WO2004091589A1 - Agent calmant et sedatif administrable par voie transdermique - Google Patents

Agent calmant et sedatif administrable par voie transdermique Download PDF

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Publication number
WO2004091589A1
WO2004091589A1 PCT/DE2004/000766 DE2004000766W WO2004091589A1 WO 2004091589 A1 WO2004091589 A1 WO 2004091589A1 DE 2004000766 W DE2004000766 W DE 2004000766W WO 2004091589 A1 WO2004091589 A1 WO 2004091589A1
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
layer
transdermal system
adhesive
active ingredient
Prior art date
Application number
PCT/DE2004/000766
Other languages
German (de)
English (en)
Inventor
Till S. Mutzbauer
Original Assignee
Mutzbauer Till S
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 Mutzbauer Till S filed Critical Mutzbauer Till S
Publication of WO2004091589A1 publication Critical patent/WO2004091589A1/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
    • 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
    • A61K31/05—Phenols
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • psychotropic drugs e.g. Benzodiazepines, in particular tetracyclic benzodiazepines such as midazolam, furthermore propofol, ketamine, and the long-established barbituric acid derivatives such as thiopental sodium (“trapanal”).
  • Benzodiazepines in particular tetracyclic benzodiazepines such as midazolam, furthermore propofol, ketamine, and the long-established barbituric acid derivatives such as thiopental sodium (“trapanal”).
  • a transdermally effective system is known, with which an ACE inhibitor can be administered and with which a depot effect should also be achievable, and which consists of an impermeable backing layer, a layer-like one Element with a cavity, an agent that controls the release of the active ingredient and a removable cover layer (release liner) on a paper basis.
  • EP-A2-0 439 430 (reservoir- ⁇ S) and EP-A2-0 468 875 (Matrix-TTS), according to EP-A2-0 468 875 Silicone elastomers as Matrix material (ie as an adhesive containing active ingredient) can be used.
  • EP-A3-0 452 837 describes a transdermal system with a matrix based, inter alia, on polyisobutylene rubber and containing, inter alia, ACE inhibitors. In addition to polyisobutylene rubbers, polymers of the acrylic resin type iWS and silicone rubbers are also listed as other possible matrices.
  • Acetylsalicylic acid (2-acetoxybenzoic acid; aspirin) has also already been proposed as a transdermally applicable medicament (WO 00/76315) and also dextromethorphan [(+) - 3-methoxy-17-methyl-9a, 13a, 14a-morphinan] and its pharmacologically acceptable Compounds as a remedy for coughing fits. It is known from Anesthesia Analgesia 2000/91 1479-82 that racemic ketamine can be administered transdermally, but not alone, but as support for pain-relieving postoperative treatment after gynecological abdominal surgery.
  • a further object of the invention is to propose a system for the transdermal supply of an anti-conscious medication with a sedative, sedative and / or short anesthetic function, with which a prolonged
  • Effectiveness of this agent can be achieved, for example, for up to about a week, so that a therapeutically effective plasma level can be achieved for a corresponding period of time by continuous release of active ingredient.
  • Benzodiazepines but also classic agents such as barbiturates and agents from various other families.
  • Examples include propofol, etomidate, midazolam, 4-hydroxybutyric acid and their pharmaceutically acceptable salts and / or derivatives, S-ketamine, triazolam, temazepam, tetrazepam, lorazepam, nitrazepam, flunitrazepam, lormetazepam, diazepam, melperidol, zperpidem zopiclone,
  • a pharmacologically effective amount of propofol with a matrix, for. B. mixed on the basis of polyisobutylene or butyl rubber and, if necessary, one or more emulsifiers of the type and applied to a neutral plaster base.
  • Immediate subject matter of the invention is a layered arrangement in the form of a plaster, which contains an effective amount of propofol in at least one layer and is preferably composed of: (1) a first backing layer
  • matrix which contains at least the active substance and agents which control the delivery and mode of action of the active substance
  • a release liner to be removed before use based on a plastic film or a coated paper.
  • Another object of the invention is an arrangement of the above type, which contains the active ingredient directly embedded in the adhesive layer (4), with the proviso that in this case a special layer (2) and the carrier layer having a cavity for receiving the layer (3) eliminated.
  • a release rate of the active ingredient from 0.01 to 0.1 mg active ingredient / cm2 / 24 hours and in particular from 0.025 to 0.050 mg of active ingredient / cm2 / 24 hr can be achieved, for example, from a polymer matrix, such that a transdermal system according to Inventions offers a plasma concentration of active ingredient in a therapeutically effective amount.
  • a therapeutically effective concentration in the blood of more than about 0.5 ng / ml can be achieved for propofol. aim.
  • the propofol in the transdermal system according to the invention, can be present in a concentration of at least 0.1%, preferably at least 5% by weight and in particular in a concentration of 10 to 20% by weight (based on the matrix). It is surprising that the propofol hitherto used as a short anesthetic is suitable as a long-term active ingredient in the application according to the invention without the need for a further injection or administration of another active ingredient.
  • Propofol can be in substance or as a therapeutically active salt.
  • the active ingredient can likewise be embedded in a body which delays the release of the active ingredient, that is to say a carrier. It is preferably a surface-rich body of the type of an ion exchanger or a silica gel with a large inner surface. Because of the purely external application, no particular consideration needs to be given to the physiological tolerance of this vehicle.
  • the transdermal system according to the invention can comprise a permeation enhancer, for example 2-octyldodecanol and in particular DMSO (dimethyl sulfoxide).
  • a permeation enhancer for example 2-octyldodecanol and in particular DMSO (dimethyl sulfoxide).
  • transdermal systems for example matrix- or membrane-controlled systems.
  • Matrix-controlled means that the rate of release essentially depends on the rate of diffusion of the active substance within the matrix body becomes.
  • Membrane-controlled means that the rate of drug release is mainly determined by a membrane upstream of the matrix, in the sense that the drug first (relatively quickly) travels through the matrix and then according to the specific rate of diffusion through the film.
  • Cellulose and its derivatives such as ethyl cellulose, are preferably suitable as film material.
  • Microporous or semipermeable membranes are also obtained from certain inert polymers which can be provided with pores of different widths during the manufacturing process, for example polypropylene, polyvinyl acetate or silicone. If such a membrane is provided, it can, depending on the pore size, have an effect which controls the release of the active substance or also no influence on the active substance release from the system.
  • the transdermal system according to the invention can be characterized by
  • a self-adhesive polyisobutylene adhesive can be used as the matrix.
  • the covering layer can be formed, for example, from polyester, polypropylene, polyethylene or polyurethane.
  • a fabric or fleece-reinforced film is used, such as that which is available from Beiersdorf under the trade name "Fixomull® Stretch".
  • a measured amount of a preparation according to the invention can be applied to the skin and with the correspondingly tailored one Foil are covered.
  • the doctor in charge has the ability to dose the intended amount of active ingredient himself.
  • the peelable cover layer can be formed from polyester, polypropylene or coated paper (paper with coating), in particular with a silicone and / or polyethylene coating.
  • the transdermal system according to the invention can have a covering layer (backing foil) and / or a removable covering layer (release liner) with a thickness in the range from 5 to 100 ⁇ m.
  • Placebo approach 2ml gel containing a base of, among others, macrogol-glycerol-hydroxystearate, propylene glycol, polyacrylic acid, trometamol, isopropyl alcohol, purified water and as active ingredients: 0.075 g DMSO 75 IU heparin-Na; 0.0125 g dexpanthe nol.
  • TTS in vivo comparative study of a TTS according to the invention with an oral administration of trandolapril (capsule)
  • trandolapril capsule
  • the TTS were applied in an open 2-period cross-over design over a period of 7 days (1 TTS 4 days, then 1 TTS 3 days) and 1 capsule of 2 mg trandolapril was applied daily for 7 days.
  • Blood samples were taken after application after the following times: 0.5 - 1 - 2 - 4 - 6 - 8 - 10 - 12 - 24 - 48 - 72 - 96 - 98 - 100 - 102 - 104 - 106 - 108 - 120 - 132 - 144 - 156 - 168 h.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un agent administrable par voie externe, notamment un système transdermique utilisé pour traiter des états d'agitation ou à des fins sédatives préopératoires. Ledit agent comprend, dans une préparation pour pansement adhésif, une quantité pharmaceutiquement active de propofol (2,6-di-isopropyle-phénol) ou d'une benzodiazépine ou d'un autre agent visant à réduire l'état de conscience.
PCT/DE2004/000766 2003-04-14 2004-04-14 Agent calmant et sedatif administrable par voie transdermique WO2004091589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10317108A DE10317108A1 (de) 2003-04-14 2003-04-14 Transdermal applizierbares Beruhigungs- und Sedierungsmittel
DE10317108.8 2003-04-14

Publications (1)

Publication Number Publication Date
WO2004091589A1 true WO2004091589A1 (fr) 2004-10-28

Family

ID=33154204

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2004/000766 WO2004091589A1 (fr) 2003-04-14 2004-04-14 Agent calmant et sedatif administrable par voie transdermique

Country Status (2)

Country Link
DE (1) DE10317108A1 (fr)
WO (1) WO2004091589A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7989475B2 (en) 2003-01-27 2011-08-02 Merck Sharp & Dohme Corp. Substituted pyrazoles, compositions containing such compounds and methods of use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710497A (en) * 1983-05-20 1987-12-01 Nitto Electric Industrial Co., Ltd. Method for percutaneously administering physiologically active agents
WO1993023019A1 (fr) * 1992-05-11 1993-11-25 Sri International Dispositifs d'apport medicamenteux transcutane, compositions qui y sont associees et procedes d'utilisation
US5372819A (en) * 1992-08-07 1994-12-13 Minnesota Mining And Manufacturing Company Tramsdermal drug delivery device
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
WO2002087642A2 (fr) * 2001-05-01 2002-11-07 A.V. Topchiev Institute Of Petrochemical Synthesis Composition bioadhesive biphase absorbant l'eau

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710497A (en) * 1983-05-20 1987-12-01 Nitto Electric Industrial Co., Ltd. Method for percutaneously administering physiologically active agents
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
WO1993023019A1 (fr) * 1992-05-11 1993-11-25 Sri International Dispositifs d'apport medicamenteux transcutane, compositions qui y sont associees et procedes d'utilisation
US5372819A (en) * 1992-08-07 1994-12-13 Minnesota Mining And Manufacturing Company Tramsdermal drug delivery device
WO2002087642A2 (fr) * 2001-05-01 2002-11-07 A.V. Topchiev Institute Of Petrochemical Synthesis Composition bioadhesive biphase absorbant l'eau

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7989475B2 (en) 2003-01-27 2011-08-02 Merck Sharp & Dohme Corp. Substituted pyrazoles, compositions containing such compounds and methods of use

Also Published As

Publication number Publication date
DE10317108A1 (de) 2004-11-11

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