EP1011644A1 - Methodes et appareil de traitement de la maladie de parkinson - Google Patents

Methodes et appareil de traitement de la maladie de parkinson

Info

Publication number
EP1011644A1
EP1011644A1 EP97944077A EP97944077A EP1011644A1 EP 1011644 A1 EP1011644 A1 EP 1011644A1 EP 97944077 A EP97944077 A EP 97944077A EP 97944077 A EP97944077 A EP 97944077A EP 1011644 A1 EP1011644 A1 EP 1011644A1
Authority
EP
European Patent Office
Prior art keywords
levodopa
parkinson
pharmaceutical composition
disease
transdermal
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.)
Withdrawn
Application number
EP97944077A
Other languages
German (de)
English (en)
Other versions
EP1011644A4 (fr
Inventor
Moshe Kushnir
Eliahu Heldman
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.)
ANALYST RESEARCH LABORATORIES
Neuroderm Ltd
Original Assignee
Analyst Research Laboratories
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 Analyst Research Laboratories filed Critical Analyst Research Laboratories
Publication of EP1011644A1 publication Critical patent/EP1011644A1/fr
Publication of EP1011644A4 publication Critical patent/EP1011644A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/185—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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods and apparatus for treatment of
  • Parkinson's disease is one of the most common neuro-degenerative diseases which affect the elderly
  • Parkinson's disease - new modes of dopamine substitution Acta neurol Scand 1993, 87(suppl
  • PD Parkinsonian signs in the elderly are estimated to occur in 30% of the population over the age of 65 (Ref 2)
  • PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta PD becomes symptomatic only after degeneration of about 60- 80% of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine (Refs 3, 4)
  • Dopamine (DA) which is produced within the substantia nigra, reaches the striatum via the nigro-striatal tract and is released at the striatal synapses DA deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to be the cause of PD.
  • LD Levodopa
  • carbidopa an inhibitor that cannot penetrate the blood-brain-barrier
  • LD Adverse effects of LD, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine (Ref 5) At late stages of the disease additional types of adverse effects appear as the response to LD becomes unpredictable, fluctuative and the duration of the response is reduced " Motor fluctuations appear after about 4 - 5 years from the introduction of LD therapy in 24%-84% of the patients (Ref. 6) The most common and disabling motor complications are 1) “wearing-off” fluctuations, 2) “on-off” fluctuations and 3) peak-dose dyskinesias (Ref 7)
  • the "wearing-off effect means a reduction in the duration of the beneficial effect after each administration of LD During this period, LD must be administered more frequently than before, a problem which severely affects the quality of life of the patient Complications such as “wearing off” may arise due to limitation of storage capacity of DA in the CNS (Refs 5, 8-10) When neuronal DA storage is reduced, the clinical state of the patients becomes fully dependent on the fluctuating blood level of LD Since the normal half- life of LD in the circulation is 1-2 hours (Refs 1 1-13), LD should be administered at this stage more frequently and the effect is fluctuative Moreover, with the currently available oral preparations, the blood level of LD is a function of the rate of absorption from the gastrointestinal tract, which is irregular and uncontrollable The resulting fluctuations of the LD blood levels contribute further to the instability of the effect A continuous drug delivery, which maintains a constant blood level of LD, has been shown to improve significantly the clinical state of the fluctuating parkinsonian patients (Refs 13-18
  • Peak-dose dyskinesia is a common advanced motor complication which occurs when the blood level of LD rises to its peak This complication is observed in advanced stages of the disease when patients show a very steep dose-response curve Under such circumstances, small shifts in circulating LD levels, and thus in cerebral DA, induce major swings in the clinical state (Ref 7) In this stage of the disease, a continuous administration that keeps the circulating LD level constant, may prevent the dyskinesias Moreover, these kinds of dyskinesias, like the "on-off dyskinesia, may not develop during a continuous administration of LD (Refs 7, 16, 17, 28, 29)
  • the CR preparations do not provide the same favorable effect which was demonstrated by a continuous administration of LD such as an IV infusion (e g , Refs 5, 15, 18) 5. Sclerosis of the peripheral veins occurs frequently during an IV infusion of LD (Ref. 5).
  • transdermal delivery of LD could be the best substitution for the methods of continuous invasive infusions, free of disadvantages of the currently available strategies.
  • the present invention constitutes a solution to most of the problems associated with the currently available treatments, and thus provides a safer and more effective treatment for PD.
  • the invention describes a novel route of administration of levodopa dissolved in a formulation which is designed to maintain stability of the drug in solution and enables continuous penetration of the drug through the skin
  • This method is suggested as a treatment of Parkinson's patients, especially at advanced stages of the disease
  • the currently available LD preparations cause side effects and deterioration in the clinical state of the disease
  • the present invention helps overcome these disadvantages.
  • an alkyl- ester of LD such as levodopa-ethyl-ester (LDEE) is administered transdermally.
  • the alkyl-ester of LD is dissolved in an appropriate formulation.
  • the formulation consists of propylene glycol, a fatty acid and a detergent.
  • the LD-alkyl-ester and the formulation (the solvent) are kept separately and mixed just before the beginning of the drug application.
  • a transdermal device which includes a container connected to a patch via a narrow plastic tube is used for the transdermal delivery
  • the container is re-filled every 24 h
  • the patch is fed with the LD-alkyl-ester solution preferably by gravity, or alternatively by pump, the solution then being spread on the skin area covered by the patch
  • the patient ingests tablets of carbidopa (25 - 50 mg/tablet) three times a day
  • the patient could receive a supplemental treatment such as oral anti-parkinson's drug
  • FIG. 1 is a simplified pictorial illustration of apparatus for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention.
  • Fig. 2 is a simplified sectional illustration of apparatus of Fig. 1, taken along the lines II - II in Fig. 1.
  • the formulation is designed to dissolve a treating drug (alkyl-ester of LD) and maintain it stable in solution for the period during which a continuous transdermal penetration takes place.
  • a treating drug alkyl-ester of LD
  • the formulation provides the drug with stability and transdermal permeation properties.
  • the formulation preferably contains several components as follows:
  • Non-aqueous solvent LD and its derivatives are more stable in non-aqueous solution than in aqueous solution.
  • a preferred solvent is propylene glycol which is non-toxic, does not produce skin irritation and provides the proper constituency for dermal application.
  • Other non-aqueous solvents with similar properties may also be used for this purpose.
  • Transdermal enhancer and stabilizer A preferred transdermal enhancer and stabilizer is carboxylic acid.
  • the alkyl- esters of LD are quite soluble and much more stable in an acidic environment than in a neutral environment.
  • the carboxylic acid also keeps the LD derivative uncharged and helps permeability through the skin.
  • Figs. 1 and 2 illustrate apparatus 10 for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention.
  • Apparatus 10 preferably includes a storage compartment 12 which is in fluid communication with a dermal patch 14, preferably via a flexible plastic tube 16 Patch 14 may be made of any suitable material, such as cloth or plastic Storage compartment 12 is preferably flexible and compressible by mechanical pressure Storage compartment 12 preferably contains a fluid 18 (Fig. 2) which is a treating drug, such as an alkyl-ester of LD, dissolved in a formulation, such as described hereinabove in accordance with a preferred embodiment of the present invention
  • the alkyl- ester of LD is kept pre-weighed as a dried powder Carbidopa (25 - 50 mg/tablet) is preferably ingested two hours before the beginning of the transdermal delivery of the LD derivative and then three times a day throughout the entire treatment
  • Carbidopa 25 - 50 mg/tablet
  • the alkyl-ester of LD is placed in storage compartment 12 and a sufficient amount of formulation is added therein, and the constituents are thoroughly mixed together.
  • Storage compartment 12 is then preferably tied to an arm or any other suitable location on a patient, such as with a strap 20, and connected to patch 14 via tube 16
  • Flow of fluid 18 from storage compartment 12 to patch 14 is preferably controlled by a regulating valve 22.
  • Patch 14 is preferably attached to the skin along an adhesive periphery 24, and a central portion 26 is preferably adapted to receive and maintain a quantity of fluid 18 Fluid 18 spreads under patch 14 preferably via a system of hollow capillaries 28 (Fig 2), and penetrates the skin of a patient
  • fluid 18 flows from storage compartment 12 to patch 14 by gravity, or alternatively by a miniature pump (not shown) When necessary, flow of fluid 18 may be increased by exerting mechanical pressure on storage compartment 12 or by increasing the pump rate.
  • Apparatus 10 is preferably disposable The location of apparatus 10 on the patient's skin may be changed periodically Supplemental oral treatment may be given during the transdermal delivery according to clinical needs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Une composition pharmaceutique de traitement de la maladie de Parkinson comprend un composé de lévodopa dissous dans un solvant non dégradant permettant l'administration transdermique de lévodopa. Le composé de lévodopa est un alkyl-ester de lévodopa et le solvant est une formulation comprenant un solvant sensiblement non aqueux, un activateur transdermique et un détergent. L'alkyl-ester de lévodopa est de préférence un lévodopa-éthyl-ester (LDEE).
EP97944077A 1996-10-13 1997-10-09 Methodes et appareil de traitement de la maladie de parkinson Withdrawn EP1011644A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IL11941796 1996-10-13
IL11941796A IL119417A (en) 1996-10-13 1996-10-13 Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease
PCT/IL1997/000327 WO1998016208A1 (fr) 1996-10-13 1997-10-09 Methodes et appareil de traitement de la maladie de parkinson

Publications (2)

Publication Number Publication Date
EP1011644A1 true EP1011644A1 (fr) 2000-06-28
EP1011644A4 EP1011644A4 (fr) 2006-02-08

Family

ID=11069375

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97944077A Withdrawn EP1011644A4 (fr) 1996-10-13 1997-10-09 Methodes et appareil de traitement de la maladie de parkinson

Country Status (6)

Country Link
EP (1) EP1011644A4 (fr)
JP (2) JP2002513389A (fr)
AU (1) AU4570297A (fr)
CA (1) CA2268455C (fr)
IL (1) IL119417A (fr)
WO (1) WO1998016208A1 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6746688B1 (en) 1996-10-13 2004-06-08 Neuroderm Ltd. Apparatus for the transdermal treatment of Parkinson's disease
IL119417A (en) * 1996-10-13 2003-02-12 Moshe Kushnir Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease
AU1681799A (en) * 1997-12-17 1999-07-05 Sekisui Chemical Co., Ltd. Percutaneously absorbable levodopa-containing preparation
WO2001001962A1 (fr) * 1999-07-05 2001-01-11 Idea Ag. Procede d'amelioration du transport a travers des barrieres semi-permeables compatibles
US7858112B2 (en) 2002-02-28 2010-12-28 Lintec Corporation Percutaneous absorption system and percutaneous absorption method
JP4608187B2 (ja) * 2002-02-28 2011-01-05 リンテック株式会社 経皮吸収型製剤
DE10261807A1 (de) * 2002-12-19 2004-07-01 Turicum Drug Development Ag Deuterierte Catecholaminderivate sowie diese Verbindungen enthaltende Arzneimittel
US8815950B2 (en) 2003-08-29 2014-08-26 Janssen Biotech, Inc. Pharmaceutical compositions and method of using levodopa and carbidopa
AT500095B8 (de) * 2004-01-23 2007-02-15 Braun Werner Mag Transdermales abgabesystem
EP2389930A1 (fr) * 2006-03-31 2011-11-30 Erasmus University Medical Center Rotterdam Nouvelle composition pour le controle de la croissance tumorale
JP5902705B2 (ja) * 2010-11-15 2016-04-13 ニューロダーム リミテッドＮｅｕｒｏｄｅｒｍ Ｌｔｄ Ｌ−ドーパ、ドーパデカルボキシラーゼ阻害剤、カテコール−ｏ−メチルトランスフェラーゼ阻害剤、およびそれらのための組成物の継続的投与
WO2012079072A2 (fr) * 2010-12-10 2012-06-14 Synagile Corporation Compositions de promédicament de lévodopa perfusable par voie sous-cutanée
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
ES2967693T3 (es) 2014-03-13 2024-05-03 Neuroderm Ltd Composiciones del inhibidor de la dopa descarboxilasa
EP3075723B1 (fr) * 2015-03-30 2017-05-24 Berlirem GmbH Esters de glycérol l-dopa hautement solubles
CA3019382A1 (fr) * 2015-03-30 2016-10-06 Berlirem Gmbh Esters de l-dopa solubles dans l'eau
AU2016258179B2 (en) 2015-05-06 2021-07-01 Synagile Corporation Pharmaceutical suspensions containing drug particles, devices for their administration, and methods of their use
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1989009051A1 (fr) * 1988-03-29 1989-10-05 Sandoz Ag Deprenyle pour administration transdermique systemique
US4927408A (en) * 1988-10-03 1990-05-22 Alza Corporation Electrotransport transdermal system
WO1995011016A1 (fr) * 1993-10-18 1995-04-27 Teva Pharmaceutical Industries Ltd. R-enantiomere de n-propargyl-1-amino-indane, sels, compositions et utilisation de ce compose

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ATE76747T1 (de) * 1986-06-10 1992-06-15 Chiesi Farma Spa Levodopa-methyl-ester enthaltende pharmazeutische zusammensetzungen, ihre herstellung und therapeutische verwendungen.
US5474783A (en) * 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
JPH04261119A (ja) * 1991-02-13 1992-09-17 Lintec Corp 経皮吸収型貼付剤
US5354885A (en) * 1992-12-24 1994-10-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Process for preparing ethyl ester of L-DOPA
IL119417A (en) * 1996-10-13 2003-02-12 Moshe Kushnir Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989009051A1 (fr) * 1988-03-29 1989-10-05 Sandoz Ag Deprenyle pour administration transdermique systemique
US4927408A (en) * 1988-10-03 1990-05-22 Alza Corporation Electrotransport transdermal system
WO1995011016A1 (fr) * 1993-10-18 1995-04-27 Teva Pharmaceutical Industries Ltd. R-enantiomere de n-propargyl-1-amino-indane, sels, compositions et utilisation de ce compose

Non-Patent Citations (1)

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Title
See also references of WO9816208A1 *

Also Published As

Publication number Publication date
JP2009001588A (ja) 2009-01-08
IL119417A0 (en) 1997-01-10
IL119417A (en) 2003-02-12
EP1011644A4 (fr) 2006-02-08
AU4570297A (en) 1998-05-11
WO1998016208A1 (fr) 1998-04-23
JP2002513389A (ja) 2002-05-08
CA2268455C (fr) 2007-05-15
CA2268455A1 (fr) 1998-04-23

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