AU726094B2 - Acetylsalicylic acid-containing transdermal therapeutic system with absorption enhancement - Google Patents

Acetylsalicylic acid-containing transdermal therapeutic system with absorption enhancement Download PDF

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Publication number
AU726094B2
AU726094B2 AU59862/98A AU5986298A AU726094B2 AU 726094 B2 AU726094 B2 AU 726094B2 AU 59862/98 A AU59862/98 A AU 59862/98A AU 5986298 A AU5986298 A AU 5986298A AU 726094 B2 AU726094 B2 AU 726094B2
Authority
AU
Australia
Prior art keywords
limonene
acetylsalicylic acid
transdermal therapeutic
dimethylisosorbide
therapeutic system
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.)
Ceased
Application number
AU59862/98A
Other versions
AU5986298A (en
Inventor
Gerd Hoffmann
Michael Horstmann
Heinrich Kindel
Theresa Maria Murphy
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.)
LTS Lohmann Therapie Systeme AG
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
Publication of AU5986298A publication Critical patent/AU5986298A/en
Application granted granted Critical
Publication of AU726094B2 publication Critical patent/AU726094B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Description

Acetylsalicylic acid-containing transdermal therapeutic system with absorption enhancement The invention relates to an acetylsalicylic acid-containing transdermal therapeutic system with an essentially active ingredient- and moisture-impermeable backing layer, an active ingredient reservoir and, where appropriate, a redetachable protective layer.
Transdermal therapeutic systems (TTS) have already been launched on the market in the medicinal treatment of a number of disorders.
The ability in principle of the active ingredient acetylsalicylic acid to permeate through the human skin and thus be suitable as ingredient of transdermal therapeutic systems is also known. Thus, Rougier et al. Pharm. Sci.
176, 451-454, 1987) have already described the (rather low) dependence of the rate of acetylsalicylic acid uptake into the skin on the selected area of skin.
Acetylsalicylic acid is a relatively safe medicinal substance with a high therapeutic index. In very high doses (more than one gram a day) it is used as antirheumatic agent, in intermediate doses (250-500 mg) as antipyretic/analgesic and in low dosage (30 to 150 mg per day) as platelet aggregation inhibitor. Acetylsalicylic acid is a substance which melts at a low temperature (about 139 0 C) and shows marked volatility at this temperature.
Because of the unstable ester group, acetylsalicylic acid is susceptible to hydrolysis and transesterification.
Various stabilization methods have therefore already been considered, such as elimination of water, alcohols and esters as possible partners in a transesterification or TRA rolysis reaction; addition of acetic acid or acetic 2 anhydride or adjustment to pH 2-3. US-A 4,228,162 also mentions dimethylisosorbide as stabilizing solvent.
A major impediment of the development of acetylsalicylic acid-containing pharmaceutically effective transdermal therapeutic systems is moreover the low permeability, by comparison with the high therapeutic daily dose required, of the active ingredient through the skin. A large number of permeation accelerants have therefore already been proposed as additives, such as azones, carboxylic esters, surface-active substances etc.
US-A 5,164,416 also indicates limonene as permeationenhancing substance for acetylsalicylic acid but, according to this, its use is restricted to the simultaneous addition of a possibly irritating alkaline additive. Furthermore the permeation rates which can be achieved for acetylsalicylic acid following this teaching are still insufficiently high.
It has now been found, surprisingly, that combined addition of limonene and dimethylisosorbide in particular ratios of amounts leads to a considerable improvement, which was not predictable, in acetylsalicylic acid permeation through the skin.
Accordingly, the transdermal therapeutic system according to the invention of the type mentioned at the outset is essentially characterized by a content of limonene and dimethylisosorbide in a mixing ratio of at least 50:50 limonene to dimethylisosorbide in the active ingredient-active region.
This solution to the problem is surprising inasmuch as the te to a medicinal form with better bioavailability leads the skilled person via basic substances which are good 3 solvents, whereas limonene shows an extremely low solubility for acetylsalicylic acid even on addition of dimethylisosorbide.
Particular features of the invention are evident from the claims and the following description.
The principle according to the invention can be utilized both in matrix systems and in reservoir/membrane systems.
It is also immaterial which polymers, resins and possibly other additives are added as long as the formulation is suitable for delivering the basic substances acetylsalicylic acid, limonene and dimethylisosorbide to the skin.
In the simplest case it is possible for all three characterizing starting materials to be dispersed or dissolved in a solution of basic polymers, and for the mixture to be coated onto a suitable substrate, as a rule a siliconized thermoplastic sheet and, after evaporation of the solvent contents, where appropriate intensified by input of heat, to be covered with another sheet which forms the later rear side of the transdermal therapeutic system. Transdermal therapeutic systems are obtained from such a laminate by cutting out flat structures with the required geometric shape (circle, rounded rectangle etc.).
However, further embodiments may comprise forming a two-layer matrix consisting of a layer on the skin side, which contains the active ingredient in dispersed or dissolved form, and a second layer facing away from the skin, which contains limonene and dimethylisosorbide in the desired mixing ratio. These design variants are, however, only the simplest of a number of possible conceptions of the system known to the skilled person. Thus, matrix jptems with more than two layers are, of course, possible 4 and, where appropriate, further active ingredients can be provided.
Suitable basic polymers for the system according to the invention are, in particular, acrylate copolymers, styrene/diene copolymers, silicone polymers, mixtures of polyisobutylene with suitable thermoplastic resins. This list is far from complete but indicates the wide applicability of the principle according to the invention.
The mixing ratio of limonene to dimethylisosorbide is, in particular, in the range from 50:50 to 99:1, preferably from 85:15 to 95:5 and specifically in the region of 90:10.
It is moreover possible and expedient to provide a limonene content which is of the order of magnitude of the acetylsalicylic acid concentration.
Example 1: g of micronized acetylsalicylic acid g of limonene and 1 g of dimethylisosorbide are dissolved or dispersed in 600 g of an acrylate copolymer solution (solids content: 50% g/g).
The composition is coated onto a siliconized polyester sheet (100 pm thick) to result in a layer with a weight per unit area of 150 g per m 2 Drying takes place under mild conditions by storing at room temperature in the air for hours. The matrix obtained in this way is laminated with another sheet (polyester sheet 15 pm thick), and punches are used to cut out circles with a size of 20 cm 2 This results in transdermal therapeutic systems which can ^plpplied to the skin directly after detachment of the siliconized polyester sheet in order to produce the desired therapeutic effect.
Example 2: 20 g of micronized acetylsalicylic acid are dispersed in 160 g of an acrylate copolymer solution (solids content: The composition is coated onto a siliconized polyester sheet (100 pm thick) to result in a layer with a weight per unit area of 52 g/m 2 Drying takes place by storing at room temperature in the air for 10 hours. The matrix obtained in this way is laminated with another sheet (polyester sheet 15 pm thick).
20 g of micronized acetylsalicylic acid are dispersed in 160 g of an acrylate copolymer solution (solids content: The composition is coated onto a siliconized polyester sheet (100 pm thick) to result in a layer with a weight per unit area of 93 g/m 2 Drying takes place by storing at room temperature in the air for 10 hours.
A circular disc of fabric (cotton) 2.54 cm 2 in size is applied to the adhesive area of the laminate from mg of a mixture of 10% dimethylisosorbide and limonene, which has previously been saturated with acetylsalicylic acid by stirring at room temperature for hours and then filtering, are applied dropwise to the disc of fabric. Laminate from and disc of fabric are covered on the adhesive side with layer so as to result in a sandwich of polyester sheet (15 pm), 52 g/m 2 polyacrylate with acetylsalicylic acid, doped disc of fabric 2.54 cm 2 and 93 g/m 2 polyacrylate with acetylsalicylic acid, which is then covered on the adhesive side by a siliconized polyester protective sheet with an abhesive action.
6 7.10 cm 2 circles are cut of this laminate in such a way that the disc of fabric is located in the middle. After application to excized rat skin, the permeation is determined in vitro.
The average permeation found after 48 hours was 632.6 gg/cm 2 acetylsalicylic acid.
Example 3 (example comparing with Example 2): Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cm 2 in size is applied to the adhesive area of the laminate from mg of pure dimethylisosorbide which has previously been saturated with acetylsalicylic acid by stirring at room temperature for 5 hours and then filtering, are applied dropwise to the disc of fabric. Laminate from and disc of fabric are cut out into 7.10 cm 2 specimens in analogy to Example 2. A determination of the permeation of excised rat skin was also carried out in the same way.
The average permeation found after 48 hours was 130.4 g/cm 2 acetylsalicylic acid.
Example 4: (example comparing with Example 2): Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cm 2 in size is applied to the adhesive area of the laminate from mg of pure limonene which has previously been saturated with acetylsalicylic acid by stirring at room temperature for 5 hours and then filtering, are applied dropwise to the *Sc of fabric. Laminate from and disc of fabric are ctt\out into 7.10 cm 2 specimens in analogy to Example 2. A 7 determination of the permeation of excised rat skin was also carried out in the same way.
The average permeation found after 48 hours was 253.3 gg/cm 2 acetylsalicylic acid.
Example 5: (example comparing with Example 2): Layer 1 and 2 are produced in accordance with Example 2.
A circular disc of fabric (cotton) 2.54 cm 2 in size is applied to the adhesive area of the laminate from No dropwise application of medium takes place. Laminate from and disc of fabric are cut out into 7.10 cm 2 specimens in analogy to Example 2. A determination of the permeation of excised rat skin was also carried out in the same way.
The average permeation found after 48 hours was 52.9 pg/cm 2 acetylsalicylic acid.
Comparison of the permeation results for Examples 2 to clearly shows the superiority of the system according to the invention.

Claims (4)

1. Acetylsalicylic acid-containing transdermal thera- peutic system with an essentially active ingredient- and moisture-impermeable backing layer, an active ingredient reservoir and, where appropriate, a redetachable protective layer, characterized by a content of limonene and dimethylisosorbide in a mixing ratio of at least 50:50 limonene to dimethyl- isosorbide in the active ingredient-active region.
2. Transdermal therapeutic system according to Claim 1, characterized by a monolayer or multilayer matrix as active ingredient reservoir, of which at least one layer contains limonene and dimethylisosorbide in a mixing ratio of 50:50 to 99:1 (limonene to dimethyl- isosorbide).
3. Transdermal therapeutic system according to Claim 1 or 2, characterized by a mixing ratio of limonene to dimethylisosorbide of 85:15 to 95:5 in particular 90:10.
4. Transdermal therapeutic system according to any of the preceding claims, characterized in that acetyl- salicylic acid, limonene and dimethylisosorbide are present dissolved or dispersed in basic polymers. Transdermal therapeutic system according to any of the preceding claims, characterized by an at least two-layer matrix whose layer facing away from the skin contains limonene and dimethylisosorbide in the stated mixing ratio. s6. Transdermal therapeutic system according to any of the preceding claims, characterized by a limonene content of the order of magnitude of the acetylsalicylic acid concentration.
AU59862/98A 1997-01-15 1998-01-03 Acetylsalicylic acid-containing transdermal therapeutic system with absorption enhancement Ceased AU726094B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19701059A DE19701059C2 (en) 1997-01-15 1997-01-15 Transdermal therapeutic system with absorption enhancement containing acetylsalicylic acid
DE19701059 1997-01-15
PCT/EP1998/000013 WO1998031348A1 (en) 1997-01-15 1998-01-03 Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption

Publications (2)

Publication Number Publication Date
AU5986298A AU5986298A (en) 1998-08-07
AU726094B2 true AU726094B2 (en) 2000-11-02

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AU59862/98A Ceased AU726094B2 (en) 1997-01-15 1998-01-03 Acetylsalicylic acid-containing transdermal therapeutic system with absorption enhancement

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EP (1) EP1023053A1 (en)
JP (1) JP2001508069A (en)
KR (1) KR20000070228A (en)
AU (1) AU726094B2 (en)
CA (1) CA2277366A1 (en)
DE (1) DE19701059C2 (en)
NO (1) NO993435L (en)
WO (1) WO1998031348A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19949202A1 (en) * 1999-10-13 2001-05-03 Lohmann Therapie Syst Lts Transdermal therapeutic system for the delivery of acetylsalicylic acid and / or salicylic acid
DE19949252B4 (en) * 1999-10-13 2004-02-12 Lts Lohmann Therapie-Systeme Ag Use of a superficial therapeutic system for the topical application of acetylsalicylic acid for the treatment of acne disorders and process for its preparation
DE19959913A1 (en) * 1999-12-11 2001-06-28 Lohmann Therapie Syst Lts Transdermal system for the treatment of migraines containing acetylsalicylic acid
KR100448469B1 (en) * 2001-10-26 2004-09-13 신풍제약주식회사 Transdermal composition and device of anti-inflammatory agents
WO2003037303A1 (en) 2001-11-01 2003-05-08 Nektar Therapeutics Spray drying methods and compositions thereof
DE10338162B3 (en) † 2003-08-20 2005-06-02 Haldex Brake Products Gmbh Method for operating a compressed air procurement system of a motor vehicle and compressed air treatment device
DE102005033543A1 (en) * 2005-07-14 2007-01-18 Grünenthal GmbH A fragrance-containing transdermal therapeutic system
DE102005050431A1 (en) * 2005-10-21 2007-04-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for the administration of lipophilic and / or less skin-permeable active ingredients
IT202000014578A1 (en) * 2020-06-18 2021-12-18 Poli Md S R L MEDICAL DEVICE INCLUDING ACETYL SALICYLIC ACID

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4228162A (en) * 1979-07-09 1980-10-14 Research Corporation Dimethyl isosorbide in liquid formulation of aspirin
US5164416A (en) * 1989-02-03 1992-11-17 Lintec Corporation Transdermal therapeutic formulation containing a limonene
DE4332094C2 (en) * 1993-09-22 1995-09-07 Lohmann Therapie Syst Lts Active substance plaster which can be produced without solvent and process for its preparation
DE4332093C2 (en) * 1993-09-22 1995-07-13 Lohmann Therapie Syst Lts Transdermal therapeutic system with the active ingredient acetylsalicylic acid and process for its preparation

Also Published As

Publication number Publication date
CA2277366A1 (en) 1998-07-23
NO993435D0 (en) 1999-07-12
DE19701059A1 (en) 1998-07-16
DE19701059C2 (en) 2000-12-21
WO1998031348A1 (en) 1998-07-23
NO993435L (en) 1999-07-12
AU5986298A (en) 1998-08-07
JP2001508069A (en) 2001-06-19
KR20000070228A (en) 2000-11-25
EP1023053A1 (en) 2000-08-02

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FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired