Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-05-01
2001-01-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S449000
Reexamination Certificate
active
06174546
ABSTRACT:
BACKGROUND OF THE PRESENT INVENTION
The present invention is directed to a pressure sensitive adhesive useful in transdermal administration of pharmacologically active agents, in particular estrogen and/or progestin 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, including hormones such as estrogen and/or progestin.
It is known to administer steroidal hormones such as estrogen and/or progestin active agents by transdermal means to a patient. See, for example, U.S. Pat. Nos. 5,108,995; 5,223,261; 5,242,951; 5,422,119; 5,460,820; and WO 96/08229. It has been found that such active agents are susceptible to crystallization within the adhesive matrix over time. Such crystallization inhibits the ability of the transdermal device to deliver the active agent to the patient.
The prior art does not provide a transdermal pressure sensitive adhesive which both serves as a satisfactory matrix for the delivery of an estrogen and/or progestin active agent as well as inhibiting the crystallization of such active agent in order to enhance the long-term effectiveness of the delivery system.
OBJECTS AND SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a pressure sensitive adhesive drug delivery system which possesses acceptable compatibility with active drug agents while maintaining the appropriate viscoelastic characteristics for adequate skin adhesion.
It is also an object of the present invention to provide a pressure sensitive adhesive drug delivery system which reduces the tendency of hormones to crystallize within the transdermal drug delivery system.
In accordance with the present invention, there is thus provided a transdermal drug delivery composition having pressure sensitive adhesive properties comprised of (1) a graft copolymer comprised of a (meth)acrylic ester backbone copolymer optionally including at least one N-vinyl lactam monomer and having an optionally crooslinked polymeric moiety grafted thereto containing hydrophilic repeat units, and (2) a pharmacologically active agent in homogeneous admixture with said macromer reinforced base polymer.
In accordance with the present invention, there is also provided a transdermal drug delivery system for administering a pharmacologically active agent comprising a flexible backing material impermeable to said pharmacologically active agent and an adhesive layer on at least a portion of said backing material, the improvement wherein said adhesive layer comprises an optionally crosslinked graft copolymer comprised of a (meth)acrylic ester backbone copolymer optionally including at least one N-vinyl lactam monomer and having a polymeric moiety grafted thereto containing hydrophilic repeat units.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a pressure sensitive adhesive transdermal drug delivery composition comprised of a graft copolymer as well as a transdermal delivery device utilizing such a composition.
The graft copolymer pressure sensitive adhesive employed in the present invention is comprised of a backbone polymer having a polymeric moiety grafted thereto. The graft copolymer comprises the reaction product of at least one (meth)acrylic acid ester A monomer (as defined), at least optional B monomer, optionally a polymeric graft moiety C having a T
g
greater than 20° C., and a polymeric graft moiety D containing hydrophilic repeat units.
The graft copolymer includes at least one A monomer consisting of a monomeric (meth)acrylic acid ester of a non-tertiary alcohol where the alcohol portion has from 1 to 30 carbon atoms. 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.
Advantageously, it has been found useful to employ at least one A monomer formed from an alcohol having at least 12 carbon atoms. The use of an A monomer formed from an alcohol having at least 18 carbon atoms is particularly desirable. Such exemplary A monomers include but are not limited to lauryl acrylate (C
12
), tridecylacrylate (C
13
), myristyl acrylate (C
14
), palmityl acrylate (C
16
), and stearyl acrylate (C
18
). Such monomers are known to those skilled in the art.
The presence of an A monomer having a carbon chain of at least 12 carbon atoms has been found to enhance the compatibility of the adhesive with oily or non-water soluble drug flux or skin permeation enhancers which may be employed. Such enhancers have not been found to be particularly compatible with conventional transdermal adhesives containing a major portion of A monomers formed from alcohols having from 4 to 12 carbon atoms. While the use of A monomers formed from alcohols having from 4 to 12 carbon atoms in the adhesive of the present invention is appropriate, it is preferable for the at least one A monomer component to comprise at least 30 percent by weight of an A monomer formed from an alcohol having greater than 12 carbon atoms. The at least one A monomer component (if more than one A monomer is present) will exhibit an average number of carbon atoms in the alcohol portion of the total acrylic or (meth)acrylic acid esters of from 4 to 16, and preferably at least 10.
One or more optional polymerizable B monomers may be incorporated in the copolymer which B monomer(s) is copolymerizable with the A monomer. Such additional B monomer(s) may be either hydrophilic or hydrophobic.
Exemplary optional B monomers include vinyl monomers having at least one nitrogen atom. Such monomers (each of which exhibit a T
g
of <20° C.) include but are not limited to N-mono-substituted acrylamides such as acrylamide, methacrylamide, N-methylacrylamide, N-ethylacrylamide, N-methylolacrylamide, N-hydroxyethylacrylamide, and diacetone acrylamide; N,N-disubstituted acrylamides such as N,N-dimethylacrylamide, N,N-diethylacrylamide, N-ethyl-N-aminoethylacrylamide, N-ethyl-N-hydroxyethylacrylamide, N,N-dimethylolacrylamide, and N,N-dihydroxyethylacrylamide, etc.
Other optional B monomers may include, for example, various vinyl monomers such as acrylic and methacrylic acid, methoxyethyl acrylate, or methacrylate, ethyoxyethyl acrylate or methacrylate, glycerol acrylate or methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, beta-carboxyethyl acrylate, vinyl pyrrolidone and vinyl caprolactam (each of which also exhibit a T
g
of <20° C.).
The at least one B monomer preferably comprises an N-vinyl lactam monomer. Exemplary N-vinyl lactam monomers include but are not limited to N-vinyl-2-pyrrolidone; 5-methyl-N-vinyl-2-pyrrolidone; 5-ethyl-N-vinyl-2-pyrrolidone; 3,3-dimethyl-N-vinyl-2-pyrrolidone; 3-methyl-N-vinyl-2-pyrrolidone; 3-ethyl-N-vinyl-2-pyrrolidone; 4-methol-N-vinyl-2-pyrrolidone; 4-ethyl-N-vinyl-2-pyrrolidone; N-vinyl-2-valerolactam; N-vinyl-2-caprolactam; and mixtures of any of the foregoing. Preferably, the N-vinyl lactam is N-vinyl-2-pyrrolidone.
The optional graft polymeric moiety C has a
T
g
greater than 20° C. Graft polymeric moiety C has the formula X—Z wherein X is a group copolymerizable with monomers A and B or capable of attachment to copolymerized A and B monomers and Z is a polymeric graft moiety having a T
g
greater than 20° C. The Z moiety is essentially unreactive under copolymerization conditions.
More specifically, the X moiety is an unsaturated polymerizable moiety the composition of which is not critical. The X moiety may be, for example, when intended to be copolymerizable with monomers A and B, simp
Stutzman Barbara A.
Therriault Donald J.
Zajaczkowski Michael J.
Adhesives Research Inc.
Page Thurman K.
Seidleck Brian K.
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