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WO2000002537A1 - Composition de trinitrate de glycerine, son procede de fabrication et son utilisation - Google Patents

Composition de trinitrate de glycerine, son procede de fabrication et son utilisation Download PDF

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Publication number
WO2000002537A1
WO2000002537A1 PCT/EP1999/004610 EP9904610W WO0002537A1 WO 2000002537 A1 WO2000002537 A1 WO 2000002537A1 EP 9904610 W EP9904610 W EP 9904610W WO 0002537 A1 WO0002537 A1 WO 0002537A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
self
glycerol trinitrate
preparation
vinyl acetate
Prior art date
Application number
PCT/EP1999/004610
Other languages
German (de)
English (en)
Inventor
Achim Berthold
Original Assignee
Lts Lohmann Therapie-Systeme Ag
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 Lts Lohmann Therapie-Systeme Ag filed Critical Lts Lohmann Therapie-Systeme Ag
Priority to IL14073999A priority Critical patent/IL140739A0/xx
Priority to BR9911984-6A priority patent/BR9911984A/pt
Priority to CA002336704A priority patent/CA2336704A1/fr
Priority to MXPA01000127A priority patent/MXPA01000127A/es
Priority to JP2000558797A priority patent/JP2002520268A/ja
Priority to AU47814/99A priority patent/AU4781499A/en
Priority to KR1020017000346A priority patent/KR20010074687A/ko
Priority to PL99345545A priority patent/PL345545A1/xx
Priority to EP99931244A priority patent/EP1094793A1/fr
Publication of WO2000002537A1 publication Critical patent/WO2000002537A1/fr

Links

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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • composition containing glycerol trinitrate process for its preparation and its use
  • the invention relates to a preparation for the transdermal therapeutic application of glycerol trinitrate through human skin into an organism, containing a therapeutically effective portion of the active ingredient in a polyacrylate-based self-adhesive layer with an active ingredient-impermeable backing layer, furthermore a process for the preparation of the preparation and its use.
  • the preparation is aimed at a continuous and constantly meterable delivery of glycerol trinitrate to or through the skin, whereby it serves as an active substance reservoir.
  • Patches for the transdermal delivery of medicinally active substances have been known for many years and are used successfully in medicine. With the known preparations, a slow and metered release of the substances is generally to be achieved, the preparation serving as an active ingredient depot. It is desirable that the active ingredient is released slowly and over a longer period of time.
  • the transdermal application has the great advantage that the intestinal and the hematological first pass effect is avoided. As a result, the bioavailability of substances that are subject to strong metabolism during the absorption process from the intestine and the first passage through the liver is increased. Furthermore, the repeated daily application of substances with a short elimination half-life can be avoided since the plasma curves obtained with a transdermal system are similar to those of a continuous infusion.
  • Active agents that are customary in therapy and are used for prophylaxis or for the treatment of coranary heart disease are organic esters of nitric acid. Glycerol trinitrate is preferably used. This active ingredient relaxes the smooth vascular muscles, leads to peripheral vasodilation and reduces the cardiac preload and afterload.
  • Glycerol trinitrate also reduces the extravascular component of the conor resistance and thereby improves the oxygen supply.
  • Acute attacks of angina pectoris can be treated quickly and effectively by sublingual glycerol trinitrate.
  • This type of application quickly leads to a high concentration of active substances in the plasma.
  • the plasma half-life of glycerol trinitrate is only 1-3 minutes, the plasma concentration flattens very quickly and does not maintain the plasma concentration in the therapeutic range over a longer period of time. Sublingual administration is therefore not suitable for seizure prophylaxis.
  • Transdermal administration is more suitable for preventing angina pectoris attacks.
  • the systemic uptake of glycerol trinitrate through the skin is about 20 ⁇ g / cm 2 / h, depending on the application site. It is advantageous here that the biological availability is not seriously reduced as a result of circumventing the extensive intestinal or hepatic first-pass effect.
  • a bioavailability of approximately 70% results when glycerol trinitrate is administered transdermally.
  • the stratum corneum of the skin and the size of the application area are decisive factors for the amount of active ingredient circulating in the blood.
  • a relatively constant steady state plasma concentration is achieved over a longer period of time.
  • the steady-state plasma concentration depends on the dose of the patch and the corresponding absorption rate. With an absorption tion rate of 0.4 mg / h, for example, the plasma concentration averages 0.2 ⁇ l / 1.
  • transdermal administration of glycerol trinitrate is the method of choice for effective angina pectoris prophylaxis.
  • glycerol trinitrate Numerous preparations for the transdermal application of glycerol trinitrate are state of the art. Patch-like systems are predominant. Glycerol trinitrate is either dissolved or adsorbed on an auxiliary. Simple matrix systems, for example in accordance with US Pat. No. 4,751,087, are also known as complex reservoir systems, for example in accordance with US Pat. No. 4,725,272, and systems which contain the active ingredient in microcapsules, for example in accordance with US Pat. No. 3,742,951 and US Pat. No. 4,336,243.
  • the active ingredient is released from the preparation to a therapeutically effective extent and then the skin is permeated. While the release properties of the preparation are determined by active substances and auxiliary substances, the transdermal absorption of the active substance is decisively determined by the stratum corneum of the skin. The absorption can be increased by using additives which improve performance.
  • the use of N-methyl-2-pyrrolidone and oleic acid to increase the glycerol trinitrate absorption is described in US Pat. No. 5,262,165.
  • Synthetic acrylate polymers are often used as a preparation base due to their non-allergenic character, for example according to US 4,505,891.
  • the disadvantage is that most acrylate polymers dissolve glycerol trinitrate very well.
  • the good solubility is synonymous with low thermodynamic activity.
  • glycerol trinitrate must therefore be used in a high concentration. be worked to achieve a therapeutically satisfactory release of active ingredients.
  • EP 0 622 075 A1 describes a preparation which contains glycerol trinitrate in a concentration of 50-65% by weight.
  • the disadvantage of such high amounts of glycerol trinitrate is due to its properties. Glycerol trinitrate reacts adversely to thermal and mechanical loads with explosions or leads to undesirable changes in the adhesive properties e.g. to reduce stickiness, adhesion and cohesion.
  • US Pat. No. 5,474,783 describes the possibility of modifying the thermodynamic activity of acrylate polymers by adding a polysiloxane.
  • Polysiloxanes have a low solubility for glycerol trinitrate, which reduces the overall solubility in the preparation. The reduced saturation solubility is reflected in an increased release rate. The release kinetics can be controlled by varying the amount of polysiloxane added. Since the system described is a multi-phase system, segregation and thus inhomogeneities can occur during production.
  • the present invention is based on the object of specifying a preparation for the transdermal therapeutic application of glycerol trinitrate by human skin of the type mentioned in the preamble of claim 1 and a process for its preparation which develops a high thermodynamic activity while overcoming the aforementioned difficulties and technical limits, in order to avoid the problems caused by avoiding comparatively high proportions of the active ingredient glycerol trinitrate and, with significantly increased bioavailability, to enable effective drug therapy with long-lasting and constantly controllable active ingredient release, which it is also inexpensive to manufacture and user-friendly to use.
  • a self-adhesive composition based on polyacrylate is used for the active substance-containing layer
  • the concentration of active substance in the mass is at most 25% by weight.
  • the preparation has a high thermodynamic activity, which ensures a high release rate when using small amounts of active ingredient.
  • This high thermodynamic activity is achieved by reducing the saturation solubility of the corresponding active ingredient.
  • This can be achieved by using a base material for the preparation, which as such has a low solubility in the active ingredient, and avoiding additives which lead to an increase in the solubility of the active ingredient.
  • a self-adhesive composition based on polyacrylate is used for the composition according to the invention.
  • the mass is characterized according to the invention in that the vinyl acetate content is at most 6% by weight.
  • This reduction in the vinyl acetate content is due to the fact that, as will be demonstrated in the following, vinyl acetate leads to a decrease in the release rate of glycerol trinitrate with increasing concentration.
  • vinyl acetate is used both as a copolymer of the acrylate polymer and as a set homopolymer reduces the release rate.
  • the glycerol trinitrate content is generally in a range from 10-30% by weight, preferably below 25% by weight.
  • FIG. 1 shows the rate of peracetate of glycerol trinitrate through an artificial membrane as a function of the vinyl acetate concentration of a polyacrylate composition.
  • vinyl acetate in the form of a homopoly er polyvinyl acetate
  • the figure shows that the permeation rate or release rate is increasingly increased as the vinyl acetate content decreases.
  • FIG. 2 describes the permeation of glycerol trinitrate through whole human skin.
  • a vinyl acetate-free polyacrylate composition shown as filled squares, or a polyacrylate-vinyl acetate copolymer, shown as empty circles, were used to produce the compositions. It can be seen that the use of vinyl acetate-free polyacrylate increases the degree of permeation through the full human skin.
  • the decrease in permeation caused by vinyl acetate can be explained by an increased solubility of glycerol trinitrate in the self-adhesive polyacrylate composition.
  • Vinyl acetate acts as a solubilizer. Due to the increased solubility, the migration of the active substance from the mass into a membrane is reduced, since a substance is distributed between two phases in accordance with the saturation solubility. As a result, permeation is also reduced because the flow of active substance through a membrane is in a proportional relationship to the distribution coefficient.
  • the self-adhesive composition based on polyacrylate used to produce a composition according to the invention is characterized in that acrylic acid and / or alkyl acrylic acid, in particular methacrylic acid or their derivatives, in particular the alkyl esters, are used for their preparation.
  • alkyl esters those with 1 to 18 carbon atoms in the alkyl radical are preferred, in particular methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, Isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate.
  • other comonomers can be involved in the construction of the polymer / copolymer.
  • Examples are acrylic and / or methacrylamide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and / or methacrylic acid, nitrogen-containing monomers of acrylic and / or methacrylic acid or their salts, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate,. Vinyl pyrrolidone, vinyl chloride, vinyl toluene, acrylonitrile, styrene and the like.
  • a backing layer connected to the self-adhesive composition. This is impermeable to the active ingredient and has an occlusive character.
  • Any materials that are used in conventional preparations can be used. Examples of such materials are cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminum.
  • the composition may further contain: tackifiers, penetration enhancers or agents for relieving skin irritation and metal ions, for example aluminum or titanium.
  • Plasticizers, paraffins, cyclic hydrocarbons or vegetable oils can be added to increase cohesion. Rosin, polyterpene resin, petroleum resin, coumarone-indene resin, terpene-phenol resin, hydrocarbon resin or liquid polybutene resin can be used as an agent for increasing the stickiness.
  • agents which improve the penetration of the active ingredient are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol ester polyglyceramate fatty acid derivatives, glycerol fatty acid derivatives, Dialkyl sulfoxides, urea and derivatives, glycerol, native oils, laurocaprame, phospholipids, ide, amino acids, N, N-dimethylformamide, N-methylformamide, acetonides, calcium thio-glycolate, propylene glycol, polyethylene glycol, alkyl sulfate ⁇ , sodium lauryl sulfate, tetrahydrofuran ,
  • composition according to the invention can also contain to relieve skin irritation.
  • relief agents are: bisabolol, chamomile oil, allantin, glycerin or dipanthenol.
  • 163 g of acrylic adhesive e.g. Durotak® 387-2353
  • 19 g of dioctylcyclohexane (Cetiol S)
  • 19 g of hydrogenated rosin e.g. Staybelite Ester 3E
  • 50 g of glycerol trinitrate 22.1% by weight in ethyl acetate
  • 50 g of ethyl acetate 15 g of acetyl acetone
  • 0.1 g of aluminum acetylacetonate 4% by weight in ethyl acetate
  • the moist film was dried at 40 ° C. for 30 minutes and then laminated with a polyester film (eg Hostaphan®).
  • the weight per unit area of an adhesive film produced in this way was approximately 67 g / m 2 .
  • the desired size of plaster was punched out of the laminate by means of a punch and the in vitro permeation through isolated human skin was measured. The results of skin permeation are shown in FIG. 2 (filled squares). By using the vinyl acetate-free composition, the permeation was increased by about 65 s.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Préparation pour application thérapeutique transdermique de trinitrate de glycérine, à travers la peau humaine, dans un organisme, renfermant, dans une couche auto-adhésive à base de polyacrylate, avec couche arrière imperméable à la substance active, une fraction thérapeutiquement efficace de la substance active, caractérisée en ce qu'il est prévu d'intercaler dans la couche renfermant la substance active, une matière auto-adhésive à base de polyacrylate, en ce que la concentration d'acétate de vinyle dans ladite matière est au maximum de 6 % en poids, et la concentration de la substance active dans ladite matière est au maximum de 25 % en poids.
PCT/EP1999/004610 1998-07-09 1999-07-02 Composition de trinitrate de glycerine, son procede de fabrication et son utilisation WO2000002537A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
IL14073999A IL140739A0 (en) 1998-07-09 1999-07-02 Glyceryl trinitrate-containing preparation, method for its production, and its use
BR9911984-6A BR9911984A (pt) 1998-07-09 1999-07-02 Composição contento trinitrato de gricerol, processos para sua preparação e sua aplicação
CA002336704A CA2336704A1 (fr) 1998-07-09 1999-07-02 Composition de trinitrate de glycerine, son procede de fabrication et son utilisation
MXPA01000127A MXPA01000127A (es) 1998-07-09 1999-07-02 Compuesto que contiene trinitrato de glicerol, metodo para su obtencion y aplicacion.
JP2000558797A JP2002520268A (ja) 1998-07-09 1999-07-02 グリセロールトリニトレートを含む組成物、その組成物の製造方法、およびその使用
AU47814/99A AU4781499A (en) 1998-07-09 1999-07-02 Composition containing glycerol trinitrate, method for producing said composition and use of the same
KR1020017000346A KR20010074687A (ko) 1998-07-09 1999-07-02 글리세롤트리니트레이트 함유 조성물, 상기 조성물의제조방법 및 용도
PL99345545A PL345545A1 (en) 1998-07-09 1999-07-02 Composition containing glycerol trinitrate, method for producing said composition and use of the same
EP99931244A EP1094793A1 (fr) 1998-07-09 1999-07-02 Composition de trinitrate de glycerine, son procede de fabrication et son utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19830648A DE19830648A1 (de) 1998-07-09 1998-07-09 Glyceroltrinitrathaltige Zusammensetzung, Verfahren zu ihrer Herstellung und ihre Verwendung
DE19830648.2 1998-07-09

Publications (1)

Publication Number Publication Date
WO2000002537A1 true WO2000002537A1 (fr) 2000-01-20

Family

ID=7873427

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/004610 WO2000002537A1 (fr) 1998-07-09 1999-07-02 Composition de trinitrate de glycerine, son procede de fabrication et son utilisation

Country Status (15)

Country Link
EP (1) EP1094793A1 (fr)
JP (1) JP2002520268A (fr)
KR (1) KR20010074687A (fr)
CN (1) CN1308526A (fr)
AU (1) AU4781499A (fr)
BR (1) BR9911984A (fr)
CA (1) CA2336704A1 (fr)
DE (1) DE19830648A1 (fr)
HU (1) HUP0104950A3 (fr)
IL (1) IL140739A0 (fr)
MX (1) MXPA01000127A (fr)
PL (1) PL345545A1 (fr)
TR (1) TR200100020T2 (fr)
WO (1) WO2000002537A1 (fr)
ZA (1) ZA200100173B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002235155A1 (en) * 2000-12-05 2002-06-18 Noven Pharmaceuticals, Inc. Crystallization inhibition of drugs in transdermal drug delivery systems
JP5681883B2 (ja) * 2009-03-27 2015-03-11 株式会社 メドレックス 核酸を有効成分とする外用剤組成物
JP5816881B2 (ja) * 2014-05-21 2015-11-18 株式会社 メドレックス 核酸を有効成分とする外用剤組成物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505891A (en) * 1980-10-20 1985-03-19 Nichiban Co., Ltd. Medicinal adhesive sheets for heart diseases and a process for the preparation thereof
US4751087A (en) * 1985-04-19 1988-06-14 Riker Laboratories, Inc. Transdermal nitroglycerin delivery system
EP0379045A1 (fr) * 1989-01-11 1990-07-25 Noven Pharmaceuticals, Inc. Système pour délivrer une drogue transdermique, à base d'un multipolymère acrylique
EP0450986A2 (fr) * 1990-04-06 1991-10-09 Sekisui Kagaku Kogyo Kabushiki Kaisha Préparation pharmaceutique pour l'administration percutanée de nitroglycérine
US5474783A (en) * 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA29400C2 (uk) * 1991-06-10 2000-11-15 Шварц Фарма Аг Пластир для трансдермального введення нітрогліцерину та спосіб його виготовлення
DE856311T1 (de) * 1996-12-10 1999-02-25 Rotta Research B.V., Amsterdam Transdermales Arzneistoff-Verabreichungssystem zur Behandlung von Herzerkrankungen

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4505891A (en) * 1980-10-20 1985-03-19 Nichiban Co., Ltd. Medicinal adhesive sheets for heart diseases and a process for the preparation thereof
US4751087A (en) * 1985-04-19 1988-06-14 Riker Laboratories, Inc. Transdermal nitroglycerin delivery system
US4751087B1 (fr) * 1985-04-19 1993-03-02 Riker Laboratories Inc
US5474783A (en) * 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
EP0379045A1 (fr) * 1989-01-11 1990-07-25 Noven Pharmaceuticals, Inc. Système pour délivrer une drogue transdermique, à base d'un multipolymère acrylique
EP0450986A2 (fr) * 1990-04-06 1991-10-09 Sekisui Kagaku Kogyo Kabushiki Kaisha Préparation pharmaceutique pour l'administration percutanée de nitroglycérine

Also Published As

Publication number Publication date
HUP0104950A3 (en) 2002-07-29
IL140739A0 (en) 2002-02-10
KR20010074687A (ko) 2001-08-09
CA2336704A1 (fr) 2000-01-20
JP2002520268A (ja) 2002-07-09
ZA200100173B (en) 2001-08-10
DE19830648A1 (de) 2000-01-13
CN1308526A (zh) 2001-08-15
TR200100020T2 (tr) 2001-07-23
MXPA01000127A (es) 2002-06-04
AU4781499A (en) 2000-02-01
BR9911984A (pt) 2001-03-27
PL345545A1 (en) 2001-12-17
HUP0104950A2 (en) 2002-06-29
EP1094793A1 (fr) 2001-05-02

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