WO2006024339A2 - Controlled-release multilayer patch for the topical use - Google Patents

Controlled-release multilayer patch for the topical use Download PDF

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Publication number
WO2006024339A2
WO2006024339A2 PCT/EP2005/007326 EP2005007326W WO2006024339A2 WO 2006024339 A2 WO2006024339 A2 WO 2006024339A2 EP 2005007326 W EP2005007326 W EP 2005007326W WO 2006024339 A2 WO2006024339 A2 WO 2006024339A2
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
adhesive
patch
silicon
liner
Prior art date
Application number
PCT/EP2005/007326
Other languages
French (fr)
Other versions
WO2006024339A3 (en
Inventor
Paola Stefanelli
Alberto Scarsetto
Maurizio Di Grigoli
Pierbruno Romelli
Original Assignee
Bouty S.P.A.
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 Bouty S.P.A. filed Critical Bouty S.P.A.
Publication of WO2006024339A2 publication Critical patent/WO2006024339A2/en
Publication of WO2006024339A3 publication Critical patent/WO2006024339A3/en

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
    • A61K9/7084—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

  • the present invention relates to multilayer transdermal patches wherein the adhesive matrix contains at least one active ingredient as well as lipophilic excipients which reduce adhesivity.
  • Controlled-release matrix therapeutical systems are presently manufactured by incorporatiom of active ingredients in polymeric matrices consisting of a mixture of adhesive polymers and other excipients. To ensure the correct contact to the skin surface, the matrices must have good adhesivity, which can vary in time depending on perspiration, on the occlusion degree of the system and on the excipients.
  • low-adhesive masses containing lipophilic excipients can be used.
  • a number of multilayer patches are commercially available, wherein the matrix consists of different layers of materials placed one on top of the other.
  • the presence of different layers ensures a concentration gradient of active ingredient among the various layers or, when one layer contains the active ingredient (a.i.) and the others contain the excipients, the solubilisation of the a.i.. to promote its diffusion.
  • Patches wherein one layer serves as an adhesive to anchor an adhesive matrix to the liner are not yet available.
  • US 5.505.956 discloses patches consisting of 2-5 different adhesive layers contained between a backing and a liner. Each adhesive layer has different water absorption capacity; this characteristic is given by the presence in the different layers of 0.1 to 30% concentrations of one or more of the following adsorbing materials: PVA, PVP, alginic acid, hyaluronic acid, cellulose, chitine, zinc oxide, calcium oxide, silica, kaolin, talc and titanium dioxide.
  • WO0033812 discloses a 4 layer transdermal patch for the administration of a volatile liquid drug, wherein the top backing is impermeabile to the drug, the second adhesive silicone layer contains the drag, the third layer comprises an acrylic adhesive containing the drag in diffusional contact with the silicon adhesive layer, and the fourth layer is a removable liner.
  • - 1 st layer a moisture-permeable backing consisting of TNT, polyurethane or polyester
  • - 2 nd layer a moisture non-permeable layer consisting of an acrylic (or gum-based) adhesive soluble in ethyl acetate
  • - 3 rd layer a ketoprofen layer and an emulsion of a solution of PVA (and/or EVA) and adhesive acrylic polymer;
  • adhesive layer consisting of an acrylic adhesive, which controls the release of the a.i.;
  • - 5* layer a silicon liner.
  • the invention relates to a multilayer patch comprising an adhesive layer, a protective backing for said adhesive layer, an acrylic and/or silicon polymer matrix containing at least one active ingredient and a removable liner in contact with said matrix, characterized in that the matrix contains lipophilic excipients able to reduce the matrix adhesivity.
  • lipophilic excipients to adhesive matrices for transdermal controlled-release systems improves the skin affinity.
  • Matrices with additives cannot be properly supported by inert backings due to their low adhesivity, it is therefore necessary to interpose an adhesive between the matrix and the backing.
  • the adhesive layer is applied on the backing in a first step, and only afterwards the low-adhesive matrix is anchored; in this way the low-adhesive mass remains anchored to the backing and can be applied to the skin.
  • the patch of the invention is schematically represented in the Figure, wherein reference number 1 indicates the backing layer, number 2 indicates the adhesive layer, number 3 indicates the matrix containing the a.i. and the lipophilic excipients and number 4 indicates the liner layer.
  • Backing layer 1 is made of a conventional material such as polyethylene, PVC, polyester, natural fibre, polyurethane, polypropylene.
  • Adhesive layer 2 typically comprises a water- or solvent-based acrylic and/ or silicon polymer.
  • Matrix 3 further to a mixture of acrylic and/or silicon polymers, contains lipophilic excipients preferably selected from lanolin, vaseline, polyethylene glycols and esters thereof, glycerin and esters thereof, fatty acids, vegetable oil, beeswax, synthetic wax.
  • the excipients are added in weight percentage ranging from 15 to 50% based on the dry weight of the final formulation.
  • liner 4 consists of a conventional material for transdermal patches such as silicon and/or fluorinated polyester, high- or low-density polyethylene.
  • the invention allows to formulate any active ingredients having therapeutical, dermatological or cosmetic activity when administered through the topical and/or transdermal route.
  • non steroidal antiinflammatories such as
  • Diclofenac Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphenbutazone,
  • Piroxicam Suprofen, Celecoxib and other COX-2 selective inhibitors and the like.
  • the patches of the invention are prepared through a process which comprises the following steps: a) formation of the adhesive film by spreading the mass onto a silicon liner, subsequent removal of the solvent and coupling of the adhesive film to the backing; b) formation of the active ingredient-containing adhesive matrix by spreading the mass onto a silicon liner, subsequent removal of the solvent and coupling to the adhesive film.
  • Example 1 The invention is illustrated in greater detail in the following examples.
  • Example 1 The invention is illustrated in greater detail in the following examples.
  • the first adhesive layer (Uceacryl MC808®) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to HO 0 C, then coupled to the polyethylene backing. This first step allows to prepare the semi-manufactured product 1.
  • the low-adhesive mass is prepared by mixing 80 kg of Uceacryl MC808®, 15 kg of lanoline/vaseline in 1/1 ratio and 5 kg of dry vegetable extracts.
  • the homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 110 0 C, then coupled to the semi-manufactured product 1.
  • Example 2 The finished product is ready to be cut and formed.
  • the first adhesive layer (Durotak® 87-2852) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O 0 C, then coupled to the non-woven backing. This first step allows to prepare the semi-manufactured product 1.
  • the low-adhesive mass is prepared by mixing 80 kg of
  • Uceacryl MC808 19 kg of viscous vaseline/vaseline in 1/1 ratio and 1 kg of Tiocolchicoside.
  • the homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 110 0 C, then coupled to the semi-manufactured product 1.
  • the finished product is ready to be cut and formed.
  • the first adhesive layer (Durotak® 87-2852) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O 0 C, coupled to the polyethylene backing. This first step allows to prepare the semi-manufactured product 1.
  • the low-adhesive mass is prepared by mixing together
  • Diclofenac sodium The homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O 0 C, then coupled to the semi-manufactured product 1.
  • the finished product is ready to be cut and formed.

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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A multilayer patch comprising an adhesive layer (2), a protective backing (1) for said adhesive layer (2), an acrylic and/or silicon polymer matrix (3) containing at least one active ingredient and a removable liner (4) in contact with the matrix, characterized in that the matrix (3) contains lipophilic excipients which reduce matrix adhesivity.

Description

CONTROLLED-RELEASE MULTILAYER PATCH FOR THE TOPICAL USE
The present invention relates to multilayer transdermal patches wherein the adhesive matrix contains at least one active ingredient as well as lipophilic excipients which reduce adhesivity.
TECHNOLOGICAL BACKGROUND Controlled-release matrix therapeutical systems are presently manufactured by incorporatiom of active ingredients in polymeric matrices consisting of a mixture of adhesive polymers and other excipients. To ensure the correct contact to the skin surface, the matrices must have good adhesivity, which can vary in time depending on perspiration, on the occlusion degree of the system and on the excipients.
To avoid the excessive increase in patch adhesivity as well as the irritation of the skin when removing the patch, low-adhesive masses containing lipophilic excipients can be used.
However, these matrices cannot be properly supported by inert backings (polyethylene, PVC, polyester, polyurethane).
A number of multilayer patches are commercially available, wherein the matrix consists of different layers of materials placed one on top of the other. The presence of different layers ensures a concentration gradient of active ingredient among the various layers or, when one layer contains the active ingredient (a.i.) and the others contain the excipients, the solubilisation of the a.i.. to promote its diffusion. Patches wherein one layer serves as an adhesive to anchor an adhesive matrix to the liner are not yet available.
For example, US 5.505.956 discloses patches consisting of 2-5 different adhesive layers contained between a backing and a liner. Each adhesive layer has different water absorption capacity; this characteristic is given by the presence in the different layers of 0.1 to 30% concentrations of one or more of the following adsorbing materials: PVA, PVP, alginic acid, hyaluronic acid, cellulose, chitine, zinc oxide, calcium oxide, silica, kaolin, talc and titanium dioxide. WO0033812 discloses a 4 layer transdermal patch for the administration of a volatile liquid drug, wherein the top backing is impermeabile to the drug, the second adhesive silicone layer contains the drag, the third layer comprises an acrylic adhesive containing the drag in diffusional contact with the silicon adhesive layer, and the fourth layer is a removable liner.
US 6.190.690 discloses a ketoprofen patch having the following structure:
- 1st layer: a moisture-permeable backing consisting of TNT, polyurethane or polyester; - 2nd layer: a moisture non-permeable layer consisting of an acrylic (or gum-based) adhesive soluble in ethyl acetate;
- 3rd layer: a ketoprofen layer and an emulsion of a solution of PVA (and/or EVA) and adhesive acrylic polymer;
- 4th layer: adhesive layer consisting of an acrylic adhesive, which controls the release of the a.i.;
- 5* layer: a silicon liner.
DISCLOSURE OF THE INVENTION
The invention relates to a multilayer patch comprising an adhesive layer, a protective backing for said adhesive layer, an acrylic and/or silicon polymer matrix containing at least one active ingredient and a removable liner in contact with said matrix, characterized in that the matrix contains lipophilic excipients able to reduce the matrix adhesivity.
The addition of lipophilic excipients to adhesive matrices for transdermal controlled-release systems improves the skin affinity.
Matrices with additives cannot be properly supported by inert backings due to their low adhesivity, it is therefore necessary to interpose an adhesive between the matrix and the backing. The adhesive layer is applied on the backing in a first step, and only afterwards the low-adhesive matrix is anchored; in this way the low-adhesive mass remains anchored to the backing and can be applied to the skin.
The patch of the invention is schematically represented in the Figure, wherein reference number 1 indicates the backing layer, number 2 indicates the adhesive layer, number 3 indicates the matrix containing the a.i. and the lipophilic excipients and number 4 indicates the liner layer.
Backing layer 1 is made of a conventional material such as polyethylene, PVC, polyester, natural fibre, polyurethane, polypropylene.
Adhesive layer 2 typically comprises a water- or solvent-based acrylic and/ or silicon polymer.
Matrix 3, further to a mixture of acrylic and/or silicon polymers, contains lipophilic excipients preferably selected from lanolin, vaseline, polyethylene glycols and esters thereof, glycerin and esters thereof, fatty acids, vegetable oil, beeswax, synthetic wax. The excipients are added in weight percentage ranging from 15 to 50% based on the dry weight of the final formulation.
Finally, liner 4 consists of a conventional material for transdermal patches such as silicon and/or fluorinated polyester, high- or low-density polyethylene. The invention allows to formulate any active ingredients having therapeutical, dermatological or cosmetic activity when administered through the topical and/or transdermal route.
Examples of drugs which can be advantageously formulated according to the invention comprise: non steroidal antinflammatory agents, corticosteroids, local anaesthetics, alpha-adrenergic agonists, analgesics, antimigraine drugs, antiallergics, antihistaminics, antimicrobials, antiemetics, anticholinergics, broncodilators, antivirals, myorelaxants, cholinergic agents, central nervous system stimulators, cardioactive agents, beta-adrenergic agonists, hormones, anxiolytics, antidepressants, antipsychotics, opioid antagonists, coronary dilators.
Particularly preferred are non steroidal antiinflammatories such as
Diclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphenbutazone,
Piroxicam, Suprofen, Celecoxib and other COX-2 selective inhibitors and the like.
The patches of the invention are prepared through a process which comprises the following steps: a) formation of the adhesive film by spreading the mass onto a silicon liner, subsequent removal of the solvent and coupling of the adhesive film to the backing; b) formation of the active ingredient-containing adhesive matrix by spreading the mass onto a silicon liner, subsequent removal of the solvent and coupling to the adhesive film.
The invention is illustrated in greater detail in the following examples. Example 1
The first adhesive layer (Uceacryl MC808®) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to HO0C, then coupled to the polyethylene backing. This first step allows to prepare the semi-manufactured product 1.
In a second step, the low-adhesive mass is prepared by mixing 80 kg of Uceacryl MC808®, 15 kg of lanoline/vaseline in 1/1 ratio and 5 kg of dry vegetable extracts. The homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 1100C, then coupled to the semi-manufactured product 1.
The finished product is ready to be cut and formed. Example 2
The first adhesive layer (Durotak® 87-2852) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O0C, then coupled to the non-woven backing. This first step allows to prepare the semi-manufactured product 1. In a second step, the low-adhesive mass is prepared by mixing 80 kg of
Uceacryl MC808, 19 kg of viscous vaseline/vaseline in 1/1 ratio and 1 kg of Tiocolchicoside. The homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 1100C, then coupled to the semi-manufactured product 1. The finished product is ready to be cut and formed.
Example 3
The first adhesive layer (Durotak® 87-2852) is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O0C, coupled to the polyethylene backing. This first step allows to prepare the semi-manufactured product 1.
In a second step, the low-adhesive mass is prepared by mixing together
80 kg of Durotak® 87-2852, 17 kg of lanoline/vaseline in 1/1 ratio and 3 kg of
Diclofenac sodium. The homogeneous mixture is spread on silicon paper and dried in a static dryer at a temperature ranging from 60 to 8O0C, then coupled to the semi-manufactured product 1.
The finished product is ready to be cut and formed.

Claims

1. A multilayer patch comprising an adhesive layer (2), a protective backing (1) for said adhesive layer (2), an acrylic and/or silicon polymer matrix (3) containing at least one active ingredient, and a removable liner (4) in contact with said matrix, characterized in that the matrix (3) contains lipophilic excipients which reduce matrix adhesivity.
2. The patch as claimed in claim 1 wherein the backing layer (1) consists of polyethylene, PVC, polyester, natural fibre, polyurethane, polypropylene.
3. The patch as claimed in claim 1 or 2 wherein the adhesive layer (2) comprises a water- or solvent-based acrylic and/or silicon polymer.
4. The patch as claimed in any one of claims 1 to 3 wherein the lipophilic excipients added to the matrix (3) are selected from lanolin, vaseline, polyethylene glycols and esters thereof, glycerin and esters thereof, fatty acids, vegetable oil, beeswax, synthetic wax.
5. The patch as claimed in any one of claims 1 to 4 wherein the liner (4) consists of silicon and/or fluorinated polyester or high- or low-density polyethylene.
6. Process for the preparation of the patches of claims 1-5 which comprises the following steps: a) formation of the adhesive film by spreading the mass on a silicon liner, subsequent removal of the solvent and coupling of the adhesive film to the backing; b) formation of the adhesive matrix containing the active ingredient by spreading the mass on a silicon liner, subsequent removal of the solvent and coupling to the adhesive film.
PCT/EP2005/007326 2004-09-03 2005-07-07 Controlled-release multilayer patch for the topical use WO2006024339A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20041697 ITMI20041697A1 (en) 2004-09-03 2004-09-03 THERAPEUTIC SYSTEM WITH CONTROLLED RELEASE FOR TOPICAL USE IN THE FORM OF A MULTI-LAYER PATCH
ITMI2004A001697 2004-09-03

Publications (2)

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WO2006024339A2 true WO2006024339A2 (en) 2006-03-09
WO2006024339A3 WO2006024339A3 (en) 2006-08-17

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0279977A2 (en) * 1987-02-26 1988-08-31 Alza Corporation Transdermal administration of progesterone, estradiol esters and mixtures thereof
EP0425968A2 (en) * 1989-10-23 1991-05-08 G.D. Searle & Co. Novel multiple layer transdermal drug administration system
US5230898A (en) * 1989-04-01 1993-07-27 Lts Lohmann Therapie-Systeme Gmbh & Co. K.G. Transdermal therapeutic system exhibiting an increased active substance flow and process for the production thereof
US5505956A (en) * 1992-11-30 1996-04-09 Pacific Chemical Co., Ltd. Medicinal adhesive for percutaneous administration
WO2000033812A2 (en) * 1998-12-07 2000-06-15 Elan Corporation, Plc Transdermal patch for delivering volatile liquid drugs
US6190690B1 (en) * 1996-07-03 2001-02-20 Stc Corporation Sustained/immediate acting ketoprofen patch and process for manufacturing the same
WO2005046653A1 (en) * 2003-11-17 2005-05-26 Icure Antiphlogistic and analgesic plaster comprising felbinac compound

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0279977A2 (en) * 1987-02-26 1988-08-31 Alza Corporation Transdermal administration of progesterone, estradiol esters and mixtures thereof
US5230898A (en) * 1989-04-01 1993-07-27 Lts Lohmann Therapie-Systeme Gmbh & Co. K.G. Transdermal therapeutic system exhibiting an increased active substance flow and process for the production thereof
EP0425968A2 (en) * 1989-10-23 1991-05-08 G.D. Searle & Co. Novel multiple layer transdermal drug administration system
US5505956A (en) * 1992-11-30 1996-04-09 Pacific Chemical Co., Ltd. Medicinal adhesive for percutaneous administration
US6190690B1 (en) * 1996-07-03 2001-02-20 Stc Corporation Sustained/immediate acting ketoprofen patch and process for manufacturing the same
WO2000033812A2 (en) * 1998-12-07 2000-06-15 Elan Corporation, Plc Transdermal patch for delivering volatile liquid drugs
WO2005046653A1 (en) * 2003-11-17 2005-05-26 Icure Antiphlogistic and analgesic plaster comprising felbinac compound

Also Published As

Publication number Publication date
WO2006024339A3 (en) 2006-08-17
ITMI20041697A1 (en) 2004-12-03

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