CA2039586A1 - Crosslinked pressure-sensitive adhesives tolerant of alcohol-based excipients used in transdermal delivery devices and method of preparing same - Google Patents
Crosslinked pressure-sensitive adhesives tolerant of alcohol-based excipients used in transdermal delivery devices and method of preparing sameInfo
- Publication number
- CA2039586A1 CA2039586A1 CA002039586A CA2039586A CA2039586A1 CA 2039586 A1 CA2039586 A1 CA 2039586A1 CA 002039586 A CA002039586 A CA 002039586A CA 2039586 A CA2039586 A CA 2039586A CA 2039586 A1 CA2039586 A1 CA 2039586A1
- Authority
- CA
- Canada
- Prior art keywords
- acrylate
- sensitive adhesive
- kgy
- alcohol
- dyne
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J133/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Adhesives based on derivatives of such polymers
-
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/58—Adhesives
Abstract
Docket No. 43885CAN1A
ABSTRACT
A crosslinked, acrylate-based pressure-sensitive adhesive is provided to obtain a creep compliance value of the pressure-sensitive adhesive of between 1.1 x 10-5 cm2/dyne to about 2.3 x 105 cm2 /dyne in the presence of alcohol-based excipients, such as ethanol serving as a solvent or a penetration enchancing agent used with transdermal delivery devices. The method of preparing such crosslinked pressure-sensitive adhesive by using electron beam radiation of from 5 kGy to 200 kGy, and medical articles using the crosslinked pressure-sensitive adhesive as a layer therein to contact skin are also provided.
ABSTRACT
A crosslinked, acrylate-based pressure-sensitive adhesive is provided to obtain a creep compliance value of the pressure-sensitive adhesive of between 1.1 x 10-5 cm2/dyne to about 2.3 x 105 cm2 /dyne in the presence of alcohol-based excipients, such as ethanol serving as a solvent or a penetration enchancing agent used with transdermal delivery devices. The method of preparing such crosslinked pressure-sensitive adhesive by using electron beam radiation of from 5 kGy to 200 kGy, and medical articles using the crosslinked pressure-sensitive adhesive as a layer therein to contact skin are also provided.
Description
0395~i PATENT
Docket No. 4388~CANlA
CROSSLIN~ED PRESSUR~-~ENSITIY~ ADHESIV~ TOLE~ANT OF
ALCOHOL-BA ED EXCIPIENT~ U~D IN TRANSDB~MAL D~IV~RY
D~VICE5 AND ME~HOD OF PREPARIN~ 8A~E
Field of the Invention This invention relates to acrylate-based pressure-sensitive adhesives crosslink~d by electron beam radiation to become tolerant o~ alcohol-based excipients such as penetration enhancing agents used in transdermal delivery devices.
Backqround of the Invention Pressure-sensitive adhesive tapes have been used for more than half a century for a variety of marking, holding, protecting, sealing, anA masking purposesO The earliest medical applications where the product was referred to as an adhesive plaster were not pressure-sensitive adhesives. These were, in fact, crude mixtures of natural rubber plasticized and tackified with wood rosin derivatives and turpentine and heavily pigmented with zinc oxide. These tape-like products served their purpose, ~ut with the advent of truly pressure-sensitive adhesives, they were replaced.
The term "pressure-sensitive adhesive" (PSA) has a precise technical definition and has been dealt with extensively in the technical literature, examples of which are Cllapter 17 of Houwink and Salomon "Adhesion and Adhesives", Volume 2, Elsivier Publishing Company, 1967, and the 'Handbook of Pressure-Sensitive Technology", Second Edition, Edited by Donatas Satas, Van Nostrand Reinhold Company, 1989.
Fundamentally, PSAs require a delicate balance of viscous and elastic properties which result in a 4-fold balance of adhesion, cohesion, s~retchiness, and -2- ~39~6 elasticity. In essence, PSA products have sufficient cohesiveness and elasticity so that, despite their aggressive tackiness, they can be handled with the fingers and removed from smooth surfaces without leaving residue.
The difficulty of adhering tape or other devices to the human skin has long been recognized. The irregular and complex surface of the skin presents diffioulties in itself and the wide variation in the skin surface fxom individual to individual and from location to location on the same individual multiply these difficulties.
Adhesives used in applications that contact the skin require clinical testing that supports a claim that the adhesive is hypoallergenic. These clinical studies are used to confirm that the PSA is neither irritating nor sensitizing to skin.
Acrylic PSAs have been used for many years in medical and surgical applications to adhere items to the skin. U.S. Patent 3,121,021 (Copeland) used an acrylic copolymer of the type described in U.S. Patent 2,884,126/RE24,906 (Ulrich) to provide a porous, surgical adhesive tape with very acceptable skin adhesion performance. A disadvantage encountered using some acrylic PSAs was adhesion build, also known as compliance failure, when the acrylic PS~ was in contact with the skin for long periods of time.
In U.S. Patent 3,475,363 (Gander), the compliance failure in acrylate PSAs was overcome by employing a crosslinking agent, dimethylaminoethyl methacrylate, to ensure adhesion to the skin without deleterious effects.
other crosslinking agents have been described for the same purpose: U.S. Patent 4,693,776 (Krampe et al.) and U.S.
Patent 4,732,808 (Krampe et al.) both describe a skin adhesive of an acrylic polymer having grafted to the backbone, polymeric moieties having a glass transition temperature greater than about 20C and a weight average molecular weight above about 2000, in order to provide an adhesive composition with a creep compliance value of greater than 1.2 x 10-5 cm2/dyne. U.S. Patent 3,532,652 _3_ ~3~6 (zang) describes the partial crosslinking o~ an acrylate polymer with polyisocyanate to overcome weakening of the cohesive strength o~ the polymer by migration of skin oils and the like into the adhesive.
Compliance failure can also be remedied by crosslinking an acrylate PSA with a mono-ethylenically unsaturated aromatic ketone monomer using ultra-violet radiation, as described in U.S. Patent 4,737,559 (KPllen et al.). Whila such ultra-violet irradiation of a crosslin~ing agent with an acrylate PSA in the presence of a photoinitiator may be useful for some medical applications, it is not useful ~or medical devices which have a component, e.g. a drug, with the potential of interaction with any residual unreacted photoinitiator, crosslinking agent, or detrimental byproducts of the ultra-violet radiation exposure.
One type of medical device having components which may be susceptible to deleterious interaction is a transdermal delivery device having among other components, a pressure-sensitive adhesive layer and an active agent to be released under controlled conditions to and through the sur~ace of the skin. In U.S. Patent 4,714,655 (Bordoloi et al.), a heat-sensitive material, such as medicaments, fragxances, or repellants, is mixed with a fluid pre-polymer and subjected to ultra-violet xadiation, electron beam radiation, or a combination thereof to achieve chain extension and/or crosslinking polymerization, in order to achieve a pressure-sensitive adhesive having the heat-sensitive material entrained therein to yield a transdermal delivery system known as drug-in-adhesive.
Other types of transdermal delivery devices provide multiple-layered constructions where the pressure-sensitive adhesive layer is between the skin and the active agent, typically a pharmaceutical potentially susceptible to processing conditions and potentially reactive with other compounds. Thus, the components in the transdermal delivery device must be inert to the active agent and must be free of unreacted raw materials, by-products and the like which are common to both chemical crosslinking and ultra-violet photoinitiated crosslinking of acrylic PSA ' S .
Further, the number of active agents suitable for transdermal delivery devices is restricted by the inability of molecules with either ~a~ a molecular weight too high, or (b) a solubility profile not compatible with the skin structure, to permeate the skin at an acceptable -rate for optimal therapeutic blood levels. Therefore, the active agent is often formulated with an excipient, such as a penetration enhancing agent, at a concentration that enables the drug to permeate the skin at the targeted permeation rate and achieve therapeutic blood levels.
Incorporation of penetration enhancing agents in a transdermal device has led to failure of the physical integrity of the construction of the device. Penetration enhancing agents are used in conjunction with the drug to enable the drug to flow through the skin. The transdermal delivery devica is often constructed in such a manner that the penetration enhancing agent comes into contact with the pressure sensitive adhesiveO The physical properties of the pressure sensitive adhesive can change due to the possible plasticization of the pressure sensitive adhesive by the penetration enhancing agent. The alteration of physical properties can result in delamination of the transdermal delivery device construction, cohesive ~ailure of the pressure sensitive adhesive, and other losses of the ideal physical properties required for a skin adhesive during the course of its storage and usage.
In addition to penetration enhancing agents, other excipients, including alcohol-based drug excipients, are often used with a pharmaceutical for formulation processing, dilution, or other handling reason~. These excipients also can come into contact with the pressure sensitive adhesive with similar potential ~or alteration of physical properties and similar potential for causing deleterious results for the transdermal device.
Docket No. 4388~CANlA
CROSSLIN~ED PRESSUR~-~ENSITIY~ ADHESIV~ TOLE~ANT OF
ALCOHOL-BA ED EXCIPIENT~ U~D IN TRANSDB~MAL D~IV~RY
D~VICE5 AND ME~HOD OF PREPARIN~ 8A~E
Field of the Invention This invention relates to acrylate-based pressure-sensitive adhesives crosslink~d by electron beam radiation to become tolerant o~ alcohol-based excipients such as penetration enhancing agents used in transdermal delivery devices.
Backqround of the Invention Pressure-sensitive adhesive tapes have been used for more than half a century for a variety of marking, holding, protecting, sealing, anA masking purposesO The earliest medical applications where the product was referred to as an adhesive plaster were not pressure-sensitive adhesives. These were, in fact, crude mixtures of natural rubber plasticized and tackified with wood rosin derivatives and turpentine and heavily pigmented with zinc oxide. These tape-like products served their purpose, ~ut with the advent of truly pressure-sensitive adhesives, they were replaced.
The term "pressure-sensitive adhesive" (PSA) has a precise technical definition and has been dealt with extensively in the technical literature, examples of which are Cllapter 17 of Houwink and Salomon "Adhesion and Adhesives", Volume 2, Elsivier Publishing Company, 1967, and the 'Handbook of Pressure-Sensitive Technology", Second Edition, Edited by Donatas Satas, Van Nostrand Reinhold Company, 1989.
Fundamentally, PSAs require a delicate balance of viscous and elastic properties which result in a 4-fold balance of adhesion, cohesion, s~retchiness, and -2- ~39~6 elasticity. In essence, PSA products have sufficient cohesiveness and elasticity so that, despite their aggressive tackiness, they can be handled with the fingers and removed from smooth surfaces without leaving residue.
The difficulty of adhering tape or other devices to the human skin has long been recognized. The irregular and complex surface of the skin presents diffioulties in itself and the wide variation in the skin surface fxom individual to individual and from location to location on the same individual multiply these difficulties.
Adhesives used in applications that contact the skin require clinical testing that supports a claim that the adhesive is hypoallergenic. These clinical studies are used to confirm that the PSA is neither irritating nor sensitizing to skin.
Acrylic PSAs have been used for many years in medical and surgical applications to adhere items to the skin. U.S. Patent 3,121,021 (Copeland) used an acrylic copolymer of the type described in U.S. Patent 2,884,126/RE24,906 (Ulrich) to provide a porous, surgical adhesive tape with very acceptable skin adhesion performance. A disadvantage encountered using some acrylic PSAs was adhesion build, also known as compliance failure, when the acrylic PS~ was in contact with the skin for long periods of time.
In U.S. Patent 3,475,363 (Gander), the compliance failure in acrylate PSAs was overcome by employing a crosslinking agent, dimethylaminoethyl methacrylate, to ensure adhesion to the skin without deleterious effects.
other crosslinking agents have been described for the same purpose: U.S. Patent 4,693,776 (Krampe et al.) and U.S.
Patent 4,732,808 (Krampe et al.) both describe a skin adhesive of an acrylic polymer having grafted to the backbone, polymeric moieties having a glass transition temperature greater than about 20C and a weight average molecular weight above about 2000, in order to provide an adhesive composition with a creep compliance value of greater than 1.2 x 10-5 cm2/dyne. U.S. Patent 3,532,652 _3_ ~3~6 (zang) describes the partial crosslinking o~ an acrylate polymer with polyisocyanate to overcome weakening of the cohesive strength o~ the polymer by migration of skin oils and the like into the adhesive.
Compliance failure can also be remedied by crosslinking an acrylate PSA with a mono-ethylenically unsaturated aromatic ketone monomer using ultra-violet radiation, as described in U.S. Patent 4,737,559 (KPllen et al.). Whila such ultra-violet irradiation of a crosslin~ing agent with an acrylate PSA in the presence of a photoinitiator may be useful for some medical applications, it is not useful ~or medical devices which have a component, e.g. a drug, with the potential of interaction with any residual unreacted photoinitiator, crosslinking agent, or detrimental byproducts of the ultra-violet radiation exposure.
One type of medical device having components which may be susceptible to deleterious interaction is a transdermal delivery device having among other components, a pressure-sensitive adhesive layer and an active agent to be released under controlled conditions to and through the sur~ace of the skin. In U.S. Patent 4,714,655 (Bordoloi et al.), a heat-sensitive material, such as medicaments, fragxances, or repellants, is mixed with a fluid pre-polymer and subjected to ultra-violet xadiation, electron beam radiation, or a combination thereof to achieve chain extension and/or crosslinking polymerization, in order to achieve a pressure-sensitive adhesive having the heat-sensitive material entrained therein to yield a transdermal delivery system known as drug-in-adhesive.
Other types of transdermal delivery devices provide multiple-layered constructions where the pressure-sensitive adhesive layer is between the skin and the active agent, typically a pharmaceutical potentially susceptible to processing conditions and potentially reactive with other compounds. Thus, the components in the transdermal delivery device must be inert to the active agent and must be free of unreacted raw materials, by-products and the like which are common to both chemical crosslinking and ultra-violet photoinitiated crosslinking of acrylic PSA ' S .
Further, the number of active agents suitable for transdermal delivery devices is restricted by the inability of molecules with either ~a~ a molecular weight too high, or (b) a solubility profile not compatible with the skin structure, to permeate the skin at an acceptable -rate for optimal therapeutic blood levels. Therefore, the active agent is often formulated with an excipient, such as a penetration enhancing agent, at a concentration that enables the drug to permeate the skin at the targeted permeation rate and achieve therapeutic blood levels.
Incorporation of penetration enhancing agents in a transdermal device has led to failure of the physical integrity of the construction of the device. Penetration enhancing agents are used in conjunction with the drug to enable the drug to flow through the skin. The transdermal delivery devica is often constructed in such a manner that the penetration enhancing agent comes into contact with the pressure sensitive adhesiveO The physical properties of the pressure sensitive adhesive can change due to the possible plasticization of the pressure sensitive adhesive by the penetration enhancing agent. The alteration of physical properties can result in delamination of the transdermal delivery device construction, cohesive ~ailure of the pressure sensitive adhesive, and other losses of the ideal physical properties required for a skin adhesive during the course of its storage and usage.
In addition to penetration enhancing agents, other excipients, including alcohol-based drug excipients, are often used with a pharmaceutical for formulation processing, dilution, or other handling reason~. These excipients also can come into contact with the pressure sensitive adhesive with similar potential ~or alteration of physical properties and similar potential for causing deleterious results for the transdermal device.
3~6 Specifically formulated or processed pressure-sensitive adhesives used for a variety of purposes not involving active agents like pharmaceuticals have been known to be resistant to solvents. U.S. Patent 2,973,286 (Ulrich) employed benzoyl peroxide or other organic peroxides to resist the effects of solvents af~ecting the manufacture of PSA industrial tapes. U.S. Patent 2,925,174 (Stow) provided improved solvent resi~tance by reaction with liquid epoxy resins and with 2-ethylhexane diol-1,3 for pressure-sensitive adhesive tapes. U.S.
Patent 2,956,904 (Hendricks) describes approximately doubling the cohesive strength of pressure-sensitive adhesive used for electrical tapes by high-energy electron beam irradiation such that the crosslinked elastomers were no longer dispersible in the solvents used in coating the adhesive layer on the carrier web or in other common solvents.
Electron beam curing of other pressure~sensitive adhesives to provide solvent resistance has also been described.in U.S. Patent 4,695,604 (Amirsakis) for polyurethane resins/ in U.S. Patent 4,432,848 tXorpman~ for an A-B-~ block copolymer, where A represents a poly(monoalkenylarene) block and where B represents a polyisoprene block; in "Formulating to Enhance the Radiation Crosslinking of Thermal Plastic Rubber for Hot Melt Pressure-Sensitive Adhesives", tEwins, Jr. and Erickson, Tappi Journal, June, 1988, pages 155-158), describing styrene-isoprene-styrene polymers crosslinked with electron beam radiation; and in PCT Patent Publication WO 89/00106 (Plamthottam et al.) for double-coated acrylic and rubber based pressure sensitive adhesive foam-like tapes.
Further, U.S. Patents 4,699,146 and 4~750,482 describe a hydrophilic pressure-sensitive adhesive produced by ionizing radiation.
What i5 lacking in the art is a transdermal delivery device pressure-sensitive adhesive which is tolerant of excipients, such as penetration enhancing ~q:)3~S~6 agents used in conjunction with the active agent being delivered at a rate through the device to the skin that achieves a therapeutic level.
While certain advances have been made in the minimizing compliance ~ailure for skin PSA'S, none have succeeded without employing chemical crosslinking agents alone or in combination with ultra-violet radiation initiated polymerization.
WhilP other pressure-sensitive adhesives have been rendered solvent resistant through electron beam radiation, none of those pressure-sensitive adhesives have been used or contemplated for use in a device, having an active agent and its excipients, where that device is to be maintained in adhesive contact with human skin.
Nhile transdermal delivery systems have been described which use electron beam radiatiun for polymerization of a liquid pre-polymer into a pressure-sensitive adhesive, the transdermal delivery system described therein does not employ the penetration enhancing agents now often used or desired to be used in transdermal delivery devices.
Thus, what is needed in the art of transdermal delivery devices is a hypoallergenic pressure-sensitive adhesive whic.h is unreactive with the active agent to be delivered to the skin and which is tolerant of penetration enhancing agents and other excipients used with the active agent, such ~hat there is no effective compliance failure of the pressure-sensitive adhesive during storage and usage.
Summary of the Inventlon The present invention solves the problems existing in the art of transdermal delivery devices by providing a crosslinked, hypoallergenic pressure sensitive adhesive (PSA). The crosslinked PSA is prepared from an acrylate-based pressure-sensitive adhesive copolymer having an inherent viscosity between about 1.2 dl/g to about 2.0 dl/g. That copolymer is crosslinked by electron beam 2~39~6 radiation of from about 5 kGy to about 200 kGy. After crosslinking, the crosslinked PSA has a cre~p compliance value of ~rom about 1.1 x 10-~ cm2/dyne to about 2.3 10-5 cm2/dyne notwithstanding exposure to alcohol-based excipients, such as penetration enhancing agents, used or desired to be used with active agents in transdermal delivery devices.
In this description, reference to "pressure-sensitive adhesive copolymer" means the lo acrylate-based copolymer has not been crosslinked throuyh exposure to electron beam radiation. By contrast, reference in this description to "crosslinked PSA" means the acrylate-based copolymer has been subjected to the desired dose of electron beam radiation.
Therefore, the invention provides an acrylate-based pressure-sensitive adhesive copolvmex and subject it to electron beam radiation, which does not require the photoinitiators needed for ultra-violet polymerization nor the activators or catalysts needed for chemical crosslinking.
The invention also provides the use of an acrylate-based pressure sensitive adhesive copolymer which has an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking by electron-beam irradiation in order to provide a crosslinked PSA having a creep compliance value within the range of about 1.1 x 105 cm2/dyne to about 2.3 x 105 cm2/dyne which is acceptable ~or use as a hypoallergenic skin adhesive.
The invention also provides a crosslinked PSA
that is tolerant of alcohol-based excipients, including penetration enhancing agents such as ethanol, to the extent that preferred adhesive properties represented by a range of creep compliance values remain after exposure to such alcohol-based excipients in a transdermal delivery device.
The invention also provides a method for crosslinking a previously polymerized pressure-sensitive adhesive copolymer with electron-beam radiation in a manner which minimizes introduction of undesirable by-products of ~03~
chemical or photochemical reaction into the resulting crosslinked PSA and minimizes retention of unreacted raw materials in the resulting crosslinked PSA. Such a crosslinking method minimizes interaction of such by-products or raw matexials with an active agent present in the transdermal delivery device.
The invention also provides a transdermal delivery device having a crosslinked PSA layer which is tolerant of alcohol-based excipients useful for the delivery of active agents to the skin to which the crosslinked PSA is adhered.
The invention is achieved by polymerizing an acrylate-based polymerizable monomer and an ethylenically unsat~rated monomer in a weight fraction ratio of the acrylate-based polymerizable monomer to the ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure-sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g, followed by irradiating that pressure-sensitive adhesive copolymer with an electron-beam radiation dose of from about 5 kGy to about 200 kGy to yield a crosslinked PSA having a creep compliance value of -Erom about 1.1 x 10-5 cm2/dyne to about 2.3 x 10-5 cm~/dyne even after exposure to alcohol-based excipients used with an activ~- agent in a transdermal delivery device.
The invention is also achieved by an acrylate-based crosslinked PSA having such properties and so prepared.
The invention is also achieved by providing a transdermal delivery device comprising a acrylate-based crosslinked PSA layer so prepared and a therapeutic mixture in contact with and often deliverable through the crosslinked PSA layer, the mixture comprising a transdermally therapeutic active agent and an alcohol-based excipient.
An advantage of khe present invention is the acrylate-based crosslinked PSA maintains acceptable skin-adhesion properties represented by a range of creep 3~
g compliance values after electron-beam irradiation and even after exposure to alcohol-based excipients in weight/weight concentrations of as much as 10 percent of the crosslinked PSA for as long as is needed for product stability duriny storage and usage.
"Creep compliance value", also known as "J
value", is a measure of a ~undamental rheological property of pressure-sensitive adhesives. The fundamentals of creep compliance as they relate to polymeric materials and in lQ particular viscoelastic pol~mers are described in the following publications: (1) "Viscoelastic Properties of Polymers", John D. Ferry, Third Edition, John Wiley Sons,.1980, Chapter 1; (2) "Treatise on Adhesion and Adhesives", Volume 2, "Materials", Pressure Sensitive Adhesives, R.L. Patrick, Editor, Marcel Dekker, Inc., 1969;
(3) "Properties and Structure of Polymers", To~olsky, John Wiley & Sons, 1960, Chapter II, Section 6, wh~rein the five regions of viscoelastic behavior are discussed; and (4) C.A. Dahlquist writing in "HandbooX of Pressure-Sensitive Adhesive Technology", edited by Donatas Satas, Van Nostrand Reinhold Company,.Second Edition, 1989, Chapter 5, wherein it is described that the stress-strain behavior of pressure sensitive adhesives can be treated as a creep compliance phenomenon.
For purpose of the present invention, a range of creep compliance values has been found to be useful in presenting a ~uantitative determination of preferred skin adhesion properties for the crosslinked PSA.
Because adhesion to human skin is most difficult to measure and no synthetic material adequately simulates human skin when testing for skin adhesion, creep compliance values serve to correlate an adhesive physical property to the qualitative assessment of acceptable skin adhesion.
For example, a creep compliance value of greater than about 2.3 x 1o-5 cm2/dyne would correlate to a qualitative assessment that the pressure sensitive adhesive skin adhesion is too "gooey." On the other hand, a creep 2C~395~36 compliance value of less than about 1.1 x 10-5 cm2/dyne would correlate to a qualitative assessment that the pressure sensitive adhesive skin adhesion is too "stiff."
Pressure sensitive adhesives having a creep compliance value between 1.1 x 10~5 cm2/dyne and 2.3 x 10-5 cm2/dyne provide an acceptable level of initial adhesion to skin and sufficiently maintain adhesive integrity during storage and usage, without cohesive failure or adhesion loss. The crosslinked PSAs of the present invention maintain such physical properties even when in contact with alcohol-based excipients otherwise harmful to such physical properties.
Additional aspects of the invention are describ~d in Embodiments of the Invention below, including non-limiting examples.
Embodiments of the Invention THE PRESSURE-SENSITIVE ADHESIVE COPOLYMER
The pressure-sensitive adhesive copolymer is an acrylate-based and has an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g. Desirably, the inherent viscosity ranges from about 1.4 dl/g to about 1.9 dl/g in order to provide a creep compliance value within the acceptable range after the copolymer is irradiated with a dose of electron-beam radiation and exposed to alcohol-based excipients. Preferably, the inherent viscosity is about 1.7 dl/g.
Inherent viscosity is a logarithmic viscosity number used to measure polymer molecular weight for linear polymers. The test procedure followed and the apparatus than can be used to measure inherent viscosity are describad in detain in Testing Procedures below.
~he pressure-sensitive adhesive copolymer should be tacky at room temperature as well as at the skin temperature of patients. Also, the adhesive should be hypoallergenic, i.e., after continuous contact with skin, )39~i~6 there is no significant skin sensitization or irritation during adhesion. Often, to determine if an adhesive is hypoallergenic, the following evaluations are conducted:
cell cytotoxicity, skin irritation, and sensitization potential. The United States Food and Drug Administration recommends such evaluations in a Tripartite Biocompatibility Draft Guidance for Medical Devices.
The acrylate-based pressure-sensitive adhesive copolymer is the reaction product of the polymerization of at least one A monomer and at lea-~t one B monomer.
The A monomer is a polymerizable monomer comprising an acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols with the alcohols having from I to 14 carbon atoms and desirably averaging about ~ to 12 carbon atoms.
The B monomer is an ethylenically unsaturated compound and desirably may be acrylic acid, methacrylic-acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinyl pyrrolidone, or combinations thereof.
The A monomer is polymerizable and contributes the viscoelastic properties of the pressure-sensitive adhesive copolymer. Non-limiting examples of such A
monomers include the esters of acrylic acid or methacrylic acid with non-tertiary alkyl alcohol such as 1-butanol, l-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, l-methyl-l-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 2-ethyl-1-hexanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, l-decanol, l-dodecanol, and the like. Such monomeric acrylic or methacrylic esters are known in the art, and many are commercially available.
The B monomer is an ethylenically unsaturated compound copolymerized with the A monomer to affect the physical properties of the resultin~ pressure-senRitive adhesive copolymer. In general, the presence of the B
monomer will rPduce the flexibility of the resulting pressure-sensitive adhesive copolymer.
Thus, the weight pexcentages of the A monomer and the B monomer should be balanced in order to provide a pressure-sensitive adhesive copolymer haviny an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g. The weight percentage ratio ranges from about 92:8 to about 98:2 and desirably from about 93:7 to 97:3.
In a preferred embodiment of the invention, the pressure-sensitive adhesive copolymer is the reaction product of isooctyl acrylate and acrylic acid having a weight percentage ratio of from about 92:8 to about 97:3 and preferably having a weight percentage ratio of about 95.5:4.5.
The pressure-sensitive adhesive copolymer may be copolymerized using known polymerization techniques in a manner such that the inherent viscosity of the resulting copolymer is from about 1.2 dl/g to about 2.0 dl/g. Known polymerization techniques include emulsion polymerization and solution polymerization. Sources of polymerization preparation and techniques include "Organic Polymer Chemistry", K.J. Saunders, Chapman and Hall (Halsted Publishing, New York, 1973), Applied Polymer Science, R.W.
Tess and G.W. Poehlein, American Chemical Society (~merican Chemical Society, Washington, DC, 1981), Principles of Polymerization, G. Odien, Wiley-InterScience (John Wiley &
Sons, New York, 1981), and the Handbook of Pressure-Sensitive Adhesive Technology, Second Edition, referenced above.
Specifically, the acrylate-based pressure-sensitive adhesive copolymers may be prepared according to U.S. Patent 2,884,126/RE24,906.
W~en prepared by solution copolymerization, the A
monomer and B monomer are dissolv~d in an inert organic solvent and copolymerized ir. a nitrogen purged reactor at a temperature of about 55~C for about 24 hours using a suitable free radical initiator, such as azobisisobutyronitrile. Suitable solvents include ethyl ~C139~
acetate, mixtures of ethyl acetate and ethanol, and n-heptane.
When prepared by emulsion copolymerization, the A
monomer and B monomer are dispersed in deionized water using the procedure desc~ibed in Example 5 of U.S. Patent 2,884,126/RE24,906, except that the amount of tertiary dodecyl mercaptan may be varied to provide copolymers having a range of inherent viscosities, and that the resulting copolymer is dissolvad in a heptane-isopropanol (70:30) solution.
THE CROSSLINKED PSA
The pressure-sensitive adhesive copolymer may be crosslinked using electron-beam radiation in doses of from about 5 kGy (0.5 Mrads.) to about 200 kGy (20 mrads.).
Desirably, the electron-beam radiation dose is from about 10 kGy to about 50 kGy and may be delivered using one pass or multiple passes through the electron beam.
In a preferred embodiment of the invention, when the pressure-sensitive adhesive copol~mer is prepared from the copolymerization of isooctyl acrylate . and acrylic acid, electron-beam radiation in a dose of about 30 kGy yields an acceptable crosslinked PSA for use in a transdermal delivery device.
The method of irradiation by electron-beam is performed by passing the pressure-sensitive adhesive copolymer on suitable substrates through an electron beam unit as available from Energy Scisnces Inc., such as a Model rB 250/30/20 30 cm Electro-Curtain electron beam 30 system or a Model CB 150/15/lOL 15 cm Electro-Curtain electron beam system, configured to operate and provide the acceptable dosages indicated above. In the embodiment of providing a dose of 30 kGy of electron beam radiation, the equipment is operated at a voltage of 175 kV at a line speed of 15.24 meters per minute with an oxygen content of less than 100 parts per million.
The electron-~eam radiation results in crosslinking the pressure-æensitive adhesive copolymer ~395~16 without otherwise affecting the pressure-sensitive adhesive properties useful for medical applications.
TESTING PROCEDURES
Inherent Viscosity Measurement Procedure The inherent viscosities of the pressure sensitive adhesive copolymers wexe obtained using a Cannon-Fenske #50 viscometer in a deionized water bath controlled at 25C to measure the flow time o~ lOml of the copolymer solution (0.15 g/dl of copolymer in ethyl acetate.) The test procedure followed and a drawing of a viscometer, then known as a Ostwald-Fenske, are described in "Textbook of Polymer Science", F.W. Billmeyer, Wiley-Interscience, Second Edition, 1971, Pages 84 and 85.
Creep Compliance Value Procedure To m~asure the creep compliance value of the skin adhesive pressure-sensitive adhesive copolymer before crosslinking, after crosslinking, and after crosslinking and exposure to the penetration enhancing agents, a 150-micrometer thickness of the pressure-sensitive adhesive copolymer is knife-coated onto a smooth film of polytetrafluoroethylene. The coated film is then dried to a constant weight by placing it in an air-circulating oven for at least 30 minutes at 65C to remove solvent and reduce the level of unreacted monomer.
The adhesive, thus dried, is stripped from the polytetrafluoroethylene and two test pieces of equal area are die-cut and placed in the parallel plate creep compliance rheometer, one piece being on each side of the center plate, with an outer plate contacting the exposed surface of each. Screws which connect the two outer plates are then tightened so as to compress the interposed layers of adhesive approximately 10 percent. The parallel plates are placed in a horizontal arrangement and one end of-the center plate is connected to a chart recorder. A hook is attached to the opposite end of the center plate with a ~)3~ 36 flexible wire extending horizontally from the hook and then downward over a pulley, the outer plates being held in a fixed position. A suitable weight (one sufficient to measurably deform the sample at distance no greater than its thickness) is attached to the free end of the wire, then the strip chart recorder is started. The weight typically used to exert the stress on the adhesive films is about 500 grams. From the strip chart recorder, the time and displacement (strain) are read and the applied force ~stress) is recorded. The creep compliance at a given temperature is then calculated using the equation:
J(t) hf where t is the time at which the measurement is taken, A is the area of one face of the adhesive samples, h is the thickness of the adhesive mass, x is the displacement at time t (where X is less than h) and ~ is the force due to the mass attached to the wire connected to the middle plate. When A is expressed in cm2, h in centimeters, X in centimeters, and f in dynes, the compliance value or J
value, J(,) is given in cm2/dyne.
When the creep compliance value has been measured at the end of a 3 minute period of stress application according to the procedure described above, a pressure-sensitive adhesive having a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 x 10 5 cm2/dyne exhibits acceptable adhesion to skin.
In general, the higher the creep compliance value, the lower the cohesiveness of the pressure sensitive adhesive and the higher the adhesion level to the skin.
For a pressure-sensitive adhesive having a creep compliance value higher than about 2.3 x 10-5 cm2/dyne, the pressure-sensitive adhesive has a higher adhesion with lower internal or cohesive strength, resulting in excessive residue remaining on the skin at the time of adhesive removal. When the value is less than about 1.1 X 10-5 cm2/dyne, the pressure-sensitive adhesive exhibits lower tack and higher cohesive strength, resulting in poor initial adhesion.
Skin Adhesion Procedure The evaluation of the s~in adhesives of this invention is highly subjective when the performance in contact with and upon removal from the human skin surface becomes part of the evaluation. For this reason a protocol was developed using a prescribed test panel of individuals who were selected to embrace the normal variations in skin surface that are encountered in medical practice. The result of this designed study enables one to get values which can be considered controlled and comparative. while these values are observational in respect to adhesive residue, sample lift and adhesion build-up, the procedures followed are in accord with care~ully developed assessments of similar properties as is known in the art.
It should be noted that there is an inherent variability in skin adhesion between different individuals and for the same individual, depending in each instance on the type of skin, the time of the year, the climatic conditions, the level of exercise, and other factors.
Thus, while certain values are reported here, there are wide ranges of adhesion values possible due to oth~r factors in actual usage.
The initial skin adhesion value (To) and the skin adhesion value after 24 or 48 hours in contact with the skin (T24 or T48) are essentially the widely accepted PSTC-l, peel adhesion test for single coated skin adhesive tapes measured at 180 angle. PSTC-1 is test method No. 1 of the Pressure Sensitive Tape Counsel, Glenview, Illinois, Seventh Edition (1976); developed by the Speci~^ications and Technical Committee of the Counsel. The test has been modified only to the extent that the tape is applied to the human skin surface on a selected area on the individual's back. otherwise the steps in the procedure are as follows:
~395~6 l. Tape samples 2.54 cm wide by 5.08 cm long are placed on the back of a human subject.
2. Each tape is rolled down with one forward and one reverse pass, using a l-kilogram taps roller (described in ~ppendix B, Sections 2.7.1, 2.8.1, and 2.8.2 of Pressure Sensitive Tape Counsel) moved at the rate of about 30 cm per minute.
3. Adhesion to the skin is measured as the peel force xequired to remove the tape at 1800 angle (PSTC-1).
The peel force values are measured through the use of a strain-gauge mounted on a motor-driven carriage.
The force of removal is reported in grams of adhesion per 2.54 cm of width of sample. The rate of removal is 15 cm per minute.
Patent 2,956,904 (Hendricks) describes approximately doubling the cohesive strength of pressure-sensitive adhesive used for electrical tapes by high-energy electron beam irradiation such that the crosslinked elastomers were no longer dispersible in the solvents used in coating the adhesive layer on the carrier web or in other common solvents.
Electron beam curing of other pressure~sensitive adhesives to provide solvent resistance has also been described.in U.S. Patent 4,695,604 (Amirsakis) for polyurethane resins/ in U.S. Patent 4,432,848 tXorpman~ for an A-B-~ block copolymer, where A represents a poly(monoalkenylarene) block and where B represents a polyisoprene block; in "Formulating to Enhance the Radiation Crosslinking of Thermal Plastic Rubber for Hot Melt Pressure-Sensitive Adhesives", tEwins, Jr. and Erickson, Tappi Journal, June, 1988, pages 155-158), describing styrene-isoprene-styrene polymers crosslinked with electron beam radiation; and in PCT Patent Publication WO 89/00106 (Plamthottam et al.) for double-coated acrylic and rubber based pressure sensitive adhesive foam-like tapes.
Further, U.S. Patents 4,699,146 and 4~750,482 describe a hydrophilic pressure-sensitive adhesive produced by ionizing radiation.
What i5 lacking in the art is a transdermal delivery device pressure-sensitive adhesive which is tolerant of excipients, such as penetration enhancing ~q:)3~S~6 agents used in conjunction with the active agent being delivered at a rate through the device to the skin that achieves a therapeutic level.
While certain advances have been made in the minimizing compliance ~ailure for skin PSA'S, none have succeeded without employing chemical crosslinking agents alone or in combination with ultra-violet radiation initiated polymerization.
WhilP other pressure-sensitive adhesives have been rendered solvent resistant through electron beam radiation, none of those pressure-sensitive adhesives have been used or contemplated for use in a device, having an active agent and its excipients, where that device is to be maintained in adhesive contact with human skin.
Nhile transdermal delivery systems have been described which use electron beam radiatiun for polymerization of a liquid pre-polymer into a pressure-sensitive adhesive, the transdermal delivery system described therein does not employ the penetration enhancing agents now often used or desired to be used in transdermal delivery devices.
Thus, what is needed in the art of transdermal delivery devices is a hypoallergenic pressure-sensitive adhesive whic.h is unreactive with the active agent to be delivered to the skin and which is tolerant of penetration enhancing agents and other excipients used with the active agent, such ~hat there is no effective compliance failure of the pressure-sensitive adhesive during storage and usage.
Summary of the Inventlon The present invention solves the problems existing in the art of transdermal delivery devices by providing a crosslinked, hypoallergenic pressure sensitive adhesive (PSA). The crosslinked PSA is prepared from an acrylate-based pressure-sensitive adhesive copolymer having an inherent viscosity between about 1.2 dl/g to about 2.0 dl/g. That copolymer is crosslinked by electron beam 2~39~6 radiation of from about 5 kGy to about 200 kGy. After crosslinking, the crosslinked PSA has a cre~p compliance value of ~rom about 1.1 x 10-~ cm2/dyne to about 2.3 10-5 cm2/dyne notwithstanding exposure to alcohol-based excipients, such as penetration enhancing agents, used or desired to be used with active agents in transdermal delivery devices.
In this description, reference to "pressure-sensitive adhesive copolymer" means the lo acrylate-based copolymer has not been crosslinked throuyh exposure to electron beam radiation. By contrast, reference in this description to "crosslinked PSA" means the acrylate-based copolymer has been subjected to the desired dose of electron beam radiation.
Therefore, the invention provides an acrylate-based pressure-sensitive adhesive copolvmex and subject it to electron beam radiation, which does not require the photoinitiators needed for ultra-violet polymerization nor the activators or catalysts needed for chemical crosslinking.
The invention also provides the use of an acrylate-based pressure sensitive adhesive copolymer which has an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking by electron-beam irradiation in order to provide a crosslinked PSA having a creep compliance value within the range of about 1.1 x 105 cm2/dyne to about 2.3 x 105 cm2/dyne which is acceptable ~or use as a hypoallergenic skin adhesive.
The invention also provides a crosslinked PSA
that is tolerant of alcohol-based excipients, including penetration enhancing agents such as ethanol, to the extent that preferred adhesive properties represented by a range of creep compliance values remain after exposure to such alcohol-based excipients in a transdermal delivery device.
The invention also provides a method for crosslinking a previously polymerized pressure-sensitive adhesive copolymer with electron-beam radiation in a manner which minimizes introduction of undesirable by-products of ~03~
chemical or photochemical reaction into the resulting crosslinked PSA and minimizes retention of unreacted raw materials in the resulting crosslinked PSA. Such a crosslinking method minimizes interaction of such by-products or raw matexials with an active agent present in the transdermal delivery device.
The invention also provides a transdermal delivery device having a crosslinked PSA layer which is tolerant of alcohol-based excipients useful for the delivery of active agents to the skin to which the crosslinked PSA is adhered.
The invention is achieved by polymerizing an acrylate-based polymerizable monomer and an ethylenically unsat~rated monomer in a weight fraction ratio of the acrylate-based polymerizable monomer to the ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure-sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g, followed by irradiating that pressure-sensitive adhesive copolymer with an electron-beam radiation dose of from about 5 kGy to about 200 kGy to yield a crosslinked PSA having a creep compliance value of -Erom about 1.1 x 10-5 cm2/dyne to about 2.3 x 10-5 cm~/dyne even after exposure to alcohol-based excipients used with an activ~- agent in a transdermal delivery device.
The invention is also achieved by an acrylate-based crosslinked PSA having such properties and so prepared.
The invention is also achieved by providing a transdermal delivery device comprising a acrylate-based crosslinked PSA layer so prepared and a therapeutic mixture in contact with and often deliverable through the crosslinked PSA layer, the mixture comprising a transdermally therapeutic active agent and an alcohol-based excipient.
An advantage of khe present invention is the acrylate-based crosslinked PSA maintains acceptable skin-adhesion properties represented by a range of creep 3~
g compliance values after electron-beam irradiation and even after exposure to alcohol-based excipients in weight/weight concentrations of as much as 10 percent of the crosslinked PSA for as long as is needed for product stability duriny storage and usage.
"Creep compliance value", also known as "J
value", is a measure of a ~undamental rheological property of pressure-sensitive adhesives. The fundamentals of creep compliance as they relate to polymeric materials and in lQ particular viscoelastic pol~mers are described in the following publications: (1) "Viscoelastic Properties of Polymers", John D. Ferry, Third Edition, John Wiley Sons,.1980, Chapter 1; (2) "Treatise on Adhesion and Adhesives", Volume 2, "Materials", Pressure Sensitive Adhesives, R.L. Patrick, Editor, Marcel Dekker, Inc., 1969;
(3) "Properties and Structure of Polymers", To~olsky, John Wiley & Sons, 1960, Chapter II, Section 6, wh~rein the five regions of viscoelastic behavior are discussed; and (4) C.A. Dahlquist writing in "HandbooX of Pressure-Sensitive Adhesive Technology", edited by Donatas Satas, Van Nostrand Reinhold Company,.Second Edition, 1989, Chapter 5, wherein it is described that the stress-strain behavior of pressure sensitive adhesives can be treated as a creep compliance phenomenon.
For purpose of the present invention, a range of creep compliance values has been found to be useful in presenting a ~uantitative determination of preferred skin adhesion properties for the crosslinked PSA.
Because adhesion to human skin is most difficult to measure and no synthetic material adequately simulates human skin when testing for skin adhesion, creep compliance values serve to correlate an adhesive physical property to the qualitative assessment of acceptable skin adhesion.
For example, a creep compliance value of greater than about 2.3 x 1o-5 cm2/dyne would correlate to a qualitative assessment that the pressure sensitive adhesive skin adhesion is too "gooey." On the other hand, a creep 2C~395~36 compliance value of less than about 1.1 x 10-5 cm2/dyne would correlate to a qualitative assessment that the pressure sensitive adhesive skin adhesion is too "stiff."
Pressure sensitive adhesives having a creep compliance value between 1.1 x 10~5 cm2/dyne and 2.3 x 10-5 cm2/dyne provide an acceptable level of initial adhesion to skin and sufficiently maintain adhesive integrity during storage and usage, without cohesive failure or adhesion loss. The crosslinked PSAs of the present invention maintain such physical properties even when in contact with alcohol-based excipients otherwise harmful to such physical properties.
Additional aspects of the invention are describ~d in Embodiments of the Invention below, including non-limiting examples.
Embodiments of the Invention THE PRESSURE-SENSITIVE ADHESIVE COPOLYMER
The pressure-sensitive adhesive copolymer is an acrylate-based and has an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g. Desirably, the inherent viscosity ranges from about 1.4 dl/g to about 1.9 dl/g in order to provide a creep compliance value within the acceptable range after the copolymer is irradiated with a dose of electron-beam radiation and exposed to alcohol-based excipients. Preferably, the inherent viscosity is about 1.7 dl/g.
Inherent viscosity is a logarithmic viscosity number used to measure polymer molecular weight for linear polymers. The test procedure followed and the apparatus than can be used to measure inherent viscosity are describad in detain in Testing Procedures below.
~he pressure-sensitive adhesive copolymer should be tacky at room temperature as well as at the skin temperature of patients. Also, the adhesive should be hypoallergenic, i.e., after continuous contact with skin, )39~i~6 there is no significant skin sensitization or irritation during adhesion. Often, to determine if an adhesive is hypoallergenic, the following evaluations are conducted:
cell cytotoxicity, skin irritation, and sensitization potential. The United States Food and Drug Administration recommends such evaluations in a Tripartite Biocompatibility Draft Guidance for Medical Devices.
The acrylate-based pressure-sensitive adhesive copolymer is the reaction product of the polymerization of at least one A monomer and at lea-~t one B monomer.
The A monomer is a polymerizable monomer comprising an acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols with the alcohols having from I to 14 carbon atoms and desirably averaging about ~ to 12 carbon atoms.
The B monomer is an ethylenically unsaturated compound and desirably may be acrylic acid, methacrylic-acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinyl pyrrolidone, or combinations thereof.
The A monomer is polymerizable and contributes the viscoelastic properties of the pressure-sensitive adhesive copolymer. Non-limiting examples of such A
monomers include the esters of acrylic acid or methacrylic acid with non-tertiary alkyl alcohol such as 1-butanol, l-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, l-methyl-l-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 2-ethyl-1-hexanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, l-decanol, l-dodecanol, and the like. Such monomeric acrylic or methacrylic esters are known in the art, and many are commercially available.
The B monomer is an ethylenically unsaturated compound copolymerized with the A monomer to affect the physical properties of the resultin~ pressure-senRitive adhesive copolymer. In general, the presence of the B
monomer will rPduce the flexibility of the resulting pressure-sensitive adhesive copolymer.
Thus, the weight pexcentages of the A monomer and the B monomer should be balanced in order to provide a pressure-sensitive adhesive copolymer haviny an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g. The weight percentage ratio ranges from about 92:8 to about 98:2 and desirably from about 93:7 to 97:3.
In a preferred embodiment of the invention, the pressure-sensitive adhesive copolymer is the reaction product of isooctyl acrylate and acrylic acid having a weight percentage ratio of from about 92:8 to about 97:3 and preferably having a weight percentage ratio of about 95.5:4.5.
The pressure-sensitive adhesive copolymer may be copolymerized using known polymerization techniques in a manner such that the inherent viscosity of the resulting copolymer is from about 1.2 dl/g to about 2.0 dl/g. Known polymerization techniques include emulsion polymerization and solution polymerization. Sources of polymerization preparation and techniques include "Organic Polymer Chemistry", K.J. Saunders, Chapman and Hall (Halsted Publishing, New York, 1973), Applied Polymer Science, R.W.
Tess and G.W. Poehlein, American Chemical Society (~merican Chemical Society, Washington, DC, 1981), Principles of Polymerization, G. Odien, Wiley-InterScience (John Wiley &
Sons, New York, 1981), and the Handbook of Pressure-Sensitive Adhesive Technology, Second Edition, referenced above.
Specifically, the acrylate-based pressure-sensitive adhesive copolymers may be prepared according to U.S. Patent 2,884,126/RE24,906.
W~en prepared by solution copolymerization, the A
monomer and B monomer are dissolv~d in an inert organic solvent and copolymerized ir. a nitrogen purged reactor at a temperature of about 55~C for about 24 hours using a suitable free radical initiator, such as azobisisobutyronitrile. Suitable solvents include ethyl ~C139~
acetate, mixtures of ethyl acetate and ethanol, and n-heptane.
When prepared by emulsion copolymerization, the A
monomer and B monomer are dispersed in deionized water using the procedure desc~ibed in Example 5 of U.S. Patent 2,884,126/RE24,906, except that the amount of tertiary dodecyl mercaptan may be varied to provide copolymers having a range of inherent viscosities, and that the resulting copolymer is dissolvad in a heptane-isopropanol (70:30) solution.
THE CROSSLINKED PSA
The pressure-sensitive adhesive copolymer may be crosslinked using electron-beam radiation in doses of from about 5 kGy (0.5 Mrads.) to about 200 kGy (20 mrads.).
Desirably, the electron-beam radiation dose is from about 10 kGy to about 50 kGy and may be delivered using one pass or multiple passes through the electron beam.
In a preferred embodiment of the invention, when the pressure-sensitive adhesive copol~mer is prepared from the copolymerization of isooctyl acrylate . and acrylic acid, electron-beam radiation in a dose of about 30 kGy yields an acceptable crosslinked PSA for use in a transdermal delivery device.
The method of irradiation by electron-beam is performed by passing the pressure-sensitive adhesive copolymer on suitable substrates through an electron beam unit as available from Energy Scisnces Inc., such as a Model rB 250/30/20 30 cm Electro-Curtain electron beam 30 system or a Model CB 150/15/lOL 15 cm Electro-Curtain electron beam system, configured to operate and provide the acceptable dosages indicated above. In the embodiment of providing a dose of 30 kGy of electron beam radiation, the equipment is operated at a voltage of 175 kV at a line speed of 15.24 meters per minute with an oxygen content of less than 100 parts per million.
The electron-~eam radiation results in crosslinking the pressure-æensitive adhesive copolymer ~395~16 without otherwise affecting the pressure-sensitive adhesive properties useful for medical applications.
TESTING PROCEDURES
Inherent Viscosity Measurement Procedure The inherent viscosities of the pressure sensitive adhesive copolymers wexe obtained using a Cannon-Fenske #50 viscometer in a deionized water bath controlled at 25C to measure the flow time o~ lOml of the copolymer solution (0.15 g/dl of copolymer in ethyl acetate.) The test procedure followed and a drawing of a viscometer, then known as a Ostwald-Fenske, are described in "Textbook of Polymer Science", F.W. Billmeyer, Wiley-Interscience, Second Edition, 1971, Pages 84 and 85.
Creep Compliance Value Procedure To m~asure the creep compliance value of the skin adhesive pressure-sensitive adhesive copolymer before crosslinking, after crosslinking, and after crosslinking and exposure to the penetration enhancing agents, a 150-micrometer thickness of the pressure-sensitive adhesive copolymer is knife-coated onto a smooth film of polytetrafluoroethylene. The coated film is then dried to a constant weight by placing it in an air-circulating oven for at least 30 minutes at 65C to remove solvent and reduce the level of unreacted monomer.
The adhesive, thus dried, is stripped from the polytetrafluoroethylene and two test pieces of equal area are die-cut and placed in the parallel plate creep compliance rheometer, one piece being on each side of the center plate, with an outer plate contacting the exposed surface of each. Screws which connect the two outer plates are then tightened so as to compress the interposed layers of adhesive approximately 10 percent. The parallel plates are placed in a horizontal arrangement and one end of-the center plate is connected to a chart recorder. A hook is attached to the opposite end of the center plate with a ~)3~ 36 flexible wire extending horizontally from the hook and then downward over a pulley, the outer plates being held in a fixed position. A suitable weight (one sufficient to measurably deform the sample at distance no greater than its thickness) is attached to the free end of the wire, then the strip chart recorder is started. The weight typically used to exert the stress on the adhesive films is about 500 grams. From the strip chart recorder, the time and displacement (strain) are read and the applied force ~stress) is recorded. The creep compliance at a given temperature is then calculated using the equation:
J(t) hf where t is the time at which the measurement is taken, A is the area of one face of the adhesive samples, h is the thickness of the adhesive mass, x is the displacement at time t (where X is less than h) and ~ is the force due to the mass attached to the wire connected to the middle plate. When A is expressed in cm2, h in centimeters, X in centimeters, and f in dynes, the compliance value or J
value, J(,) is given in cm2/dyne.
When the creep compliance value has been measured at the end of a 3 minute period of stress application according to the procedure described above, a pressure-sensitive adhesive having a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 x 10 5 cm2/dyne exhibits acceptable adhesion to skin.
In general, the higher the creep compliance value, the lower the cohesiveness of the pressure sensitive adhesive and the higher the adhesion level to the skin.
For a pressure-sensitive adhesive having a creep compliance value higher than about 2.3 x 10-5 cm2/dyne, the pressure-sensitive adhesive has a higher adhesion with lower internal or cohesive strength, resulting in excessive residue remaining on the skin at the time of adhesive removal. When the value is less than about 1.1 X 10-5 cm2/dyne, the pressure-sensitive adhesive exhibits lower tack and higher cohesive strength, resulting in poor initial adhesion.
Skin Adhesion Procedure The evaluation of the s~in adhesives of this invention is highly subjective when the performance in contact with and upon removal from the human skin surface becomes part of the evaluation. For this reason a protocol was developed using a prescribed test panel of individuals who were selected to embrace the normal variations in skin surface that are encountered in medical practice. The result of this designed study enables one to get values which can be considered controlled and comparative. while these values are observational in respect to adhesive residue, sample lift and adhesion build-up, the procedures followed are in accord with care~ully developed assessments of similar properties as is known in the art.
It should be noted that there is an inherent variability in skin adhesion between different individuals and for the same individual, depending in each instance on the type of skin, the time of the year, the climatic conditions, the level of exercise, and other factors.
Thus, while certain values are reported here, there are wide ranges of adhesion values possible due to oth~r factors in actual usage.
The initial skin adhesion value (To) and the skin adhesion value after 24 or 48 hours in contact with the skin (T24 or T48) are essentially the widely accepted PSTC-l, peel adhesion test for single coated skin adhesive tapes measured at 180 angle. PSTC-1 is test method No. 1 of the Pressure Sensitive Tape Counsel, Glenview, Illinois, Seventh Edition (1976); developed by the Speci~^ications and Technical Committee of the Counsel. The test has been modified only to the extent that the tape is applied to the human skin surface on a selected area on the individual's back. otherwise the steps in the procedure are as follows:
~395~6 l. Tape samples 2.54 cm wide by 5.08 cm long are placed on the back of a human subject.
2. Each tape is rolled down with one forward and one reverse pass, using a l-kilogram taps roller (described in ~ppendix B, Sections 2.7.1, 2.8.1, and 2.8.2 of Pressure Sensitive Tape Counsel) moved at the rate of about 30 cm per minute.
3. Adhesion to the skin is measured as the peel force xequired to remove the tape at 1800 angle (PSTC-1).
The peel force values are measured through the use of a strain-gauge mounted on a motor-driven carriage.
The force of removal is reported in grams of adhesion per 2.54 cm of width of sample. The rate of removal is 15 cm per minute.
4. The adhesion to skin is measured immediately after initial application (To) and after 24 or 48 hours of continuous contact with the skin (T24 or T48).
Preferred skin adhesive will generally exhibit a To of between 50 grams to about 200 grams and a T24 of between 50 grams and 200 grams.
EXCIPIENT EXPOSURE PROCEDURE
To measure the effect of the exposure of the pressure-sensitive adhesive copolymer and the crosslinked PSA to the alcohol-based excipient, samples of the copolymer and the crosslinked PSA were sprayed with ethanol, a frequently used penetration enhancing agent and solvent excipient. The ethanol is sprayed either in a series of five sprays at a distance of 15.24 cm or in a single spray at a distance.of 25.4 cm. After hand-laminating the sample exposed to ethanol to a sample not exposed to ethanol, these samples were allowed to dwell at room t~mperature for five days before the creep compliance procedure was performed. Care should be taken during hand-lamination not to introduce air-pockets, lint, or any other contaminants. Some ethanol may flow from the ~?3~6 samples having five sprays during hand-lamination. It is believed that the procedure of five sprays at a distance of 15.24 cm provides a 10 percent weight/weight amount of ethanol in the pressure-sensi~ive adhesive whereas a single coating spray at 25.4 cm provides a 5 percent weight/weight amount of ethanol in the pressure-sensitive adhesive.
ALCOHOL-BASED EXCIPIENT EXPOSIJRE
A comparison of identically prepared pressure-sensitive adhesive samples demonstrates that electron-beam irradiation in specific dosages unexpectedly results in a crosslinked PSA which maintains its creep compliance value within an acceptable range after exposure to ethanol.
With a pressure-sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g, the creep compliance value before exposura to ethanol may be within the acceptable range of about 1.1 x 105 cm2/dyne to about 2.3 x 10-5 x cm2/dyne.
Without electron-beam irradiation of the pressure-sensitive adhesive copolymer, after exposure to ethanol, only the pressure-sensitive adhesive copolymer samples having the highest inherent viscosity in the acceptable range retain a creep compliance value below about 2.3 x 10-5 cm2/dyne. The remaining samples of pressure-sensitive adhesive copolymer exceed the acceptable range of creep compliance value and demonstrate dramatic loss of cohesive strength.
Unexpectedly, after samples of the pressure-sensitive adhesive copolymer having an inhsrent viscosity within the acceptable range are irradiated with an electron-beam, the creep compliance values for the samples remain within the acceptable range even after exposure for as much as 5 days to the presence of ethanol in weight fractions as much as 10 percent weight/weight to the PSA.
~3~35~j Because the electron-beam irradiation of the pressure-sensitive adhesive copolymer causes retention of-the cohesive strength of the crosslinked Ps~ in the presence o~ a penetration enhancing agent, it is also possible within the scope of this invention to begin with a pressure-sensitive adhesive copolymer having a creep compliance value less than about 1.1 x ~0-5 cm2/dyne. After irradiation, this adhesive may be us~d in a transdermal delivery device having an alcohol-based excipient, such as a penetration enhancing agent, such that ~fter exposure to such excipient, the crosslinke~ PSA layer has a creep compliance value lower than about 2.3 x 10-5 cm2/dyne.
It should be understood fxom this invention that one skilled in the art can select a pressure sensitive adhesive copolymer having otherwise acceptable skin adhesion properties, and subject that copolymer to electron-beam radiation to produce a crosslinked PSA which has acceptable skin adhesion properties even in the presence of a specific alcohol-based excipient which otherwise would decrease the cohesive strength of the un-crosslinked pressure-sensitive adhesive copolymer.
USEFULNESS OF THE INVENTION
As described above, the crosslinked PSA may be used as the adhesive layer in a transdermal delivery device in a medical or surgical application. in other circumstances where skin adhesion stability is desired, medical applications such as dressings, bandages, drapes, and the like may be improved by use of the crosslinked PSA's of this invention. Regardless of the medical application, the product can have an extended shel~ life even if the crosslinked PSA is in contact with an alcohol-based excipient, including penetration enhancing agents like ethanol. Further, the maintenance of creep compliance values within the acceptable range reduces the likelihood of a painful removal of the medical article due to lower build of adhesion of the crosslinked PSA during Z~)395~
extended use. The number of excipients used with a therapeutic agent and especially those penetration enhancing agents available for use with the acrylate-based pressure-sensitive adhesive may now be expanded because of the tolerance of the crosslinked PSA to such alcohol-based materials. More importantly, the range of active agents that can be administered transdermally can now be expanded to include those which must use an alcohol-based excipient as a solvent or penetration enhancing agent.
Non-limiting examples of alcohol-based excipients of which the crosslinked PSA's of this invention are tolerant include ethanol, octanol, eugenol, and any N-alkanol, branched alkanol, or cyclic alkanol. other alcohol-based excipients are alcohol-based penetration enhancing agents known to those skilled in the art, as disclosed in U.S. Patents 4,849,224 and 4,855,294.
Non-limiting examples of active agents useful in a transdermal delivery device with such alcohol-based excipients as solvents, penetration enhancing agents and the like, are estradiol, nicotine, nitroglycerine, clonidine, and scopolamine. other active agents are identified as drugs or pharmacologically active agents and are also disclosed in U.S. Patents 4,849,224 and 4,855,294.
One type of transdermal delivery device typically places the pressure sensitive adhesive against the skin with a reservoir of a therapeutic mixture in communication therewith. The therapeutic mixture comprising the active agent and the alcohol-based excipient is deliverable through the crosslinked PSA layer according to the natural flow of the therapeutic mixture, or using rate controlling membranes or the like.
Another type of transdermal delivery device places the pressure sensitive adhesive contiguous with, but not between, the reservoir containing the therapeutic mixture and the skin. For example, a construction where the adhesive is about a periphery of the reservoir is often employed in the art.
~( i39~
Either type of transdermal delivery device has contact between the alcohol-based excipient and the pressure sensitive adhesive. The crosslinked PSA's of the present invention minimize loss of preferred adhesive properties when used in either type o~ transdermal delivery device.
Because the pressure-sensitive adhesive copolymer is crosslinked by electron-beam radiation without the use of crosslinking agents, initiators, or the like, the number of materials with which the active agent may interact is,minimized. With the benefit of this invention, one skilled in the art can refine the skin adhesion properties of the crosslinked PSA layer without affecting the transport of the active agent through the PSA layer and into the skin. Indeed, the number of active agents available for transdermal delivsry can now be expanded for use with alcohol-based excipients serving as solvents or penetration enhancing agents that no longer cause cohesive failure of the crosslinked PSA layer necessary to hold the transdermal delivery device together or to the skin.
For a greater appreciation of the scope of the invention, non-limiting examples are provid~d.
25Preparation of the Pressure-Sensitive Adhesive Copolymer Having a Range of Inherent Visco~ities A series of acrylate-based pressure sensitive adhesive copolymers were prepared by emulsion polymerization, described as follows: A mixture of 104 parts by weight of deionized water, 8 parts of a 28~
solution of alkylated aryl polyether sodium sulfonate ("Triton X-200" sold by Rohm and Haas), 95.5 parts of isooctyl acrylate, 4.5 parts acrylic acid and amounts tertiary dodecyl mercaptan described helow to vary inherent viscosity was purged with nitrogen and brought to 30UC with agitation. To this were added 0.2 parts potassium persulfate and 0.067 parts sodium metabisulphite.
20;39~
Copolymerization proceeded rapidly with evolution of heat.
The copolymer was recovered from the emulsion, dried, and dispersed in a mixture of heptane/isopropanol (70/30) to a coatable viscosity. Inherent viscosities were measured using the Inherent Viscosity Procedure described above in ethyl acetate at a concentration of 0.15 g/dl. To yield a series of copolymers having a range of inherent viscosities from about 1.0 dl/g to about 2.0 dl/g, for Examples 1-5, respectively, in weight percent to total monomer weight, the amount of tertiary dodecyl mercaptan added was 0.13%
for Example 1, 0.11% for Example 2, 0.07% for Example 3, 0.06% for Example ~, and none for Example 5. ~he samples of copolymer were hand-spread on a 15.24 cm coater at a nominal 4.6 mg/cm2(11 grain) coverage on a 0.05mm untreated polyester film. These samples were then covered with a paper liner-available as No. 1361 from 3M Company.
Crosslinking by Electron-Beam Irradiation Copolymer samples of Examples 1-5 were then irradiated with an electron beam to yield crosslinked PSA
sambles of Examples 6-10. The Examples 6-10 correspond to Examples 1-5, respectively, except for the electron-heam radiation crosslinking. Each of the copolymer samples were irradiated with an electron-beam on an Energy Sciences Inc.
"ESI Model CB 250/30/20" 30 cm Electro-Curtain electron beam unit operating at a voltage of 175 kV at a line speed of 15.24 meters per minute having an oxygen content of less than 100 parts per million to achieve an electron-beam dosage of 30 kGy (3.0 Mrads.) Exposurs to Ethanol Portions of adhesive prPpared according to the procedures used for each of Examples 1-10, each approximately 500 cm2 in size, were exposed to ethanol (100~) according to single spray and 5-spray variations of ~3~ 6 the Excipient Exposure Procedure described above. Other samples of Examples 1-10 were not exposed to ethanol.
During laminating, some ethanol of the s-Spray samples was pressed out. The ethanol exposed samples were stored at room temperature for 5 days prior to performing the creep compliance procedure. It was believed that the single spray procedure added about 5 percent (w/w) ethanol to the sample and the 5-spray procedure added 10 percent (w/w) ethanol to the sample.
10 The creep compliance procedure described above was performed for 10 samples each of Examples 1-10 under three conditions: unexposed to ethanol, exposed to ethanol at about 5 percent, and exposed to ethanol at about 10 percent. Table I demonstrates the results obtained for an average of the samples.
TABLE I
Electron~ Cree~ Compliance Inherent Beam (x10 cm2/dyne) ViscosityDosage Ethanol % (w/w) Example A(dl~q~ kGy) 0% 5%~ 10%
25 1 1.02 0 2.3486.414 6.053 2 1.16 0 2.1423.839 5.167 3 1.44 0 1.6952.295 5.384 4 1.69 0 1.5201.~02 3.788 1.94 0 1.2501.82~ 2.179 6 1.02 30 3.7663.566 4.015 7 1.16 30 1.4052.518 2.953 8 1.44 30 1.1~01.538 2.066 9 1.69 30 1.3901.650 1.787 3510 1.94 30 1.1701.620~ 2.305 The underscored creep compliance values in Table I are in the acceptable range for skin-adhesion performance of a pressure-sensitive adhesive. Referring to Examples 1, 2, 6, and 7, notwithstanding the crosslinking by the electron-beam irradiation, the creep compliance values in the presence of ethanol were outside the acceptable range ~0~9~
~24-even though the values may be acceptable prior to exposurP
to ethanol. Therefore, the initial inherent viscosity of the pressure-sensitive adhesive copolymer should be between about 1.2 dl/g and about 2.0 dl/g.
A comparison of Examples 3 and 4 with Examples and 9, respectively, shows the benefit of crosslinking using the electron-beam irradiation. While some exposure to ethanol can be tolerated in Examples 3 and 4, cohesive strength of the copolymers in Examples 3 and 4 is lost upon 10 percent ethanol exposure. on the other hand, with electron-beam irradiation of the same pressure~sensitive adhesive copolymers, the creep compliance values of the crosslinked PSA's of Examples 8 and 9 are within the acceptable range despite exposure to ethanol in either amount.
A comparison of Examples 5 and 10 shows that at the upper boundary of the inherent viscosity range, it is possible to provide tolerance to ethanol at the levels of ethanol exposure tested even though crosslinking may initially depress the creep compliance value such that it approaches the lower boundary of the acceptable range prior to exposure to ethanol. Even with a pressure-sensitive adhesive copolymer having a high inherent viscosity of greater than 1.90, it is preferable to crosslink the copolymer to form the crosslinked PSA to assure a creep compliance value within the acceptable range. This is an example of the selection available to one skilled in the art to "fine tune" the pres~ure-sensitive adhesive properties in a transdermal delivery device when it is known that an alcohol-based excipient will be present.
Examples 11-13 were prepared from IOA/AA
(95.5:4.5) copolymers prepared according to the procedure described with respect to Examples 1-5, using 0.05% to 0.07% of monomer weight of tertiary dodecyl mercaptan to yield an inherent viscosity in the range of 1.4 dl/g to 1.6 dl/g. The samples of Example 1~ were not irradiated. The ~39~
samples of Example 12 were irradiated with an electron-beam dosage of 30 kGy in one pass in the ESI electron beam unit.
The samples of Example 13 were irradiated three times with a dosage of 10 kGy during each pass.
Samples of Pach of the three examples were prepared according to the skin adhesion procedure described above and tested on human skin surface. Table II reports the results obtained based on an average of the samples.
TABLE II
Skin Adhesion Inherent Electron-Beam (g/2.54 cm) Example Viscosity (dl/q) Dosage (kGy) ~ T
11 1.4 - 1.6 OOO ~00 175 12 1.4 - 1.6 30 ~5 ~5 13 1.4 - 1.6 10+10+10 60 90 All of the examples were within or close to the preferred range of 50 grams to 200 grams on initial skin adhesion. After 24 hours, the skin adhesion for Example 13 rose although staying within the preferred range of skin adhesion.
Unexpectedly, the increase in skin adhesion for the first 24 hours was dramatically less for Examples 12 and 13 which were exposed to electron-beam radiation. The rate of increase for Examples 12 and 13 compared with Example ll was lower both on a percentage basis and on an absolute basis. Further, the rate of increase for the crosslinked PSA was not dependent on the method of delivery of the dose of electron-beam radiation.
Thus, while all of the examples show acceptable skin adhesion, the electron-beam crosslinking o~
pressure-sensitive adhesive copolymers to yield crosslinked PSA's minimizes the increase in skin adhesion over as much as a 24 hour period. This translates into easier removal of the transdermal delivery device or other medical article prepared according to the present invention after its intended purpose on the human skin has been accomplished.
Z~39~
While several embodiments and examples have been provided, the scope of the invention is not limited thereto.
Preferred skin adhesive will generally exhibit a To of between 50 grams to about 200 grams and a T24 of between 50 grams and 200 grams.
EXCIPIENT EXPOSURE PROCEDURE
To measure the effect of the exposure of the pressure-sensitive adhesive copolymer and the crosslinked PSA to the alcohol-based excipient, samples of the copolymer and the crosslinked PSA were sprayed with ethanol, a frequently used penetration enhancing agent and solvent excipient. The ethanol is sprayed either in a series of five sprays at a distance of 15.24 cm or in a single spray at a distance.of 25.4 cm. After hand-laminating the sample exposed to ethanol to a sample not exposed to ethanol, these samples were allowed to dwell at room t~mperature for five days before the creep compliance procedure was performed. Care should be taken during hand-lamination not to introduce air-pockets, lint, or any other contaminants. Some ethanol may flow from the ~?3~6 samples having five sprays during hand-lamination. It is believed that the procedure of five sprays at a distance of 15.24 cm provides a 10 percent weight/weight amount of ethanol in the pressure-sensi~ive adhesive whereas a single coating spray at 25.4 cm provides a 5 percent weight/weight amount of ethanol in the pressure-sensitive adhesive.
ALCOHOL-BASED EXCIPIENT EXPOSIJRE
A comparison of identically prepared pressure-sensitive adhesive samples demonstrates that electron-beam irradiation in specific dosages unexpectedly results in a crosslinked PSA which maintains its creep compliance value within an acceptable range after exposure to ethanol.
With a pressure-sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g, the creep compliance value before exposura to ethanol may be within the acceptable range of about 1.1 x 105 cm2/dyne to about 2.3 x 10-5 x cm2/dyne.
Without electron-beam irradiation of the pressure-sensitive adhesive copolymer, after exposure to ethanol, only the pressure-sensitive adhesive copolymer samples having the highest inherent viscosity in the acceptable range retain a creep compliance value below about 2.3 x 10-5 cm2/dyne. The remaining samples of pressure-sensitive adhesive copolymer exceed the acceptable range of creep compliance value and demonstrate dramatic loss of cohesive strength.
Unexpectedly, after samples of the pressure-sensitive adhesive copolymer having an inhsrent viscosity within the acceptable range are irradiated with an electron-beam, the creep compliance values for the samples remain within the acceptable range even after exposure for as much as 5 days to the presence of ethanol in weight fractions as much as 10 percent weight/weight to the PSA.
~3~35~j Because the electron-beam irradiation of the pressure-sensitive adhesive copolymer causes retention of-the cohesive strength of the crosslinked Ps~ in the presence o~ a penetration enhancing agent, it is also possible within the scope of this invention to begin with a pressure-sensitive adhesive copolymer having a creep compliance value less than about 1.1 x ~0-5 cm2/dyne. After irradiation, this adhesive may be us~d in a transdermal delivery device having an alcohol-based excipient, such as a penetration enhancing agent, such that ~fter exposure to such excipient, the crosslinke~ PSA layer has a creep compliance value lower than about 2.3 x 10-5 cm2/dyne.
It should be understood fxom this invention that one skilled in the art can select a pressure sensitive adhesive copolymer having otherwise acceptable skin adhesion properties, and subject that copolymer to electron-beam radiation to produce a crosslinked PSA which has acceptable skin adhesion properties even in the presence of a specific alcohol-based excipient which otherwise would decrease the cohesive strength of the un-crosslinked pressure-sensitive adhesive copolymer.
USEFULNESS OF THE INVENTION
As described above, the crosslinked PSA may be used as the adhesive layer in a transdermal delivery device in a medical or surgical application. in other circumstances where skin adhesion stability is desired, medical applications such as dressings, bandages, drapes, and the like may be improved by use of the crosslinked PSA's of this invention. Regardless of the medical application, the product can have an extended shel~ life even if the crosslinked PSA is in contact with an alcohol-based excipient, including penetration enhancing agents like ethanol. Further, the maintenance of creep compliance values within the acceptable range reduces the likelihood of a painful removal of the medical article due to lower build of adhesion of the crosslinked PSA during Z~)395~
extended use. The number of excipients used with a therapeutic agent and especially those penetration enhancing agents available for use with the acrylate-based pressure-sensitive adhesive may now be expanded because of the tolerance of the crosslinked PSA to such alcohol-based materials. More importantly, the range of active agents that can be administered transdermally can now be expanded to include those which must use an alcohol-based excipient as a solvent or penetration enhancing agent.
Non-limiting examples of alcohol-based excipients of which the crosslinked PSA's of this invention are tolerant include ethanol, octanol, eugenol, and any N-alkanol, branched alkanol, or cyclic alkanol. other alcohol-based excipients are alcohol-based penetration enhancing agents known to those skilled in the art, as disclosed in U.S. Patents 4,849,224 and 4,855,294.
Non-limiting examples of active agents useful in a transdermal delivery device with such alcohol-based excipients as solvents, penetration enhancing agents and the like, are estradiol, nicotine, nitroglycerine, clonidine, and scopolamine. other active agents are identified as drugs or pharmacologically active agents and are also disclosed in U.S. Patents 4,849,224 and 4,855,294.
One type of transdermal delivery device typically places the pressure sensitive adhesive against the skin with a reservoir of a therapeutic mixture in communication therewith. The therapeutic mixture comprising the active agent and the alcohol-based excipient is deliverable through the crosslinked PSA layer according to the natural flow of the therapeutic mixture, or using rate controlling membranes or the like.
Another type of transdermal delivery device places the pressure sensitive adhesive contiguous with, but not between, the reservoir containing the therapeutic mixture and the skin. For example, a construction where the adhesive is about a periphery of the reservoir is often employed in the art.
~( i39~
Either type of transdermal delivery device has contact between the alcohol-based excipient and the pressure sensitive adhesive. The crosslinked PSA's of the present invention minimize loss of preferred adhesive properties when used in either type o~ transdermal delivery device.
Because the pressure-sensitive adhesive copolymer is crosslinked by electron-beam radiation without the use of crosslinking agents, initiators, or the like, the number of materials with which the active agent may interact is,minimized. With the benefit of this invention, one skilled in the art can refine the skin adhesion properties of the crosslinked PSA layer without affecting the transport of the active agent through the PSA layer and into the skin. Indeed, the number of active agents available for transdermal delivsry can now be expanded for use with alcohol-based excipients serving as solvents or penetration enhancing agents that no longer cause cohesive failure of the crosslinked PSA layer necessary to hold the transdermal delivery device together or to the skin.
For a greater appreciation of the scope of the invention, non-limiting examples are provid~d.
25Preparation of the Pressure-Sensitive Adhesive Copolymer Having a Range of Inherent Visco~ities A series of acrylate-based pressure sensitive adhesive copolymers were prepared by emulsion polymerization, described as follows: A mixture of 104 parts by weight of deionized water, 8 parts of a 28~
solution of alkylated aryl polyether sodium sulfonate ("Triton X-200" sold by Rohm and Haas), 95.5 parts of isooctyl acrylate, 4.5 parts acrylic acid and amounts tertiary dodecyl mercaptan described helow to vary inherent viscosity was purged with nitrogen and brought to 30UC with agitation. To this were added 0.2 parts potassium persulfate and 0.067 parts sodium metabisulphite.
20;39~
Copolymerization proceeded rapidly with evolution of heat.
The copolymer was recovered from the emulsion, dried, and dispersed in a mixture of heptane/isopropanol (70/30) to a coatable viscosity. Inherent viscosities were measured using the Inherent Viscosity Procedure described above in ethyl acetate at a concentration of 0.15 g/dl. To yield a series of copolymers having a range of inherent viscosities from about 1.0 dl/g to about 2.0 dl/g, for Examples 1-5, respectively, in weight percent to total monomer weight, the amount of tertiary dodecyl mercaptan added was 0.13%
for Example 1, 0.11% for Example 2, 0.07% for Example 3, 0.06% for Example ~, and none for Example 5. ~he samples of copolymer were hand-spread on a 15.24 cm coater at a nominal 4.6 mg/cm2(11 grain) coverage on a 0.05mm untreated polyester film. These samples were then covered with a paper liner-available as No. 1361 from 3M Company.
Crosslinking by Electron-Beam Irradiation Copolymer samples of Examples 1-5 were then irradiated with an electron beam to yield crosslinked PSA
sambles of Examples 6-10. The Examples 6-10 correspond to Examples 1-5, respectively, except for the electron-heam radiation crosslinking. Each of the copolymer samples were irradiated with an electron-beam on an Energy Sciences Inc.
"ESI Model CB 250/30/20" 30 cm Electro-Curtain electron beam unit operating at a voltage of 175 kV at a line speed of 15.24 meters per minute having an oxygen content of less than 100 parts per million to achieve an electron-beam dosage of 30 kGy (3.0 Mrads.) Exposurs to Ethanol Portions of adhesive prPpared according to the procedures used for each of Examples 1-10, each approximately 500 cm2 in size, were exposed to ethanol (100~) according to single spray and 5-spray variations of ~3~ 6 the Excipient Exposure Procedure described above. Other samples of Examples 1-10 were not exposed to ethanol.
During laminating, some ethanol of the s-Spray samples was pressed out. The ethanol exposed samples were stored at room temperature for 5 days prior to performing the creep compliance procedure. It was believed that the single spray procedure added about 5 percent (w/w) ethanol to the sample and the 5-spray procedure added 10 percent (w/w) ethanol to the sample.
10 The creep compliance procedure described above was performed for 10 samples each of Examples 1-10 under three conditions: unexposed to ethanol, exposed to ethanol at about 5 percent, and exposed to ethanol at about 10 percent. Table I demonstrates the results obtained for an average of the samples.
TABLE I
Electron~ Cree~ Compliance Inherent Beam (x10 cm2/dyne) ViscosityDosage Ethanol % (w/w) Example A(dl~q~ kGy) 0% 5%~ 10%
25 1 1.02 0 2.3486.414 6.053 2 1.16 0 2.1423.839 5.167 3 1.44 0 1.6952.295 5.384 4 1.69 0 1.5201.~02 3.788 1.94 0 1.2501.82~ 2.179 6 1.02 30 3.7663.566 4.015 7 1.16 30 1.4052.518 2.953 8 1.44 30 1.1~01.538 2.066 9 1.69 30 1.3901.650 1.787 3510 1.94 30 1.1701.620~ 2.305 The underscored creep compliance values in Table I are in the acceptable range for skin-adhesion performance of a pressure-sensitive adhesive. Referring to Examples 1, 2, 6, and 7, notwithstanding the crosslinking by the electron-beam irradiation, the creep compliance values in the presence of ethanol were outside the acceptable range ~0~9~
~24-even though the values may be acceptable prior to exposurP
to ethanol. Therefore, the initial inherent viscosity of the pressure-sensitive adhesive copolymer should be between about 1.2 dl/g and about 2.0 dl/g.
A comparison of Examples 3 and 4 with Examples and 9, respectively, shows the benefit of crosslinking using the electron-beam irradiation. While some exposure to ethanol can be tolerated in Examples 3 and 4, cohesive strength of the copolymers in Examples 3 and 4 is lost upon 10 percent ethanol exposure. on the other hand, with electron-beam irradiation of the same pressure~sensitive adhesive copolymers, the creep compliance values of the crosslinked PSA's of Examples 8 and 9 are within the acceptable range despite exposure to ethanol in either amount.
A comparison of Examples 5 and 10 shows that at the upper boundary of the inherent viscosity range, it is possible to provide tolerance to ethanol at the levels of ethanol exposure tested even though crosslinking may initially depress the creep compliance value such that it approaches the lower boundary of the acceptable range prior to exposure to ethanol. Even with a pressure-sensitive adhesive copolymer having a high inherent viscosity of greater than 1.90, it is preferable to crosslink the copolymer to form the crosslinked PSA to assure a creep compliance value within the acceptable range. This is an example of the selection available to one skilled in the art to "fine tune" the pres~ure-sensitive adhesive properties in a transdermal delivery device when it is known that an alcohol-based excipient will be present.
Examples 11-13 were prepared from IOA/AA
(95.5:4.5) copolymers prepared according to the procedure described with respect to Examples 1-5, using 0.05% to 0.07% of monomer weight of tertiary dodecyl mercaptan to yield an inherent viscosity in the range of 1.4 dl/g to 1.6 dl/g. The samples of Example 1~ were not irradiated. The ~39~
samples of Example 12 were irradiated with an electron-beam dosage of 30 kGy in one pass in the ESI electron beam unit.
The samples of Example 13 were irradiated three times with a dosage of 10 kGy during each pass.
Samples of Pach of the three examples were prepared according to the skin adhesion procedure described above and tested on human skin surface. Table II reports the results obtained based on an average of the samples.
TABLE II
Skin Adhesion Inherent Electron-Beam (g/2.54 cm) Example Viscosity (dl/q) Dosage (kGy) ~ T
11 1.4 - 1.6 OOO ~00 175 12 1.4 - 1.6 30 ~5 ~5 13 1.4 - 1.6 10+10+10 60 90 All of the examples were within or close to the preferred range of 50 grams to 200 grams on initial skin adhesion. After 24 hours, the skin adhesion for Example 13 rose although staying within the preferred range of skin adhesion.
Unexpectedly, the increase in skin adhesion for the first 24 hours was dramatically less for Examples 12 and 13 which were exposed to electron-beam radiation. The rate of increase for Examples 12 and 13 compared with Example ll was lower both on a percentage basis and on an absolute basis. Further, the rate of increase for the crosslinked PSA was not dependent on the method of delivery of the dose of electron-beam radiation.
Thus, while all of the examples show acceptable skin adhesion, the electron-beam crosslinking o~
pressure-sensitive adhesive copolymers to yield crosslinked PSA's minimizes the increase in skin adhesion over as much as a 24 hour period. This translates into easier removal of the transdermal delivery device or other medical article prepared according to the present invention after its intended purpose on the human skin has been accomplished.
Z~39~
While several embodiments and examples have been provided, the scope of the invention is not limited thereto.
Claims (10)
1. A composition useful for the transdermal delivery of an active agent in the presence of an alcohol-based excipient, comprising:
a crosslinked, acrylate-based pressure sensitive adhesive having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking using a dose of electron beam radiation of from about 5 kGy to about 200 kGy and a creep compliance value after crosslinking and after exposure to the alcohol-based excipient of from about 1.1 X 10-5 cm2 /dyne to about 2.3 x 10-5 cm2/dyne.
a crosslinked, acrylate-based pressure sensitive adhesive having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking using a dose of electron beam radiation of from about 5 kGy to about 200 kGy and a creep compliance value after crosslinking and after exposure to the alcohol-based excipient of from about 1.1 X 10-5 cm2 /dyne to about 2.3 x 10-5 cm2/dyne.
2. A composition according to Claim 1, wherein said acrylate-based pressure sensitive adhesive is prepared from the copolymerization of an acrylate-based polymerizable monomer and an ethylenically unsaturated monomer, the weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer being from about 92:8 to about 98:2; and wherein said acrylate-based polymerizable monomer comprises at least one acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12; and wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof.
3. A composition according to Claim 2, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid; and wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said electron beam radiation dose is from about 10 to about 50 kGy.
4. A composition according to Claim 5, wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of about 95.5:4.5;
wherein said electron beam radiation dose is about 30 kGy; and wherein said pressure sensitive adhesive has said creep compliance value after exposure to ethanol.
wherein said electron beam radiation dose is about 30 kGy; and wherein said pressure sensitive adhesive has said creep compliance value after exposure to ethanol.
5. A method of preparing the pressure sensitive adhesive of Claim 1 comprising:
(a) polymerizing at least one acrylate-based polymerizable monomer and at least one ethylenically unsaturated monomer in a weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g; and (b) irradiating said copolymer with an electron beam radiation dose of about 5.0 kGy to about 200 kGy to yield a crosslinked pressure sensitive adhesive having a creep compliance value of from about 1.1 x 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to the alcohol-based excipient.
(a) polymerizing at least one acrylate-based polymerizable monomer and at least one ethylenically unsaturated monomer in a weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g; and (b) irradiating said copolymer with an electron beam radiation dose of about 5.0 kGy to about 200 kGy to yield a crosslinked pressure sensitive adhesive having a creep compliance value of from about 1.1 x 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to the alcohol-based excipient.
6. A method according to Claim 5, wherein said acrylate-based polymerizable monomer comprises an acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiarv alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12;
wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof; and wherein said irradiating is in a dose of from about 10 kGy to about 50 kGy.
wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof; and wherein said irradiating is in a dose of from about 10 kGy to about 50 kGy.
7. A method according to Claim 6, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid;
wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said irradiating is in a dose of about 30 kGy.
wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said irradiating is in a dose of about 30 kGy.
8. A medical article adhering to skin to deliver an active agent transdermally, comprising:
a layer of crosslinked, acrylate-based pressure sensitive adhesive of Claim 1; and a therapeutic mixture, in communication with said adhesive layer, comprising (a) a transdermally therapeutic active agent ; and (b) an alcohol-based excipient;
whereby said adhesive layer has a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to said excipient.
a layer of crosslinked, acrylate-based pressure sensitive adhesive of Claim 1; and a therapeutic mixture, in communication with said adhesive layer, comprising (a) a transdermally therapeutic active agent ; and (b) an alcohol-based excipient;
whereby said adhesive layer has a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to said excipient.
9. A medical article, according to Claim 8 wherein said adhesive layer is between said therapeutic mixture and the skin.
10. A medical article, according to Claim 8, wherein said adhesive layer is contiguous with, but not between, said therapeutic mixture and the skin.
Docket No. 43885CAN1A
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A composition useful for the transdermal delivery of an active agent in the presence of an alcohol-based excipient, comprising:
a crosslinked, acrylate-based pressure sensitive adhesive having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking using a dose of electron beam radiation of from about 5 kGy to about 200 kGy and a creep compliance value after crosslinking and after exposure to the alcohol-based excipient of from about 1.1 X 10-5 cm2 /dyne to about 2.3 x 10-5 cm2/dyne.
2. A composition according to Claim 1, wherein said acrylate-based pressure sensitive adhesive is prepared from the copolymerization of an acrylate-based polymerizable monomer and an ethylenicallv unsaturated monomer, the weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer being from about 92:8 to about 98:2; and wherein said acrylate-based polymerizable monomer comprises at least one acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12; and wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof.
3. A composition according to Claim 2, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid; and wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said electron beam radiation dose is from about 10 to about 50 kGy.
4. A composition according to Claim 5, wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of about 95.5:4.5;
wherein said electron beam radiation dose is about 30 kGy; and wherein said pressure sensitive adhesive has said creep compliance value after exposure to ethanol.
5. A method of preparing the pressure sensitive adhesive of Claim 1 comprising:
(a) polymerizing at least one acrylate-based polymerizable monomer and at least one ethylenically unsaturated monomer in a weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g; and (b) irradiating said copolymer with an electron beam radiation dose of about 5.0 kGy to about 200 kGy to yield a crosslinked pressure sensitive adhesive having a creep compliance value of from about 1.1 x 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to the alcohol-based excipient.
6. A method according to Claim 5, wherein said acrylate-based polymerizable monomer comprises an acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12;
wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof; and wherein said irradiating is in a dose of from about 10 kGy to about 50 kGy.
7. A method according to Claim 6, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid;
wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said irradiating is in a dose of about 30 kGy.
8. A medical article adhering to skin to deliver an active agent transdermally, comprising:
a layer of crosslinked, acrylate-based pressure sensitive adhesive of Claim 1; and a therapeutic mixture, in communication with said adhesive layer, comprising (a) a transdermally therapeutic active agent ; and (b) an alcohol-based excipient;
whereby said adhesive layer has a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to said excipient.
9. A medical article, according to Claim 8 wherein said adhesive layer is between said therapeutic mixture and the skin.
10. A medical article, according to Claim 8, wherein said adhesive layer is contiguous with, but not between, said therapeutic mixture and the skin.
Docket No. 43885CAN1A
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A composition useful for the transdermal delivery of an active agent in the presence of an alcohol-based excipient, comprising:
a crosslinked, acrylate-based pressure sensitive adhesive having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g prior to crosslinking using a dose of electron beam radiation of from about 5 kGy to about 200 kGy and a creep compliance value after crosslinking and after exposure to the alcohol-based excipient of from about 1.1 X 10-5 cm2 /dyne to about 2.3 x 10-5 cm2/dyne.
2. A composition according to Claim 1, wherein said acrylate-based pressure sensitive adhesive is prepared from the copolymerization of an acrylate-based polymerizable monomer and an ethylenicallv unsaturated monomer, the weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer being from about 92:8 to about 98:2; and wherein said acrylate-based polymerizable monomer comprises at least one acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12; and wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof.
3. A composition according to Claim 2, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid; and wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said electron beam radiation dose is from about 10 to about 50 kGy.
4. A composition according to Claim 5, wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of about 95.5:4.5;
wherein said electron beam radiation dose is about 30 kGy; and wherein said pressure sensitive adhesive has said creep compliance value after exposure to ethanol.
5. A method of preparing the pressure sensitive adhesive of Claim 1 comprising:
(a) polymerizing at least one acrylate-based polymerizable monomer and at least one ethylenically unsaturated monomer in a weight fraction ratio of said acrylate-based polymerizable monomer to said ethylenically unsaturated monomer of from about 92:8 to about 98:2 to yield a pressure sensitive adhesive copolymer having an inherent viscosity of from about 1.2 dl/g to about 2.0 dl/g; and (b) irradiating said copolymer with an electron beam radiation dose of about 5.0 kGy to about 200 kGy to yield a crosslinked pressure sensitive adhesive having a creep compliance value of from about 1.1 x 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to the alcohol-based excipient.
6. A method according to Claim 5, wherein said acrylate-based polymerizable monomer comprises an acrylate or methacrylate ester of a non-tertiary alcohol or a mixture of non-tertiary alcohols, said alcohols having from 1 to 14 carbon atoms with the average number being about 4-12;
wherein said ethylenically unsaturated monomer comprises acrylic acid, methacrylic acid, itaconic acid, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, vinyl acetate, N-vinylpyrrolidone, or combinations thereof; and wherein said irradiating is in a dose of from about 10 kGy to about 50 kGy.
7. A method according to Claim 6, wherein said acrylate-based polymerizable monomer comprises isooctyl acrylate and wherein said ethylenically unsaturated monomer comprises acrylic acid;
wherein said isooctyl acrylate and said acrylic acid have a weight fraction ratio of from about 93:7 to about 97:3; and wherein said irradiating is in a dose of about 30 kGy.
8. A medical article adhering to skin to deliver an active agent transdermally, comprising:
a layer of crosslinked, acrylate-based pressure sensitive adhesive of Claim 1; and a therapeutic mixture, in communication with said adhesive layer, comprising (a) a transdermally therapeutic active agent ; and (b) an alcohol-based excipient;
whereby said adhesive layer has a creep compliance value of from about 1.1 X 10-5 cm2/dyne to about 2.3 X 10-5 cm2/dyne after exposure to said excipient.
9. A medical article, according to Claim 8 wherein said adhesive layer is between said therapeutic mixture and the skin.
10. A medical article, according to Claim 8, wherein said adhesive layer is contiguous with, but not between, said therapeutic mixture and the skin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51792790A | 1990-05-02 | 1990-05-02 | |
| US07/517,927 | 1990-05-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2039586A1 true CA2039586A1 (en) | 1991-11-03 |
Family
ID=24061819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002039586A Abandoned CA2039586A1 (en) | 1990-05-02 | 1991-04-02 | Crosslinked pressure-sensitive adhesives tolerant of alcohol-based excipients used in transdermal delivery devices and method of preparing same |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5618899A (en) |
| EP (1) | EP0455458B1 (en) |
| JP (1) | JPH04270217A (en) |
| KR (1) | KR0179351B1 (en) |
| CA (1) | CA2039586A1 (en) |
| DE (1) | DE69115977T2 (en) |
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| DE4403487C2 (en) * | 1994-02-04 | 2003-10-16 | Lohmann Therapie Syst Lts | Pharmaceutical patches with UV-crosslinkable acrylate copolymers |
| EP0781122B1 (en) | 1994-09-14 | 2000-07-05 | Minnesota Mining And Manufacturing Company | Matrix for transdermal drug delivery |
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| US6077527A (en) * | 1997-10-28 | 2000-06-20 | National Starch And Chemical Investment Holding Corporation | Enhancer tolerant pressure sensitive adhesives for transdermal drug delivery |
| DE19749467C2 (en) * | 1997-11-08 | 1999-09-23 | Beiersdorf Ag | Active substance-containing patches |
| US5879759A (en) * | 1997-12-22 | 1999-03-09 | Adhesives Research, Inc. | Two-step method for the production of pressure sensitive adhesive by radiation curing |
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| DE10141652B4 (en) * | 2001-08-24 | 2011-04-07 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system based on polyacrylate pressure-sensitive adhesives without functional groups and its use |
| US7261734B2 (en) * | 2002-04-23 | 2007-08-28 | Boston Scientific Scimed, Inc. | Resorption-controllable medical implants |
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| CN101541314A (en) * | 2006-06-14 | 2009-09-23 | 爱若涂层制品有限公司 | Device for delivering active ingredients to humans, animals and plants |
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| US10463529B2 (en) * | 2012-11-05 | 2019-11-05 | Jennifer Sparr | Device and method for deterring back-lying snoring posture |
| JP2015510956A (en) | 2012-03-14 | 2015-04-13 | メディパックス インコーポレイテッド | Smart polymer materials containing overreactive molecules |
| JP2013248030A (en) * | 2012-05-30 | 2013-12-12 | Dainippon Printing Co Ltd | Medical adhesive sheet |
| EP2695926A1 (en) * | 2012-08-07 | 2014-02-12 | tesa SE | EBC-crosslinked adhesive tape for, in particular bundling cables and its use for bundling |
| US20220411561A1 (en) * | 2019-07-19 | 2022-12-29 | Arkema France | Curable compositions useful for obtaining non-sensitizing cured products |
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| US2553816A (en) * | 1948-02-16 | 1951-05-22 | Minnesota Mining & Mfg | Pressure-sensitive adhesive and adhesive tape |
| US2956904A (en) * | 1954-11-04 | 1960-10-18 | Minnesota Mining & Mfg | Pressure-sensitive adhesive tapes |
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| US5011867A (en) * | 1987-09-28 | 1991-04-30 | Avery International Corporation | Electron-beam cured emulsion pressure-sensitive adhesives |
-
1991
- 1991-04-02 CA CA002039586A patent/CA2039586A1/en not_active Abandoned
- 1991-04-16 JP JP3084085A patent/JPH04270217A/en active Pending
- 1991-04-29 DE DE69115977T patent/DE69115977T2/en not_active Expired - Fee Related
- 1991-04-29 EP EP91303875A patent/EP0455458B1/en not_active Expired - Lifetime
- 1991-05-01 KR KR1019910007026A patent/KR0179351B1/en not_active IP Right Cessation
-
1995
- 1995-05-30 US US08/454,496 patent/US5618899A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5618899A (en) | 1997-04-08 |
| EP0455458A2 (en) | 1991-11-06 |
| KR910020143A (en) | 1991-12-19 |
| EP0455458A3 (en) | 1991-12-18 |
| DE69115977D1 (en) | 1996-02-15 |
| JPH04270217A (en) | 1992-09-25 |
| EP0455458B1 (en) | 1996-01-03 |
| DE69115977T2 (en) | 1996-09-19 |
| KR0179351B1 (en) | 1999-04-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |