CA2171911C - Drug flux enhancer-tolerant pressure sensitive adhesive composition - Google Patents
Drug flux enhancer-tolerant pressure sensitive adhesive composition Download PDFInfo
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- CA2171911C CA2171911C CA002171911A CA2171911A CA2171911C CA 2171911 C CA2171911 C CA 2171911C CA 002171911 A CA002171911 A CA 002171911A CA 2171911 A CA2171911 A CA 2171911A CA 2171911 C CA2171911 C CA 2171911C
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- active agent
- penetration enhancer
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Classifications
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- 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
- C09J133/04—Homopolymers or copolymers of esters
- C09J133/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, the oxygen atom being present only as part of the carboxyl radical
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
- C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
- C08F290/04—Polymers provided for in subclasses C08C or C08F
- C08F290/044—Polymers of aromatic monomers as defined in group C08F12/00
Abstract
A drug flux enhancer-tolerant pressure sensitive adhesive composition is provided comprised of a mixture of (1) a percutaneous penetration enhancer to increase permeability of skin to transdermally administered pharmacologically active agents and (2) a macromer reinforced base polymer, said base polymer comprising a phase separated graft copolymer composition comprised of copolymerized monomers A
and B to form a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a non-tertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and a monomer B is a polar monomer which is copolymerizable with monomer A.
and B to form a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a non-tertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and a monomer B is a polar monomer which is copolymerizable with monomer A.
Description
~1?'191 I
DRUG FLUX ENHANCER-TOLERANT PRESSURE
SENSITIVE ADHESIVE COMPOSITION
BACKGROUND OF THE PRESENT INVENTION
The present invention is directed to a pressure sensitive adhesive composition useful in transdermal administration of pharmacologically active agents.
The transdermal delivery of therapeutic agents has been the subject of intense research and development for over 20 years. These efforts have resulted in the creation of several commercially successful products whose advantages over other dosage forms are well documented.
The skin, however, is an exceptionally well designed barrier. As a result, only a relatively small number of drug molecules are suitable for transdermal delivery.
Various techniques have been explored in an attempt to enhance the permeation of compounds which are not otherwise suitable for transdermal delivery. The most promising approaches have been found to be iontophoresis, electroporation, sonophoresis, and chemical enhancement. Of these methods, chemical enhancement is the more established, and is currently commercially employed.
Chemical enhancers, or percutaneous penetration enhancers, have a broad spectrum of chemical structure depending on the application in which they are to be employed. The most common enhancers belong to the following groups: non-ionic surfactants, alcohols, fatty acid esters, and amines.
In order for enhancers to function properly, they must be present at the skin/device interface in sufficiently high quantity (generally 5-40%
percent by weight based on the weight of the adhesive). As most transdermal drug delivery devices utilize pressure sensitive adhesives as a means of providing intimate contact between the drug delivery means and the skin, it is essential that the adhesive polymer be compatible with the specific enhancer used. In this way, adequate concentrations of the enhancer~can be achieved by proper formulation with the adhesive without disrupting the physical integrity of the adhesive.
Polyacrylates are well suited to obtain the desired compatibility in that the polarity of the pendant moieties can be altered to accommodate the structure of the enhancer. Unfortunately, it is generally observed that when enhancers are compounded with these adhesives, the compatibility may be too great, resulting in dramatic reduction in the cohesive strength of the adhesive system.
To reduce the loss of adhesive integrity, attempts have been made to cross-link the adhesive polymers. Although this does increase the cohesive strength, the adhesive often does not possess sufficient flow to allow for long term adhesion to skin.
Clearly, then, the proper balance of enhancer compatibility, cohesive strength, and polymer flow is required for properly designed adhesive/enhancer systems.
Polymeric compositions are known which are comprised of backbone polymers having grafted thereto pendant polymeric moieties. The type of backbone polymer and graft polymeric moiety employed varies depending upon the desired characteristics of the end product. See, for z17~91~
DRUG FLUX ENHANCER-TOLERANT PRESSURE
SENSITIVE ADHESIVE COMPOSITION
BACKGROUND OF THE PRESENT INVENTION
The present invention is directed to a pressure sensitive adhesive composition useful in transdermal administration of pharmacologically active agents.
The transdermal delivery of therapeutic agents has been the subject of intense research and development for over 20 years. These efforts have resulted in the creation of several commercially successful products whose advantages over other dosage forms are well documented.
The skin, however, is an exceptionally well designed barrier. As a result, only a relatively small number of drug molecules are suitable for transdermal delivery.
Various techniques have been explored in an attempt to enhance the permeation of compounds which are not otherwise suitable for transdermal delivery. The most promising approaches have been found to be iontophoresis, electroporation, sonophoresis, and chemical enhancement. Of these methods, chemical enhancement is the more established, and is currently commercially employed.
Chemical enhancers, or percutaneous penetration enhancers, have a broad spectrum of chemical structure depending on the application in which they are to be employed. The most common enhancers belong to the following groups: non-ionic surfactants, alcohols, fatty acid esters, and amines.
In order for enhancers to function properly, they must be present at the skin/device interface in sufficiently high quantity (generally 5-40%
percent by weight based on the weight of the adhesive). As most transdermal drug delivery devices utilize pressure sensitive adhesives as a means of providing intimate contact between the drug delivery means and the skin, it is essential that the adhesive polymer be compatible with the specific enhancer used. In this way, adequate concentrations of the enhancer~can be achieved by proper formulation with the adhesive without disrupting the physical integrity of the adhesive.
Polyacrylates are well suited to obtain the desired compatibility in that the polarity of the pendant moieties can be altered to accommodate the structure of the enhancer. Unfortunately, it is generally observed that when enhancers are compounded with these adhesives, the compatibility may be too great, resulting in dramatic reduction in the cohesive strength of the adhesive system.
To reduce the loss of adhesive integrity, attempts have been made to cross-link the adhesive polymers. Although this does increase the cohesive strength, the adhesive often does not possess sufficient flow to allow for long term adhesion to skin.
Clearly, then, the proper balance of enhancer compatibility, cohesive strength, and polymer flow is required for properly designed adhesive/enhancer systems.
Polymeric compositions are known which are comprised of backbone polymers having grafted thereto pendant polymeric moieties. The type of backbone polymer and graft polymeric moiety employed varies depending upon the desired characteristics of the end product. See, for z17~91~
example, U.S. Patent Nos. 3,786,116; 3,832,423;
3,842,146; 3,862,077; 3,879,494; 3,928,255;
3,989,768; 4,085,168; 4,551,388; 4,554,324;
3,842,146; 3,862,077; 3,879,494; 3,928,255;
3,989,768; 4,085,168; 4,551,388; 4,554,324;
4,656,213; 4,693,776; 4,732,808; 4,871,812; and 5,352,516. These patents disclose various types of such polymers which may or may not exhibit pressure sensitive adhesive properties.
Typical of the type of polymeric compositions disclosed in the above patents are compositions comprised of a backbone polymer such as an acrylic or methacrylic backbone polymer having attached thereto a graft polymer comprised of a polymerizable macromolecular monomer such .as styrene or alpha-methylstyrene. See, for example, U.S. Patent No. 4,554,324, and commonly-assigned U.S. Patent No. 5,352,516, among others, in this regard.
The acrylic pressure sensitive adhesives such as described in U.S. Patent No. 4,554,324 and U.S.
Patent No. 5,352,516 may be made from an acrylic ester and a polar acrylic monomer. The polar acrylic monomer can be one or a mixture of acrylic acid, acrylamide, acrylonitrile, itaconic acid, etc. The acrylic ester can be any aliphatic ester of acrylic acid. Such monomers are typically polymerized free radically by solution, suspension or emulsion polymerization. The acrylate portion of the copolymer is generally present in a generally high concentration and renders the polymer tacky. The polar monomer increases the ability of the adhesive to bond to a surface.
U.S. Patent Nos. 4,693,776 and 4,732,808 also disclose a pressure sensitive skin adhesive composition comprised of a macromer-reinforced acrylate copolymer. U.S. Patent No. 4,871,812 discloses a moldable medical adhesive comprising a blend of an acrylate terpol_ymer adhe~>ive containing a hydrophilic macromer moiety, and a reinforcing material which is a carbonylamido group containing polymer. U.S. Patent No. 4,656,213 is directed to an acrylic hot melt pressure sensitive adhesive comprising a polyacrylate graft copolymer which may be plasticized to enhance the adhesives properties thereof.
Such adhE:sives have been found to suffer from the disadvantage that their adhesive properties are not sufficiently compatible with the skin (due to inadequate long term tack) with the result that adhesive failure may occur after a short ~~ime due to movement of the skin.
It has accordingly been that reinforcement of the adhesive through the u;~e of graft polymeric moieties or macromers, followed by plasticization with conventional percutaneous penetration enhancers, allows for the desired level of cohesiveness while allowing for a degree of adhesive flow which is essential for long germ adhesion to skin.
In accordance with one embodiment of the present invention there is provided a d~_°ug flux enhancer-tolerant pressure U,~' .Y OF THE INVENTION
sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration en:hancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer, wherein the ba.s~e polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein. monomer A is a monomeric acrylic or methacrylic esiter of a :nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copol~Tmerizable with monomer A; with the proviso that the composition does nc6t comprise each of (a) a (C4_lo alkyl) acrylate or a (C4_lo a.ll~:y1) methacrylate monomer A, (b) an ethylenically unsaturated monomer B, (c) a polymer graft moiety which is a macromonomer having a molecular weight in the range 500 - 500,000,, and (d) a percutaneous penetration enhancer which is a generally oily material that raises the compliance value or lowers the glass transition temperature (Tg) of the composition as compared to the base polymer, and wherein (e) the structure and amount of the comonomers in the base polymer, the inherent viscosity o:f the base polymer, and the amount and structure of the active agent and the oily material provide the composition with a compliance value in the range of 2 x 10-1 cmz /N ( 2 x 10-6 cm2 /dyne ) to 4 x 10 2 cm2 /N ( 4 x 10-3 cm2/dyne).
In accordance with another embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administi°a:ble pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer,, wherein the base polymer component comprises a phase se~aa.rated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moietiE~s grafted thereto, wherein monomer A
is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 t.o 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein that at least one monomer B is selected from vinyl acetate, (3-carbox;yethyl acrylate or a polyethoxylated monomer.
In accordance with a further embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetrat~'~on enhancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer, wherein the base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomer;5 A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A
is a monomeric acrylic:: or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein the graft polymeric moiety is present in an amount of from 1.5 to 2..5 graft moieties per polymer backbone chain on average.
In accordance with a still further embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensii~ive adhesive composition comprised of a transdermal:Ly administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin too the active agent in admixture with a macromer reinforced base polymer, wherein the base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A
is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A wherein the copolymer is obtainable by copolymerizing monomer A, monomer B in an amount of up to 12$ by weight of the total weight of all monomers, and monomer C of the general formula X-Z, wherein X is a group copolymerizable with the monomers A and B, and Z is a polymeric graft moiety having a Tg greater than 20°C and formed from a monomer selected from acrylonitrile and methacrylonitrile; organic isocyanates:
organic diisoc:yanates; c:~~-C6 alkyl and allyl acrylates and 6a methacrylates: vinyl esters of aliphatic carboxylic acids;
vinyl lower C1-C6 ethe:r.s; conjugated dienes: 2-oxazolines;
vinyl unsaturated amides and N, N-di (C1-C6 alkyl ) acrylamides .
A transde:rmal delivery system which includes the compositions of the present invention is also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains to a pressure sensitive adhesive compo~;ition comprised of a mixture of a percutaneous penetration enhancer and a phase-separated graft copolymer as well as transdermal dru<~ delivery devices utilizing such a composition.
Specifica7.ly, the phase separated graft copolymer is comprised of copolymerized monomers A and B to form a backbone polymer having a polymeric moiety grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic acid ester of a non-tertiary alcohol having from 1 to 14 carbon atoms with the average number of carbon atoms being in the range of about 4 to 12, anti monomer B is a polar monomer which is copolymerizablE~ with monomer A.
Exemplary A monomers include but are not limited to esters of acrylic acid or methacrylic acid with non-tertiary alcohols such as 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, 1-dodecanol, etc.
Such monomers are known to those skilled in the art.
Exemplary B monomers include but are not limited to one or more of acrylic acid, '~ 2171911 methacrylic acid, itaconic acid, acrylamide, methylacrylamide, acrylonitrile, methacrylonitrile, diacetone acrylamide, and 2-carboxyl ethyl esters of acrylic acid.
The A monomer will generally be present in the copolymer in an amount with the range of from about 50 to 80 percent by weight, based on the total weight of the copolymer, with any additional monomers employed (such as the~B monomer) and the polymeric graft moiety comprising the remaining portion of the copolymer. Further, the graft polymeric moiety will generally comprise from about 2 to 30 percent by weight of the combined amount of the B monomer and the graft polymeric moiety.
Preferably, the polymer graft is a polymeric moiety having a Tg greater than 20°C.
The composition of the present invention successfully overcomes the deficiencies of prior art adhesive compositions by providing for the presence of graft polymeric moieties while also providing for the presence of graft polymer chains in an amount sufficient to provide a reinforcing function which inhibits or restricts flow of the polymer backbone in the presence of the enhancer and/or in the presence of water (such as moisture on the skin).
The copolymer of the present invention is characterized as being "phase-separated". That is, the backbone of the copolymer and the attached graft are incompatible and thus do not mix together to form a homogeneous phase. Instead, the copolymer backbone forms a continuous phase within which is dispersed the attached graft phase. The dispersed graft discontinuous phase thus acts to mechanically reinforce the continuous phase.
The polymer graft may be attached to the polymer backbone by conventional techniques such as (1) copolymerization with the respective monomers of the backbone polymer (i.e., monomers A and B together with graft polymeric monomer moiety C) or (2) attachment of the polymeric graft moiety to a preformed backbone polymer via a suitable functional group subsequent to formation of same by copolymerization of monomers A and B.
With regard to technique (1) which comprises the preferred technique, the copolymer of the present invention may be formed from copolymerized monomers A, B and C, wherein (1) monomer A is a monomeric acrylic or methacrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 14 carbon atoms with the average number of carbon atoms being in the range of about 4 to 12, (2) monomer B is a polar monomer copolymerizable with said monomer A, the B monomer being present in an amount of up to about 12% by weight of the total weight of all monomers, and (3) monomer C has the general formula X-Z
wherein X is a group copolymerizable with said monomers A and B (preferably a vinyl group), and Z is a polymeric graft moiety having a Tg greater than 20°C., said moiety Z being essentially unreactive under copolymerization conditions, and wherein said group X of said monomer C and said monomers A and B are copolymerized to form a polymeric backbone chain having pendant therefrom graft polymeric moiety Z.
A graft polymeric moiety may be prepared as a macromer and copolymerized with one or more A
and 8 monomers which form the backbone polymer such as acrylic acid, acrylamide, methacrylic acid, methacrylamide and alkyl acrylates where the alkyl groups contain from 1 to 24 carbon atoms (e. g., methyl, sahyl, propyl, isopropyl, butyl, amyl, hexyl, 2-ethylhexyl and other octyl, nonyl and decyl acrylates). See,.for instance, the disclosure of U.S. Patent No. 3,786,116 in this regard.
T~,rpical copolymerization techniques include but are not limited to conventional free radical initiated copolymerization techniques in the presence of a solvent. Suitable copolymerization temperatures range from about 20°C to 150°C for periods of time of from 2 to 24 hours until the desired degree of conversion occurs.
Upon completion of the polymerization process, the solvent is removed and a tacky acrylate copolymer results having an acceptable balance of tack and shear adhesive properties at high temperatures.
Depending upon the properties imparted to the backbone polymer as a result of the molecular weight: of the particular graft employed, the resulting copolymer adhesive may need to be used in solution or emulsion form rather than as a melt adhesive. That is, if the molecular weight of the graft is sufficiently high, the resultant adhesive may be applied to a backing material or substrate in emulsion or solution form, with the water or solvent being removed upon application to the substrate.
With regard to the polymeric graft moiety portion of the adhesive composition, U.S. Patent Nos. 3,786,116; 3,842,057; 3,842,058; 3,842,059;
3,862,098 ; 3,862,101, 3,862,102 and 4,554,324 5 disclose polymerizable macromers which are suitable for use as graft moieties on a backbone polymer as defined.
Preferably, the polymeric moiety Z is formed from a vinyl aromatic monomer. such as styrene, 10 alpha-methylstyrene, indene and p-tert butylstyrene. However, the polymeric moiety Z may also be formed from vinyl toluene, acenaphthalene, acrylonitrile and methacrylonitrile; organic isocyanates including lower alkyl, phenyl, lower alkyl phenyl and halophenyl isocyanates; organic diisocyanates including lower alkylene, phenylene, and tolylene diisocyanates; lower alkyl and allyl acrylates and methacrylates, including methyl, t-butyl acrylates, and methacrylates; lower olefins, such as ethylene, propylene, butylene, isobutylene, pentene, hexene, etc.; vinyl esters of aliphatic carboxylic acids such as vinyl acetate, vinyl propionate, vinyl octoate, vinyl oleate, vinyl stearate, vinyl benzoate, vinyl lower alkyl ethers; conjugated dimes such as isoprene and butadiene; 2-oxazolines such as 2-ethyl-2-oxazoline; and vinyl unsaturated amides such as acrylamide, methylacrylamide, N,N-di(lower alkyl) acrylamides such as N,N-dimethylacrylamide.
The selection of the specific polymerizable monomer for the polymer graft is not critical, since as the above listing suggests, a wide variety of monomers (and the resulting polymeric moieties) can be used with success as a polymeric graft in the claimed composition.
A variety of functional groups may be employed to attach the graft Z to the polymer backbone.
Exemplary functional groups include but are not O
n limited to -C-O-CHR-CH2- ;
O O
n a -C-O-CH2CH2-NH-C-O-CHR-CHl-to a n CH2-O-CHR-CH2-; -O-C-CH2-O-CHR-CH2- ; and -OCH2 CH2 -O-CHR--CH2 , where R is a hydrogen atom or a lower alkyl group.
The molecular weight of the graft polymeric moiety must be: sufficient to result in the formation of a "phase-separated" graft copolymer composition. Generally the molecular weight of the graft polymeric moiety will be within the range of from 2,000 to 60,000.
Preferably, the polymer graft is present in the copolymer in an amount of between 1.5 to 2.5 polymeric moieties per polymer backbone on average to enhance the high performance properties of the adhesive:. See U.S. Patent No. 5,352,516 in this regard..
The presence of the polymer graft on the backbone polymer in the manner stated has previously been found to result in a composition in which the respective polymeric backbone chains remain bound to ane another at temperatures above the Tg of the backbone polymer. That is, the respective separate phases of the backbone polymers and the graft polymeric moieties are caused to be bound together without disadvantageously affecting the adhesive characteristics of the composition.
The percutaneous penetration enhancer employed has the ability to increase permeability of skin to transdermally administered pharmacologically active agents. Such enhancers are well-known in the art, and are discussed at length in U.S.
Patent Nos. 5, 059, 426 and 5, 175, 052. By way of brief summary, such enhancers include but are not limited to surfactants (anionic, nonionic, cationic, zwitterionic), lipophilic solvents (terpenes, lactams), hydrophilic solvents (polyols, fatty acid esters, alcohols, sulfoxides), etc. Preferably, such enhance:rs are selected from the group consisting of sorbitols, ethoxylated alkyl phenols, glycerol, propylene, glycol, polyethylene glycols, fatty acid esters, alcohols, and amines, and may be either water-soluble or non-water-soluble.
It has been found that the desirable adhesive properties of the graft-reinforced base polymers used in the present invention ca:n be used with advantage upon admixture of percutaneous penetration enhancers with the base polymer to form a drug flux enhancer-tolerant pressure sensitive adhesive composition. That is, the enhancer can be admixed with the base polymer to maximize the ability of an incorporated pharmacologically active agent to be absorbed into the skin without adversely aff..ecting the adhesive properties of the adhesive. advantageously, it has been found that the percutaneous penetration enhancer can be used in amounts up to about 40 percent by weight, based on the weight of the composition, without adversely affecting the physical integrity of the adhesive or its adhesive properties. Preferably, the enhancer will be employed in an amount within the range of from 5 to 30 percent by weight, based on the weight of the composition.
The adhesive composition of the present invention may be used with advantage in a variety of conventional transdermal drug delivery devices.
Such devices may take many forms. Generally, such devices comprise a backing material and an adhesive layer on at least a portion of the backing material. A release liner covers the adhesive layer until use at which time the liner is removed and the adhesive layer placed on the skin. The backing material is impermeable to the pharmacologically active agent. The pharmacologically active agent may be contained in either a liquid reservoir within the backing layer, within a matrix layer on said backing layer disposed between the adhesive layer and the backing layer, or within a layer of the drug flux enhancer-adhesive composition of the present invention. The manner of formulation of such various transdermal drug delivery systems is within the ability of one skilled in the art.
In order to demonstrate the advantageous properties of the adhesive compositions of the present invention, various polymeric adhesive 3o compositions were prepared having the compositions described in the following Examples.
Examples 1-8 depict various phase-separated graft copolymers which may be employed in the composition of the present invention.
A. polyacrylate polymer having a polystyrene graft having a molecular weight of 13,000 is prepared by the following method. In a glass 1 liter reaction ~ressel the following charge stock was incrementally polymerized und er a nitrogen atmosphere at T3C over 5 1/2 hours with agitation to a viscosity of 4300 centipoise:
Isooct.yl Acrylate (A monomer) . 134 grams Acrylic Acid (B monomer) 3 grams *Qm-824 (B monomer) 25 grams Vinyl Acetate (B monomer) 20 grams Acryla,mide (B monomer) 3.15 grams Diacet:one Acrylamide (B monomer) 3.15 grams Polyst:yrene Methacrylate Macromer 8.58 grams Macromer (Graf:t) Benzoyl PeroxidE: (Initiator) .62 grams Ethyl Acetate (Solvent) 367 grams Note: Qm-824 i:a a Rohm & ~iaas product identified as f~-Carboxyethyl Acrylate A polyacrylate polymer having a polystyrene graft having a molecular weight of 20,000 is prepared by the method of Example 1 from the following charge: stock:
Isooct~yl Acrylate 134 grams Acryluc Acid 3 grams Qm-82~~ 25 grams Vinyl Acetate 20 grams 3 0 Acryl<~mide 3 . grams Diacei~one Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 14.39 grams Benzoyl Peroxide .64 grams Ethyl Acetate 378 grams *Trade-mark A polyacrylate polymer solution having a viscosity of 2,200 cps and having a polystyrene graft having a molecular weight of 30,000 is 5 prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 . 25 grams 10 Vinyl Acetate 20 grams Acrylamide 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 19.8 grams Benzoyl Peroxide .65 grams 15 Ethyl Acetate 388 grams A polyacrylate polymer solutio n having a viscosity of 200,000 cp and having a polystyrene graft having a molecular weight of 47,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 25 grams Vinyl Acetate 20 grams Acrylamide 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 30 grams Benzoyl Peroxide .64 grams Ethyl Acetate 372 grams A polyacrylate polymer solution having a viscosity of 4,700 cps after dilution with 150 grams of ethyl acetate and having a polystyrene graft having a molecular weight of 54,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 25 grams Vinyl Acetate 20 grams Acrylamide , 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 35.64 grams Benzoyl Peroxide .62 grams Ethyl Acetate 368 grams A polyacrylate polymer solution hav ing a viscosity of 11,600 cps and having a poly-alpha-methylstyrene graft having a molecular weight of 6,600 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 66.4 grams Acrylic Acid 1.48 grams Qm-824 12.34 grams Vinyl Acetate 9.87 grams Acrylamide 1.55 grams Diacetone Acrylamide 1.55 grams Poly Alpha-Methyl Styrene Macromer 2.62 grams Benzoyl Peroxide .31 grams Ethyl Acetate 181.4 grams A polyacrylate polymer solution having a viscosity of 18,000 cps and having a poly-alpha-methylstyrene graft having a molecular weight of 12,100 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 51.1 grams Acrylic Acid 1.14 grams Qm-824 9.5 grams Vinyl Acetate 7.6 grams Acrylamide 1.2 grams Diacetone Acrylamide 1.2 grams Poly Alpha-Methyl Styrene Macromer 3.26 grams l0 Benzoyl Peroxide .24 grams Ethyl Acetate 139.7 grams A polyacrylate polymer having a viscosity of 1,750 cps and having a poly-alpha-methylstyrene graft having a molecular weight o f 30,0 00 is prepared by the method of Example 1 fro m the following charge stock:
Isooctyl Acrylate 53.8 grams Acrylic Acid 1.2 grams Qm-824 10 grams Vinyl Acetate 8 grams Acrylamide 1.26 grams Diacetone Acrylamide 1.26 grams Poly Alpha-Methyl Styrene Macromer 7.92 grams Benzoyl Peroxide .26 grams Ethyl Acetate 88.6 grams Toluene 59 grams When the polymers described above are mixed with the percutaneous penetration enhancers, viscoelastics properties are obtained in accordance with the desired limits. Once formulated, the adhesives can be attached to any number of substrate materials (such as skin) by conventional means.
When mixed with the desired enhancer at the appropriate levE:l, the resulting viscoelastic propert:ies are such that the material is pressure sensitive and exhibits good long term skin adhesion. The basis for evaluation of the viscoelastic characteristics of the resulting enhancs:r/polymer composition is the determination of storage modulus (G'), loss modulus (G"), and tan delta values via dynamic mechanical analysis in a frequency :range of from 0.01 to 100 rad/sec.
Desirable defining parameters for long term skin adhesion are: (.,' at 0.01 rad/sec of from 5 X 10~3 dynes/cm~2 to 1 X 10~G dynes/cm~2, and a tan delta at 0.0~. rad/sec of from 0.3 to 0.8.
Tree following samples will serve to illustrate the versatility of these adhesive system: .
A polyacrylate base polymer having a polystyrene graft: of molecular weight of 20,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 275.3 grams *CD 504 57.4 grams Polyst~~rene Macromer 16.4 grams Hydroxypropyl Methacrylate 32.5 grams Benzoyl. Peroxide 0.94 grams Ethyl Acetate 439 grams Note: CD 504 is a polyethoxylated monomer available from Sartomer *Trade-mark 2~W91.~
The thus-formed polyacrylate is then mixed with 20.1 grams of isopropyl myristate as a percutaneous penetration enhancer.
A sample is prepared by casting the solution onto a siliconized PET release sheet to a wet film thickness of 24 mils, and dried in a 150°F oven until no solvent remains. The dried adhesive is then folded upon itself until a slab of 1.0 to 1.5 mm thickness and having no,obvious flaws is obtained.
The slab is then tested via dynamic mechanical analysis on a Rheometrics RAA DMA using a 12.5 mm disk arranged in a parallel plate configuration. The sample is tested using a frequency range of from 0.01 to 100 rad/sec, and 1% strain.
The sample is measured to have a G' at 0.01 rad/sec of 1.2 X 10~4 dynes/cm~2 and a tan delta at 0.01 rad/sec of 0.4.
The base polymer of Example 9 is mixed with 20.1 grams of N,N-Diethyl m- Toluamide (DEET) as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec being 4.5 X 10~4 dynes/cm~2 with a tan delta of 0.3.
The base polymer of. Example 9 is mixed with 20.1 grams lauryl alcohol as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec 21'1911 being 3.6 X 10~4 dynes/cm~2 with a tan delta of 0.30.
A polymeric base polymer having a polystyrene 5 graft of molecular weight 20,000 is prepared as in Example 1 from the following charge stock:
Isooctyl Acrylate 77.8 grams Acrylic Acid 1.8 ,grams Acrylamide 1.9 grams 10 Diacetone Acrylamide 1.9 grams Polystyrene Macromer 5.5 grams Vinyl Acetate 12.1 grams Ethyl Acetate 154.0 grams Benzoyl Peroxide 0.4 grams 15 The base polymer is then mixed with 25.3 grams of DEET as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec being 1.0 X 10~5 dynes/cm~2 with a tan delta of 20 0.32.
The base polymer of Example 12 is prepared and mixed with 43.0 grams of DEET as penetration enhancer.
A sample is prepared and tested as per Example 9, with the measured G' at 0.01 rad/sec being 4.6 X 10~4 dynes/cm~2 with a tan delta of 0.3.
The base polymer of Example 12 is prepared and mixed with 25.3 grams of lauryl alcohol as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 5.9 X 10~4 dynes/cm~2 with a tan delta of 0.39.
The base polymer of Example 12 is prepared and mixed with 25.3 grams of polysorbate 80 as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 7.6 X 10~4 dynes/cm~2 with a tan delta of 0.31.
The base polymer of Example 12 is prepared and mixed with 43.0 grams of isopropyl myristate as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 3.1 X 10~4 dynes/cm~2 with a tan delta of 0.41.
The pharmacologically active agent to be administered by use of the transdermal drug delivery mens is employed in a conventional manner. Suitable active agents include those that are compatible with the administration system of the present invention and exhibit the expected 'benefit upon percutaneous administration. Such active agents include, without limitation, antiinflammatory drugs, bacteriostatic agents, antifungal agents, coronary vasodilators, etc.
Exemplary of the most commonly transdermally-administered active agents are clonidine, estrodiol, nicotine, nitroglycerine and scopolamine, each commercially available in transdermal devices. See U.S. Patent No. 5,372,819, for a more detailed discussion of suitable percutaneous administered active agents.
Typical of the type of polymeric compositions disclosed in the above patents are compositions comprised of a backbone polymer such as an acrylic or methacrylic backbone polymer having attached thereto a graft polymer comprised of a polymerizable macromolecular monomer such .as styrene or alpha-methylstyrene. See, for example, U.S. Patent No. 4,554,324, and commonly-assigned U.S. Patent No. 5,352,516, among others, in this regard.
The acrylic pressure sensitive adhesives such as described in U.S. Patent No. 4,554,324 and U.S.
Patent No. 5,352,516 may be made from an acrylic ester and a polar acrylic monomer. The polar acrylic monomer can be one or a mixture of acrylic acid, acrylamide, acrylonitrile, itaconic acid, etc. The acrylic ester can be any aliphatic ester of acrylic acid. Such monomers are typically polymerized free radically by solution, suspension or emulsion polymerization. The acrylate portion of the copolymer is generally present in a generally high concentration and renders the polymer tacky. The polar monomer increases the ability of the adhesive to bond to a surface.
U.S. Patent Nos. 4,693,776 and 4,732,808 also disclose a pressure sensitive skin adhesive composition comprised of a macromer-reinforced acrylate copolymer. U.S. Patent No. 4,871,812 discloses a moldable medical adhesive comprising a blend of an acrylate terpol_ymer adhe~>ive containing a hydrophilic macromer moiety, and a reinforcing material which is a carbonylamido group containing polymer. U.S. Patent No. 4,656,213 is directed to an acrylic hot melt pressure sensitive adhesive comprising a polyacrylate graft copolymer which may be plasticized to enhance the adhesives properties thereof.
Such adhE:sives have been found to suffer from the disadvantage that their adhesive properties are not sufficiently compatible with the skin (due to inadequate long term tack) with the result that adhesive failure may occur after a short ~~ime due to movement of the skin.
It has accordingly been that reinforcement of the adhesive through the u;~e of graft polymeric moieties or macromers, followed by plasticization with conventional percutaneous penetration enhancers, allows for the desired level of cohesiveness while allowing for a degree of adhesive flow which is essential for long germ adhesion to skin.
In accordance with one embodiment of the present invention there is provided a d~_°ug flux enhancer-tolerant pressure U,~' .Y OF THE INVENTION
sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration en:hancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer, wherein the ba.s~e polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein. monomer A is a monomeric acrylic or methacrylic esiter of a :nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copol~Tmerizable with monomer A; with the proviso that the composition does nc6t comprise each of (a) a (C4_lo alkyl) acrylate or a (C4_lo a.ll~:y1) methacrylate monomer A, (b) an ethylenically unsaturated monomer B, (c) a polymer graft moiety which is a macromonomer having a molecular weight in the range 500 - 500,000,, and (d) a percutaneous penetration enhancer which is a generally oily material that raises the compliance value or lowers the glass transition temperature (Tg) of the composition as compared to the base polymer, and wherein (e) the structure and amount of the comonomers in the base polymer, the inherent viscosity o:f the base polymer, and the amount and structure of the active agent and the oily material provide the composition with a compliance value in the range of 2 x 10-1 cmz /N ( 2 x 10-6 cm2 /dyne ) to 4 x 10 2 cm2 /N ( 4 x 10-3 cm2/dyne).
In accordance with another embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administi°a:ble pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer,, wherein the base polymer component comprises a phase se~aa.rated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moietiE~s grafted thereto, wherein monomer A
is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 t.o 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein that at least one monomer B is selected from vinyl acetate, (3-carbox;yethyl acrylate or a polyethoxylated monomer.
In accordance with a further embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetrat~'~on enhancer to increase permeability of skin to the active agent in admixture with a macromer reinforced base polymer, wherein the base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomer;5 A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A
is a monomeric acrylic:: or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein the graft polymeric moiety is present in an amount of from 1.5 to 2..5 graft moieties per polymer backbone chain on average.
In accordance with a still further embodiment of the present invention there is provided a drug flux enhancer-tolerant pressure sensii~ive adhesive composition comprised of a transdermal:Ly administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin too the active agent in admixture with a macromer reinforced base polymer, wherein the base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A
is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A wherein the copolymer is obtainable by copolymerizing monomer A, monomer B in an amount of up to 12$ by weight of the total weight of all monomers, and monomer C of the general formula X-Z, wherein X is a group copolymerizable with the monomers A and B, and Z is a polymeric graft moiety having a Tg greater than 20°C and formed from a monomer selected from acrylonitrile and methacrylonitrile; organic isocyanates:
organic diisoc:yanates; c:~~-C6 alkyl and allyl acrylates and 6a methacrylates: vinyl esters of aliphatic carboxylic acids;
vinyl lower C1-C6 ethe:r.s; conjugated dienes: 2-oxazolines;
vinyl unsaturated amides and N, N-di (C1-C6 alkyl ) acrylamides .
A transde:rmal delivery system which includes the compositions of the present invention is also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention pertains to a pressure sensitive adhesive compo~;ition comprised of a mixture of a percutaneous penetration enhancer and a phase-separated graft copolymer as well as transdermal dru<~ delivery devices utilizing such a composition.
Specifica7.ly, the phase separated graft copolymer is comprised of copolymerized monomers A and B to form a backbone polymer having a polymeric moiety grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic acid ester of a non-tertiary alcohol having from 1 to 14 carbon atoms with the average number of carbon atoms being in the range of about 4 to 12, anti monomer B is a polar monomer which is copolymerizablE~ with monomer A.
Exemplary A monomers include but are not limited to esters of acrylic acid or methacrylic acid with non-tertiary alcohols such as 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol, 1-dodecanol, etc.
Such monomers are known to those skilled in the art.
Exemplary B monomers include but are not limited to one or more of acrylic acid, '~ 2171911 methacrylic acid, itaconic acid, acrylamide, methylacrylamide, acrylonitrile, methacrylonitrile, diacetone acrylamide, and 2-carboxyl ethyl esters of acrylic acid.
The A monomer will generally be present in the copolymer in an amount with the range of from about 50 to 80 percent by weight, based on the total weight of the copolymer, with any additional monomers employed (such as the~B monomer) and the polymeric graft moiety comprising the remaining portion of the copolymer. Further, the graft polymeric moiety will generally comprise from about 2 to 30 percent by weight of the combined amount of the B monomer and the graft polymeric moiety.
Preferably, the polymer graft is a polymeric moiety having a Tg greater than 20°C.
The composition of the present invention successfully overcomes the deficiencies of prior art adhesive compositions by providing for the presence of graft polymeric moieties while also providing for the presence of graft polymer chains in an amount sufficient to provide a reinforcing function which inhibits or restricts flow of the polymer backbone in the presence of the enhancer and/or in the presence of water (such as moisture on the skin).
The copolymer of the present invention is characterized as being "phase-separated". That is, the backbone of the copolymer and the attached graft are incompatible and thus do not mix together to form a homogeneous phase. Instead, the copolymer backbone forms a continuous phase within which is dispersed the attached graft phase. The dispersed graft discontinuous phase thus acts to mechanically reinforce the continuous phase.
The polymer graft may be attached to the polymer backbone by conventional techniques such as (1) copolymerization with the respective monomers of the backbone polymer (i.e., monomers A and B together with graft polymeric monomer moiety C) or (2) attachment of the polymeric graft moiety to a preformed backbone polymer via a suitable functional group subsequent to formation of same by copolymerization of monomers A and B.
With regard to technique (1) which comprises the preferred technique, the copolymer of the present invention may be formed from copolymerized monomers A, B and C, wherein (1) monomer A is a monomeric acrylic or methacrylic acid ester of a non-tertiary alcohol, said alcohol having from 1 to 14 carbon atoms with the average number of carbon atoms being in the range of about 4 to 12, (2) monomer B is a polar monomer copolymerizable with said monomer A, the B monomer being present in an amount of up to about 12% by weight of the total weight of all monomers, and (3) monomer C has the general formula X-Z
wherein X is a group copolymerizable with said monomers A and B (preferably a vinyl group), and Z is a polymeric graft moiety having a Tg greater than 20°C., said moiety Z being essentially unreactive under copolymerization conditions, and wherein said group X of said monomer C and said monomers A and B are copolymerized to form a polymeric backbone chain having pendant therefrom graft polymeric moiety Z.
A graft polymeric moiety may be prepared as a macromer and copolymerized with one or more A
and 8 monomers which form the backbone polymer such as acrylic acid, acrylamide, methacrylic acid, methacrylamide and alkyl acrylates where the alkyl groups contain from 1 to 24 carbon atoms (e. g., methyl, sahyl, propyl, isopropyl, butyl, amyl, hexyl, 2-ethylhexyl and other octyl, nonyl and decyl acrylates). See,.for instance, the disclosure of U.S. Patent No. 3,786,116 in this regard.
T~,rpical copolymerization techniques include but are not limited to conventional free radical initiated copolymerization techniques in the presence of a solvent. Suitable copolymerization temperatures range from about 20°C to 150°C for periods of time of from 2 to 24 hours until the desired degree of conversion occurs.
Upon completion of the polymerization process, the solvent is removed and a tacky acrylate copolymer results having an acceptable balance of tack and shear adhesive properties at high temperatures.
Depending upon the properties imparted to the backbone polymer as a result of the molecular weight: of the particular graft employed, the resulting copolymer adhesive may need to be used in solution or emulsion form rather than as a melt adhesive. That is, if the molecular weight of the graft is sufficiently high, the resultant adhesive may be applied to a backing material or substrate in emulsion or solution form, with the water or solvent being removed upon application to the substrate.
With regard to the polymeric graft moiety portion of the adhesive composition, U.S. Patent Nos. 3,786,116; 3,842,057; 3,842,058; 3,842,059;
3,862,098 ; 3,862,101, 3,862,102 and 4,554,324 5 disclose polymerizable macromers which are suitable for use as graft moieties on a backbone polymer as defined.
Preferably, the polymeric moiety Z is formed from a vinyl aromatic monomer. such as styrene, 10 alpha-methylstyrene, indene and p-tert butylstyrene. However, the polymeric moiety Z may also be formed from vinyl toluene, acenaphthalene, acrylonitrile and methacrylonitrile; organic isocyanates including lower alkyl, phenyl, lower alkyl phenyl and halophenyl isocyanates; organic diisocyanates including lower alkylene, phenylene, and tolylene diisocyanates; lower alkyl and allyl acrylates and methacrylates, including methyl, t-butyl acrylates, and methacrylates; lower olefins, such as ethylene, propylene, butylene, isobutylene, pentene, hexene, etc.; vinyl esters of aliphatic carboxylic acids such as vinyl acetate, vinyl propionate, vinyl octoate, vinyl oleate, vinyl stearate, vinyl benzoate, vinyl lower alkyl ethers; conjugated dimes such as isoprene and butadiene; 2-oxazolines such as 2-ethyl-2-oxazoline; and vinyl unsaturated amides such as acrylamide, methylacrylamide, N,N-di(lower alkyl) acrylamides such as N,N-dimethylacrylamide.
The selection of the specific polymerizable monomer for the polymer graft is not critical, since as the above listing suggests, a wide variety of monomers (and the resulting polymeric moieties) can be used with success as a polymeric graft in the claimed composition.
A variety of functional groups may be employed to attach the graft Z to the polymer backbone.
Exemplary functional groups include but are not O
n limited to -C-O-CHR-CH2- ;
O O
n a -C-O-CH2CH2-NH-C-O-CHR-CHl-to a n CH2-O-CHR-CH2-; -O-C-CH2-O-CHR-CH2- ; and -OCH2 CH2 -O-CHR--CH2 , where R is a hydrogen atom or a lower alkyl group.
The molecular weight of the graft polymeric moiety must be: sufficient to result in the formation of a "phase-separated" graft copolymer composition. Generally the molecular weight of the graft polymeric moiety will be within the range of from 2,000 to 60,000.
Preferably, the polymer graft is present in the copolymer in an amount of between 1.5 to 2.5 polymeric moieties per polymer backbone on average to enhance the high performance properties of the adhesive:. See U.S. Patent No. 5,352,516 in this regard..
The presence of the polymer graft on the backbone polymer in the manner stated has previously been found to result in a composition in which the respective polymeric backbone chains remain bound to ane another at temperatures above the Tg of the backbone polymer. That is, the respective separate phases of the backbone polymers and the graft polymeric moieties are caused to be bound together without disadvantageously affecting the adhesive characteristics of the composition.
The percutaneous penetration enhancer employed has the ability to increase permeability of skin to transdermally administered pharmacologically active agents. Such enhancers are well-known in the art, and are discussed at length in U.S.
Patent Nos. 5, 059, 426 and 5, 175, 052. By way of brief summary, such enhancers include but are not limited to surfactants (anionic, nonionic, cationic, zwitterionic), lipophilic solvents (terpenes, lactams), hydrophilic solvents (polyols, fatty acid esters, alcohols, sulfoxides), etc. Preferably, such enhance:rs are selected from the group consisting of sorbitols, ethoxylated alkyl phenols, glycerol, propylene, glycol, polyethylene glycols, fatty acid esters, alcohols, and amines, and may be either water-soluble or non-water-soluble.
It has been found that the desirable adhesive properties of the graft-reinforced base polymers used in the present invention ca:n be used with advantage upon admixture of percutaneous penetration enhancers with the base polymer to form a drug flux enhancer-tolerant pressure sensitive adhesive composition. That is, the enhancer can be admixed with the base polymer to maximize the ability of an incorporated pharmacologically active agent to be absorbed into the skin without adversely aff..ecting the adhesive properties of the adhesive. advantageously, it has been found that the percutaneous penetration enhancer can be used in amounts up to about 40 percent by weight, based on the weight of the composition, without adversely affecting the physical integrity of the adhesive or its adhesive properties. Preferably, the enhancer will be employed in an amount within the range of from 5 to 30 percent by weight, based on the weight of the composition.
The adhesive composition of the present invention may be used with advantage in a variety of conventional transdermal drug delivery devices.
Such devices may take many forms. Generally, such devices comprise a backing material and an adhesive layer on at least a portion of the backing material. A release liner covers the adhesive layer until use at which time the liner is removed and the adhesive layer placed on the skin. The backing material is impermeable to the pharmacologically active agent. The pharmacologically active agent may be contained in either a liquid reservoir within the backing layer, within a matrix layer on said backing layer disposed between the adhesive layer and the backing layer, or within a layer of the drug flux enhancer-adhesive composition of the present invention. The manner of formulation of such various transdermal drug delivery systems is within the ability of one skilled in the art.
In order to demonstrate the advantageous properties of the adhesive compositions of the present invention, various polymeric adhesive 3o compositions were prepared having the compositions described in the following Examples.
Examples 1-8 depict various phase-separated graft copolymers which may be employed in the composition of the present invention.
A. polyacrylate polymer having a polystyrene graft having a molecular weight of 13,000 is prepared by the following method. In a glass 1 liter reaction ~ressel the following charge stock was incrementally polymerized und er a nitrogen atmosphere at T3C over 5 1/2 hours with agitation to a viscosity of 4300 centipoise:
Isooct.yl Acrylate (A monomer) . 134 grams Acrylic Acid (B monomer) 3 grams *Qm-824 (B monomer) 25 grams Vinyl Acetate (B monomer) 20 grams Acryla,mide (B monomer) 3.15 grams Diacet:one Acrylamide (B monomer) 3.15 grams Polyst:yrene Methacrylate Macromer 8.58 grams Macromer (Graf:t) Benzoyl PeroxidE: (Initiator) .62 grams Ethyl Acetate (Solvent) 367 grams Note: Qm-824 i:a a Rohm & ~iaas product identified as f~-Carboxyethyl Acrylate A polyacrylate polymer having a polystyrene graft having a molecular weight of 20,000 is prepared by the method of Example 1 from the following charge: stock:
Isooct~yl Acrylate 134 grams Acryluc Acid 3 grams Qm-82~~ 25 grams Vinyl Acetate 20 grams 3 0 Acryl<~mide 3 . grams Diacei~one Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 14.39 grams Benzoyl Peroxide .64 grams Ethyl Acetate 378 grams *Trade-mark A polyacrylate polymer solution having a viscosity of 2,200 cps and having a polystyrene graft having a molecular weight of 30,000 is 5 prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 . 25 grams 10 Vinyl Acetate 20 grams Acrylamide 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 19.8 grams Benzoyl Peroxide .65 grams 15 Ethyl Acetate 388 grams A polyacrylate polymer solutio n having a viscosity of 200,000 cp and having a polystyrene graft having a molecular weight of 47,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 25 grams Vinyl Acetate 20 grams Acrylamide 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 30 grams Benzoyl Peroxide .64 grams Ethyl Acetate 372 grams A polyacrylate polymer solution having a viscosity of 4,700 cps after dilution with 150 grams of ethyl acetate and having a polystyrene graft having a molecular weight of 54,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 134 grams Acrylic Acid 3 grams Qm-824 25 grams Vinyl Acetate 20 grams Acrylamide , 3.15 grams Diacetone Acrylamide 3.15 grams Polystyrene Methacrylate Macromer 35.64 grams Benzoyl Peroxide .62 grams Ethyl Acetate 368 grams A polyacrylate polymer solution hav ing a viscosity of 11,600 cps and having a poly-alpha-methylstyrene graft having a molecular weight of 6,600 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 66.4 grams Acrylic Acid 1.48 grams Qm-824 12.34 grams Vinyl Acetate 9.87 grams Acrylamide 1.55 grams Diacetone Acrylamide 1.55 grams Poly Alpha-Methyl Styrene Macromer 2.62 grams Benzoyl Peroxide .31 grams Ethyl Acetate 181.4 grams A polyacrylate polymer solution having a viscosity of 18,000 cps and having a poly-alpha-methylstyrene graft having a molecular weight of 12,100 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 51.1 grams Acrylic Acid 1.14 grams Qm-824 9.5 grams Vinyl Acetate 7.6 grams Acrylamide 1.2 grams Diacetone Acrylamide 1.2 grams Poly Alpha-Methyl Styrene Macromer 3.26 grams l0 Benzoyl Peroxide .24 grams Ethyl Acetate 139.7 grams A polyacrylate polymer having a viscosity of 1,750 cps and having a poly-alpha-methylstyrene graft having a molecular weight o f 30,0 00 is prepared by the method of Example 1 fro m the following charge stock:
Isooctyl Acrylate 53.8 grams Acrylic Acid 1.2 grams Qm-824 10 grams Vinyl Acetate 8 grams Acrylamide 1.26 grams Diacetone Acrylamide 1.26 grams Poly Alpha-Methyl Styrene Macromer 7.92 grams Benzoyl Peroxide .26 grams Ethyl Acetate 88.6 grams Toluene 59 grams When the polymers described above are mixed with the percutaneous penetration enhancers, viscoelastics properties are obtained in accordance with the desired limits. Once formulated, the adhesives can be attached to any number of substrate materials (such as skin) by conventional means.
When mixed with the desired enhancer at the appropriate levE:l, the resulting viscoelastic propert:ies are such that the material is pressure sensitive and exhibits good long term skin adhesion. The basis for evaluation of the viscoelastic characteristics of the resulting enhancs:r/polymer composition is the determination of storage modulus (G'), loss modulus (G"), and tan delta values via dynamic mechanical analysis in a frequency :range of from 0.01 to 100 rad/sec.
Desirable defining parameters for long term skin adhesion are: (.,' at 0.01 rad/sec of from 5 X 10~3 dynes/cm~2 to 1 X 10~G dynes/cm~2, and a tan delta at 0.0~. rad/sec of from 0.3 to 0.8.
Tree following samples will serve to illustrate the versatility of these adhesive system: .
A polyacrylate base polymer having a polystyrene graft: of molecular weight of 20,000 is prepared by the method of Example 1 from the following charge stock:
Isooctyl Acrylate 275.3 grams *CD 504 57.4 grams Polyst~~rene Macromer 16.4 grams Hydroxypropyl Methacrylate 32.5 grams Benzoyl. Peroxide 0.94 grams Ethyl Acetate 439 grams Note: CD 504 is a polyethoxylated monomer available from Sartomer *Trade-mark 2~W91.~
The thus-formed polyacrylate is then mixed with 20.1 grams of isopropyl myristate as a percutaneous penetration enhancer.
A sample is prepared by casting the solution onto a siliconized PET release sheet to a wet film thickness of 24 mils, and dried in a 150°F oven until no solvent remains. The dried adhesive is then folded upon itself until a slab of 1.0 to 1.5 mm thickness and having no,obvious flaws is obtained.
The slab is then tested via dynamic mechanical analysis on a Rheometrics RAA DMA using a 12.5 mm disk arranged in a parallel plate configuration. The sample is tested using a frequency range of from 0.01 to 100 rad/sec, and 1% strain.
The sample is measured to have a G' at 0.01 rad/sec of 1.2 X 10~4 dynes/cm~2 and a tan delta at 0.01 rad/sec of 0.4.
The base polymer of Example 9 is mixed with 20.1 grams of N,N-Diethyl m- Toluamide (DEET) as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec being 4.5 X 10~4 dynes/cm~2 with a tan delta of 0.3.
The base polymer of. Example 9 is mixed with 20.1 grams lauryl alcohol as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec 21'1911 being 3.6 X 10~4 dynes/cm~2 with a tan delta of 0.30.
A polymeric base polymer having a polystyrene 5 graft of molecular weight 20,000 is prepared as in Example 1 from the following charge stock:
Isooctyl Acrylate 77.8 grams Acrylic Acid 1.8 ,grams Acrylamide 1.9 grams 10 Diacetone Acrylamide 1.9 grams Polystyrene Macromer 5.5 grams Vinyl Acetate 12.1 grams Ethyl Acetate 154.0 grams Benzoyl Peroxide 0.4 grams 15 The base polymer is then mixed with 25.3 grams of DEET as penetration enhancer.
A sample is prepared and tested as per Example 9 with the measured G' at 0.01 rad/sec being 1.0 X 10~5 dynes/cm~2 with a tan delta of 20 0.32.
The base polymer of Example 12 is prepared and mixed with 43.0 grams of DEET as penetration enhancer.
A sample is prepared and tested as per Example 9, with the measured G' at 0.01 rad/sec being 4.6 X 10~4 dynes/cm~2 with a tan delta of 0.3.
The base polymer of Example 12 is prepared and mixed with 25.3 grams of lauryl alcohol as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 5.9 X 10~4 dynes/cm~2 with a tan delta of 0.39.
The base polymer of Example 12 is prepared and mixed with 25.3 grams of polysorbate 80 as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 7.6 X 10~4 dynes/cm~2 with a tan delta of 0.31.
The base polymer of Example 12 is prepared and mixed with 43.0 grams of isopropyl myristate as penetration enhancer.
A sample is prepared and tested per Example 9 with the measured G' at 0.01 rad/sec being 3.1 X 10~4 dynes/cm~2 with a tan delta of 0.41.
The pharmacologically active agent to be administered by use of the transdermal drug delivery mens is employed in a conventional manner. Suitable active agents include those that are compatible with the administration system of the present invention and exhibit the expected 'benefit upon percutaneous administration. Such active agents include, without limitation, antiinflammatory drugs, bacteriostatic agents, antifungal agents, coronary vasodilators, etc.
Exemplary of the most commonly transdermally-administered active agents are clonidine, estrodiol, nicotine, nitroglycerine and scopolamine, each commercially available in transdermal devices. See U.S. Patent No. 5,372,819, for a more detailed discussion of suitable percutaneous administered active agents.
Claims (36)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to said active agent in admixture with a macromer reinforced base polymer, wherein said base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A
with the proviso that the composition does not comprise each of (a) a (C4-10 alkyl) acrylate or a (C4-10 alkyl) methacrylate monomer A, (b) an ethylenically unsaturated monomer B, (c) a polymer graft moiety which is a macromonomer having a molecular weight in the range 500 - 500,000, and (d) a percutaneous penetration enhancer which is a generally oily material that raises the compliance value or lowers the glass transition temperature (Tg) of the composition as compared to the base polymer, and wherein (e) the structure and amount of the comonomers in the base polymer, the inherent viscosity of the base polymer, and the amount and structure of the active agent and the oily material provide the composition. with a compliance value in the range of 2 × 10-1 cm2 /N (2 × 10-6 cm2 /dyne ) to 4 × 10 2 cm2 /N
(4 × 10-3 cm2 /dyne ).
with the proviso that the composition does not comprise each of (a) a (C4-10 alkyl) acrylate or a (C4-10 alkyl) methacrylate monomer A, (b) an ethylenically unsaturated monomer B, (c) a polymer graft moiety which is a macromonomer having a molecular weight in the range 500 - 500,000, and (d) a percutaneous penetration enhancer which is a generally oily material that raises the compliance value or lowers the glass transition temperature (Tg) of the composition as compared to the base polymer, and wherein (e) the structure and amount of the comonomers in the base polymer, the inherent viscosity of the base polymer, and the amount and structure of the active agent and the oily material provide the composition. with a compliance value in the range of 2 × 10-1 cm2 /N (2 × 10-6 cm2 /dyne ) to 4 × 10 2 cm2 /N
(4 × 10-3 cm2 /dyne ).
2. A drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to said active agent in admixture with a macromer reinforced base polymer, wherein said base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein that at least one monomer B is selected from vinyl acetate, .beta.-carboxyethyl acrylate or a polyethoxylated monomer.
3. A composition as claimed in claim 2, wherein said one monomer B is vinyl acetate.
4. A composition as claimed in claim 2, wherein said one monomer B is .beta.-carboxyethyl acrylate.
5. A composition as claimed in claim 3, wherein both vinyl acetate and .beta.-carboxyethyl acrylate are monomers B.
6. A composition as claimed in any one of claims 2 to 5, wherein the graft polymeric moiety is polystyrene methacrylate macromer or poly .alpha.-methyl styrene macromer.
7. A composition as claimed in claim 2, wherein said one monomer B is a polyethoxylated monomer.
8. A composition as claimed in claim 7, wherein the graft polymeric moiety is polystyrene macromer.
9. A composition as claimed in any one of claims 2 to 8, wherein monomer A is isooctyl acrylate.
10. A drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to said active agent in admixture with a macromer reinforced base polymer, wherein said base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A, wherein the graft polymeric moiety is present in an amount of from 1.5 to 2.5 graft moieties per polymer backbone chain on average.
11. A drug flux enhancer-tolerant pressure sensitive adhesive composition comprised of a transdermally administrable pharmacologically active agent and a percutaneous penetration enhancer to increase permeability of skin to said active agent in admixture with a macromer reinforced base polymer, wherein said base polymer component comprises a phase separated graft copolymer comprised of copolymerized monomers A and B forming a backbone polymer having polymeric moieties grafted thereto, wherein monomer A is a monomeric acrylic or methacrylic ester of a nontertiary alcohol having from 1 to 14 carbon atoms, with the average number of carbon atoms being in the range of about 4 to 12, and monomer B is a polar monomer which is copolymerizable with monomer A
wherein said copolymer is obtainable by copolymerizing monomer A, monomer B in an amount of up to 12% by weight of the total weight of all monomers, and monomer C of the general formula X-Z, wherein X is a group copolymerizable with said monomers A and B, and Z is a polymeric graft moiety having a Tg greater than 20°C and formed from a monomer selected from acrylonitrile and methacrylonitrile; organic isocyanates; organic diisocyanates;
C2-C6 alkyl and allyl acrylates and methacrylates; vinyl esters of aliphatic carboxylic acids; vinyl lower C1-C6 ethers conjugated dienes; 2-axazolines; vinyl unsaturated amides and N, N-di (C1-C6 alkyl) acrylamides.
wherein said copolymer is obtainable by copolymerizing monomer A, monomer B in an amount of up to 12% by weight of the total weight of all monomers, and monomer C of the general formula X-Z, wherein X is a group copolymerizable with said monomers A and B, and Z is a polymeric graft moiety having a Tg greater than 20°C and formed from a monomer selected from acrylonitrile and methacrylonitrile; organic isocyanates; organic diisocyanates;
C2-C6 alkyl and allyl acrylates and methacrylates; vinyl esters of aliphatic carboxylic acids; vinyl lower C1-C6 ethers conjugated dienes; 2-axazolines; vinyl unsaturated amides and N, N-di (C1-C6 alkyl) acrylamides.
12. A composition as claimed in claim 11, wherein Z is formed from monomer selected from acrylonitrile and methacrylonitrile; C1-C6 alkyl, phenyl, (C1-C6 alkyl) phenyl and halophenyl isocyanates; C1-C6 alkylene, phenylene, and tolylene diisocyantes; methyl, t-butyl acrylates and methacrylates, vinyl acetate, vinyl propionate, vinyl octoate, vinyl oleate, vinyl stearate, vinyl benzoate: isoprene and butadiene; 2-ethyl-2-oxazoline; acrylamide. methacrylamide, and N,N-dimethylacrylamide.
13. A composition as claimed in claim 11 or claim 12, wherein X is a vinyl group.
14. A composition as claimed in claim 11 or claim 12, wherein Z is attached to the polymer backbone by a functional group selected from -CH2-O-CHR-CH2- ;
and -OCH2CH2-O-CHR-CH2-;
where R is a hydrogen atom or a C1-C6 alkyl group.
and -OCH2CH2-O-CHR-CH2-;
where R is a hydrogen atom or a C1-C6 alkyl group.
15. A composition as claimed in claim 1 or claim 10, wherein said graft polymeric moiety is a polymerized monoalkenyl-substituted aromatic hydrocarbon.
16. A composition as claimed in claim 15, wherein said polymerized monoalkenyl-substituted aromatic hydrocarbon comprises polystyrene.
17. A composition as claimed in any one of claims 1 and to 15, wherein said percutaneous penetration enhancer is N,N-diethyl m-toluamide.
18. A composition as claimed in any one of claims 1 and 10 to 15, wherein said percutaneous penetration enhancer is polysorbate 80.
19. A composition as claimed in any one of claims 1 and 10 to 15, wherein said percutaneous penetration enhancer is selected from sorbitols, ethoxylated alkyl phenols, glycerol, propylene glycol, polyethylene glycols, fatty acid esters, alcohols, and amines.
20. A composition as claimed in any one of claims 1 and 10 to 19, wherein the molecular weight of said graft polymeric moiety is in the range of from about 30,000 to 60,000.
21. A composition as claimed in any one of claims 1 and 11 to 20, wherein the graft polymeric moiety is present in an amount of from 1.5 to 2.5 graft moieties per polymer backbone chain on average.
22. A composition as claimed in claim 10 or claim 21, wherein said graft polymeric moiety is present in a amount of about 2 polymeric moieties per polymeric backbone chain on average.
23. A composition as claimed in any one of claims 1 and to 22, wherein said graft polymeric moiety comprises from 2 to 30 percent by weight of the combined weight of the B
monomer and the graft polymeric moiety.
monomer and the graft polymeric moiety.
24. A composition as claimed in any one of claims 1 and 10 to 23, wherein said B monomer is selected from acrylic acid, methacrylic acid, itaconic acid, acrylamide, methylacrylamide, acrylonitrile, methacrylonitrile, diacetone acrylamide, and 2-carboxyl ethyl esters of acrylic acid.
25. A composition as claimed in any one of claims 1 and 10 to 24, wherein said base polymer comprises from 50 to 80 percent by weight of said A monomer (based on the total weight of the copolymer).
26. A composition as claimed in any one of claims 1 and 10 to 25, wherein said A monomer comprises an ester of acrylic or methacrylic acid with a non-tertiary alcohol selected from 1-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-heptanol, 2-octanol, 1-decanol and 1-dodecanol.
27. A composition as claimed in any one of claims 1 and to 26, wherein said percutaneous penetration enhancer is present in said composition in an amount of up to 40 percent by weight.
28. A composition as claimed in claim 27, wherein said percutaneous penetration enhancer is present in said composition in an amount in the range of from 5 to 30 percent by weight.
29. A transdermal delivery system for administering at least one pharmacologically active agent comprising a flexible backing material impermeable to said active agent and an adhesive layer on at least a portion of said backing material, wherein said adhesive layer comprises a pressure sensitive adhesive composition as defined in claim 1.
30. A delivery system as claimed in claim 29, wherein said percutaneous penetration enhancer and/or said graft copolymer is as defined in any one of claims 17 to 28.
31. A transdermal delivery system for administering at least one pharmacologically active agent comprising a flexible backing material impermeable to said active agent and an adhesive layer on at least a portion of said backing material, wherein said adhesive layer comprises a pressure sensitive adhesive composition as defined in claim 2.
32. A delivery system as claimed in claim 31, wherein said percutaneous penetration enhancer and/or said graft copolymer is as defined in any one of claims 3 to 9.
33. A transdermal delivery system for administering at least one pharmacologically active agent comprising a flexible backing material impermeable to said active agent and an adhesive layer on at least a portion of said backing material, wherein said adhesive layer comprises a pressure sensitive adhesive composition as defined in claim 10.
34. A delivery system as claimed in claim 33, wherein said percutaneous penetration enhancer and/or said graft copolymer is as defined in any one of claims 17 to 28.
35. A transdermal delivery system for administering at least one pharmacologically active agent comprising a flexible backing material impermeable to said active agent and an adhesive layer on at least a portion of said backing material, wherein said adhesive layer comprises a pressure sensitive adhesive composition as defined in claim 11.
36. A delivery system as claimed in claim 35, wherein said percutaneous penetration enhancer and/or said graft copolymer is as defined in any one of claims 12, 13, 14 and 17 to 28.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/405,872 | 1995-03-17 | ||
| US08/405,872 US5573778A (en) | 1995-03-17 | 1995-03-17 | Drug flux enhancer-tolerant pressure sensitive adhesive composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2171911A1 CA2171911A1 (en) | 1996-09-18 |
| CA2171911C true CA2171911C (en) | 2005-06-14 |
Family
ID=23605591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002171911A Expired - Fee Related CA2171911C (en) | 1995-03-17 | 1996-03-15 | Drug flux enhancer-tolerant pressure sensitive adhesive composition |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5573778A (en) |
| EP (1) | EP0732100B1 (en) |
| JP (1) | JPH08319464A (en) |
| KR (1) | KR100418489B1 (en) |
| AT (1) | ATE243509T1 (en) |
| AU (1) | AU4808596A (en) |
| CA (1) | CA2171911C (en) |
| DE (1) | DE69628776T2 (en) |
| ES (1) | ES2204996T3 (en) |
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-
1996
- 1996-03-14 AU AU48085/96A patent/AU4808596A/en not_active Abandoned
- 1996-03-15 AT AT96301769T patent/ATE243509T1/en not_active IP Right Cessation
- 1996-03-15 ES ES96301769T patent/ES2204996T3/en not_active Expired - Lifetime
- 1996-03-15 CA CA002171911A patent/CA2171911C/en not_active Expired - Fee Related
- 1996-03-15 DE DE69628776T patent/DE69628776T2/en not_active Revoked
- 1996-03-15 EP EP96301769A patent/EP0732100B1/en not_active Revoked
- 1996-03-16 KR KR1019960007140A patent/KR100418489B1/en not_active IP Right Cessation
- 1996-03-18 JP JP8060861A patent/JPH08319464A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU4808596A (en) | 1996-09-26 |
| EP0732100A2 (en) | 1996-09-18 |
| EP0732100B1 (en) | 2003-06-25 |
| DE69628776T2 (en) | 2004-08-05 |
| CA2171911A1 (en) | 1996-09-18 |
| KR100418489B1 (en) | 2005-02-02 |
| ATE243509T1 (en) | 2003-07-15 |
| EP0732100A3 (en) | 1998-07-08 |
| US5573778A (en) | 1996-11-12 |
| DE69628776D1 (en) | 2003-07-31 |
| ES2204996T3 (en) | 2004-05-01 |
| KR960034348A (en) | 1996-10-22 |
| JPH08319464A (en) | 1996-12-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20090316 |