WO1995034262A1 - Traitement transdermique du paludisme - Google Patents

Traitement transdermique du paludisme Download PDF

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Publication number
WO1995034262A1
WO1995034262A1 PCT/US1995/007696 US9507696W WO9534262A1 WO 1995034262 A1 WO1995034262 A1 WO 1995034262A1 US 9507696 W US9507696 W US 9507696W WO 9534262 A1 WO9534262 A1 WO 9534262A1
Authority
WO
WIPO (PCT)
Prior art keywords
antimalarial
composition
mice
com
compound
Prior art date
Application number
PCT/US1995/007696
Other languages
English (en)
Inventor
Arba Agar
Lawrence Fleckenstein
Ai J. Lin
Daniel KLAYMAN
Original Assignee
Department Of The Army, Us Government
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 Department Of The Army, Us Government filed Critical Department Of The Army, Us Government
Publication of WO1995034262A1 publication Critical patent/WO1995034262A1/fr

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the prophylactic protection from and treatment of local and systemic effects of Plasmodium species which cause malaria by transdermal administration of artelinic acid or an analog thereof using artelinic acid and analogues thereof.
  • Malaria is the most prevalent infectious disease on this planet. The disease is endemic throughout the tropics and the warmer parts of the temperate zone. Providing prophylaxis and treatment of large numbers of persons in warm climates where poverty is common and medical facilities are minimal presents particular problems for the clinician. Methods of treatment that require minimal expense and equipment for administration of antimalarial agents are needed if appropriate treatment of large populations is to become a reality.
  • artelinic acid and its analogues for treatment of malaria.
  • usual methods of administration for systemic effects such as oral or parenteral administration of the artelinic acid analogues has presented problems, since side effects seen with systemic administration are sometimes severe.
  • first-pass metabolism such as occurs when medications are given orally may result in failure of the active agent to reach the target tissue.
  • U.S. Patent 4,978,676 teaches topical administration of artemisinin derivatives for treatment of cutaneous conditions such as psoriasis, tumors, and untoward responses to ltravio- let light. That patent teaches topical administration of artemisinin, dihydroartemisinin, its semisyntheticderivatives, and synthetic analogues of the formula:
  • R is a member selected from the group consisting of
  • R' is a member selected from the groups consisting of 0 0 0 0 0
  • the administration of agents which are effective against malaria using means which are inexpensive and do not require use of highly trained medical personnel for administration of the therapeutics is much needed.
  • the administration of antimalarials transdermally as taught herein provides many advantages for treatment of large populations.
  • the use of patch technology, a more preferred embodiment of the invention, makes it possible to treat large populations at low cost by non-invasive means.
  • the patch provides active agents on solid supports.
  • the supports with the active agents may advanta ⁇ geously be packaged in such a way that small bandages with water-proof backing having extensions with adhesives for attachment to the skin are packaged with a protective covering over the bandage portion containing the active agent. The protective covering is easily removed when the bandages are to be used.
  • the active agents used by the inventive method are artemisinin-type antimalarials which are effective when administered at dosages of about 0.1 mg/kg to 60 mg/kg in mammals. In larger mammals such as man, the dosage is about 0.1 mg/kg to 30 mg/kg in the patc .
  • the antimalarial agents are administered transdermally to provide systemic response. Thus administered the active agents are useful for effecting both prophylaxis and treatment of malaria.
  • Artemisinin and artesunate have been known as antimalarial drugs.
  • administration of this class of compounds has presented problems since the artemisinin is poorly soluble in water or oil, and the artesunate has a short plasma half-life when given parenterally.
  • the administration of artemisinin- like compounds by the application of patches having the active agents on a support such as gauze or cellulose now provides an inexpensive and easy means of application.
  • the use of patches allows administration of controlled dosage. Agents which are not readily absorbed into the body from the intestinal tract or might be destroyed chemically or enzy ati- cally if administered by mouth can be administered effectively using the methods of the invention.
  • the invention was tested using mice infected with Plasmodium berqhei, a widely accepted model for testing effectiveness against infection with the malaria-causing Plasmodium species in mammals.
  • Compunds for used in the method of the invention include those of the structure:
  • R' The compounds having an acid moiety on substituent R' appear to be less effective for use in the patch. Generally, agents lacking either acid or ester moieties on the R' substituent were most effective.
  • the most preferred compounds are those wherein R' is an alkyl ether wherein R' is an alkyl ether such as methoxy, ethoxy, propoxy or butoxy or a silyl ether such as tri ethylsilyl ether or triethylsilyl ether.
  • a solution was prepared containing 8 ml of absolute ethanol, 32 ml dimethyl phthalate and 0.8 gm. of the test compound.
  • a gel was formulated by gradual addition of 4 gm. of ethylcellulose to the solution. Stirring was continued until a clear solution was formed.
  • the preparation had a consistency of a thin gel with a volume of 45 ml and a drug concentration of 18 mg/ml.
  • mice were determined in CD/1 Swiss outbred four-week-old mice weighing 20 g. These mice were maintained at 84° F and fed Purina mouse chow and water ad libidum. The mice were infected with 5.98 x 10 5 P. bercfhei-parasitized mouse erythrocytes injected intraperitoneally. The day of inoculation was defined as day 0, with treatment days being counted in relation to that day. Assessment of the curative properties of a dosage regimen was made by comparing the survival times of treated mice with those of the untreated controls. The untreated mice died on either day 6 or 7.
  • a dosage regimen was considered to be curative if the treated mice survived to day 60 and active if the survival time of the treated mice was greater than twice that of the controls, i.e., 12-14 days.
  • blood films were taken immediately before drug application and on days 1-7 and thereafter weekly until day 60. Newly positive para- sitemias and deaths that occurred after 12-14 days were attributed to recrudescences. Mice designated cured had a negative parasitemia on day 60.
  • Prophylactic properties of the drug regimens were appraised by comparison of survival times of mice that were treated on day 0 with those of infected, untreated controls.
  • a dosage regimen was considered to have prophylactic activity (i.e., no infection was established) if the treated mice survived to day 60 and to be active if the survival time of the treated mice was greater than twice that of the untreated control mice, i.e., 12-14 days.
  • Mouse parasitemias were determined on those days as described in the previous para ⁇ graph.
  • mice that survived 60 days postinfection were inoculated with P. ber hei (5.98 x 10 5 parasitized erythro- cytes) to determine if they were completely cured. If the mice were susceptible to reinfection, they were considered to be totally parasite-free and subsequently to have lost their premunition type of immune status.
  • P. ber hei 5.98 x 10 5 parasitized erythro- cytes
  • mice Five mice were used in each test group- and each mouse received the formulation twice a day for 3 consecutive days. Although all of the gell appeared to be absorbed within eight hours, the bare skin was cleaned with 70% isopropyl alcohol before being re-treated. Mice were treated twice a day—in the morning and 8 or 12 hours later. Although the mice were not observed to lick the applied medication from their own backs or from the backs of the other treated mice, animals were housed in individual cages to avoid possibility of such activity.
  • the transdermal formulation When the transdermal formulation was evaluated as a curative agent, the gel was applied beginning on day 3, when the parasitemias in the mice were typically 15%. When the formulation was evaluated for its prophylactic activity, it was typically applied 0.5 hours after inoculation with the parasite. Table I gives data relating to curative treatment. Table II give data related to prophylactic use.
  • Example 2 Transdermal application using a patch
  • mice Male mice (CD-I) used were 5 weeks old and weighted 20 gm on day 0. The fur was carefully removed with a hair clipper from the backs of mice from both the left and right sides between the hip and shoulder blade to give a denuded area of approximately 3 cm x 3 cm. The skin had no cut or abrasions. The mice were inoculated intraperitoneally with 5.98 x 10 5 parasites of Plasmodium berghei. Within 1/2 hour after infection, one group of mice was treated with the active agents applied directly to the skin. The gel was applied with a gloved finger and rubbed. For another group, the active agents were applied to a patch.
  • the patches with the medicinals applied thereto were then affixed to the denuded skin area, where they remained for 24 hours.
  • the mice were housed individually. The three doses were administered at 24 hour intervals. The mice were followed for 60 days. Infected, non- treated control mice and vehicle control mice routinely died within 7 or 8 days postinfection. Mice surviving 60 days were considered cured.
  • Table III agent each dose total dose patch day of cured/prolonged mg mg Y/N death
  • the active agent may be effectively prepared in any manner that will effectively cause the active agent to be placed on the support and, after application of the support surface to the skin, deliver the active agent to the skin.
  • the active agent may be dissolved in carrier material containing DMSO and alcohol, then applied to a patch.
  • the antimalarials in solution may be added to another carrier such as glycerol before application of the composition to the support material of the patch.
  • U.S. Patent 4,978,532 describes use of patch technology. That reference is incorporated herein by reference.
  • the patch may, for example, be a discoid in which a pressure-sensitive silicone adhesive matrix containing the active agent may be covered with a non-permeable backing.
  • the discoid may either contain the active agent in the adhesive which can also act as a support or may have attached thereto a support made of material such as polyurethane foam, cellulose or gauze that will hold the active agent.
  • the active agents incorporated into a solid support and applied to the skin can release the medicinal to provide sustained release to effect more cinsistent levels of the agent.

Abstract

L'invention concerne des antipaludiques du type artémisinine qui sont efficaces lorsqu'ils sont administrés par voie transdermique à des mammifères en doses d'environ 0,1 mg/kg à 60 mg/kg. Chez les mammifères tels que l'homme, le dosage est d'environ 0,1 mg/kg à 30 mg/kg dans le timbre. Les agents antipaludiques sont administrés par voie transdermique pour produire une réponse systémique. Lorsqu'ils sont administrés de cette manière, les agents actifs sont utiles à la fois pour la prophylaxie et le traitement du paludisme.
PCT/US1995/007696 1994-06-16 1995-06-16 Traitement transdermique du paludisme WO1995034262A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25861794A 1994-06-16 1994-06-16
US08/258,617 1994-06-16

Publications (1)

Publication Number Publication Date
WO1995034262A1 true WO1995034262A1 (fr) 1995-12-21

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/007696 WO1995034262A1 (fr) 1994-06-16 1995-06-16 Traitement transdermique du paludisme

Country Status (1)

Country Link
WO (1) WO1995034262A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1150984A1 (fr) * 1999-01-12 2001-11-07 Hauser, Inc. Composes dimeres de trioxane presentant des activites antiproliferative, et antitumorale
US6692918B2 (en) 1999-09-13 2004-02-17 Nugen Technologies, Inc. Methods and compositions for linear isothermal amplification of polynucleotide sequences
WO2007045116A1 (fr) * 2005-10-20 2007-04-26 Epipharm Gmbh Traitement et prevention de manifestations pigmentaires (naevus) benignes grace a l'utilisation d'artemisinine et de ses derives
WO2008037176A1 (fr) * 2006-09-29 2008-04-03 Beijing Zhongyan Tongrentang Chinese Medicine R & D Co., Ltd. Préparations transdermiques comprenant de l'artémisinine et/ou ses dérivés
CN101125135B (zh) * 2007-08-22 2010-05-19 昆明制药集团股份有限公司 蒿甲醚巴布剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4438258A (en) * 1981-06-12 1984-03-20 National Research Development Corporation Hydrogels
US4791135A (en) * 1987-08-20 1988-12-13 The United States Of America As Represented By The Secretary Of The Army Novel antimalarial dihydroartemisinin derivatives
US4978676A (en) * 1987-07-31 1990-12-18 Thornfeldt Carl R Treatment of skin diseases with artemisinin and derivatives
US5130139A (en) * 1990-07-06 1992-07-14 Alza Corporation Reduction or prevention of skin irritation by drugs
US5219865A (en) * 1987-05-08 1993-06-15 Hoechst Aktiengesellschaft Pharmaceutical combination for the prophylaxis and therapy of malaria
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4438258A (en) * 1981-06-12 1984-03-20 National Research Development Corporation Hydrogels
US5219865A (en) * 1987-05-08 1993-06-15 Hoechst Aktiengesellschaft Pharmaceutical combination for the prophylaxis and therapy of malaria
US4978676A (en) * 1987-07-31 1990-12-18 Thornfeldt Carl R Treatment of skin diseases with artemisinin and derivatives
US4791135A (en) * 1987-08-20 1988-12-13 The United States Of America As Represented By The Secretary Of The Army Novel antimalarial dihydroartemisinin derivatives
US5130139A (en) * 1990-07-06 1992-07-14 Alza Corporation Reduction or prevention of skin irritation by drugs
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1150984A1 (fr) * 1999-01-12 2001-11-07 Hauser, Inc. Composes dimeres de trioxane presentant des activites antiproliferative, et antitumorale
EP1150984A4 (fr) * 1999-01-12 2002-06-19 Hauser Inc Composes dimeres de trioxane presentant des activites antiproliferative, et antitumorale
US6692918B2 (en) 1999-09-13 2004-02-17 Nugen Technologies, Inc. Methods and compositions for linear isothermal amplification of polynucleotide sequences
WO2007045116A1 (fr) * 2005-10-20 2007-04-26 Epipharm Gmbh Traitement et prevention de manifestations pigmentaires (naevus) benignes grace a l'utilisation d'artemisinine et de ses derives
JP2009523703A (ja) * 2005-10-20 2009-06-25 エピフアルマ・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング アルテミシニン及びその誘導体を使用する良性色素性ホクロ（母斑）の処置及び予防
US8013011B2 (en) 2005-10-20 2011-09-06 Epipharm Gmbh Treatment and prevention of benign pigmented moles (naevi) using artemisinine and the derivatives thereof
AU2006303809B2 (en) * 2005-10-20 2012-11-15 Epipharm Ag Treatment and prevention of benign pigmented moles (naevi) using artemisinine and the derivatives thereof
WO2008037176A1 (fr) * 2006-09-29 2008-04-03 Beijing Zhongyan Tongrentang Chinese Medicine R & D Co., Ltd. Préparations transdermiques comprenant de l'artémisinine et/ou ses dérivés
CN101125135B (zh) * 2007-08-22 2010-05-19 昆明制药集团股份有限公司 蒿甲醚巴布剂

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