WO2003097021A2 - Utilisation de systemes topiques transdermiques pour la prevention et le traitement de la dysmenorrhere - Google Patents

Utilisation de systemes topiques transdermiques pour la prevention et le traitement de la dysmenorrhere Download PDF

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Publication number
WO2003097021A2
WO2003097021A2 PCT/IB2003/002048 IB0302048W WO03097021A2 WO 2003097021 A2 WO2003097021 A2 WO 2003097021A2 IB 0302048 W IB0302048 W IB 0302048W WO 03097021 A2 WO03097021 A2 WO 03097021A2
Authority
WO
WIPO (PCT)
Prior art keywords
use according
nsaids
transdermal
ketoprofen
days
Prior art date
Application number
PCT/IB2003/002048
Other languages
English (en)
Other versions
WO2003097021A3 (fr
Inventor
Stefano Camponovo
Original Assignee
Technipharma L.L.C.
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 Technipharma L.L.C. filed Critical Technipharma L.L.C.
Priority to AU2003230136A priority Critical patent/AU2003230136A1/en
Publication of WO2003097021A2 publication Critical patent/WO2003097021A2/fr
Publication of WO2003097021A3 publication Critical patent/WO2003097021A3/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
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil

Definitions

  • the present invention relates to a new therapeutic use of transdermal topical systems comprising at least a non-steroidal anti-inflammatory drug and, more particularly, it relates to the use of said systems in the prevention and treatment of painful symptoms associated with primary dysmenorrhea.
  • Dysmenorrhea is clinically defined as "painful menstruation". In its essential or primary form, that is the one not depending on a specific pathological reason, it is believed to involve, at least for some period of life, about 50% of women in their fertile age.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • the preferred pharmacological therapy of the painful symptoms of primary dysmenorrhea is represented by the oral administration of non-steroidal anti- inflammatory drugs (NSAIDs) that, by inhibiting the synthesis of prostaglandins, reduce their local or systemic effects [Clinical Therap. (1990), 12, 398-409].
  • NSAIDs non-steroidal anti- inflammatory drugs
  • physicians are particularly oriented towards NSAIDs having a good analgesic effect.
  • the oral NSAIDs are only suitable for short periods of treatment and for the reduction of painful symptoms after they have appeared.
  • several other methods for treating dysmenorrhea consisting, for example, in administering new medicinal compositions and associations (synergistic combination of xanthines and.
  • such a treatment should be of the preventive type, allowing to intervene 2-3 days in advance with respect to the starting of the flow with the aim to avoid the manifestation of symptoms, of non invasive type and easy to be used by patients, should avoid scarcely practicable administration routes such as the intrauterine or intravaginal ones, and should be characterized by low side effects, in particular it should not have the gastro-damaging effects of orally taken NSAIDs.
  • Suitable topical systems are for example the matrix patches, both multilayers and monolayer, the hydrogel cataplasms, the hydrocolloidal plasters and in general the transdermal systems for the topical administration of NSAIDs known in the field, for example those described in the international patent application O02/02086 (Labtec Ges Fuer Technsammlung) or in the Italian patent application n. MI2001A002827, filed on December 28,
  • Preferably said systems have dimensions such as to cover a skin surface comprised between 50 and 150 cm 2 .
  • the NSAIDs usable, alone or in admixture, according to the present invention are generally all the NSAIDs, both as free acids and as salts and, more particular, arylpropionic or arylacetic NSAIDs, such as for example ibuprofen, ketoprofen, naproxen, flurbiprofen, fenoprofen, pranoprofen, indomethacin, diclofenac, sulindac, ibufenac, ketorolac and aclofenac, or salicylates such as for example salicylic acid and methyl salycilate, the oxicams, such as for example piroxicam, or the fenamates, such as for example flufenamic acid.
  • ketoprofen and diclofenac are particularly preferred.
  • the above NSAIDs are used in the transdermal systems as free acids or, alternatively, as organic or inorganic salts.
  • Preferred organic salts are those with basic aminoacids, such as for example lysine or arginine, while preferred inorganic salts are alkaline or earth-alkaline salts, more preferably sodium or potassium salts.
  • both the isolated optical isomers, preferably the active ones, and any admixture thereof are encompassed within the scope of the present invention.
  • transdermal topical systems usable in the- resent invention generally allow a constant release of the active drug during the 24 hours.
  • said systems comprise an amount of NS JDD up to about 1000 mg, preferably from 10 mg to 400 mg, more preferably from 10 mg to 200 mg, even more preferably from 30 mg to 150 mg per dosage unit.
  • the preferred range is from 30 mg to 200 mg, preferably from 30 mg to 110 mg for ketoprofen and from 50 mg to 150 mg, preferably from 120 mg to
  • a transdermal matrix patch comprising from 30 mg to 200 mg, preferably from 30 to 150 mg of ketoprofen or diclofenac is applied onto the lumbar or low abdomen region once a day, starting from 1-2 days before the expected onset menstrual flow, up to symptoms resolution for a rninimum duration of 3 days and for a maximum duration not exceeding 5 days.
  • Ketoprofen was used for the class of arylpropionic derivatives. Ibuprofen, naproxen and flurbiprofen pertain to this class too.
  • a ketoprofen matrix patch having a size of 90 cm 2 was used.
  • This patch is a matrix transdermal system, made by a polyester woven fabric on which a mass containing the active drug is distributed (solution of ketoprofen and adhesive - acrylate copolymer) and by a protective layer, as described for example in the already mentioned international patent application WO02/02086 (Labtec Ges Fuer Technologische).
  • Diclofenac was used for the class of arylacetic derivatives in a matrix patch of 140 cm 2 containing 140 mg of diclofenac sodium salt.
  • This matrix patch is made by a non-woven fabric on which a mass containing the active drug is distributed (suspension of sodium diclofenac in polyhydroxylated hydrogenated castor oil, an" aminoallcylmethacrylate - methacrylate copolymer, one or more cross-linking agents, and adhesive system and other optional excipients) and by a protective layer, such as the one described in the already mentioned patent application n. MI2001A002827.
  • the above-mentioned patches were evaluated in a "cross-over" pilot study on 6 volunteers that showed an anamnesis of primary dysmenorrhea for at least three preceding cycles.
  • D - diclofenac patch containing 140 mg of sodium diclofenac
  • Each patch was applied onto the region of low abdomen for the 3 days preceding the cycle and for the subsequent first 3 days of the flow, a patch every 24 hours.
  • Figure 1 shows the significant difference in the severity of the pain pointed out during the three days of the cycle between the control and the treatments with the two NSAIDs.
  • the first day of the cycle such a difference is already at its highest point, thus demonstrating a preventive effect elicited by the application of the
  • transdermal systems used in the present study were the following:
  • T 2 patch with a surface of 90 cm 2 (size: 8.2x11 cm), containing 100 mg of ketoprofene (name: Ketoprofen TDS 100 mg patch).
  • the volunteers were females from 18 to 40 years of age with a history of primary dysmenorrhea of at least 4 months duration, suffering from a moderate pain
  • the regimen of application of the patches or plasters in the lumbar or lower abdominal area was of 1 patch (plaster) a day, starting 1-2 days before the onset of the menstrual flow and following during menstruation up to symptoms resolution for a minimum duration of 3 days and for a maximum duration not exceeding 5 days.
  • the total duration of the treatment was of 4 months.
  • Two menstrual cycles with patient's usual medication used to treat dysmenorrhea symptoms mainly NSAIDs, but also analgesics and muscle- relaxants, by oral or rectal route, at need
  • the same patient's usual medication at need were taken as rescue medication during the treatment periods with NSAIDs patches or plasters.
  • the efficacy of the treatments was evaluated on 29 volunteers (per protocol population, PP) according to the following patient's parameters: pain intensity, intensity of symptoms, ability to perform activities of daily living, measured starting from 1-2 days before the expected onset of menstrual flow up to symptoms resolution; global efficacy judgment, medication ranking with respect to the usual therapy, amount and frequency of rescue medication.
  • the safety of the therapy was evaluated on 36 volunteers (intent to treat population, ITT) taking into consideration the adverse events occurrence, the global investigator's and patient's judgment on tolerability, clinical laboratory analyses, vital signs and physical examination.
  • Figure 4 shows the mean pain vs. time curve for the treated periods in comparison to control periods.
  • the analysis of primary end-point demonstrates that both diclofenac sodiu and ketoprofen patches were significantly superior to control therapy in reducing the menstrual pain.
  • Figure 5 relates to the total scoring (calculated as arithmetic sum) of the subjective evaluation of the other menstrual symptoms (pelvic pain, headache, nervousness, depression, nausea, vomiting, diarrhea, tachycardia, fatigue, dizziness, backache, myalgia, etc.) on all days of menstruation.
  • the statistical analysis found a significant improvement in symptoms scoring after both diclofenac sodium and ketoprofen treatment as compared to control.
  • diclofenac sodium and ketoprofen patches were significantly superior to control therapy.
  • Figure 6 discloses that the total rescue medication consumption significantly decreased during TI and T2 treatment periods as compared to control.
  • Tables I and II disclose a summary of the statistical results of primary and secondary end-points on the per-protocol population.
  • 100 mg patches administered once a day for 3-5 days as prevention treatments, are effective in lowering the intensity of dysmenorrhea pain and symptoms and in reducing consumption of other systemic medications.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des systèmes d'administration transdermique de médicaments anti-inflammatoires non stéroïdaux dans la prévention et le traitement de symptômes douloureux liés à la dysménorrhée primaire.
PCT/IB2003/002048 2002-05-21 2003-05-15 Utilisation de systemes topiques transdermiques pour la prevention et le traitement de la dysmenorrhere WO2003097021A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003230136A AU2003230136A1 (en) 2002-05-21 2003-05-15 Use of transdermal topical systems for the prevention and treatment of primary dysmenorrhea

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2002MI001078A ITMI20021078A1 (it) 2002-05-21 2002-05-21 Uso di sistemi topici transdermali per la prevenzione e cura della dismenorrea primaria
ITMI2002A001078 2002-05-21

Publications (2)

Publication Number Publication Date
WO2003097021A2 true WO2003097021A2 (fr) 2003-11-27
WO2003097021A3 WO2003097021A3 (fr) 2004-01-29

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PCT/IB2003/002048 WO2003097021A2 (fr) 2002-05-21 2003-05-15 Utilisation de systemes topiques transdermiques pour la prevention et le traitement de la dysmenorrhere

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AU (1) AU2003230136A1 (fr)
IT (1) ITMI20021078A1 (fr)
WO (1) WO2003097021A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2278947A1 (fr) * 2008-05-21 2011-02-02 Teikoku Pharma USA, Inc. Traitement d'une dysménorrhée par administration transdermique de médicaments anti-inflammatoires non stéroïdiens

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197327B1 (en) * 1997-06-11 2001-03-06 Umd, Inc. Device and method for treatment of dysmenorrhea
US20010038861A1 (en) * 1999-12-16 2001-11-08 Tsung-Min Hsu Transdermal administration of nonsteroidal anti-inflammatory drugs using hydroxide-releasing agents as permeation enhancers
WO2002002086A1 (fr) * 2000-07-05 2002-01-10 LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH Systeme therapeutique dermique contenant de l'acide 2-(3-benzophenyl)-propionique ou de l'acide '0-(2,6-dichloranilino)-phenyl!-acetique
DE10032132A1 (de) * 2000-07-01 2002-01-17 Lohmann Therapie Syst Lts Dermales Therapeutisches System enthaltend nichtsteroidale Antiphlogistika mit selektiver COX-2-Hemmung
DE10049225A1 (de) * 2000-09-28 2002-04-11 Labtec Gmbh Dermales System, enthaltend Diclofenac

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197327B1 (en) * 1997-06-11 2001-03-06 Umd, Inc. Device and method for treatment of dysmenorrhea
US20010038861A1 (en) * 1999-12-16 2001-11-08 Tsung-Min Hsu Transdermal administration of nonsteroidal anti-inflammatory drugs using hydroxide-releasing agents as permeation enhancers
DE10032132A1 (de) * 2000-07-01 2002-01-17 Lohmann Therapie Syst Lts Dermales Therapeutisches System enthaltend nichtsteroidale Antiphlogistika mit selektiver COX-2-Hemmung
WO2002002086A1 (fr) * 2000-07-05 2002-01-10 LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH Systeme therapeutique dermique contenant de l'acide 2-(3-benzophenyl)-propionique ou de l'acide '0-(2,6-dichloranilino)-phenyl!-acetique
DE10049225A1 (de) * 2000-09-28 2002-04-11 Labtec Gmbh Dermales System, enthaltend Diclofenac

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2278947A1 (fr) * 2008-05-21 2011-02-02 Teikoku Pharma USA, Inc. Traitement d'une dysménorrhée par administration transdermique de médicaments anti-inflammatoires non stéroïdiens
JP2011519870A (ja) * 2008-05-21 2011-07-14 テイコク ファーマ ユーエスエー インコーポレーテッド 非ステロイド性抗炎症薬の経皮投与による月経困難症の治療
EP2278947A4 (fr) * 2008-05-21 2013-11-06 Teikoku Pharma Usa Inc Traitement d'une dysménorrhée par administration transdermique de médicaments anti-inflammatoires non stéroïdiens

Also Published As

Publication number Publication date
AU2003230136A1 (en) 2003-12-02
ITMI20021078A0 (it) 2002-05-21
ITMI20021078A1 (it) 2003-11-21
WO2003097021A3 (fr) 2004-01-29

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