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WO1999055327A1 - Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate - Google Patents

Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate Download PDF

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Publication number
WO1999055327A1
WO1999055327A1 PCT/EP1999/002609 EP9902609W WO9955327A1 WO 1999055327 A1 WO1999055327 A1 WO 1999055327A1 EP 9902609 W EP9902609 W EP 9902609W WO 9955327 A1 WO9955327 A1 WO 9955327A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
polyterpene
composition according
nitroglycerin
preparation
Prior art date
Application number
PCT/EP1999/002609
Other languages
German (de)
English (en)
Inventor
Walter Müller
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 CA002330934A priority Critical patent/CA2330934A1/fr
Priority to AU38184/99A priority patent/AU3818499A/en
Priority to KR1020007012034A priority patent/KR20010043139A/ko
Priority to EP99920701A priority patent/EP1079822A1/fr
Priority to JP2000545526A priority patent/JP2002512958A/ja
Publication of WO1999055327A1 publication Critical patent/WO1999055327A1/fr
Priority to NO20005299A priority patent/NO20005299D0/no

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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

  • the invention relates to a composition for applying nitroglycerin to the skin.
  • the composition contains: an acrylate copolymer containing 25-40% by weight methyl acrylate, 50-70% by weight 2-ethylhexyl acrylate, 1-10% by weight acrylic acid, a polyterpene based on alpha Pinene or beta-pinene and at least nitroglycerin as an active ingredient.
  • the melting point of the polyterpene is in the range from 37 ° C to 140 ° C; its proportion is not greater than 30% by weight based on the dry weight of the composition.
  • the composition is preferably used for prophylaxis or for the treatment of coronary heart disease, in particular angina pectoris.
  • Active agents for prophylaxis or for the treatment of coronary heart disease are esters of nitric acid.
  • Nitroglycerin is preferably used. Nitroglycerin leads to peripheral vasodilation and thereby reduces cardiac preload and afterload. This reduction and the resulting reduction in cardiac work reduce the heart's oxygen requirement. Nitroglycerin also reduces the extravascular component of the coronary resistance and thus leads to an improvement in the oxygen supply.
  • Acute angina attacks can be treated quickly and effectively by sublingual nitroglycerin administration.
  • This type of application quickly leads to a high active substance plasma level. Since the plasma half-life of nitroglycerin is only 1-3 minutes, the plasma concentration flattens again very quickly. Therefore sublingual administration is not suitable for seizure prophylaxis.
  • the transdermal application is more suitable for this.
  • the systemic absorption of nitroglycerin by the skin is approximately 20 ⁇ g / cm 2 / h, depending on the application site.
  • the advantage here is that by avoiding the first-pass effect in the liver, the biological availability is not seriously reduced by metabolic processes. Initially, only the stratum corneum of the skin and the size of the application area are decisive factors for the active substance circulating in the blood. A relatively constant steady state plasma concentration is achieved over a longer period of time. Transdermal nitroglycerin use is therefore the method of choice for effective angina pectoris prophylaxis.
  • nitroglycerin Numerous preparations for dermal application of nitroglycerin are currently known. Patch-like systems are predominant. Nitroglycerin is either dissolved or adsorbed on an auxiliary. Simple matrix systems (US Pat. No. 4,751,087), complex reservoir systems (US Pat. No. 4,725,272) and systems which contain the active ingredient in a type of microcapsule (US Pat. No. 3,742,951; US Pat. No. 4,336,243) are known.
  • the active substance is released from the preparation to an appropriate extent and then the skin permeates. While the release properties of the preparation are determined by the auxiliary substances used, the transdermal absorption of the active substance is decisively influenced by the stratum corneum Skin determined. The absorption can be improved by using penetration enhancers. be increased.
  • the use of N-methyl-2-pyrrolidone and oleic acid to increase the nitroglycerol 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 nature.
  • the disadvantage is that polyacrylates dissolve nitroglycerin very well.
  • the good solubility is synonymous with a low thermodynamic activity. Therefore, a high concentration of nitroglycerin has to be incorporated in order to achieve the required drug releases.
  • EP 0 622 075 A1 describes a preparation which contains nitroglycerin in a concentration of 50-65% by weight.
  • the disadvantage of such high amounts of nitroglycerin lies in its properties. Nitroglycerin reacts to thermal and mechanical stress with an explosion, or it leads to undesirable changes in the adhesive properties (reduction in adhesion and excessive softness).
  • the thermodynamic activity can be modified by adding a polysiloxane according to US Pat. No. 5,474,783. Polysiloxanes have a low solubility for nitroglycerin, 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 to a certain extent by varying the added polysiloxane constriction.
  • the aim of the present invention is to produce a preparation which contains nitroglycerin.
  • the less allergenic acrylate polymers are used as the base material.
  • the preparation should have a high thermodynamic activity, resulting in a high release rate when used lower amounts of active ingredient is ensured.
  • a high thermodynamic activity can be achieved by reducing the saturation solubility of the corresponding active ingredient. This can be achieved, on the one hand, by adding an auxiliary agent which influences the solubility of the active ingredient to the preparation, or by using a base material which as such has a low solubility of the active ingredient.
  • a polyacrylate containing 25-40% by weight of methyl acrylate, 50-70% by weight of 2-ethylhexyl acrylate and 1-10% by weight of acrylic acid is used as the base material. Furthermore, it is important that the vinyl acetate content is less than 5% by weight, since vinyl acetate leads to a reduction in the release rate with increasing concentration (FIGS. 1 and 2). It should be taken into account here that vinyl acetate can be present as a copolymer of the acrylate or as a homopolymer.
  • a polyterpene based on alpha-pinene or beta-pinene is added to the mass.
  • Polyterpenes are both naturally occurring substances which, due to their biogenesis, generally obey the isoprene rule and consist of (C 10 ) n units, and synthetic hydrocarbon resins (terpene resins) which can be prepared by polymerizing monoterpenes.
  • the melting point of the polyterpene is in the range from 37 ° C to 140 ° C.
  • Examples include: Dercolyte A40, Dercolyte S40, Dercolyte A85, Dercolyte S85, Dercolyte A100, Dercolyte SlOO, Dercolyte A115, Dercolyte S115, Dercolyte A125, Dercolyte S125, Dercolyte A135 and Dercolyte S135.
  • the influence of the polyterpenes on the release rate is shown in FIG. 3. From this it can be concluded that polyterpenes are able to increase the themodynamic activity of nitroglycerin.
  • the preparation can also contain: metal compounds (aluminum, titanium, and other metal compounds known to those skilled in the art); Plasticizers (paraffins, cyclic hydrocarbons, vegetable oils and other plasticizers known to those skilled in the art); Penetration improvers (surface-active substances, lipophilic solvents, hydrophilic solvents); Tackifiers (rosins, hydrocarbons and other tackifiers known to those skilled in the art); carrier or protective films impermeable to the active ingredient (polyester, polypropylene, polyethylene and other materials known to the person skilled in the art).
  • metal compounds aluminum, titanium, and other metal compounds known to those skilled in the art
  • Plasticizers paraffins, cyclic hydrocarbons, vegetable oils and other plasticizers known to those skilled in the art
  • Penetration improvers surface-active substances, lipophilic solvents, hydrophilic solvents
  • Tackifiers rosins, hydrocarbons and other tackifiers known to those skilled in the art

Landscapes

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

Abstract

L'invention concerne une composition s'appliquant sur la peau et contenant a) un copolymère d'acrylate renfermant 25-40 % en poids de méthylacrylate, 50-70 % en poids de 2-éthylhexylacrylate, 1-10 % en poids d'acide acrylique, b) un polyterpène et c) de la nitroglycérine. Cette composition sert à la prophylaxie ou au traitement de la cardiopathie coronarienne.
PCT/EP1999/002609 1998-04-28 1999-04-19 Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate WO1999055327A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002330934A CA2330934A1 (fr) 1998-04-28 1999-04-19 Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate
AU38184/99A AU3818499A (en) 1998-04-28 1999-04-19 Composition containing polyacrylate, polyterpene, nitroglycerine and possibly polyvinyl acetate
KR1020007012034A KR20010043139A (ko) 1998-04-28 1999-04-19 폴리아크릴레이트, 폴리테르핀, 니트로글리세린 및 추가로폴리비닐아세테이트를 함유하는 조성물
EP99920701A EP1079822A1 (fr) 1998-04-28 1999-04-19 Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate
JP2000545526A JP2002512958A (ja) 1998-04-28 1999-04-19 ポリアクリレート、ポリテルペン、ニトログリセリンおよび任意でポリビニルアセテートを含む組成物
NO20005299A NO20005299D0 (no) 1998-04-28 2000-10-20 Sammensetning som inneholder polyacrylat, polyterpen, nitroglyserin og valgfri polyvinylacetat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19818955A DE19818955C2 (de) 1998-04-28 1998-04-28 Zusammensetzung, enthaltend Polyacrylat, Polyterpen, Nitroglycerin und wahlweise Polyvinylacetat
DE19818955.9 1998-04-28

Publications (1)

Publication Number Publication Date
WO1999055327A1 true WO1999055327A1 (fr) 1999-11-04

Family

ID=7866045

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/002609 WO1999055327A1 (fr) 1998-04-28 1999-04-19 Composition contenant du polyacrylate, du polyterpene, de la nitroglycerine et eventuellement du polyvinyle acetate

Country Status (8)

Country Link
EP (1) EP1079822A1 (fr)
JP (1) JP2002512958A (fr)
KR (1) KR20010043139A (fr)
AU (1) AU3818499A (fr)
CA (1) CA2330934A1 (fr)
DE (1) DE19818955C2 (fr)
NO (1) NO20005299D0 (fr)
WO (1) WO1999055327A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002328328B2 (en) * 2001-08-24 2007-03-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system with fentanyl or related substances

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008026A2 (fr) * 2001-07-16 2003-01-30 Pneumoflex Systems, L.L.C. Dispositif et procede de reanimation cardio-pulmonaire par la toux autonome

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0059441A1 (fr) * 1981-03-02 1982-09-08 Füssener Textil AG Agent biologiquement actif à base de terpène/acide alpha-céto-carboxylique
EP0518113A1 (fr) * 1991-06-10 1992-12-16 Schwarz Pharma Ag Pancement de nitroglycerine et son procédé de préparation
WO1993000058A1 (fr) * 1991-06-27 1993-01-07 Noven Pharmaceuticals, Inc. Systeme d'apport de medicaments fonde sur un parametre de solubilite et procede modifiant la concentration de saturation d'un medicament
JPH06321780A (ja) * 1993-05-07 1994-11-22 Daikyo Yakuhin Kogyo Kk ニトログリセリン貼付剤及びその製造方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713239A (en) * 1979-05-29 1987-12-15 Vsesojuny Kardiologichesky Nauchny Tsentr Adkaemii Meditsinski Nauk Sssr Antianginal film and method of treating ischemic heart disease
US4725272A (en) * 1981-06-29 1988-02-16 Alza Corporation Novel bandage for administering beneficial drug
US4751087A (en) * 1985-04-19 1988-06-14 Riker Laboratories, Inc. Transdermal nitroglycerin delivery system
US5262165A (en) * 1992-02-04 1993-11-16 Schering Corporation Transdermal nitroglycerin patch with penetration enhancers
US5762952A (en) * 1993-04-27 1998-06-09 Hercon Laboratories Corporation Transdermal delivery of active drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0059441A1 (fr) * 1981-03-02 1982-09-08 Füssener Textil AG Agent biologiquement actif à base de terpène/acide alpha-céto-carboxylique
EP0518113A1 (fr) * 1991-06-10 1992-12-16 Schwarz Pharma Ag Pancement de nitroglycerine et son procédé de préparation
WO1993000058A1 (fr) * 1991-06-27 1993-01-07 Noven Pharmaceuticals, Inc. Systeme d'apport de medicaments fonde sur un parametre de solubilite et procede modifiant la concentration de saturation d'un medicament
JPH06321780A (ja) * 1993-05-07 1994-11-22 Daikyo Yakuhin Kogyo Kk ニトログリセリン貼付剤及びその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9506, Derwent World Patents Index; Class A96, AN 95-041185, XP002113370 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002328328B2 (en) * 2001-08-24 2007-03-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system with fentanyl or related substances

Also Published As

Publication number Publication date
EP1079822A1 (fr) 2001-03-07
NO20005299L (no) 2000-10-20
DE19818955A1 (de) 1999-11-11
CA2330934A1 (fr) 1999-11-04
AU3818499A (en) 1999-11-16
NO20005299D0 (no) 2000-10-20
KR20010043139A (ko) 2001-05-25
JP2002512958A (ja) 2002-05-08
DE19818955C2 (de) 2000-06-29

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