WO1994013302A1 - Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie contre le cancer - Google Patents

Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie contre le cancer Download PDF

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Publication number
WO1994013302A1
WO1994013302A1 PCT/EP1993/003231 EP9303231W WO9413302A1 WO 1994013302 A1 WO1994013302 A1 WO 1994013302A1 EP 9303231 W EP9303231 W EP 9303231W WO 9413302 A1 WO9413302 A1 WO 9413302A1
Authority
WO
WIPO (PCT)
Prior art keywords
acetylsalicylic acid
administration system
transdermal administration
asa
pharmaceutically acceptable
Prior art date
Application number
PCT/EP1993/003231
Other languages
German (de)
English (en)
Inventor
Frank Becher
Thomas Kissel
Original Assignee
Lts Lohmann Therapie-Systeme Gmbh & Co. Kg
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
Priority claimed from DE4241128A external-priority patent/DE4241128C2/de
Application filed by Lts Lohmann Therapie-Systeme Gmbh & Co. Kg filed Critical Lts Lohmann Therapie-Systeme Gmbh & Co. Kg
Priority to EP94900819A priority Critical patent/EP0671916A1/fr
Priority to AU55632/94A priority patent/AU694410B2/en
Priority to JP51371294A priority patent/JP3799502B2/ja
Priority to NZ258129A priority patent/NZ258129A/en
Priority to KR1019950702301A priority patent/KR100267359B1/ko
Priority to SK754-95A priority patent/SK75495A3/sk
Priority to PL93309285A priority patent/PL174770B1/pl
Publication of WO1994013302A1 publication Critical patent/WO1994013302A1/fr
Priority to NO952234A priority patent/NO952234L/no
Priority to FI952805A priority patent/FI120719B/fi

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
    • 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
    • A61K31/60—Salicylic acid; Derivatives 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
    • 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
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

  • ASA acetylsalicylic acid
  • antithrombotic therapy is used in the following, these indications are essentially included.
  • acetylsalicylic acid is often used as a non-steroidal anti-inflammatory, analgesic and antipyretic agent.
  • ASA affects platelet function and prevents thrombosis by irreversibly inhibiting thromboxane A2 synthesis (M. Buchanan et al., "Aspirin inhibits platelet function independent of cyclooxygenase", Thrombosis Res. 25, 363-373 (1982)).
  • ASA is quickly absorbed after oral administration.
  • the biological half-life in the body circulation is very short, it only lasts 15-20 minutes (M.
  • Acetylsalicylic acid is continuously ingested by large sections of the population, particularly in the USA. According to a work by Thun et al., "Aspirin Use and Reduced Risk of Fatal Colon Cancer", New Engl. J. Med..225. 1593-1596 (1991), ASA reduced the mortality caused by colon cancer to about half when ASA was taken continuously, at least 16 days a month. The investigation included more than 660,000 people who had taken ASA for at least one year and lived in all 50 states in the United States, the Columbia District, and Puerto Rico. Although reference was only made to the use of ASA without further details regarding the mode of administration and the dose, it can nevertheless be assumed that the ASA had been taken orally and that the substance responsible for the action is not the hydrolysis product salicylic acid, but ASA itself.
  • ASS is mentioned in US Pat. No. 3,598,122 as a possible antipyretic active substance in a membrane-controlled transdermal therapeutic system.
  • FR-M 1757 describes the dermal topical application of an oil-in-water emulsion which contains 5% ASA for acute pain.
  • FR-A 2 297 612 claims rubbing agents and ointments which contain ASA as an analgesic agent.
  • ASS is used in US Pat. No. 4,012,508 for topical use in dermatological indications. US Pat. No.
  • ASS-containing gel is applied topically in EP-A 0055635 for anti-inflammatory, analgesic and antipyretic indications.
  • a device for the transdermal application of ASA from an aqueous system to achieve anti-inflammatory and analgesic effects is the subject of US Pat. No. 4,460,368.
  • ASS is applied topically from ethanolic solution in US Pat. No. 4,665,063 against dermatological disorders.
  • An increase in the penetration rate of ASA in the case of transdermal application is achieved in US Pat. No. 4,640,689 with electric current.
  • JP-OS 61 167 615 ASS is applied to the skin with the aid of a film.
  • US Pat. No. 4,810,699 describes combinations of ASA with other active substances for the transdermal treatment of inflammation, pain and fever.
  • Special penetration accelerators for the transdermal application of ASA as a pain reliever are contained in JP-PS 1 203 336.
  • Further substances of this type for ASA in transdermal application for inhibiting inflammation can be found in JP-PS 1, 242,521.
  • Storage-stable solutions from ASS for topical application with the aim of reducing inflammation and relieving pain are the subject of US Pat. No. 4,975,269.
  • transdermal system is used for the administration of acetylsalicylic acid and / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for prophylaxis against cancer, preferably one which contains acetylsalicylic acid or the salts contains in a matrix that substantially suppresses or does not permit the hydrolysis of acetylsalicylic acid.
  • the system is preferably free of substances which, under the storage conditions or during use, cause the acetyl group to be split off.
  • a transdermal delivery system offers the following advantages in anti-thrombotic therapy:
  • ASA in its pharmacologically active form, is given directly to the body's circulation, thereby avoiding metabolism in the gastrointestinal tract.
  • the ASA content in such an administration unit is generally 5 to 500, preferably 30 to 200 mg or the corresponding amount of a pharmaceutically acceptable salt.
  • the ASS salts that can be used here are all non-toxic, pharmacologically active salts such as the lithium, sodium, potassium, magnesium and calcium salts or salts of ASS with basic organic compounds such as lysine, arginine or cetrimonium bromide (hexadecyltrimethylam onium bromide).
  • the rate and extent of the transdermal transfer of ASA into the body naturally depends on the amount, the type of compound (free acid or salt) and, if appropriate, also on the presence of auxiliaries such as penetration accelerators.
  • the system is expediently adjusted in such a way that an ASA blood level value between 0.1 and 1.0 ⁇ g / ml is established.
  • the content is expediently based on the type of matrix, the recommended wearing time of the F-Tlaster, the intended indication, the body weight (children or adults), the permeability of the matrix or membrane of the patch and the permeation through the skin Voted.
  • ASA blood level values between 0.1 and 1.0 ⁇ g / ml.
  • ASA is rapidly absorbed after oral administration, this type of administration is unfavorable, especially because of the hydrolysis of ASA to salicylic acid if the short biological half-life and the fact that the most constant possible administration is desirable for prophylaxis.
  • the transdermal treatment proposed according to the invention gives fairly constant and reproducible ASA blood level values which are particularly effective in anthrhrombotic therapy and are suitable for cancer prophylaxis.
  • a transdermal delivery system according to the invention ensures constant and reproducible ASA blood levels which are effective in antithrombotic therapy.
  • cancer prophylaxis e.g. understood one against cancer with tumor formation, e.g. in the gastrointestinal tract, such as colon cancer.
  • the transdermal administration system for ASA and / or ASA salts according to the invention can be implemented in a variety of ways, e.g. as a particularly pressure-sensitive adhesive plaster, as a film, as a spray, cream, ointment and the like.
  • Preferred is the form of administration of the pressure-sensitive adhesive plaster, which has an impermeable backing layer, an associated active substance reservoir made of a polymer matrix, in the absence of other control mechanisms, a membrane that controls the release of the active substance, a pressure-sensitive adhesive device for attaching the system to the skin and, if necessary includes a protective layer that can be removed before the system is applied.
  • care must be taken that the matrix forming the active substance reservoir is selected in such a way that the hydrolysis of ASA is avoided or at least strongly suppressed.
  • a hydrophobic setting of the matrix leads to the goal here rather than a hydrophilic one.
  • acylating agents preferably acetylating agents, in particular acetic anhydride, e.g. in an amount of 0.01 to 3, preferably 0.1 to 2 wt .-%, based on acetylsalicylic acid.
  • transdermal pressure-sensitive adhesive plasters which can be used according to the invention are all plasters which are known to the person skilled in the art from the prior art. They can largely be assigned to two basic control principles: matrix diffusion control and membrane control, only the latter having a zero-order release of active ingredient.
  • An F-raster with matrix diffusion control is described for example in DE-PS 33 15 272. It consists of an impermeable backing layer, an associated reservoir made of a polymer matrix, which contains the active ingredient in a concentration above the juicing concentration, a pressure-sensitive adhesive layer connected to the reservoir, permeable to the active ingredient, and a protective layer covering the adhesive layer, which can be removed again for use, e.g. a siliconized film made of polyester, especially polyethylene terephthalate. If the reservoir matrix itself is already pressure sensitive, you can use the additional adhesive layer can be dispensed with. However, systems with lower than the saturation concentration are also possible.
  • plasters with membrane control reference is made, for example, to US Pat. Nos. 3,742,951, 3,797,494, 3,996,934 and 4,031, 894.
  • These plasters basically consist of a backing layer (e.g. a film made of a polyester such as polyethylene terephthalate, which can be aluminized, or an aluminized film made of a synthetic resin such as polypropylene, nylon, polycaprolactam), which is one of the surfaces, a membrane, one for the Active substance permeable adhesive layer that represents the other surface and ultimately a reservoir that contains the active substance between the two layers forming the surfaces.
  • the active ingredient can also be contained in a large number of microcapsules which are distributed within the permeable adhesive layer.
  • the active ingredient is continuously released from the reservoir or the microcapsules through a membrane into the adhesive layer which is permeable to the active ingredient and which is in contact with the skin of the person to be treated.
  • the capsule material can also act as a membrane. Substances suitable for membranes and microcapsules are e.g. in U.S. Patent 3,996,934.
  • the plasters can contain various additives in addition to the matrix forming the reservoir and the active ingredient, which also includes combinations of ASA and their salts, in order to obtain the desired property profile.
  • Additives that promote the permeation of ASA and / or their pharmaceutically acceptable salts through the skin should be particularly mentioned.
  • a precise list of the additives is unnecessary for the person skilled in the art in this field, but mention may be made, for example, of glycerol, 1, 2-propanediol, the monomethyl or monoethyl ether of ethylene glycol, 2-octyldodecanol, the laurate, palmitate, stearate or oleate of sorbitol, C 8 -
  • the amount is generally from 0 to 20, preferably from 0.5 to 10,% by weight. %, based on the total components of the matrix. It depends on the type of matrix, the permeability of the matrix or membrane of the patch, the dissolving power of the penetration accelerator for the active ingredient and the permeation through the skin.
  • the invention is illustrated by the following examples:
  • the solution is then spread 300 ⁇ m thick on a siliconized, 100 ⁇ m thick polyester film. In the finished system, this film takes over the function of the removable protective layer and must be removed before use.
  • the moist film is dried at 50 ° C. for 20 minutes and then has a weight per unit area of 100 g / m 2 .
  • the dried film is then laminated with a 12 ⁇ m thick polyester film.
  • the finished plasters are punched out of the laminate.
  • the finished system consists of a removable protective layer, a skin adhesive layer, a non-adhesive reservoir, an active substance-impermeable back layer and a well-adhesive primer layer which is located between the reservoir layer and the back layer and has the task of anchoring the non-adhesive reservoir on the back layer.
  • a block polymer made of polystyrene and polyisoprene e.g. Cariflex TR-1 107, Shell
  • the reservoir coat obtained under B is laminated onto the skin gash line A and then the more siliconized film mentioned under B is removed. Now the primer coat C is applied in the same way and a 12 ⁇ m thick polyester film is laminated on after removing the more siliconized film mentioned under C.
  • the finished plasters are punched out of the total laminate.
  • a heat-sealable laminate made of a flexible polyester film and a film made of a polyethylene / vinyl acetate copolymer is sealed against a 50 ⁇ m thick membrane made of a polyethylene / vinyl acetate copolymer with a vinyl acetate content of 19% in accordance with the dimensions and shapes of the later plasters Kind of flat bag arises.
  • the sealing seam should have a width of 4 mm.
  • a liquid preparation made from a silicone oil with 10% acetylsalicylic acid and 0.05% acetic anhydride.
  • the membrane side of the pouch is then laminated onto a silicone-based skin adhesive layer located on a suitable, abhesively finished film. This film is identical to the removable protective layer.
  • the finished systems are punched out so that a bag with a 3 mm thick sealing edge remains.

Landscapes

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

Abstract

L'invention concerne un système d'administration transdermique pour la thérapie antithrombotique et la prophylaxie contre le cancer, contenant, comme principe actif, de l'acide acétylsalicylique et/ou des sels de cet acide pharmaceutiquement acceptables.
PCT/EP1993/003231 1991-12-20 1993-11-18 Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie contre le cancer WO1994013302A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP94900819A EP0671916A1 (fr) 1992-12-07 1993-11-18 Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie contre le cancer
AU55632/94A AU694410B2 (en) 1992-12-07 1993-11-18 Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prevention of cancer
JP51371294A JP3799502B2 (ja) 1992-12-07 1993-11-18 抗血栓治療および癌予防のためのアセチルサリチル酸を含有する経皮投与システム
NZ258129A NZ258129A (en) 1992-12-07 1993-11-18 Transdermal system for applying acetylsalicylic acid or salts thereof for antithrombotic treatment or cancer proplylaxis
KR1019950702301A KR100267359B1 (ko) 1991-12-20 1993-11-18 항혈전성 치료 및 암 예방을 위한 아세틸살리실산을 함유하는 경피 투여 시스템
SK754-95A SK75495A3 (en) 1992-12-07 1993-11-18 Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy and the prophylaxis of cancer
PL93309285A PL174770B1 (pl) 1992-12-07 1993-11-18 Przezskórny układ terapeutyczny do terapii przeciwzakrzepowej i/lub zapobiegania chorobom nowotworowym oraz sposób wytwarzania przezskórnego układu terapeutycznego do terapii przeciwzakrzepowej i/lub zapobiegania chorobom nowotworowym
NO952234A NO952234L (no) 1992-12-07 1995-06-06 Transdermalt administreringsystem inneholdende acetylsalisylsyre for antitromboseterapi og forebygging av kreft
FI952805A FI120719B (fi) 1992-12-07 1995-06-07 Menetelmä asetyylisalisyylihappoa sisältävän transdermaalisen järjestelmän valmistamiseksi

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4142483 1991-12-20
DE4241128A DE4241128C2 (de) 1991-12-20 1992-12-07 Verwendung eines transdermalen Verabreichungssystems, das als Wirkstoff Acetylsalicylsäure und/oder pharmazeutisch akzeptable Salze davon enthält
DEP4241128.9 1992-12-07

Publications (1)

Publication Number Publication Date
WO1994013302A1 true WO1994013302A1 (fr) 1994-06-23

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PCT/EP1993/003231 WO1994013302A1 (fr) 1991-12-20 1993-11-18 Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie contre le cancer

Country Status (1)

Country Link
WO (1) WO1994013302A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803254A1 (fr) * 1996-04-25 1997-10-29 LUITPOLD PHARMA GmbH Solutions alcooliques contenant de l'acide acétylsalicylique pour l'administration percutanée, leur utilisation dans la thérapie antithrombotique en tant que médicaments

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2295753A1 (fr) * 1974-12-23 1976-07-23 Despin Jean Composition a base d'acide acetyl-salicylique a usage topique
US3996934A (en) * 1971-08-09 1976-12-14 Alza Corporation Medical bandage
EP0055635A1 (fr) * 1980-12-19 1982-07-07 Laboratoires du Docteur P. ASTIER Composition pharmaceutique sous forme d'un gel contenant de l'acide acétylsalicylique
DE3315272A1 (de) * 1983-04-27 1984-10-31 Lohmann Gmbh & Co Kg, 5450 Neuwied Pharmazeutisches produkt
DE3413052A1 (de) * 1983-06-13 1984-12-13 Rafa Labor Ltd Pharmazeutische zubereitung und deren verwendung zur behandlung von hauterkrankungen
US4640689A (en) * 1983-08-18 1987-02-03 Drug Delivery Systems Inc. Transdermal drug applicator and electrodes therefor
US4975269A (en) * 1989-07-31 1990-12-04 Leonard Chavkin Shelf stable aspirin solutions
WO1992020343A1 (fr) * 1991-04-03 1992-11-26 Gunderson Medical Foundation, Ltd. Abaissement des taux de thromboxane par administration percutanee d'aspirine
WO1993012799A1 (fr) * 1991-12-20 1993-07-08 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie du cancer

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3996934A (en) * 1971-08-09 1976-12-14 Alza Corporation Medical bandage
FR2295753A1 (fr) * 1974-12-23 1976-07-23 Despin Jean Composition a base d'acide acetyl-salicylique a usage topique
EP0055635A1 (fr) * 1980-12-19 1982-07-07 Laboratoires du Docteur P. ASTIER Composition pharmaceutique sous forme d'un gel contenant de l'acide acétylsalicylique
DE3315272A1 (de) * 1983-04-27 1984-10-31 Lohmann Gmbh & Co Kg, 5450 Neuwied Pharmazeutisches produkt
DE3413052A1 (de) * 1983-06-13 1984-12-13 Rafa Labor Ltd Pharmazeutische zubereitung und deren verwendung zur behandlung von hauterkrankungen
US4640689A (en) * 1983-08-18 1987-02-03 Drug Delivery Systems Inc. Transdermal drug applicator and electrodes therefor
US4975269A (en) * 1989-07-31 1990-12-04 Leonard Chavkin Shelf stable aspirin solutions
WO1992020343A1 (fr) * 1991-04-03 1992-11-26 Gunderson Medical Foundation, Ltd. Abaissement des taux de thromboxane par administration percutanee d'aspirine
WO1993012799A1 (fr) * 1991-12-20 1993-07-08 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Systeme d'administration transdermique contenant de l'acide acetylsalicylique pour la therapie antithrombotique et la prophylaxie du cancer

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
J. HIRSH ET AL.: "ASPIRIN AND OTHER PLATELET ACTIVE DRUGS.RELATIONSHIPS AMONG DOSE, EFFECTIVENESS, AND SIDE EFFECTS", CHEST, vol. 95, no. 2, 1989, pages 12S - 18S *
J.E.F. REYNOLDS: "MARTINDALE THE EXTRA PHARMACOPOEIA", 1989, THE PHARMACEUTICAL PRESS, LONDON *
M.J. THUN ET AL.: "ASPIRIN USE AND REDUCED RISK OF FATAL COLON CANCER", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 325, no. 23, 1991, pages 1593 - 1596, XP001097657 *
R.M. KEIMOWITZ ET AL.: "TRANSDERMAL MODIFICATION OF PLATELET FUNCTION", CIRCULATION, vol. 88, no. 2, August 1993 (1993-08-01), pages 556 - 561 *
S. NAITO ET AL.: "PERCUTANEOUS ABSORPTION OF SALICYLIC ACID DERIVATIVES", YAKURI TO CHIRYO, vol. 16, no. 1, 1988, pages 17 - 25 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0803254A1 (fr) * 1996-04-25 1997-10-29 LUITPOLD PHARMA GmbH Solutions alcooliques contenant de l'acide acétylsalicylique pour l'administration percutanée, leur utilisation dans la thérapie antithrombotique en tant que médicaments
US5900412A (en) * 1996-04-25 1999-05-04 Luitpold Pharma Gmbh Percutaneous/transdermal delivery of ASA and antithrombotic therapies based thereon

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