus.
  • Ingredients are placed in a suitable vessel and mixed to effect a solution.
  • the PEG's are placed in a suitable vessel and heated to form a uniform mixture. While the PEG mixture is cooling, the active agents are added and dispersed with mixing. After cooling, the resulting ointment may be milled to modify the physical attributes.
  • the Petrolatum and active ingredients are blended to a uniformly distributed mixture in a suitable mixture.
  • the mixture may be passed through a suitable mill to modify the product aesthetics.
  • the White Petrolatum, stearyl alcohol, PEG-40 Stearate, and mineral oil are heated in a suitable vessel and mixed to a uniform mixture.
  • the purified water is heated and the carbomer is added with mixing.
  • the oil phase mixture is added with stirring to the water phase.
  • the mixture is removed from heat and while cooling, the active ingredients are added and dispersed with mixing.
  • the preservative is added during the cooling period.
  • the pH of the cream is adjusted with the nitric acid or sodium hydroxide as necessary.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A novel method for the treatment of dermatological disorders comprising the administration of metronidazole in combination with one or more antimycotic agents, such as imidazoles, triazoles, polyenes, and grisefulvin.

Description

ANTIMYCOTICS WITH METRONIDAZOLE FOR TREATMENT OF SKIN DISORDERS
BACKGROUND OF THE INVENTION
The present invention relates to a novel method of treatment of skin disorders using coupled antibiotic therapy, particularly the use of antimycotics coupled with metronidazole.
Metronidazole, 2-Methyl-5-nitroimidazole-l-ethanol, has an extremely broad spectrum of protozoal and antimicrobial activity. Metronidazole is clinically effective in trichomoniasis, amebiasis, and giardiasis, as well as in a variety of infections caused by obligate, anaerobic, bacteria, including Bacteroides fragilis. Metronidazole is commonly administered both orally and intravenously. Metronidazole has also been reported to be effective via both oral and topically application in the treatment of skin disorders including acne, impetigo, and rosacea. See, for example, Schirner, A., and Haneke, E., "Rosacea and Metronidazole", Acta Dermatologica, 7,27-30 (1981); and Nielsen, P.G.,"A Double Blind Study of 1% Metronidazole Cream Reverses Systemic Oxytetracycline Therapy for Rosacea", British Journal of Dermatology, 109, 63-65, (1983).
Antimycotics have been used systemically and topically for the treatment of skin disorders. Many agents are available for the treatment of superficial mycosis, including imidazoles and triazoles such as, clotrimazole, miconazole, and thiabendazole, polyenes such as nystatin, amphotericin-B, and natamycin, and others such as griseofulvin, tolnaftate, and ciclopirox olamine.
Rosacea is an acneform condition primarily affecting the areas of the nose, cheeks, and forehead of adults. The condition is characterized by erythema, pustules, papules, rhinophyma, and telangiectses. The cause of Rosacea is unknown; however, dietary influence, gastrointestinal disturbances, phychologic or hormonal imbalance, sebaceous gland abnormalities, and infection have been considered but not validated. Other theories range from solar-induced dermal connective tissue damage, with resultant vascular distension to humorally mediated active vasodilatory changes. A causative role has also been suggested for the hair follicle mite, Demodex. C.E. Bonnnar, et al., "The Demodex Mite Population", J. Amer. Acad. Dematology, Vol. 28, No. 3, pp. 443-447, March 1993.
Many skin disorders, including the acneform disorders such as Rosacea, are treated with a course of single antibiotic therapy, such therapies fail to yield the desired clinical results such as cosmetic improvement, elimination of pathogenic organisms, reduction of swelling, etc. These failures may be due to the complicated nature of many skin diseases in that the symptoms may be the result of changes in internal, external, or a combination of both of these environments. Frequently a change in one aspect of the subjects skin flora can lead to the opportunistic cultivation of another organism.
The method of treatment of the present invention overcomes the failures of a single course therapy with a novel coupled treatment using metronidazole in combination with one or more antimycotic agents.
SUMMARY OF THE INVENTION In accordance with the present invention, the treatment of Rosacea and other acneform skin conditions is accomplished with a coupled antibiotic therapy incorporating the use of metronidazole in combination with one or more antimycotic agents. The antibiotics may be administered either orally or topically or any combination or mixture of both. The choice of the route of administration is, in part, determined by patient intolerance, anticipated patient compliance, the nature of the condition, formulation considerations, or other problems. One of the antibiotics may be administered orally with the second antibiotic being administered topically; or, a partial dose of one or both of the antibiotics may be administered orally with the remainder of the dose being administered topically.
Numerous other advantages and features of the present invention will become readily apparent from the following description of the preferred embodiments of the invention, the accompanying examples, and the appended claims. DESCRIPTION OF THE INVENTION The term "metronidazole" as used in this specification and claims is meant to include not only 2- methyl-5-nitroimidazole-l-ethanol, but also those analogs and derivatives of metronidazole which are pharmaceutically desirable and which have therapeutic activity when orally administered and/or topically applied. Metronidazole is employed in the treatment in a therapeutically effective amount. The actual dosage or concentration of metronidazole may vary, depending upon the nature and degree of the disorders being treated, and whether the drug is being administered for therapeutic or prophylactic purposes.
For oral drug delivery, the daily dose of metronidazole ranges from about 10 milligrams to about
2 grams, preferably from about 50 milligrams to 1000 milligrams. Topical compositions would comprise at least 0.1 wt-%, up to 5 wt-%, preferably from about 0.25 to 3 wt-%.
The antimycotic agent may be selected from any of the available compounds used for treating mycotic infections. Preferred antimycotics include, imidazoles, triazoles, polyenes, and others such as griseofulvin; preferably thiabendazole. Antimycotics for oral administration preferably have distribution concentrated in the stratum corneum, such as, griseofulvin and ketoconazole.
Reference to any antimycotic agent includes not only the agent itself, but also those analogs and derivatives which are pharmaceutically and which have therapeutic activity when administered orally and/or topically applied.
The oral daily dose of the anytimycotic agents ranges from about 10 milligrams to about 2 grams; preferably from about 25 milligrams to about 750 milligrams. Levels of the antimycotic agents in topical compositions would typically range from about 0.1 to 20 wt-%; preferably from about
3 to about 10 wt-%.
Oral administration of any antibiotic would encompass conventional and sustained release oral dosage forms, including tablets and capsules, with or without surface active coatings, (in intimate contact with either active drug,) in combination with a pharmaceutically acceptable carrier. Additional excipients would include, but are not limited to, binders, diluents, disintegrants, surfactants, film formers, polymers, and lubricants, to enhance the processability or therapeutic effectives of the therapeutic compound. Topical drug delivery systems include, but are not limited to, creams, lotions, gels, ointments, aerosols, solutions, pastes, plasters, ophthalmic solutions, ointments, etc. Topical drug delivery systems may be either aqueous or non-aqueous in composition, and may also include polymers, liposomes, surfactants, thickeners, stabilizers, buffers, and other pharmaceutically acceptable ingredients which enhance the products physical or chemical presentation or therapeutic effectiveness. Preferred topical delivery systems are emulsion based, but other topical pharmaceutical dosage forms will also be operative. The active agent or agents may be dissolved, dispersed, suspended, solubilized, coated, entrapped, or encapsulated within the formulation matrix.
Examples of pharmaceutical dosage forms are demonstrated in the following examples. These examples are meant to illustrate the invention, the scope of the invention is limited only by the appended claims. Variations in the compositions which do not adversely affect the effectiveness of the antibiotics will be evident to one skilled in the art, and or within the scope of this invention. For example, additional ingredients, such as coloring agents, sunscreens, and the like, may be included in the compositions, as long as the resulting composition retains the desirable properties, e.g., non-comedogenicity, high specific activity, and the like, described above.
EXAMPLE 1
Capsule Formulation
Ingredients Per capsule
Thiabendazole 100 milligrams Metronidazole 200 milligrams
Starch 200 milligrams
Lactose 200 milligrams
Magnesium Sterate 1.5 milligrams
Individual ingredients are passed through suitable screens. The powders are then combined and mixed until uniform. The combined powder is then placed into an appropriately sized gelatin capsule. EXAMPLE 2
Tablet Formulation
Primarv granulation
Ingredients Milligrams per tablet
Propriabendazole 25.0
Metronidazole 175.0
Fumed Silica 4.4
Chroscarmellose sodium 29.2
Povidone 9.0
Talc 29.4
Microcrystalline cellulose 268.0
Purified water* q.s.
Subtotal 540.0
* Removed during processing
Final blend
Ingredients Milligrams per tablet
Primary granulation 540.0
Talc 29.2
Microcrystalline cellulose 87.6
Chroscarmellose sodium 7.3
Magnesium stearate 5.9
Subtotal 670.0
Film Coating
Ingredients Milligrams per tablet
Hydroxypropylmethylcellulose 15 cP 5.0
Triacetin 1.0
Titanium dioxide 1.0
Purified water* q.s.
Subtotal 677.0 Individual powders are weighed and screened. The screened powders are then blended and combined and granulated with water. The wetted material is then dried. The dried combination is then screened to size the particles. The final blend ingredients are then combined with the primary granulation and compressed into tablets. The film coating is applied using a suitable spray coating apparatus.
EXAMPLE 3
Solution Formulation
Ingredients % WW
Thiabendazole 0.25
Metronidazole 0.75
Dimethylsulfoxide 99.0
Ingredients are placed in a suitable vessel and mixed to effect a solution.
EXAMPLE 4
Ointment Formulation
Ingredients %WW
Thiabendazole 10.0
Metronidazole 1.0
PEQ 400,USP 54.0
PEG 3350. IJSP 35,0
Total 100.0
The PEG's are placed in a suitable vessel and heated to form a uniform mixture. While the PEG mixture is cooling, the active agents are added and dispersed with mixing. After cooling, the resulting ointment may be milled to modify the physical attributes.
EXAMPLE 5 Ointment formulation
Ingredients %W/W
Viabendazole 20.0 Metromidazole 5.0
White Petrolatum 75.0
Total 100.0
The Petrolatum and active ingredients are blended to a uniformly distributed mixture in a suitable mixture. The mixture may be passed through a suitable mill to modify the product aesthetics.
EXAMPLE 6
Cream Formulation
Ingredients %W/W
Thiabendazole 5.0
Metromidazole 1.0
White Petrolatum 10.0
Stearyl alcohol 8.0
PEG-40 Stearate 3.0
Mineral Oil 10.0
Carbomer 0.3
Nitric acid/Sodium Hydroxide to adjust pH Preservative q.s. Purified Water* q.s. ad 100.0
Total 100.0
The White Petrolatum, stearyl alcohol, PEG-40 Stearate, and mineral oil are heated in a suitable vessel and mixed to a uniform mixture. In a separate vessel, the purified water is heated and the carbomer is added with mixing. The oil phase mixture is added with stirring to the water phase. The mixture is removed from heat and while cooling, the active ingredients are added and dispersed with mixing. The preservative is added during the cooling period. The pH of the cream is adjusted with the nitric acid or sodium hydroxide as necessary.

Claims

What is Claimed:
Claim 1 : A method for the treatment of dermatological disorders comprising the administration of metronidazole in combination with one or more antimycotic agents.
Claim 2: The treatment method of Claim 1 wherein said one or more antimycotic agents are selected from the group consisting of imidazoles, triazoles, polyenes, and griseofulvin.
Claim 3: The treatment method of Claim 1 wherein said one or more antimycotic agents are comprised of thiabendazole.
Claim 4: The method of treatment of claim 1 wherein the metronidazole is administered orally.
Claim 5: The method of Claim 1 wherein metronidazole is administered topically in a pharmaceutically acceptable topical composition.
Claim 6: The method of Claim 1 wherein said one or more antimycotic agents are administered orally.
Claim 7: The method of Claim 1 wherein said one or more antimycotic agents are administered topically.
Claim 8: The method of Claim 4 wherein the daily dose of metronidazole is from about 10 milligrams to about 2,000 milligrams.
Claim 9: The method of Claim 5 wherein the metroidazole is administered in a topical composition, said topical composition comprising from about 0.1 wt-% up to about 5 wt-% metronidazole in a pharmaceutically acceptable topical composition.
Claim 10: The method of Claim 6 when the daily dose of the antimycotic agents if from about 10 milligrams to about 2,000 milligrams. Claim 1 1 : The method of Claim 7 wherein said one or more antimycotic agents are administered in a topical composition, said topical composition from about 0.1 wt-% to about 20 wt-% of said one or more antimycotic agents in a pharmaceutically acceptalbe topical composition.
Claim 12: A pharmaceutical dosage form for oral administration used in the treatment of dermatological disorders comprising: an effective amount of metronidazole; an effective amount of an antimycotic agent; and a pharmaceutically acceptable carrier.
Claim 13: A topical drug delivery system for the treatment of dermatological disorders comprising: an effective amount of metronidazole; an effective amount of one or more antimycotic agents; and a pharmaceutically acceptable carrier.
Claim 14: A method for the treatment of Rosacea comprising the administration of metronidazole in combination with one or more antimycotic agents.
Claim 15 : The treatment method of Claim 14 wherein said one or more antimycotic agents are selected from the group consisting of imidazoles, triazoles, polyenes, and griseofulvin.
Claim 16: The treatment method of Claim 14 wherein said one or more antimycotic agents are comprised of thiabendazole.
Claim 17: The method of treatment of Claim 14 wherein the metronidazole is administered orally.
Claim 18: The method of Claim 14 wherein metronidazole is administered topically in a pharmaceutically acceptable topical composition. Claim 19: The method of Claim 14 wherein said one or more antimycotic agents are administered orally.
Claim 20: The method of Claim 14 wherein said one or more antimycotic agents are administered topically.
PCT/US1997/010301 1996-06-14 1997-06-12 Antimycotics with metronidazole for treatment of skin disorders WO1997047300A1 (en)

Applications Claiming Priority (2)

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US66389996A 1996-06-14 1996-06-14
US08/663,899 1996-06-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074290A3 (en) * 2001-03-15 2004-02-19 Agis Ind 1983 Ltd Dermatological preparations containing a nsaid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837378A (en) * 1986-01-15 1989-06-06 Curatek Pharmaceuticals, Inc. Topical metronidazole formulations and therapeutic uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837378A (en) * 1986-01-15 1989-06-06 Curatek Pharmaceuticals, Inc. Topical metronidazole formulations and therapeutic uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 101, No. 12, issued 17 September 1984, RADULESCU et al., "Polyactive Vaginal Product for Treating Polymorphous Microbial Vaginitis", Abstract No. 97676; & RO,A,82 399, (30 September 1983). *
CONTACT DERMATITIS, 1993, Vol. 28, ISU et al., "Photoaggravated Allergic Contact Dermatitis Due to Topical Thiabendazole", pages 243-244. *
DATABASE MEDLINE ON DIALOG, US NATIONAL LIBRARY OF MEDICINE, (Bethesda, MD, USA), No. 83199559, DORING et al., "Local Treatment of Rosacea with Imidazole Derivatives"; & ZEITSCHRIFT FUER HAUTKRANKHEITEN, 1983, 58(3), 141-150, 155. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074290A3 (en) * 2001-03-15 2004-02-19 Agis Ind 1983 Ltd Dermatological preparations containing a nsaid

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