CA2594183A1 - Water-absorbent adhesive compositions and associated methods of manufacture and use - Google Patents
Water-absorbent adhesive compositions and associated methods of manufacture and use Download PDFInfo
- Publication number
- CA2594183A1 CA2594183A1 CA 2594183 CA2594183A CA2594183A1 CA 2594183 A1 CA2594183 A1 CA 2594183A1 CA 2594183 CA2594183 CA 2594183 CA 2594183 A CA2594183 A CA 2594183A CA 2594183 A1 CA2594183 A1 CA 2594183A1
- Authority
- CA
- Canada
- Prior art keywords
- poly
- composition
- polymer
- eudragit
- recurring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D5/00—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures
- B05D5/10—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures to obtain an adhesive surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of 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; Compositions of derivatives of such polymers
- A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/817—Compositions of 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 a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions or derivatives of such polymers, e.g. vinylimidazol, vinylcaprolactame, allylamines (Polyquaternium 6)
- A61K8/8176—Homopolymers of N-vinyl-pyrrolidones. Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/817—Compositions of 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 a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions or derivatives of such polymers, e.g. vinylimidazol, vinylcaprolactame, allylamines (Polyquaternium 6)
- A61K8/8182—Copolymers of vinyl-pyrrolidones. Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/58—Adhesives
- A61L15/585—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/06—Ethers; Acetals; Ketals; Ortho-esters
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/10—Esters; Ether-esters
- C08K5/11—Esters; Ether-esters of acyclic polycarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- C08L33/04—Homopolymers or copolymers of esters
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L39/00—Compositions of 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 a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
- C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
- C08L39/06—Homopolymers or copolymers of N-vinyl-pyrrolidones
-
- 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
- C09J133/14—Homopolymers or copolymers of esters of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/26—Optical properties
- A61K2800/262—Transparent; Translucent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/54—Polymers characterized by specific structures/properties
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
Abstract
An adhesive composition is provided that is water-insoluble yet water-absorbent, i.e., capable of absorbing up to 15 wt.% water or more. The composition is composed of a film-forming hydrophilic polymer with at least one linear segment having a plurality of recurring polar groups along the polymer backbone, a complementary multifunctional polymer with a plurality of recurring functional groups that noncovalently bind to the polar groups on the film-forming polymer, and a plasticizer. A method for manufacturing the adhesive composition is provided as well.
Description
WATER-ABSORBENT ADHESIVE COMPOSITIONS AND
ASSOCIATED METHODS OF MANUFACTURE AND USE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. Patent Application Serial No.
10/936,887, filed September 8, 2004, which is a continuation-in-part of U.S. Patent Application Serial No.
10/359,548, filed February 5, 2003, which is a continuation-in-part of U.S.
Patent Application No. 10/137,664, filed May 1, 2002, which claims priority under 35 U.S.C.
119(e)(1) to provisional U.S. Patent Application Serial No. 60/288,008, filed May l, 2001.
TECHNICAL FIELD
ASSOCIATED METHODS OF MANUFACTURE AND USE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. Patent Application Serial No.
10/936,887, filed September 8, 2004, which is a continuation-in-part of U.S. Patent Application Serial No.
10/359,548, filed February 5, 2003, which is a continuation-in-part of U.S.
Patent Application No. 10/137,664, filed May 1, 2002, which claims priority under 35 U.S.C.
119(e)(1) to provisional U.S. Patent Application Serial No. 60/288,008, filed May l, 2001.
TECHNICAL FIELD
(0002] This invention relates generally to adhesive compositions, and more particularly relates to water-absorbent adhesive compositions composed of polymer blends.
The invention additionally relates to methods for formulating such compositions, including metliods for selecting components for inclusion in the compositions, to methods for using the compositions, and to products manufactured with the compositions. The invention finds utility in any context requiring an adhesive composition that adheres to a moist surface and neither dissolves nor loses tack upon absorption of water.
BACKGROUND ART
The invention additionally relates to methods for formulating such compositions, including metliods for selecting components for inclusion in the compositions, to methods for using the compositions, and to products manufactured with the compositions. The invention finds utility in any context requiring an adhesive composition that adheres to a moist surface and neither dissolves nor loses tack upon absorption of water.
BACKGROUND ART
[0003] Hydrophilic adhesives, particularly hydrophilic pressure-sensitive adhesives ("PSAs"), are used in a wide variety of commercially significant products, including drug delivery systems, wound dressings, bioelectrodes, tooth-whitening systems, and the like. A
general distinctive feature of hydrophilic PSAs is that they typically adhere to wet substrates, while conventional hydrophobic (rubber-based) PSAs typically lose their adhesive properties when moistened.
general distinctive feature of hydrophilic PSAs is that they typically adhere to wet substrates, while conventional hydrophobic (rubber-based) PSAs typically lose their adhesive properties when moistened.
[0004] It is important to be able to modify the adhesive properties of a PSA
according to intended use, as different applications can require very different adhesion profiles. For instance, the skin contact adhesive layer of a transdennal drug delivery system, or "patch,"
should provide for immediate adhesion following application of the patch to the skin and continued adhesion during an extended drug delivery period. As another exainple, delivery systems for application to wet surfaces, e.g., the buccal mucosa or the teeth, do not need to adhere to diy surfaces but should become tacky when applied to a hydrated or moistened surface. In another application, adhesive coinpositions used in wound dressings must become substantially nontacky following absorption of wound exudates to avoid tissue dainage upon removal.
according to intended use, as different applications can require very different adhesion profiles. For instance, the skin contact adhesive layer of a transdennal drug delivery system, or "patch,"
should provide for immediate adhesion following application of the patch to the skin and continued adhesion during an extended drug delivery period. As another exainple, delivery systems for application to wet surfaces, e.g., the buccal mucosa or the teeth, do not need to adhere to diy surfaces but should become tacky when applied to a hydrated or moistened surface. In another application, adhesive coinpositions used in wound dressings must become substantially nontacky following absorption of wound exudates to avoid tissue dainage upon removal.
[0005] A method has recently been developed for tailoring the adhesive properties of polymer compositions useful in a number of applications, including pharmaceutical and cosmetic products. The method is based on new insights into the molecular mechanisms underlying adhesive properties. See, for example, Feldstein et al. (1999) Poly7n. Mater. Sci.
Eng., 81:465-466; Feldstein et al., Gefzeral approach to the molecular design of laydr=ophilic pressure-sensitive adlzesives, Proceed. 25th Annual Meeting Adhesion Soc. and 2"d World Congress on Adhesion and Relative Phenomena, February 2002, Orlando, FL, vol.l (Oral Presentations), p. 292-294; and Chalykh et al. (2002) J. Adhesion 78(8):667-694. As discussed in the foregoing references, pressure-sensitive adhesion results from the coupling of two apparently incompatible types of molecular structures, and there is a fine balance between strong cohesive interaction energy and enhanced "free voluine."
Eng., 81:465-466; Feldstein et al., Gefzeral approach to the molecular design of laydr=ophilic pressure-sensitive adlzesives, Proceed. 25th Annual Meeting Adhesion Soc. and 2"d World Congress on Adhesion and Relative Phenomena, February 2002, Orlando, FL, vol.l (Oral Presentations), p. 292-294; and Chalykh et al. (2002) J. Adhesion 78(8):667-694. As discussed in the foregoing references, pressure-sensitive adhesion results from the coupling of two apparently incompatible types of molecular structures, and there is a fine balance between strong cohesive interaction energy and enhanced "free voluine."
[0006] That is, enhanced free volume in the molecular structure of a PSA
polymer composition correlates with high tack exhibited at the macroscopic level and a liquid-like fluidity of the PSA material, which, in turn, allow for rapid formation of an adhesive bond.
The "cohesive interaction energy" or "cohesion energy" defines the cohesive toughness of the PSA composition and provides the dissipation of detachment energy in the course of adhesive joint failure. Based on these findings, a general method for obtaining novel hydrophilic adhesives was developed and is described in U.S. Patent No. 6,576,712 to Feldstein et al. In one einbodiment, that method involves physically mixing a non-adhesive, hydrophilic, high molecular weight polymer with a relatively low molecular weight plasticizer capable of crosslinking the polymer via hydrogen bonding.
polymer composition correlates with high tack exhibited at the macroscopic level and a liquid-like fluidity of the PSA material, which, in turn, allow for rapid formation of an adhesive bond.
The "cohesive interaction energy" or "cohesion energy" defines the cohesive toughness of the PSA composition and provides the dissipation of detachment energy in the course of adhesive joint failure. Based on these findings, a general method for obtaining novel hydrophilic adhesives was developed and is described in U.S. Patent No. 6,576,712 to Feldstein et al. In one einbodiment, that method involves physically mixing a non-adhesive, hydrophilic, high molecular weight polymer with a relatively low molecular weight plasticizer capable of crosslinking the polymer via hydrogen bonding.
[0007] In PSAs, the molecular structures of the components dictate the cohesion energy and free volume, and thereby define the adhesive properties of the composition as a whole.
For instance, in acrylic PSAs, strong cohesive interaction energy is a result of hydrophobic attraction between alkyl groups in side chains, whereas large free volume results from either electrostatic repulsion of negatively charged carboxyl groups or a significant nuinber of isoalkyl radicals in the side chains. In synthetic rubbers, large free volume is obtained by adding high volume, low density tackifying resins. In hydrophilic adhesives, when a high molecular weight polyvinyl lactam, e.g., poly(N-vinyl-2-pyrrolidone) ("PVP") or polyvinyl caprolactone ("PVCap"), is blended with a polyethylene glycol ("PEG") oligomer, as described in U.S. Patent No. 6,576,712, high cohesive strength results from the hydrogen bonding interaction between the oxo (=0) moieties of the pyrrolidone or caprolactone ring and the terminal hydroxyl groups of the PEG oligomer, while enhanced free voluine is results from the spacing between polymer chains provided by the PEG bridges and the flexibility of the PEG oligoiners.
For instance, in acrylic PSAs, strong cohesive interaction energy is a result of hydrophobic attraction between alkyl groups in side chains, whereas large free volume results from either electrostatic repulsion of negatively charged carboxyl groups or a significant nuinber of isoalkyl radicals in the side chains. In synthetic rubbers, large free volume is obtained by adding high volume, low density tackifying resins. In hydrophilic adhesives, when a high molecular weight polyvinyl lactam, e.g., poly(N-vinyl-2-pyrrolidone) ("PVP") or polyvinyl caprolactone ("PVCap"), is blended with a polyethylene glycol ("PEG") oligomer, as described in U.S. Patent No. 6,576,712, high cohesive strength results from the hydrogen bonding interaction between the oxo (=0) moieties of the pyrrolidone or caprolactone ring and the terminal hydroxyl groups of the PEG oligomer, while enhanced free voluine is results from the spacing between polymer chains provided by the PEG bridges and the flexibility of the PEG oligoiners.
[0008] Accordingly, the balance between cohesive energy and free voluine, as described in the'712 patent, is in large part responsible for the adhesive properties of polymer materials.
For instance, the ratio between cohesion energy and free volume dictates the glass transition teinperature, Tg, and elastic modulus, E, of a polymeric material. That is, a composition with higher cohesion energy and lower free volume will have both a higher Tg and a higher E.
For instance, the ratio between cohesion energy and free volume dictates the glass transition teinperature, Tg, and elastic modulus, E, of a polymeric material. That is, a composition with higher cohesion energy and lower free volume will have both a higher Tg and a higher E.
[0009] When dry, the adhesive coinpositions described in U.S. Patent No.
6,576,712, e.g.
blends of high molecular weight PVP and low molecular weight PEG, exhibit relatively low adhesion toward dry surfaces. Adhesion increases, however, when the surface of a substrate is moistened or the adhesive composition absorbs water. The maximum adhesion of the PVP-PEG blends described in the'712 patent is observed when the adhesive contains 5-10 wt.% of absorbed water (i.e., when water represents about 5 wt.% to about 10 wt.% of the moistened adhesive composition) . This is usually the case when the adhesive is exposed to an atmosphere having 50% relative humidity (rh). When in direct contact with water, the adhesive dissolves. Therefore, the compositions are not optimal in applications wherein an adhesive composition is likely to undergo a significant degree of hydration during use, absorbing on the,order of 15 wt.% water or more.
6,576,712, e.g.
blends of high molecular weight PVP and low molecular weight PEG, exhibit relatively low adhesion toward dry surfaces. Adhesion increases, however, when the surface of a substrate is moistened or the adhesive composition absorbs water. The maximum adhesion of the PVP-PEG blends described in the'712 patent is observed when the adhesive contains 5-10 wt.% of absorbed water (i.e., when water represents about 5 wt.% to about 10 wt.% of the moistened adhesive composition) . This is usually the case when the adhesive is exposed to an atmosphere having 50% relative humidity (rh). When in direct contact with water, the adhesive dissolves. Therefore, the compositions are not optimal in applications wherein an adhesive composition is likely to undergo a significant degree of hydration during use, absorbing on the,order of 15 wt.% water or more.
[00010] Accordingly, there is a need in the art for water-insoluble adhesive compositions that adhere well to moist surfaces even after absorbing a significant ainount of water.
DISCLOSURE OF THE INVENTION
DISCLOSURE OF THE INVENTION
[00011] The invention is addressed to the aforementioned need in the art, and provides a water-insoluble adhesive composition that adheres well to moist surfaces even after absorbing a significant ainount (e.g., greater than 15 wt.%) water. The invention also provides a method for preparing such a water-soluble adhesive composition.
[00012] In one embodiment, then, a method for preparing a water-insoluble, water-absorbent adhesive composition is provided that comprises coinbining, under conditions effective to forin a substantially homogeneous adinixture:
[00013] (a) a film-forming, hydrophilic polymer comprising at least one linear seginent containing a plurality of recurring polar groups;
[00014] (b) a complementary multifunctional polymer containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the complementary multifunctional polyiner; and [00015] (c) a plasticizer capable of plasticizing the fihn-forming polymer, [00016] wllerein the weight fraction of the film-forming polymer in the admixture is greater than the weight fraction of either the coinplementary multifunctional polymer or the plasticizer.
[00017] In a preferred embodiment, the recurring functional groups and the recurring polar groups are ionogenic, and an ionizing agent is incorporated into the adinixture so as to ionize up to approximate 30% of the ionogenic groups.
[00018] In another embodiment, a water-insoluble, water-absorbent adhesive coinposition is provided which comprises a blend of:
[00019] (a) a fihn-forming, hydrophilic polyiner comprising at least one linear segment containing a plurality of recurring polar groups;
[00020] (b) a coinplementary multifunctional polyiner containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the coinplementary multifunctional polymer; and [00021] (c) a plasticizer capable of plasticizing the film-fonning polymer, [00022] wherein the weight fraction of the film-forming polymer in the blend is greater than the weight fraction of either the complementary multifunctional polymer or the plasticizer.
BRIEF DESCRIPTION OF THE FIGURES
BRIEF DESCRIPTION OF THE FIGURES
[00023] FIG. 1 is a schematic representation of a "ladder-like" interpolymer coinplex fonned by noncovalent association of PVP and a complementary multifunctional polyiner containing a plurality of recurring proton-donating functional groups along the polymer backbone, wherein the noncovalent association involves hydrogen bonding between the proton-donating functional groups and the oxo moieties within the pyrrolidone rings. While the formation of a "carcass-like" complex (described iiifi-a and illustrated in FIG. 2) leads to enhanced cohesive strength and free voluine, the fonnation of a ladder-like complex as illustrated in this figure is accompanied by a decrease in solubility, an increase in cohesive strength, and a decrease in free volume. For this reason, a polymer blend composed of a ladder-like inteipolymer complex provides no adhesion.
[00024] FIG. 2 is a schematic representation of a "carcass-like" complex forrned by noncovalent association of PVP and oligomeric PEG, wherein the bifunctional oligomer provides a bridge between two polymer chains and the noncovalent association involves hydrogen bonding between terminal proton-donating moieties on the PEG and the oxo moieties within the pyrrolidone rings. The complex combines high cohesive toughness (as a result of the hydrogen bonding) with a large free voluine (resulting from the length and flexibility of the PEG chains).
[00025] FIG. 3 schematically illustrates an interpolymer complex combining carcass-like and ladder-like types of crosslinking. "FFP" represents a fihn-forming polymer, "CCL"
represents a carcass-like crosslinker, and "LLC" represents a ladder-like crosslinker.
1000261 FIG. 4 schematically illustrates the structure of an interpolymer complex composed of a film-forming polymer (FFP) and ladder-like crosslinker (LLC).
The complex is mixed with a plasticizer (P) and filled with a tackifier (T).
[00027] FIG. 5 demonstrates nominal stress-strain curves for uniaxial drawing for the mixture of film-forming Eudragit E- 100 polymer with 25 wt. % of TEC and for the ladder-like interpolymer Eudragit E-100 - Eudragit L-100-55 coinplex ([FFP]:[LLC]=10:1) plasticized with the same amount of TEC. Drawing rate is 20 mm/min.
[00028] FIG. 6 shows the impact of plasticizer (TEC) concentration on probe tack stress-strain curves of the blends of Eudragit E-100 film forming copolymer and Eudragit L-100-55 ladder-like crosslinker (10:1). The TEC concentrations are indicated in the Figure.
[00029] FIG. 7 exhibits the effect of ladder-like electrostatic crosslinking of film-forming polybase (Eudragit E-100) by polyacid (Eudragit L-100-55) on probe tack stress-strain curves.
[00030] FIG. 8 compares the effects of plasticizer (TEC) and tackifier (glycerol ester of tall oil rosin) on probe tack stress-strain curves of amphiphilic adhesives based on the ladder-like electrostatic complex of Eudragit E-100 and Eudragit L-100-55 copolymers (10:1).
[00031] FIG. 9 shows the impact of tackifier content on the work of adhesive debonding for the blends of Eudragit E-100 with 25 wt. % of ATBC.
[00032] FIG. 10 compares the effects of two tackifiers - Sylvagum RE 85K rosin and PIB
(Oppanol B-15) on probe tack of Eudragit E-100 - Eudragit L-100-55 blends (10:1), plasticized with 25 wt. % of TEC.
[00033] FIG. 11 demonstrates the effect of adipic acid on adhesive properties of Eudragit E-100 / L100-55 blends with 25 % of TEC at different E100/L100-55ratios [00034] FIG. 12 represents the curve of potentiometric titration of 1% aqueous solution of Eudragit E-1 00 polybase with 0.2 N HCI. The ionization degree, f, is plotted along a top axis.
[00035] FIG. 13 represents the curve of potentiometric titration of 1% aqueous solution of Eudragit L-100-55 polyacid with 0.1 N NaOH. The ionization degree,f, is plotted along a top axis.
[00036] FIG. 14 demonstrates the effect of partial ionization of film-forming polymer (Eudragit E-100) by HCl solution on the tack of ainphiphilic adhesive containing 35 wt. % of plasticizer TEC.
[00037] FIG. 15 compares the effects of partial ionization of film-forming polymer (by HCl) and ladder-like crosslinker (by NaOH) on the probe tack stress-strain curves for ainphiphilic Eudragit E-100 - Eudragit L-100-55 adhesive containing 25 wt. %
of plasticizer TEC.
[00038] FIG. 16 represents probe tack stress-strain curves for the Eudragit E-Eudragit L-100-55 complex containing 35 wt. % of plasticizer TEC under 10 %
ionization of film-forming polymer and ladder-like crosslinker and for the coinplex fonned between partly ionized polymer components at 10 % degree of ionization.
[00039] FIG. 17 represents the effect of partial ionization of carboxyl groups in the ladder-like crosslinker on the stress-strain curves of the PVP-PEG-Eudragit L- 100-55 adhesive hydrogel containing 12 wt. % of sorbed water. The degrees of ionization (%) are shown in the Figure.
[00040] FIG. 18 coinpares the adhesive properties of interpolymer complexes of Eudragit E- 100 fihn-forining polymer with the ladder-like crosslinkers of different hydrophilicity:
Eudragit L-100-55 (Example 9) and Gantrez S-97. The content of plasticizer TEC
in blends is25wt.%.
[000411 FIG. 19 demonstrates the effect of ladder-like crosslinker (Eudragit L-100-55 or Gantrez S-97) on water absorbing capacity, expressed in terms of Swell Ratio, for Eudragit E-100 blends, plasticized with 25 % of TEC.
[00042] FIG. 20 exhibits the impact of the nature of plasticizers (TEC, ATEC, TBC and ATBC) on probe tack properties of Eudragit E-100 - Eudragit L-100-55 complexes.
Concentration of the plasticizers is 45 wt%.
[00043] FIG. 21 illustrates the influence of the nature of plasticizer in Eudragit E-100 -Eudragit L-100-55 complex on Swell Ratio of relevant blends.
[00044] FIG. 22 shows the effect of mixing the Eudragit E-100 - Eudragit L-100-complexes with PVP and with PVP-PEG blend (2:1) on water absorbing capacity expressed in terms of Swell Ratio.
[00045] FIG. 23 demonstrates the influence of hydrophilization of Eudragit E-Eudragit L-100-55 plasticized complex on the work of adhesive debonding (probe tack).
[00046] FIG. 24 deinonstrates peel force traces towards dry and wet huinan skin for Gelva acrylic PSA, water soluble adhesive based on carcass-like PVP-PEG complex outlined by US
Patent 6,576,712, hydrophilic PVP-PEG-Eudragit L-100-55 adhesive and amphiphilic adhesive based on the ladder-like Eudragit E-100 - Eudragit L-100-55 complex (Exainple 1).
[00047] FIG. 25 represents probe tack stress-strain curves for water soluble PVP-PEG (36 %) adhesive outlined by US Patent 6,576,712, amphiphilic adhesives described in Example 9 (35 % TEC) and in Exainple 10 (7 % of tackifier, 30 % TEC), hydrophilic PVP-PEG-Eudragit L-100-55 adhesive at 17 % of absorbed water in comparison with two grades of conventional PSAs: SIS-based DURO-TAKr, 34-4230 and acrylic PSA manufactured by 3M.
[00048] FIG. 26 represents the kinetics of in vitro release of silver sulfate from three adhesive hydrogel compositions used in wound dressings.
[00049] FIG. 27 demonstrates in vitro release kinetics of silver phosphate from the matrix of wound dressing based on the ladder-like interpolymer complex Eudragit E-100 - Eudragit L-100-55, plasticized with 25 wt. % of TEC.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND OVERVIEW:
[00050] It is to be understood that, unless otherwise indicated, this invention is not liinited to specific polyiners, oligomers, crosslinking agents, additives, inanufacturing processes, or adhesive products. It is also to be understood that the tenninology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[00051] In describing and claiming the present invention, the following tenninology will be used in accordance with the definitions set out below.
[00052] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a hydrophilic polymer" includes not only a single hydrophilic polyiner but also two or more hydrophilic polymers that may or may not be combined in a single composition, reference to "a plasticizer"
includes a single plasticizer as well as two or more plasticizers that may or may not be combined in a single coinposition, and the like.
[00053] A"hydrophobic" polymer absorbs only up to 1 wt. % water at 100% rh, while "hydrophilic" polymers absorb at least 1 wt.% water at 100% rh.
[00054] A "water-swellable" polymer is one that is capable of absorbing water in an amount that is at least 50% of its own weight. That is, a water-swellable polymer weighing x grams can absorb at least 0.5x grains of water, to provide a hydrated polymer weighing at least 1.5x grams and having a polymer to water (weight) ratio of at most 3:1.
[00055] The terin "crosslinked" herein refers to a polymer composition containing intramolecular and/or intermolecular noncovalent bonds. Noncovalent bonding includes hydrogen bonding, electrostatic bonding, and ionic bonding.
[00056] The term "polymer" as used herein includes both linear and branched polymers, and homopolyiners as well as copolymers, the latter including all types of copolymer structures (e.g., block copolyiners, alternating copolymers, random copolymers, etc.) as well as "higher order" copolyiners (e.g., terpolymers). Those compounds referred to herein as "oligomers" are polyiners having a molecular weight below about 1000 Da, preferably below about 800 Da.
[00057] The term "water-insoluble" is used to refer to a polymer, compound or composition whose aqueous solubility measured at 20 C is less than 5 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%. The term "insoluble" is used to refer to a polymer, coinpound or coinposition whose solubility in water, polar organic solvents, and possibly nonpolar organic solvents, measured at 20 C, is less than 5 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%.
[00058] The term "llydrogel" is used in the conventional sense to refer to water-swellable polymeric matrices that can absorb a substantial amount of water to form elastic gels, where the "matrices" are three-dimensional networks of macromolecules held together by covalent or non-covalent crosslinks. Upon placement in an aqueous environinent, dry hydrogels swell to the extent allowed by the degree of cross-linking.
[00059] The term "hydrogel composition" refers to a composition that either contains a hydrogel or is entirely composed of a hydrogel. As such, "hydrogel compositions"
encoinpass not only hydrogels per se but also compositions that comprise a hydrogel and one or more non-hydrogel components or coinpositions, e.g., hydrocolloids, which contain a hydrophilic component (which may contain or be a hydrogel) distributed in a hydrophobic phase.
[000601 The terins "tack" and "tacky" are qualitative. However, the terms "substantially nontacky," "slightly tacky," and "tacky," as used herein, may be quantified using the values obtained in a PKI tack determination, a TRBT tack determination, or a PSA tack determination/Polyken Probe (Solutia, Inc.). The term "substantially nontacky"
is used to refer to a composition having a tack value less than about 25 g-cm/sec, the term "slightly tacky" refers to a composition having a tack value in the range of about 25 g-cm/sec to about 100 g-cm/sec, and the term "tacky" refers to a composition having a tack value of at least 100 g-cm/sec.
[00061] The term "plasticizer" is used in the conventional sense of the term to refer to a relatively low molecular weight compound that is miscible with a polymer or polyiner blend and decreases the glass transition temperature and elastic modulus thereof.
[00062] It is desirable to obtain water-insoluble, water-swellable hydrophilic adhesive polymers (adhesive hydrogels) that are capable to form homogeneous filins either upon casting a solution to backing layer followed by drying, or under external pressure or by means of extrusion. The film-forming capability requires that the blend has to be free of covalent crosslinks. Blending the polymers provides a convenient way to obtain composite materials with specifically tailored properties, since the properties of the blend are typically intennediate between those of the unblended coinponents when the components are immiscible or partly miscible. In order to make the composite insoluble in water, water-insoluble materials are usually mixed with water-soluble materials. When this is done, however, a phase separation can often occur that does not favor adhesion.
Moreover, the insolubility of blend components may hainper the procedure of blend preparation, which often involves the dissolution of all the components in a common solvent, followed by casting the solution and drying.
[00063] Preparation of polymer composite materials whose properties are new and untypical of parent components requires a high skill of a material designer.
This challenge may be resolved if the blend components are capable of a strong favorable interaction to each other. More often, such interaction is hydrogen, electrostatic or ionic bonding. In this instance inixing of two or more soluble polymers can give their ladder-like complex schematically shown in FIG. 1 that is swellable, but insoluble or partly soluble.
[00064] In order to resolve these problems, this invention is directed to a method of obtaining water-insoluble, film-forming coinpositions by blending soluble polymers, more specifically by blending hydrophilic polymers with complementary macromolecules that are capable of hydrogen bonding, electrostatic or ionic bonding.
[00065] By way of overview, the adhesive coinpositions of the irivention contain at least film-forming hydrophilic polymer having at least one linear segment with a plurality of recurring polar groups thereon, at least one complementary multifunctional polyiner that serves as a "ladder-like" noncovalent crosslinker of the film-forming polymer, and at least one plasticizer compatible with (i.e., miscible with) or at least partially compatible with both the film-forming polymer and the complementary multifunctional polymer. The film-forming polyiner is present in a higher concentration than the complementary multifunctional polyiner, and it is this higher concentration that determines the film-forming characteristics.
Therefore, while there may be materials that are suitable for use as either the fihn-forming polyiner or as the complementary multifunctional polymer, their function in the composition is determined by the quantity of the component in the composition. If the recurring polar groups or the recurring functional groups are ionogenic, another factor that controls the performance of composite material is the degree of ionization or pH of the mixture.
[00066] For exainple, polyacids such as acrylate polymers bearing carboxyl proton-donating functional groups or polyols bearing hydroxyl proton-donating functional groups and proton-accepting polymers such as poly(N-vinyl lactams) or polyainines are suited for use as both the fihn-forming polymer or as the complementary multifunctional polymer. In a composition having a greater amount of an acrylate or another proton-donating polymer relative to the ainount of a poly(N-vinyl lactam), the acrylate polymer serves as the filhn-forming polymer and the poly(N-vinyl lactam) or polyamine or another proton-accepting polymer serves as the coinpleinentary multifunctional polymer, or ladder-like crosslinker.
Similarly, in a composition having a greater ainount of a poly(N-vinyl lactam) or polyainine relative to the amount of an acrylate polyiner, the poly(N-vinyl lactam) or polyamine serves as the film-forming polyiner and the acrylate polymer serves as the ladder-like crosslinker.
[00067] Maintaining a specified pH value in the blend or in an admixture used to provide the blend provides an additional factor controlling the performance of the blend when one or more ionogenic polymers are present. Ionized groups are capable of ionic, but not electrostatic or hydrogen bonding. Fully or partly ionized polyiners are always soluble in water, whereas non-ionized polymers as a rule are insoluble or poorly soluble in water.
Consequently, the degree of ionization affects appreciably the solubility and swelling of interpolymer complexes involving ionogenic polymers. Moreover, by varying the pH value and degree of ionization, the adhesive properties of composite materials can be controlled.
Indeed, adhesion is a result of specific balance between cohesive interaction energy and free volume. As polymeric coinponents bear opposite charges, cohesion is increased.
As two polymers have the same positive or negative charge, cohesion is immediately suppressed and free voluine is increased. Moreover, due to electrostatic repulsion between the functional groups of identical charge, the chain rigidity and free volume is usually increased. All these factors dramatically affect adhesive performance.
[00068] The adhesion profile of the water-insoluble, film-forming compositions of the invention can be tailored based on materials, the ratio of components in the composition, the degree of ionization and the quantity of water in the blend. The ladder-like crosslinker, its ratio to the amount of film-forming polymer, concentration of a plasticizer and ionization degree are selected so as to provide the desired adhesion profile with respect to hydration.
Generally, the compositions that are relatively slightly crosslinked through coinparatively loose hydrogen bonds and deinonstrating a large free volume provide initial tack in dry state.
When the degree of crosslinking degree and the cohesive strength of the network in the interpolymer complex is above some critical value, the energy of cohesion dominates under free volume and such coinpositions are usually non-tacky in the dry state.
However, as a free voluine is increased in this blend (e.g. by adding a suitable plasticizer), adhesion immediately appears. Because water is a good plasticizer for hydrophilic polymers, absorption of the water leads to an iinproveinent of adhesion. Because electrostatic bonds are appreciably stronger than the hydrogen bonds, the cohesion in the blends of polyiners bearing carboxyl groups is usually higher than in the materials composed of polymers having hydroxyl groups.
Adhesion in such blends appears normally with a higher concentration of absorbed water.
Flexible polymers provide higher cohesion than polyiners with rigid chains. As an exainple, for blends of poly(vinyl pyrrolidone) (PVP) as a film-forming polyiner, when the ladder-like crosslinker is a rigid-cliain cellulose ester bearing OH groups, the composition is generally tacky prior to contact with water (e.g., with a moist surface) but gradually loses tack as the composition absorbs moisture. When the ladder-like crosslinker is an acrylate polymer or copolymer with carboxyl groups, a composition is provided that is generally substantially nontacky prior to contact with water, but that becomes tacky upon contact with a moist surface.
POLYMER COMPONENTS:
[00069] The fihn-forming hydrophilic polymer and the complementary multifunctional polymer, as noted elsewhere herein, are generally selected from the same classes of polymers and copolymers, but have complementary groups along the backbone that interact to form noncovalent bonds (e.g., hydrogen bonds, electrostatic bonds, or ionic bonds), thereby forming a ladder-like complex that is insoluble in aqueous liquids, polar organic solvents, and many nonpolar organic solvents as well. By definition herein, the polymer that serves as the "film-forming" polymer represents a greater weight fraction in the mixtures and compositions of the invention than does the complementary multifunctional polymer.
Typically, the fihn-forming hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the mixtures and compositions of the invention, while the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the mixtures and compositions of the invention. Generally, although not necessarily, the film-forming polymer will also have a higher molecular weight than the complementary inultifunctional polymer.
The molecular weight of the film-forining polymer will usually be in the range of about 20,000 to 3,000,000, preferably in the range of about 100,000 to 2,000,000, and most preferably in the range of about 100,000 to 1,500,000.
[00070] The recurring polar groups on the fihn-forming polymer and the recurring functional groups on the coinpleinentary rnultif-unctional polymer may comprise backbone heteroatoms, e.g., an oxygen atom in an ether (-0-) or ester (-(CO)-O-) linkage, a nitrogen atom in an amine (-NH-), imine (-N=), or amide (-NH(CO)-) linkage, a sulfur atom in a thioether (-S-) linkage, and the like. The recurring polar groups and the recurring functional groups may also coinprise pendant groups, for instance:
[00071] hydroxyl;
[00072] sulfhydryl;
[00073] Cr-C18 hydrocarbyloxy, preferably CI-C8 alkoxy;
[00074] C2-C18 acyl, preferably C2-C8 acyl (e.g., C2-C8 alkylcarbonyl);
[00075] CZ-C18 acyloxy, preferably C2-C8 acyloxy (e.g., C2-C8 alkylcarbonyloxy);
[00076] CZ-C,$ hydrocarbyloxycarbonyl (-(CO)-O-alkyl), preferably C2-C8 alkoxycarbonyl (-(CO)-O-alkyl));
[00077] carboxy (-COOH);
[00078] carboxylato (-COO);
[00079] carbamoyl (-(CO)-NR2 wherein R is H or Ci-Clg hydrocarbyl, preferably H or Ci-C$ alkyl);
[00080] cyano(-C=N);
[00081] isocyano (-N}-C);
[00082] cyanato (-O-C=N);
[00083] isocyanato (-O-N+ =C-);
[00084] forinyl (-(CO)-H);
[00085] amino, i.e., -NR1RZ where R' and R2 are independently selected from H
and CI-CIg hydrocarbyl, preferably selected from H, C1-C8 alkyl, and C5-C12 aryl, or are linked to form an optionally substituted five- or six-membered ring, thus including mono-(Ci-C8 alkyl)-substituted amino, di-(CI-C8 alkyl)-substituted amino, mono-(C5-C]2 aryl)-substituted amino, and di-(C5-Cz2 aryl)-substituted amino), piperidinyl, pyrrolidinyl, and pyrrolidonyl;
[00086] quatemary ammonium, i.e., -[NR3R4R5] "Q- where R3, R4, and RS are Cl-hydrocarbyl, preferably C1-C8 alkyl, and most preferably C1-C4 alkyl, and Q is a negatively charged counterion, e.g., a halogen anion;
[00087] C2-C18 alkylamido, preferably C2-C8 alkylamido (-NH-(CO)-alkyl);
[00088] C6-C18 arylainido, preferably C6-CIZ alkylamido (-NH-(CO)-aryl);
[00089] nitro (-NO2);
[00090] sulfo (-S02-OH);
[00091] sulfonato (-S02-O );
[00092] C1-C18 hydrocarbylsulfanyl, preferably CI-C8 alkysulfanyl (-S-hydrocarbyl and -S-alkyl, respectively, also termed "hydrocarbylthio" and "alkylthio"); [00093]
phosphono (-P(O)(OH)2);
[00094] phosphonato (-P(O)(O)2);
[00095] phosphinato (-P(O)(O')); and [00096] phospho (-P OZ), [00097] any of which may be substituted as permitted, e.g., with hydrocarbyl groups and/or additional functional groups. The pendant groups may also be directly linked to an atom in the polymer backbone, or they may be indirectly linked through a linking group (e.g., C1-Cl8 hydrocarbylene linker such as C2-C8 alkylene linker). Additionally, there may be two or more types of polar groups on the film-forming polyiner (which may include backbone heteroatoins as well as pendant polar groups) and two or more types of functional groups on the complementary multifunctional polymer (again, which inay include backbone heteroatoins as well as pendant polar groups).
[00098] Preferred pendant groups are those present on polymers that are readily synthesized or commercially available, typically including hydroxy, C1-C$
alkoxy, carboxyl, carboxylato, sulfo, sulfonato, amino, di(CI-C8 alkyl)-substituted amino, quaternary aminoniuin, piperidinyl, pyrrolidinyl, pyrrolidinyl, and phosphono groups.
[00099] In general, it is also preferred, although not essential, that the film-forming polymer have an excess of polar groups relative to the corresponding functional groups on the coinplementary inultifunctional polymer, such that, providing that the polar groups and functional groups are ionogenic, the ladder-like complex can readily ionized in the presence of an ionizing agent, e.g., an acid or base. Typically, zero to about 30% of the ionogenic groups present on the film-forining polymer are ionized, preferably about 5%
to 10%. The degree of ionization inay be controlled by addition of a suitable ionizing agent, e.g., an acid or base.
[000100] It will be appreciated by those of ordinary skill in the art that virtually any polymers meeting the aforementioned criteria may be used herein. Suitable polymers include, but are not limited, to the following:
[000101] poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(vinyl-2-valerolactam), and poly(N-vinyl-2-caprolactam);
[000102] polyvinyl alcohols, including polyvinyl alcohol per se and polyvinyl phenol;
[000103] polyacrylamides such as poly(N-inethaciylamide), poly(N,N-diinethylacrylamide), poly(N-isopropylacrylainide) (PNIPAM), poly(N-vinyl acrylainide), and other poly(N-alkyl acrylainides and N-alkenyl acrylamides);
[000104] poly(alkylene oxides) such as polyethylene oxide (PEO) and poloxamers (i.e., copolymers of ethylene oxide and propylene oxide);
[000105] poly(oxyethylated) alcohols such as poly(oxyethylated) glycerol, poly(oxyethylated) sorbitol, and poly(oxyethylated) glucose;
[000106] polylactide and poly(lactide-co-glycolide);
[000107] poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(fumaric acid), alginic acid, and poly(sulfonic acids);
[000108] poly(vinyl amines);
[000109] poly(alkylene iinines);
[000110] cellulose esters and other cellulose derivatives, including carboxymethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose butyrate, cellulose diacetate, cellulose phthalate, cellulose propionate, cellulose propionate butyrate, cellulose triacetate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, sodium carboxymethylcellulose; and [000111] acrylate and methacrylate polymers and copolymers, including poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(hydroxyalkyl acrylates) such as poly(hydroxyethyl acrylate), and poly(hydroxyalkyl methacrylates) such as poly(hydroxyethyl methacrylate) (PoIyHEMA). Preferred acrylate polymers are those copolymers available under the tradename "Eudragit" from Rohm Pharma (Germany). The Eudragit series E, L, S, RL, RS, and NE copolymers are available as solubilized in organic solvent, in an aqueous dispersion, or as a dry powder. Preferred acrylate polyiners are copolyiners of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers. Particularly preferred such copolyiners are Eudragit L-30D-55 and Eudragit L-100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 that can be reconstituted with water). The molecular weight of the Eudragit L-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da, with a ratio of free carboxyl groups to ester groups of approximately 1:1. The copolymer is generally insoluble in aqueous fluids having a pH below 5.5. Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which differs from Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is approximately 1:2. Eudragit S-100 is insoluble at pH
below 5.5, but unlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7Ø This copolymer is soluble at pH 7.0 and above.
Eudragit L-100 inay also be used, which has a pH-dependent solubility profile between that of Eudragit L-30D-55 and Eudragit S-100, insofar as it is insoluble at a pH below 6Ø It will be appreciated by those skilled in the art that Eudragit L-30D-55, L-100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics. Other preferred Eudragit polymers are cationic, such as the Eudragit E, RS, and RL
series polymers. Eudragit E1OO and E PO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates (e.g., methyl methacrylate), while Eudragit RS and Eudragit RL polymers are analogous polymers, composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate.
[0001121 Copolymers of any of the above may also be used herein, as will be appreciated by those of ordinary skill in the art.
PLASTICIZERS:
[000113] Suitable plasticizers and softeners include, by way of illustration and not limitation: alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, tricresyl phosphate, and triphenyl phosphate; alkyl citrates and citrate esters such as trimethyl citrate, triethyl citrate and acetyl triethyl citrate, tributyl citrate and acetyl tributyl citrate, acetyl triethyl citrate, and trihexyl citrate; alkyl glycerolates; alkyl glycolates;
dialkyl adipates such as dioctyl adipate (DOA; also referred to as bis(2-ethylhexyl)adipate), diethyl adipate, di(2-methylethyl)adipate, and dihexyl adipate; dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates and mixed alkyl-aryl phthalates, including phthalic acid esters, as represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate;
dialkyl sebacates such as diethyl sebacate, dipropyl sebacate, dibutyl sebacate and dinonyl sebacate; dialkyl succinates such as diethyl succinate and dibutyl succinate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; glycol esters and glycerol esters such as glycerol diacetate, glycerol triacetate (triacetin), glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate;
hydrophilic surfactants, preferably hydrophilic non-ionic surfactants such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers, and polyethylene glycol sorbitan-fatty acid esters, as well as non-ionic surfactants such as ethylcellosolve; lower alcohols from ethyl to octyl;
sorbitol; tartaric acid esters such as dibutyl tartrate; and mixtures thereof.
[000114] A preferred plasticizer for use in conjunction with the present invention is a bifunctional oligomer that is "complementary" to the film-forming polymer as described in U.S. Patent No. U.S. Patent No. 6,576,712 to Feldstein et al., cited earlier herein.
Preferably, the complementary oligomer is terminated with hydroxyl groups, ainino or carboxyl groups. The oligomer typically has a glass transition temperature Tg in the range of about -100 C to about -30 C and a melting temperature T,n lower than about 20 C. The oligomer may be also amorphous. The difference between the Tg value of the film-forrning polymer and that of the complementary oligomer is preferably greater than about 50 C, more preferably greater than about 100 C, and most preferably in the range of about 150 C to about 300 C. Generally, the oligomer will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600. Examples of suitable oligomers include, but are not limited to, low molecular weight polyalcohols (e.g. glycerol), oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol, including carboxyl-terminated and amino-terminated derivatives of polyalkylene glycols. Polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal complementary oligomer.
[000115] The compositions of the invention may also include two or more plasticizers in combination, e.g., triethyl citrate and tributyl citrate, triethyl citrate and polyethylene glycol 400, polyethylene glyco1400 and dioctyl phthalate, etc.
REPRESENTATIVE COMPOSITIONS:
[000116] An illustrative composition includes poly(N-vinyl-2-pyrrolidone) ("PVP") as the film-forming polymer and polyethylene glycol ("PEG") as the carcass-like non-covalent crosslinker. Mixing a PVP-PEG adhesive blend with a ladder-like non-covalent crosslinker that is a moderately hydrophilic or water-insoluble polymer results in the decrease of blend hydrophilicity and dissolution rate. In order to decrease the dissolution rate further or to obtain insoluble mixtures, the PVP-PEG blend can be mixed with polyiners that bear complementary (with respect to PVP) reactive functional groups in their repeating units.
Since the PVP contains proton-accepting carbonyl groups in its repeating units, the complementary functional groups are preferably proton-donating, hydroxyl or carboxyl groups. Thus, for use with PVP and PEG, suitable ladder-like non-covalent crosslinkers are long chain polymers such as polyvinyl alcohols, polyacrylic acids, polymethaciylic acids, homo- and co-polymers thereof, as well as sulfonic acid and alginic acid.
[000117] Another illustrative composition uses a copolymer of methacrylic acid and methyl methacrylate as the ladder-like non-covalent crosslinker with the PVP/PEG noted above. This composition is used to facilitate in understanding the principles of the invention.
[000118] The PVP-PEG complex combines high cohesive toughness (due to PVP-PEG
H-bonding) with a large free volume (resulting from considerable length and flexibility of PEG chains). In order to emphasize enhanced free volume in the PVP-PEG blend, this type of complex structure is defined as a "carcass-like" structure (see FIG. 1).
The carcass-like structure of the complex, results from the location of reactive functional groups at both ends of PEG short chains. When the ladder-like non-covalent crosslinker contains reactive functional groups in repeating units of the backbone, the resulting complex has so-called "ladder-like" structure (see FIG. 2). The ladder-like type of interpolymeric coinplex was first described by Kabanov et al. (1979) Vysokonzol. Soed. 21(A):243-281. While the formation of the carcass-like complex leads to enhanced cohesive strength and free volume (which determines the adhesive properties of PVP-PEG blends), the formation of the ladder-like complex shown in FIG. 2 is accompanied by the loss of blend solubility and the increase of cohesive strength coupled with the decrease in free volume. For this reason, the structure of the ladder-like complex provides no adhesion. .
[000119] Due to the decrease in free voluine and the increase in cohesive energy, the PVP-PEG blend mixed with a long chain polymer giving the ladder-like complex with PVP, provides no or negligible initial tack. However, as the non-adhesive PVP-PEG
blend with the long chain polymer is plasticized by water, the glass transition temperature of the blend shifts toward lower values, which are typical features of pressure-sensitive adhesives, and adhesion arises.
[000120] There are certain preferred coinbinations of components in the adhesive composition. For exainple, when the film-forming polymer is a poly(N-vinyl lactam) such as poly(N-vinyl pyrrolidone) or poly(N-vinyl caprolactam), the ladder-like crosslinker is preferably a poly(dialkyl aininoalkyl aciylate), poly(dialkyl aminoalkyl methacrylate), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, poly(hydroxyalkyl acrylate), or poly(hydroxyalkyl inetllacrylate) such as poly(hydroxyethyl methacrylate).
[000121] Similarly, when the film-forming polymer is a poly(dialkyl aminoalkyl acrylate), poly(dialkyl aminoalkyl methacrylate), polyacrylic acid, polyinethacrylic acid, polyinaleic acid, polyvinyl alcohol, polyvinyl phenol, or poly(hydroxyalkyl acrylate) such as poly(hydroxyethyl methacrylate), the ladder-like crosslinker is preferably a poly(dialkyl aininoalkyl acrylate, poly(dialkyl aininoalkyl methacrylate), poly(N-vinyl lactam) such as poly(N-vinyl pyrrolidone) or poly(N-vinyl caprolactam), as well as a copolymer of poly(N-dialkylamino alkyl acrylate) with alkyl acrylate, polyethylene oxide, methacrylate or ethacrylate monomers, or a copolymer of poly(N-dialkylamino alkyl methacrylate) and alkyl acrylate, methacrylate or ethacrylate monomers.
[000122] For any of the aforementioned combinations, a preferred carcass-like crosslinker is an oligomeric alkylene glycol comprising about 1-20 alkylene oxide units in its chain such as polyethylene glycol, carboxyl-terminated oligomeric alkylene glycol such as carboxyl-terminated poly(ethylene glycol), or polyhydric alcohols.
[000123] Other exainples of suitable blends are shown in the following table:
film-forining polymer ladder-like crosslinker carcass-like crosslinker PVCap Eudragit L 100, PAA, PMA, PEG and carboxyl PVA, polyvinyl phenol and terminated PEG
Po1yHEMA
PNIPAM Eudragit L 100, L 100-55, PEG and carboxyl S-100, PAA, PMA, alginic terininated PEG
acid, PVA, and PoIyHEMA
PEO Eudragit L 100, L 100-55, Propylene glycol, S-100, PAA, PMA, alginic Glycerol, PEG, PEG-acid, GANTREZ ES-225, diacid GANTREZ ES-425, polyvinyl phenol PAA, PMA Eudragit E-100* and PEG
polyvinyl amine Eudragit E-100* PAA, PMA, Eudragit L 100, Carboxyl tenninated PEG, L 100-55, S 100 and alginic carbonic di- and polyvalent acid acids**
* Eudragit E-100 is a copolymer of 2-dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate 2:1:1, coinmercially available from Rohin Pharma Polymers ** As described in U.S. Patent No. 6,576,712 [000124] To illustrate the approacli used herein, a PVP-PEG-Eudragit blend was used as a typical example, although the approach is general and can be easily reproduced using other water-soluble, hydrophilic polymers.
[000125] The properties of adhesive polyiner blends were evaluated and are set forth in the examples. The behavior of these polymer blends was found to be typical of covalently crosslinked polymers. However, in contrast to covalently crosslinked systems, the triple polyiner blends combining the carcass-like and the ladder-like non-covalent crosslinkers can be easily prepared using a straightforward process, and, furthermore, provide film-forming properties that are unattainable using chemically crosslinked polymers.
ADDITIVES:
[000126] The adhesive coinpositions of the invention may also include one or more conventional additive, which may be combined with the polyiners and the plasticizer during adhesive formulation or incorporated thereafter. Optional additives include, without limitation, fillers, pH regulating agents, ionizing agents, tackifiers, detackifying agents, electrolytes, antimicrobial agents, antioxidants, preservatives, colorants, flavors, and combinations thereof. In certain embodiments, the compositions of the invention may also include a pharmacologically active agent or a cosmeceutically active agent.
For instance, transdermal, transmucosal, and topical delivery systems in which an adhesive coinposition of the invention serves as a drug reservoir and/or skin contact adhesive layer may be formulated for the delivery of a specific pharinacologically active agent. Cosmeceutical products such as tooth whitening gels and strips may be formulated for the delivery of one or more tooth-whitening agents. Examples of such products are described in pending U.S.
Patent Application Serial No. 10/936,887 to Feldstein et al. for "Method of Preparing Polymeric Adhesive Compositions Utilizing the Mechanism of Interaction Between The Polymer Components, filed September 8, 2004, and U.S. Patent Application Serial No.
60/638,835 to Singh et al. for "Sustained Release Tooth Whitening Systeins and Formulations," filed December 21, 2004, the disclosures of which are incorporated by reference herein.
[000127] Absorbent fillers may be advantageously incorporated to control the degree of hydration when the adhesive is on the skin or other body surface. Such fillers can include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesiuin silicate, magnesium aluminum silicate, hydrophobic starch, calciuin sulfate, calcium stearate, calcium phosphate, calcium phosphate dihydrate, woven and non-woven paper and cotton materials. Other suitable fillers are inert, i.e., substantially non-adsorbent, and include, for example, polyethylenes, polypropylenes, polyurethane polyether ainide copolymers, polyesters and polyester copolymers, nylon and rayon. A
preferred filler is colloidal silica, e.g., Cab-O-Sil (Cabot Corporation, Boston MA).
[000128] Coinpounds useful as pH regulators include, but are not limited to, glycerol buffers, citrate buffers, borate buffers, phosphate buffers, and citric acid-phosphate buffers.
Buffer systems are useful to ensure, for instance, that the pH of a composition of the invention is compatible with that of an individual's body surface.
[000129] Ionizing agents are also useful to impart a desired degree of ionization to the interpolymer complex within the adhesive coinpositions of the invention.
Suitable ionizing agents are acids and bases, depending on the group to be ionized. The acids and bases may be inorganic (hydrochloric acid, hydrobroinic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, ammoniuin carbonate, etc.) or organic (acetic acid, maleic acid, triethylainine, ethanolainine, etc.).
[000130] Tackifiers can also be included to improve the adhesive and tack properties of the compositions of the invention. The mechanism underlying tack improvement results from the large size and hydrophobic character of tackifier molecules. Exemplary tackifying materials include tacky rubbers such as polyisobutylene, polybutadiene, butyl rubber, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). Other exainples of suitable tackifiers herein are those that are conventionally used with pressure sensitive adhesives, e.g., rosins, rosin esters, polyterpenes, and hydrogenated aromatic resins. In those embodiments wherein adhesion is to be reduced or eliminated, conventional detackifying agents may also be used. Suitable detackifiers include crosslinked poly(vinylpyrrolidone), silica gel, bentonites, and so forth.
[000131] Preferred thickeners herein are naturally occurring compounds or derivatives thereof, and include, by way of example: collagen; galactomannans; starches;
starch derivatives and hydrolysates; cellulose derivatives such as methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose;
colloidal silicic acids; and sugars such as lactose, saccharose, fructose and glucose. Synthetic thickeners such as polyvinyl alcohol, vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, and polypropylene glycols may also be used.
[000132] The compositions of the invention can be rendered electrically conductive for use in biomedical electrodes and other electrotherapy contexts, i.e., to attach an electrode or other electrically conductive meinber to the body surface. For example, the composition may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue. These applications involve modification of the composition so as to contain a conductive species.
Suitable conductive species are ionically conductive electrolytes, particularly those that are normally used in the manufacture of conductive adhesives used for application to the skin or other body surface, and include ionizable inorganic salts, organic compounds, or combinations of both. Examples of ionically conductive electrolytes include, but are not limited to, ammoniuin sulfate, ammonium acetate, monoethanolamine acetate, diethanolamine acetate, sodium lactate, sodium citrate, magnesium acetate, magnesium sulfate, sodium acetate, calcium chloride, magnesium chloride, calcium sulfate, lithiuin chloride, lithium perchlorate, sodium citrate and potassiuin chloride, and redox couples such as a mixture of ferric and ferrous salts such as sulfates and gluconates. Preferred salts are potassium chloride, sodium chloride, magnesium sulfate, and magnesium acetate, and potassium chloride is most preferred for EKG applications. Although virtually any amount of electrolyte may be present in the adhesive coinpositions of the invention, it is preferable that any electrolyte present be at a concentration in the range of about 0.1 to about 15 wt.% of the hydrogel composition. The procedure described in U.S. Patent No. 5,846,558 to Nielsen et al. for fabricating biomedical electrodes may be adapted for use with the hydrogel compositions of the invention, and the disclosure of that patent is incorporated by reference with respect to manufacturing details.
Other suitable fabrication procedures may be used as well, as will be appreciated by those skilled in the art.
[000133] Antimicrobial agents may also be added to the compositions of the invention.
Antimicrobial agents function by destroying microbes, preventing their pathogenic action, and/or inhibiting their growth. Desirable properties of antimicrobial agents include, but are not limited to: (1) the ability to inactivate bacteria, viruses and fungi, (2) the ability to be effective within minutes of application and long after initial application, (3) cost, (4) compatibility with other components of composition, (5) stability at ambient teinperature, and (6) lack of toxicity.
[000134] Antioxidants may be incorporated into the compositions of the invention in lieu of or in addition to any antimicrobial agent(s). Antioxidants are agents that inhibit oxidation and thus prevent the deterioration of preparations by oxidation.
Suitable antioxidants include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, sodium ascorbate, sodium forinaldehyde sulfoxylate and sodium metabisulfite and others known to those of ordinary skill in the art. Other suitable antioxidants include, for example, vitamin C, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodiuin bisulfite, vitamin E and its derivatives, propyl gallate, sulfite derivatives, and others known to those of ordinary skill in the art.
[000135] Other preseivatives that can be incorporated into the present compositions include, by way of example, p-chloro-in-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride, cetylpyridinium chloride, chlorohexidine diacetate or gluconate, ethanol, and propylene glycol.
[000136] It will be appreciated that because the adhesive compositions of the invention are useful in a variety of contexts, the desirability or need for certain additives may differ depending on the intended use. The applications in which the adhesive coinpositions of the invention are useful include, for example: drug delivery systems; wound dressings;
conductive hydrogels; pressure-relieving cushions for application to the skin including heel cushions, elbow pads, knee pads, shin pads, forearin pads, wrist pads, finger pads, corn pads, callus pads, blister pads, bunion pads, and toe pads, all of which can include active agents;
intraoral applications such as tooth whitening strips, breath freshening films, and oral care products to treat sore throat, sores within the mouth, gingivitis, periodontal and oral infections, periodontal lesions, or dental caries or decay; adhesives for affixing medical devices, diagnostic systems and other devices to a body surface; sealants for ostomy devices, prostheses, and face masks; sound, vibration, and iinpact absorbing materials;
carriers in cosmetic and cosmeceutical gel products; and many other uses known to or readily ascertainable by those of ordinary skill in the art, or as yet undiscovered.
MANUFACTURING METHODOLOGIES:
[000137] The properties of the compositions of the invention are readily controlled by adjusting one or more parameters during fabrication. For example, the adhesive strength of the composition can be increased, decreased, or eliminated during manufacture, by varying the type and/or quantity of different components, or by changing the mode of manufacture. It should also be noted that compositions prepared using a conventional melt extrusion process generally, although not necessarily, exhibit somewhat different properties relative to coinpositions prepared using a solution cast technique; for example, melt extrusion is typically more useful for preparing adhesive compositions that having lower taclc than corresponding adhesive compositions prepared using solution casting.
[000138] The compositions described herein are generally melt extrudable, and thus may be prepared using a simple blending and extruding process. The components of the coinposition are weighed out and then adinixed, for example using a Brabender or Baker Perkins Blender, generally although not necessarily at an elevated teinperature, e.g., about 90 to 170 C, typically 100 to 140 C. Solvents or water may be added if desired.
The resulting composition can be extruded using a single or twin extruder, or pelletized.
Alternatively, the individual components can be melted one at a time, and then mixed prior to extrusion. The coinposition can be extruded to a desired thickness directly onto a suitable substrate or backing member. The composition can be also extruded first, and then be pressed against a backing member or laminated to a backing meinber. A releasable liner may also be included.
The thickness of the resulting film, for most purposes, will be in the range of about 0.050 to 0.80 mm, more usually in the range of about 0.37 to 0.47 mm.
[000139] Alternatively, the coinpositions may be prepared by solution casting, by admixing the components in a suitable solvent, e.g., a volatile solvent such as ethyl acetate, or lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred, at a concentration typically in the range of about 35 to 60 % w/v. The solution is cast onto a substrate, backing member or releasable liner, as above. Both adinixture and casting are preferably carried out at ambient teinperature. The material coated with the filin is then baked at a teinperature in the range of about 80 to 100 C, optimally about 90 C, for time period in the range of about one to four hours, optimally about two hours.
[000140) In selecting the coinponents for incorporation into an adhesive composition of the invention, the film-forming hydrophilic polymer is selected first. Then, a complementary multifunctional polymer, with recurring functional groups capable of noncovalent bonding to the recurring polar groups within at least one linear segment of the hydrophilic polymer is selected. The complementary multifunctional polymer serves as a "ladder-like"
noncovalent crosslinker in that noncovalent bonding to the film-forming polymer results in the formation of a ladder-like interpolymer complex. The plasticizer is then selected, which, as noted elsewhere herein, is a bifunctional linear oligomer capable of forming a bridge between a polar group on one film-fonning polymer chain and a polar group on a second film-forming polymer chain, thereby forming a "carcass-like" crosslinked complex. The ainount of the film-forming polymer is greater than the ainount of the complementary multifunctional -)olymer and is also greater than the amount of the bifunctional linear oligomer.
0001411 Optional additives, including phaimacologically active agents and )smeceutical agents, can be combined with the polymers and oligomer during adhesive eparation. Alter-nately, an additive can be added after the components are mixed and the nposition prepared. One method of loading the composition with an active agent, for mple, involves providing a layer of the composition on a substrate, coating the layer with a solution of the active agent, placing a release liner on top of the active agent layer, and allowing the active agent to become absorbed by the composition.
[000142] Any natural or synthetic flavorants, such as those described in Chemicals Used in Food Processing, Pub. No. 1274, National Academy of Sciences, pages 63-258, can be included in the compositions of the invention. Suitable flavorants include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils (oil of cloves) and oleoresins, as known in the art, as well as combinations thereof.
The amount of flavorant employed is normally a matter of preference, subject to such factors as flavor type, individual flavor, and strength desired.
EXPERIMENTAL:
[000143] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to manufacture the adhesive compositions of the invention, and are not intended to limit the scope of that which the inventors regard as the invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., ainounts, temperatures, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, teinperature is in degrees Celsius ( C), and pressure is at or near atmospheric.
[000144] The abbreviations used in the examples are as follows:
AA: adipic acid (Aldrich) ATBC: acetyltributyl citrate (Rohm Ainerica Inc.) ATEC: acetyltriethyl citrate (Rohm America Inc.) Cab-O-Sil M5: synthetic silicone dioxide supplied with Cabot Corporation in the form of finely micronized powder.
Carbopol 974: chemically crosslinked polyacrylic acid (Noveon, Inc.) Eudragit E100: N-dimethylaminoethyl methacrylate copolyiner (Rohm America Inc.) Eudragit L 100-55: methacrylic acid copolymer (Rohm America Inc.) Eudragit L 100: methacrylic acid copolymer (Rohin America Inc.) Eudragit S 100: methacrylic acid copolyiner (Rohin Ainerica Inc.) Gantrez ES-425: monobutyl ether of maleic acid - methylvinyl ether copolymer (ISP) Gantrez S-97: maleic acid - methylvinyl ether copolymer (ISP) HPC: hydroxypropylcellulose HPMCP: hydroxypropyl methylcellulose phthalate Kollidon CLM: physically crosslinked polyvinylpyrrolidone supplied by BASF in the forin of finely micronized powder.
Oppanol B-15: polyisobutylene (PIB) Mw 75,000 g/mol (BASF) PVP K90: Kollidon 90F polyvinylpyrrolidone (BASF) PVP K30: Kollidon 30F polyvinylpyrrolidone (BASF) PEG 400: polyethylene glycol 400 Sylvagum RE 85K: glycerol ester of tall oil rosin (Arizona Chemical) TBC: tributyl citrate (Rohm Ainerica Inc.) TEC: triethyl citrate (Rohm America Inc.) Preparation and properties of adhesive compositions based on the ladder-like interpolymer complexes [000145] In the present example, Eudragit E-100 is used as the fihn-forming polymer, which is a copolymer of 2-dimethylaminoethyl methacrylate (DMAEMA), butyl methacrylate, and methyl methacrylate (2:1:1). The monomer units of DMAEMA are capable of forming electrostatic bonds with carboxyl groups in the ladder-like crosslinker, Eudragit L 100-55 and Eudragit S- 100 (copolymer of inethacrylic acid with methyl methacrylate, 1:2). In this way, these blends represent triple blends of two Eudragit grade polymers (E-100 and L 100-55, or S-100) with appropriate plasticizers of hydrophobic units in Eudragit, such as tributyl citrate (TBC), triethyl citrate (TEC), acetyltributyl citrate(ATBC) and acetyltriethyl citrate (ATEC) (see Scheme in FIG. 4).
represents a carcass-like crosslinker, and "LLC" represents a ladder-like crosslinker.
1000261 FIG. 4 schematically illustrates the structure of an interpolymer complex composed of a film-forming polymer (FFP) and ladder-like crosslinker (LLC).
The complex is mixed with a plasticizer (P) and filled with a tackifier (T).
[00027] FIG. 5 demonstrates nominal stress-strain curves for uniaxial drawing for the mixture of film-forming Eudragit E- 100 polymer with 25 wt. % of TEC and for the ladder-like interpolymer Eudragit E-100 - Eudragit L-100-55 coinplex ([FFP]:[LLC]=10:1) plasticized with the same amount of TEC. Drawing rate is 20 mm/min.
[00028] FIG. 6 shows the impact of plasticizer (TEC) concentration on probe tack stress-strain curves of the blends of Eudragit E-100 film forming copolymer and Eudragit L-100-55 ladder-like crosslinker (10:1). The TEC concentrations are indicated in the Figure.
[00029] FIG. 7 exhibits the effect of ladder-like electrostatic crosslinking of film-forming polybase (Eudragit E-100) by polyacid (Eudragit L-100-55) on probe tack stress-strain curves.
[00030] FIG. 8 compares the effects of plasticizer (TEC) and tackifier (glycerol ester of tall oil rosin) on probe tack stress-strain curves of amphiphilic adhesives based on the ladder-like electrostatic complex of Eudragit E-100 and Eudragit L-100-55 copolymers (10:1).
[00031] FIG. 9 shows the impact of tackifier content on the work of adhesive debonding for the blends of Eudragit E-100 with 25 wt. % of ATBC.
[00032] FIG. 10 compares the effects of two tackifiers - Sylvagum RE 85K rosin and PIB
(Oppanol B-15) on probe tack of Eudragit E-100 - Eudragit L-100-55 blends (10:1), plasticized with 25 wt. % of TEC.
[00033] FIG. 11 demonstrates the effect of adipic acid on adhesive properties of Eudragit E-100 / L100-55 blends with 25 % of TEC at different E100/L100-55ratios [00034] FIG. 12 represents the curve of potentiometric titration of 1% aqueous solution of Eudragit E-1 00 polybase with 0.2 N HCI. The ionization degree, f, is plotted along a top axis.
[00035] FIG. 13 represents the curve of potentiometric titration of 1% aqueous solution of Eudragit L-100-55 polyacid with 0.1 N NaOH. The ionization degree,f, is plotted along a top axis.
[00036] FIG. 14 demonstrates the effect of partial ionization of film-forming polymer (Eudragit E-100) by HCl solution on the tack of ainphiphilic adhesive containing 35 wt. % of plasticizer TEC.
[00037] FIG. 15 compares the effects of partial ionization of film-forming polymer (by HCl) and ladder-like crosslinker (by NaOH) on the probe tack stress-strain curves for ainphiphilic Eudragit E-100 - Eudragit L-100-55 adhesive containing 25 wt. %
of plasticizer TEC.
[00038] FIG. 16 represents probe tack stress-strain curves for the Eudragit E-Eudragit L-100-55 complex containing 35 wt. % of plasticizer TEC under 10 %
ionization of film-forming polymer and ladder-like crosslinker and for the coinplex fonned between partly ionized polymer components at 10 % degree of ionization.
[00039] FIG. 17 represents the effect of partial ionization of carboxyl groups in the ladder-like crosslinker on the stress-strain curves of the PVP-PEG-Eudragit L- 100-55 adhesive hydrogel containing 12 wt. % of sorbed water. The degrees of ionization (%) are shown in the Figure.
[00040] FIG. 18 coinpares the adhesive properties of interpolymer complexes of Eudragit E- 100 fihn-forining polymer with the ladder-like crosslinkers of different hydrophilicity:
Eudragit L-100-55 (Example 9) and Gantrez S-97. The content of plasticizer TEC
in blends is25wt.%.
[000411 FIG. 19 demonstrates the effect of ladder-like crosslinker (Eudragit L-100-55 or Gantrez S-97) on water absorbing capacity, expressed in terms of Swell Ratio, for Eudragit E-100 blends, plasticized with 25 % of TEC.
[00042] FIG. 20 exhibits the impact of the nature of plasticizers (TEC, ATEC, TBC and ATBC) on probe tack properties of Eudragit E-100 - Eudragit L-100-55 complexes.
Concentration of the plasticizers is 45 wt%.
[00043] FIG. 21 illustrates the influence of the nature of plasticizer in Eudragit E-100 -Eudragit L-100-55 complex on Swell Ratio of relevant blends.
[00044] FIG. 22 shows the effect of mixing the Eudragit E-100 - Eudragit L-100-complexes with PVP and with PVP-PEG blend (2:1) on water absorbing capacity expressed in terms of Swell Ratio.
[00045] FIG. 23 demonstrates the influence of hydrophilization of Eudragit E-Eudragit L-100-55 plasticized complex on the work of adhesive debonding (probe tack).
[00046] FIG. 24 deinonstrates peel force traces towards dry and wet huinan skin for Gelva acrylic PSA, water soluble adhesive based on carcass-like PVP-PEG complex outlined by US
Patent 6,576,712, hydrophilic PVP-PEG-Eudragit L-100-55 adhesive and amphiphilic adhesive based on the ladder-like Eudragit E-100 - Eudragit L-100-55 complex (Exainple 1).
[00047] FIG. 25 represents probe tack stress-strain curves for water soluble PVP-PEG (36 %) adhesive outlined by US Patent 6,576,712, amphiphilic adhesives described in Example 9 (35 % TEC) and in Exainple 10 (7 % of tackifier, 30 % TEC), hydrophilic PVP-PEG-Eudragit L-100-55 adhesive at 17 % of absorbed water in comparison with two grades of conventional PSAs: SIS-based DURO-TAKr, 34-4230 and acrylic PSA manufactured by 3M.
[00048] FIG. 26 represents the kinetics of in vitro release of silver sulfate from three adhesive hydrogel compositions used in wound dressings.
[00049] FIG. 27 demonstrates in vitro release kinetics of silver phosphate from the matrix of wound dressing based on the ladder-like interpolymer complex Eudragit E-100 - Eudragit L-100-55, plasticized with 25 wt. % of TEC.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND OVERVIEW:
[00050] It is to be understood that, unless otherwise indicated, this invention is not liinited to specific polyiners, oligomers, crosslinking agents, additives, inanufacturing processes, or adhesive products. It is also to be understood that the tenninology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[00051] In describing and claiming the present invention, the following tenninology will be used in accordance with the definitions set out below.
[00052] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a hydrophilic polymer" includes not only a single hydrophilic polyiner but also two or more hydrophilic polymers that may or may not be combined in a single composition, reference to "a plasticizer"
includes a single plasticizer as well as two or more plasticizers that may or may not be combined in a single coinposition, and the like.
[00053] A"hydrophobic" polymer absorbs only up to 1 wt. % water at 100% rh, while "hydrophilic" polymers absorb at least 1 wt.% water at 100% rh.
[00054] A "water-swellable" polymer is one that is capable of absorbing water in an amount that is at least 50% of its own weight. That is, a water-swellable polymer weighing x grams can absorb at least 0.5x grains of water, to provide a hydrated polymer weighing at least 1.5x grams and having a polymer to water (weight) ratio of at most 3:1.
[00055] The terin "crosslinked" herein refers to a polymer composition containing intramolecular and/or intermolecular noncovalent bonds. Noncovalent bonding includes hydrogen bonding, electrostatic bonding, and ionic bonding.
[00056] The term "polymer" as used herein includes both linear and branched polymers, and homopolyiners as well as copolymers, the latter including all types of copolymer structures (e.g., block copolyiners, alternating copolymers, random copolymers, etc.) as well as "higher order" copolyiners (e.g., terpolymers). Those compounds referred to herein as "oligomers" are polyiners having a molecular weight below about 1000 Da, preferably below about 800 Da.
[00057] The term "water-insoluble" is used to refer to a polymer, compound or composition whose aqueous solubility measured at 20 C is less than 5 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%. The term "insoluble" is used to refer to a polymer, coinpound or coinposition whose solubility in water, polar organic solvents, and possibly nonpolar organic solvents, measured at 20 C, is less than 5 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%.
[00058] The term "llydrogel" is used in the conventional sense to refer to water-swellable polymeric matrices that can absorb a substantial amount of water to form elastic gels, where the "matrices" are three-dimensional networks of macromolecules held together by covalent or non-covalent crosslinks. Upon placement in an aqueous environinent, dry hydrogels swell to the extent allowed by the degree of cross-linking.
[00059] The term "hydrogel composition" refers to a composition that either contains a hydrogel or is entirely composed of a hydrogel. As such, "hydrogel compositions"
encoinpass not only hydrogels per se but also compositions that comprise a hydrogel and one or more non-hydrogel components or coinpositions, e.g., hydrocolloids, which contain a hydrophilic component (which may contain or be a hydrogel) distributed in a hydrophobic phase.
[000601 The terins "tack" and "tacky" are qualitative. However, the terms "substantially nontacky," "slightly tacky," and "tacky," as used herein, may be quantified using the values obtained in a PKI tack determination, a TRBT tack determination, or a PSA tack determination/Polyken Probe (Solutia, Inc.). The term "substantially nontacky"
is used to refer to a composition having a tack value less than about 25 g-cm/sec, the term "slightly tacky" refers to a composition having a tack value in the range of about 25 g-cm/sec to about 100 g-cm/sec, and the term "tacky" refers to a composition having a tack value of at least 100 g-cm/sec.
[00061] The term "plasticizer" is used in the conventional sense of the term to refer to a relatively low molecular weight compound that is miscible with a polymer or polyiner blend and decreases the glass transition temperature and elastic modulus thereof.
[00062] It is desirable to obtain water-insoluble, water-swellable hydrophilic adhesive polymers (adhesive hydrogels) that are capable to form homogeneous filins either upon casting a solution to backing layer followed by drying, or under external pressure or by means of extrusion. The film-forming capability requires that the blend has to be free of covalent crosslinks. Blending the polymers provides a convenient way to obtain composite materials with specifically tailored properties, since the properties of the blend are typically intennediate between those of the unblended coinponents when the components are immiscible or partly miscible. In order to make the composite insoluble in water, water-insoluble materials are usually mixed with water-soluble materials. When this is done, however, a phase separation can often occur that does not favor adhesion.
Moreover, the insolubility of blend components may hainper the procedure of blend preparation, which often involves the dissolution of all the components in a common solvent, followed by casting the solution and drying.
[00063] Preparation of polymer composite materials whose properties are new and untypical of parent components requires a high skill of a material designer.
This challenge may be resolved if the blend components are capable of a strong favorable interaction to each other. More often, such interaction is hydrogen, electrostatic or ionic bonding. In this instance inixing of two or more soluble polymers can give their ladder-like complex schematically shown in FIG. 1 that is swellable, but insoluble or partly soluble.
[00064] In order to resolve these problems, this invention is directed to a method of obtaining water-insoluble, film-forming coinpositions by blending soluble polymers, more specifically by blending hydrophilic polymers with complementary macromolecules that are capable of hydrogen bonding, electrostatic or ionic bonding.
[00065] By way of overview, the adhesive coinpositions of the irivention contain at least film-forming hydrophilic polymer having at least one linear segment with a plurality of recurring polar groups thereon, at least one complementary multifunctional polyiner that serves as a "ladder-like" noncovalent crosslinker of the film-forming polymer, and at least one plasticizer compatible with (i.e., miscible with) or at least partially compatible with both the film-forming polymer and the complementary multifunctional polymer. The film-forming polyiner is present in a higher concentration than the complementary multifunctional polyiner, and it is this higher concentration that determines the film-forming characteristics.
Therefore, while there may be materials that are suitable for use as either the fihn-forming polyiner or as the complementary multifunctional polymer, their function in the composition is determined by the quantity of the component in the composition. If the recurring polar groups or the recurring functional groups are ionogenic, another factor that controls the performance of composite material is the degree of ionization or pH of the mixture.
[00066] For exainple, polyacids such as acrylate polymers bearing carboxyl proton-donating functional groups or polyols bearing hydroxyl proton-donating functional groups and proton-accepting polymers such as poly(N-vinyl lactams) or polyainines are suited for use as both the fihn-forming polymer or as the complementary multifunctional polymer. In a composition having a greater amount of an acrylate or another proton-donating polymer relative to the ainount of a poly(N-vinyl lactam), the acrylate polymer serves as the filhn-forming polymer and the poly(N-vinyl lactam) or polyamine or another proton-accepting polymer serves as the coinpleinentary multifunctional polymer, or ladder-like crosslinker.
Similarly, in a composition having a greater ainount of a poly(N-vinyl lactam) or polyainine relative to the amount of an acrylate polyiner, the poly(N-vinyl lactam) or polyamine serves as the film-forming polyiner and the acrylate polymer serves as the ladder-like crosslinker.
[00067] Maintaining a specified pH value in the blend or in an admixture used to provide the blend provides an additional factor controlling the performance of the blend when one or more ionogenic polymers are present. Ionized groups are capable of ionic, but not electrostatic or hydrogen bonding. Fully or partly ionized polyiners are always soluble in water, whereas non-ionized polymers as a rule are insoluble or poorly soluble in water.
Consequently, the degree of ionization affects appreciably the solubility and swelling of interpolymer complexes involving ionogenic polymers. Moreover, by varying the pH value and degree of ionization, the adhesive properties of composite materials can be controlled.
Indeed, adhesion is a result of specific balance between cohesive interaction energy and free volume. As polymeric coinponents bear opposite charges, cohesion is increased.
As two polymers have the same positive or negative charge, cohesion is immediately suppressed and free voluine is increased. Moreover, due to electrostatic repulsion between the functional groups of identical charge, the chain rigidity and free volume is usually increased. All these factors dramatically affect adhesive performance.
[00068] The adhesion profile of the water-insoluble, film-forming compositions of the invention can be tailored based on materials, the ratio of components in the composition, the degree of ionization and the quantity of water in the blend. The ladder-like crosslinker, its ratio to the amount of film-forming polymer, concentration of a plasticizer and ionization degree are selected so as to provide the desired adhesion profile with respect to hydration.
Generally, the compositions that are relatively slightly crosslinked through coinparatively loose hydrogen bonds and deinonstrating a large free volume provide initial tack in dry state.
When the degree of crosslinking degree and the cohesive strength of the network in the interpolymer complex is above some critical value, the energy of cohesion dominates under free volume and such coinpositions are usually non-tacky in the dry state.
However, as a free voluine is increased in this blend (e.g. by adding a suitable plasticizer), adhesion immediately appears. Because water is a good plasticizer for hydrophilic polymers, absorption of the water leads to an iinproveinent of adhesion. Because electrostatic bonds are appreciably stronger than the hydrogen bonds, the cohesion in the blends of polyiners bearing carboxyl groups is usually higher than in the materials composed of polymers having hydroxyl groups.
Adhesion in such blends appears normally with a higher concentration of absorbed water.
Flexible polymers provide higher cohesion than polyiners with rigid chains. As an exainple, for blends of poly(vinyl pyrrolidone) (PVP) as a film-forming polyiner, when the ladder-like crosslinker is a rigid-cliain cellulose ester bearing OH groups, the composition is generally tacky prior to contact with water (e.g., with a moist surface) but gradually loses tack as the composition absorbs moisture. When the ladder-like crosslinker is an acrylate polymer or copolymer with carboxyl groups, a composition is provided that is generally substantially nontacky prior to contact with water, but that becomes tacky upon contact with a moist surface.
POLYMER COMPONENTS:
[00069] The fihn-forming hydrophilic polymer and the complementary multifunctional polymer, as noted elsewhere herein, are generally selected from the same classes of polymers and copolymers, but have complementary groups along the backbone that interact to form noncovalent bonds (e.g., hydrogen bonds, electrostatic bonds, or ionic bonds), thereby forming a ladder-like complex that is insoluble in aqueous liquids, polar organic solvents, and many nonpolar organic solvents as well. By definition herein, the polymer that serves as the "film-forming" polymer represents a greater weight fraction in the mixtures and compositions of the invention than does the complementary multifunctional polymer.
Typically, the fihn-forming hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the mixtures and compositions of the invention, while the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the mixtures and compositions of the invention. Generally, although not necessarily, the film-forming polymer will also have a higher molecular weight than the complementary inultifunctional polymer.
The molecular weight of the film-forining polymer will usually be in the range of about 20,000 to 3,000,000, preferably in the range of about 100,000 to 2,000,000, and most preferably in the range of about 100,000 to 1,500,000.
[00070] The recurring polar groups on the fihn-forming polymer and the recurring functional groups on the coinpleinentary rnultif-unctional polymer may comprise backbone heteroatoms, e.g., an oxygen atom in an ether (-0-) or ester (-(CO)-O-) linkage, a nitrogen atom in an amine (-NH-), imine (-N=), or amide (-NH(CO)-) linkage, a sulfur atom in a thioether (-S-) linkage, and the like. The recurring polar groups and the recurring functional groups may also coinprise pendant groups, for instance:
[00071] hydroxyl;
[00072] sulfhydryl;
[00073] Cr-C18 hydrocarbyloxy, preferably CI-C8 alkoxy;
[00074] C2-C18 acyl, preferably C2-C8 acyl (e.g., C2-C8 alkylcarbonyl);
[00075] CZ-C18 acyloxy, preferably C2-C8 acyloxy (e.g., C2-C8 alkylcarbonyloxy);
[00076] CZ-C,$ hydrocarbyloxycarbonyl (-(CO)-O-alkyl), preferably C2-C8 alkoxycarbonyl (-(CO)-O-alkyl));
[00077] carboxy (-COOH);
[00078] carboxylato (-COO);
[00079] carbamoyl (-(CO)-NR2 wherein R is H or Ci-Clg hydrocarbyl, preferably H or Ci-C$ alkyl);
[00080] cyano(-C=N);
[00081] isocyano (-N}-C);
[00082] cyanato (-O-C=N);
[00083] isocyanato (-O-N+ =C-);
[00084] forinyl (-(CO)-H);
[00085] amino, i.e., -NR1RZ where R' and R2 are independently selected from H
and CI-CIg hydrocarbyl, preferably selected from H, C1-C8 alkyl, and C5-C12 aryl, or are linked to form an optionally substituted five- or six-membered ring, thus including mono-(Ci-C8 alkyl)-substituted amino, di-(CI-C8 alkyl)-substituted amino, mono-(C5-C]2 aryl)-substituted amino, and di-(C5-Cz2 aryl)-substituted amino), piperidinyl, pyrrolidinyl, and pyrrolidonyl;
[00086] quatemary ammonium, i.e., -[NR3R4R5] "Q- where R3, R4, and RS are Cl-hydrocarbyl, preferably C1-C8 alkyl, and most preferably C1-C4 alkyl, and Q is a negatively charged counterion, e.g., a halogen anion;
[00087] C2-C18 alkylamido, preferably C2-C8 alkylamido (-NH-(CO)-alkyl);
[00088] C6-C18 arylainido, preferably C6-CIZ alkylamido (-NH-(CO)-aryl);
[00089] nitro (-NO2);
[00090] sulfo (-S02-OH);
[00091] sulfonato (-S02-O );
[00092] C1-C18 hydrocarbylsulfanyl, preferably CI-C8 alkysulfanyl (-S-hydrocarbyl and -S-alkyl, respectively, also termed "hydrocarbylthio" and "alkylthio"); [00093]
phosphono (-P(O)(OH)2);
[00094] phosphonato (-P(O)(O)2);
[00095] phosphinato (-P(O)(O')); and [00096] phospho (-P OZ), [00097] any of which may be substituted as permitted, e.g., with hydrocarbyl groups and/or additional functional groups. The pendant groups may also be directly linked to an atom in the polymer backbone, or they may be indirectly linked through a linking group (e.g., C1-Cl8 hydrocarbylene linker such as C2-C8 alkylene linker). Additionally, there may be two or more types of polar groups on the film-forming polyiner (which may include backbone heteroatoins as well as pendant polar groups) and two or more types of functional groups on the complementary multifunctional polymer (again, which inay include backbone heteroatoins as well as pendant polar groups).
[00098] Preferred pendant groups are those present on polymers that are readily synthesized or commercially available, typically including hydroxy, C1-C$
alkoxy, carboxyl, carboxylato, sulfo, sulfonato, amino, di(CI-C8 alkyl)-substituted amino, quaternary aminoniuin, piperidinyl, pyrrolidinyl, pyrrolidinyl, and phosphono groups.
[00099] In general, it is also preferred, although not essential, that the film-forming polymer have an excess of polar groups relative to the corresponding functional groups on the coinplementary inultifunctional polymer, such that, providing that the polar groups and functional groups are ionogenic, the ladder-like complex can readily ionized in the presence of an ionizing agent, e.g., an acid or base. Typically, zero to about 30% of the ionogenic groups present on the film-forining polymer are ionized, preferably about 5%
to 10%. The degree of ionization inay be controlled by addition of a suitable ionizing agent, e.g., an acid or base.
[000100] It will be appreciated by those of ordinary skill in the art that virtually any polymers meeting the aforementioned criteria may be used herein. Suitable polymers include, but are not limited, to the following:
[000101] poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(vinyl-2-valerolactam), and poly(N-vinyl-2-caprolactam);
[000102] polyvinyl alcohols, including polyvinyl alcohol per se and polyvinyl phenol;
[000103] polyacrylamides such as poly(N-inethaciylamide), poly(N,N-diinethylacrylamide), poly(N-isopropylacrylainide) (PNIPAM), poly(N-vinyl acrylainide), and other poly(N-alkyl acrylainides and N-alkenyl acrylamides);
[000104] poly(alkylene oxides) such as polyethylene oxide (PEO) and poloxamers (i.e., copolymers of ethylene oxide and propylene oxide);
[000105] poly(oxyethylated) alcohols such as poly(oxyethylated) glycerol, poly(oxyethylated) sorbitol, and poly(oxyethylated) glucose;
[000106] polylactide and poly(lactide-co-glycolide);
[000107] poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(fumaric acid), alginic acid, and poly(sulfonic acids);
[000108] poly(vinyl amines);
[000109] poly(alkylene iinines);
[000110] cellulose esters and other cellulose derivatives, including carboxymethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose butyrate, cellulose diacetate, cellulose phthalate, cellulose propionate, cellulose propionate butyrate, cellulose triacetate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, sodium carboxymethylcellulose; and [000111] acrylate and methacrylate polymers and copolymers, including poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(hydroxyalkyl acrylates) such as poly(hydroxyethyl acrylate), and poly(hydroxyalkyl methacrylates) such as poly(hydroxyethyl methacrylate) (PoIyHEMA). Preferred acrylate polymers are those copolymers available under the tradename "Eudragit" from Rohm Pharma (Germany). The Eudragit series E, L, S, RL, RS, and NE copolymers are available as solubilized in organic solvent, in an aqueous dispersion, or as a dry powder. Preferred acrylate polyiners are copolyiners of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers. Particularly preferred such copolyiners are Eudragit L-30D-55 and Eudragit L-100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 that can be reconstituted with water). The molecular weight of the Eudragit L-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da, with a ratio of free carboxyl groups to ester groups of approximately 1:1. The copolymer is generally insoluble in aqueous fluids having a pH below 5.5. Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which differs from Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is approximately 1:2. Eudragit S-100 is insoluble at pH
below 5.5, but unlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7Ø This copolymer is soluble at pH 7.0 and above.
Eudragit L-100 inay also be used, which has a pH-dependent solubility profile between that of Eudragit L-30D-55 and Eudragit S-100, insofar as it is insoluble at a pH below 6Ø It will be appreciated by those skilled in the art that Eudragit L-30D-55, L-100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics. Other preferred Eudragit polymers are cationic, such as the Eudragit E, RS, and RL
series polymers. Eudragit E1OO and E PO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates (e.g., methyl methacrylate), while Eudragit RS and Eudragit RL polymers are analogous polymers, composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate.
[0001121 Copolymers of any of the above may also be used herein, as will be appreciated by those of ordinary skill in the art.
PLASTICIZERS:
[000113] Suitable plasticizers and softeners include, by way of illustration and not limitation: alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, tricresyl phosphate, and triphenyl phosphate; alkyl citrates and citrate esters such as trimethyl citrate, triethyl citrate and acetyl triethyl citrate, tributyl citrate and acetyl tributyl citrate, acetyl triethyl citrate, and trihexyl citrate; alkyl glycerolates; alkyl glycolates;
dialkyl adipates such as dioctyl adipate (DOA; also referred to as bis(2-ethylhexyl)adipate), diethyl adipate, di(2-methylethyl)adipate, and dihexyl adipate; dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates and mixed alkyl-aryl phthalates, including phthalic acid esters, as represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate;
dialkyl sebacates such as diethyl sebacate, dipropyl sebacate, dibutyl sebacate and dinonyl sebacate; dialkyl succinates such as diethyl succinate and dibutyl succinate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; glycol esters and glycerol esters such as glycerol diacetate, glycerol triacetate (triacetin), glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate;
hydrophilic surfactants, preferably hydrophilic non-ionic surfactants such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers, and polyethylene glycol sorbitan-fatty acid esters, as well as non-ionic surfactants such as ethylcellosolve; lower alcohols from ethyl to octyl;
sorbitol; tartaric acid esters such as dibutyl tartrate; and mixtures thereof.
[000114] A preferred plasticizer for use in conjunction with the present invention is a bifunctional oligomer that is "complementary" to the film-forming polymer as described in U.S. Patent No. U.S. Patent No. 6,576,712 to Feldstein et al., cited earlier herein.
Preferably, the complementary oligomer is terminated with hydroxyl groups, ainino or carboxyl groups. The oligomer typically has a glass transition temperature Tg in the range of about -100 C to about -30 C and a melting temperature T,n lower than about 20 C. The oligomer may be also amorphous. The difference between the Tg value of the film-forrning polymer and that of the complementary oligomer is preferably greater than about 50 C, more preferably greater than about 100 C, and most preferably in the range of about 150 C to about 300 C. Generally, the oligomer will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600. Examples of suitable oligomers include, but are not limited to, low molecular weight polyalcohols (e.g. glycerol), oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol, including carboxyl-terminated and amino-terminated derivatives of polyalkylene glycols. Polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal complementary oligomer.
[000115] The compositions of the invention may also include two or more plasticizers in combination, e.g., triethyl citrate and tributyl citrate, triethyl citrate and polyethylene glycol 400, polyethylene glyco1400 and dioctyl phthalate, etc.
REPRESENTATIVE COMPOSITIONS:
[000116] An illustrative composition includes poly(N-vinyl-2-pyrrolidone) ("PVP") as the film-forming polymer and polyethylene glycol ("PEG") as the carcass-like non-covalent crosslinker. Mixing a PVP-PEG adhesive blend with a ladder-like non-covalent crosslinker that is a moderately hydrophilic or water-insoluble polymer results in the decrease of blend hydrophilicity and dissolution rate. In order to decrease the dissolution rate further or to obtain insoluble mixtures, the PVP-PEG blend can be mixed with polyiners that bear complementary (with respect to PVP) reactive functional groups in their repeating units.
Since the PVP contains proton-accepting carbonyl groups in its repeating units, the complementary functional groups are preferably proton-donating, hydroxyl or carboxyl groups. Thus, for use with PVP and PEG, suitable ladder-like non-covalent crosslinkers are long chain polymers such as polyvinyl alcohols, polyacrylic acids, polymethaciylic acids, homo- and co-polymers thereof, as well as sulfonic acid and alginic acid.
[000117] Another illustrative composition uses a copolymer of methacrylic acid and methyl methacrylate as the ladder-like non-covalent crosslinker with the PVP/PEG noted above. This composition is used to facilitate in understanding the principles of the invention.
[000118] The PVP-PEG complex combines high cohesive toughness (due to PVP-PEG
H-bonding) with a large free volume (resulting from considerable length and flexibility of PEG chains). In order to emphasize enhanced free volume in the PVP-PEG blend, this type of complex structure is defined as a "carcass-like" structure (see FIG. 1).
The carcass-like structure of the complex, results from the location of reactive functional groups at both ends of PEG short chains. When the ladder-like non-covalent crosslinker contains reactive functional groups in repeating units of the backbone, the resulting complex has so-called "ladder-like" structure (see FIG. 2). The ladder-like type of interpolymeric coinplex was first described by Kabanov et al. (1979) Vysokonzol. Soed. 21(A):243-281. While the formation of the carcass-like complex leads to enhanced cohesive strength and free volume (which determines the adhesive properties of PVP-PEG blends), the formation of the ladder-like complex shown in FIG. 2 is accompanied by the loss of blend solubility and the increase of cohesive strength coupled with the decrease in free volume. For this reason, the structure of the ladder-like complex provides no adhesion. .
[000119] Due to the decrease in free voluine and the increase in cohesive energy, the PVP-PEG blend mixed with a long chain polymer giving the ladder-like complex with PVP, provides no or negligible initial tack. However, as the non-adhesive PVP-PEG
blend with the long chain polymer is plasticized by water, the glass transition temperature of the blend shifts toward lower values, which are typical features of pressure-sensitive adhesives, and adhesion arises.
[000120] There are certain preferred coinbinations of components in the adhesive composition. For exainple, when the film-forming polymer is a poly(N-vinyl lactam) such as poly(N-vinyl pyrrolidone) or poly(N-vinyl caprolactam), the ladder-like crosslinker is preferably a poly(dialkyl aininoalkyl aciylate), poly(dialkyl aminoalkyl methacrylate), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, poly(hydroxyalkyl acrylate), or poly(hydroxyalkyl inetllacrylate) such as poly(hydroxyethyl methacrylate).
[000121] Similarly, when the film-forming polymer is a poly(dialkyl aminoalkyl acrylate), poly(dialkyl aminoalkyl methacrylate), polyacrylic acid, polyinethacrylic acid, polyinaleic acid, polyvinyl alcohol, polyvinyl phenol, or poly(hydroxyalkyl acrylate) such as poly(hydroxyethyl methacrylate), the ladder-like crosslinker is preferably a poly(dialkyl aininoalkyl acrylate, poly(dialkyl aininoalkyl methacrylate), poly(N-vinyl lactam) such as poly(N-vinyl pyrrolidone) or poly(N-vinyl caprolactam), as well as a copolymer of poly(N-dialkylamino alkyl acrylate) with alkyl acrylate, polyethylene oxide, methacrylate or ethacrylate monomers, or a copolymer of poly(N-dialkylamino alkyl methacrylate) and alkyl acrylate, methacrylate or ethacrylate monomers.
[000122] For any of the aforementioned combinations, a preferred carcass-like crosslinker is an oligomeric alkylene glycol comprising about 1-20 alkylene oxide units in its chain such as polyethylene glycol, carboxyl-terminated oligomeric alkylene glycol such as carboxyl-terminated poly(ethylene glycol), or polyhydric alcohols.
[000123] Other exainples of suitable blends are shown in the following table:
film-forining polymer ladder-like crosslinker carcass-like crosslinker PVCap Eudragit L 100, PAA, PMA, PEG and carboxyl PVA, polyvinyl phenol and terminated PEG
Po1yHEMA
PNIPAM Eudragit L 100, L 100-55, PEG and carboxyl S-100, PAA, PMA, alginic terininated PEG
acid, PVA, and PoIyHEMA
PEO Eudragit L 100, L 100-55, Propylene glycol, S-100, PAA, PMA, alginic Glycerol, PEG, PEG-acid, GANTREZ ES-225, diacid GANTREZ ES-425, polyvinyl phenol PAA, PMA Eudragit E-100* and PEG
polyvinyl amine Eudragit E-100* PAA, PMA, Eudragit L 100, Carboxyl tenninated PEG, L 100-55, S 100 and alginic carbonic di- and polyvalent acid acids**
* Eudragit E-100 is a copolymer of 2-dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate 2:1:1, coinmercially available from Rohin Pharma Polymers ** As described in U.S. Patent No. 6,576,712 [000124] To illustrate the approacli used herein, a PVP-PEG-Eudragit blend was used as a typical example, although the approach is general and can be easily reproduced using other water-soluble, hydrophilic polymers.
[000125] The properties of adhesive polyiner blends were evaluated and are set forth in the examples. The behavior of these polymer blends was found to be typical of covalently crosslinked polymers. However, in contrast to covalently crosslinked systems, the triple polyiner blends combining the carcass-like and the ladder-like non-covalent crosslinkers can be easily prepared using a straightforward process, and, furthermore, provide film-forming properties that are unattainable using chemically crosslinked polymers.
ADDITIVES:
[000126] The adhesive coinpositions of the invention may also include one or more conventional additive, which may be combined with the polyiners and the plasticizer during adhesive formulation or incorporated thereafter. Optional additives include, without limitation, fillers, pH regulating agents, ionizing agents, tackifiers, detackifying agents, electrolytes, antimicrobial agents, antioxidants, preservatives, colorants, flavors, and combinations thereof. In certain embodiments, the compositions of the invention may also include a pharmacologically active agent or a cosmeceutically active agent.
For instance, transdermal, transmucosal, and topical delivery systems in which an adhesive coinposition of the invention serves as a drug reservoir and/or skin contact adhesive layer may be formulated for the delivery of a specific pharinacologically active agent. Cosmeceutical products such as tooth whitening gels and strips may be formulated for the delivery of one or more tooth-whitening agents. Examples of such products are described in pending U.S.
Patent Application Serial No. 10/936,887 to Feldstein et al. for "Method of Preparing Polymeric Adhesive Compositions Utilizing the Mechanism of Interaction Between The Polymer Components, filed September 8, 2004, and U.S. Patent Application Serial No.
60/638,835 to Singh et al. for "Sustained Release Tooth Whitening Systeins and Formulations," filed December 21, 2004, the disclosures of which are incorporated by reference herein.
[000127] Absorbent fillers may be advantageously incorporated to control the degree of hydration when the adhesive is on the skin or other body surface. Such fillers can include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesiuin silicate, magnesium aluminum silicate, hydrophobic starch, calciuin sulfate, calcium stearate, calcium phosphate, calcium phosphate dihydrate, woven and non-woven paper and cotton materials. Other suitable fillers are inert, i.e., substantially non-adsorbent, and include, for example, polyethylenes, polypropylenes, polyurethane polyether ainide copolymers, polyesters and polyester copolymers, nylon and rayon. A
preferred filler is colloidal silica, e.g., Cab-O-Sil (Cabot Corporation, Boston MA).
[000128] Coinpounds useful as pH regulators include, but are not limited to, glycerol buffers, citrate buffers, borate buffers, phosphate buffers, and citric acid-phosphate buffers.
Buffer systems are useful to ensure, for instance, that the pH of a composition of the invention is compatible with that of an individual's body surface.
[000129] Ionizing agents are also useful to impart a desired degree of ionization to the interpolymer complex within the adhesive coinpositions of the invention.
Suitable ionizing agents are acids and bases, depending on the group to be ionized. The acids and bases may be inorganic (hydrochloric acid, hydrobroinic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, ammoniuin carbonate, etc.) or organic (acetic acid, maleic acid, triethylainine, ethanolainine, etc.).
[000130] Tackifiers can also be included to improve the adhesive and tack properties of the compositions of the invention. The mechanism underlying tack improvement results from the large size and hydrophobic character of tackifier molecules. Exemplary tackifying materials include tacky rubbers such as polyisobutylene, polybutadiene, butyl rubber, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). Other exainples of suitable tackifiers herein are those that are conventionally used with pressure sensitive adhesives, e.g., rosins, rosin esters, polyterpenes, and hydrogenated aromatic resins. In those embodiments wherein adhesion is to be reduced or eliminated, conventional detackifying agents may also be used. Suitable detackifiers include crosslinked poly(vinylpyrrolidone), silica gel, bentonites, and so forth.
[000131] Preferred thickeners herein are naturally occurring compounds or derivatives thereof, and include, by way of example: collagen; galactomannans; starches;
starch derivatives and hydrolysates; cellulose derivatives such as methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose;
colloidal silicic acids; and sugars such as lactose, saccharose, fructose and glucose. Synthetic thickeners such as polyvinyl alcohol, vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, and polypropylene glycols may also be used.
[000132] The compositions of the invention can be rendered electrically conductive for use in biomedical electrodes and other electrotherapy contexts, i.e., to attach an electrode or other electrically conductive meinber to the body surface. For example, the composition may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue. These applications involve modification of the composition so as to contain a conductive species.
Suitable conductive species are ionically conductive electrolytes, particularly those that are normally used in the manufacture of conductive adhesives used for application to the skin or other body surface, and include ionizable inorganic salts, organic compounds, or combinations of both. Examples of ionically conductive electrolytes include, but are not limited to, ammoniuin sulfate, ammonium acetate, monoethanolamine acetate, diethanolamine acetate, sodium lactate, sodium citrate, magnesium acetate, magnesium sulfate, sodium acetate, calcium chloride, magnesium chloride, calcium sulfate, lithiuin chloride, lithium perchlorate, sodium citrate and potassiuin chloride, and redox couples such as a mixture of ferric and ferrous salts such as sulfates and gluconates. Preferred salts are potassium chloride, sodium chloride, magnesium sulfate, and magnesium acetate, and potassium chloride is most preferred for EKG applications. Although virtually any amount of electrolyte may be present in the adhesive coinpositions of the invention, it is preferable that any electrolyte present be at a concentration in the range of about 0.1 to about 15 wt.% of the hydrogel composition. The procedure described in U.S. Patent No. 5,846,558 to Nielsen et al. for fabricating biomedical electrodes may be adapted for use with the hydrogel compositions of the invention, and the disclosure of that patent is incorporated by reference with respect to manufacturing details.
Other suitable fabrication procedures may be used as well, as will be appreciated by those skilled in the art.
[000133] Antimicrobial agents may also be added to the compositions of the invention.
Antimicrobial agents function by destroying microbes, preventing their pathogenic action, and/or inhibiting their growth. Desirable properties of antimicrobial agents include, but are not limited to: (1) the ability to inactivate bacteria, viruses and fungi, (2) the ability to be effective within minutes of application and long after initial application, (3) cost, (4) compatibility with other components of composition, (5) stability at ambient teinperature, and (6) lack of toxicity.
[000134] Antioxidants may be incorporated into the compositions of the invention in lieu of or in addition to any antimicrobial agent(s). Antioxidants are agents that inhibit oxidation and thus prevent the deterioration of preparations by oxidation.
Suitable antioxidants include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, sodium ascorbate, sodium forinaldehyde sulfoxylate and sodium metabisulfite and others known to those of ordinary skill in the art. Other suitable antioxidants include, for example, vitamin C, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodiuin bisulfite, vitamin E and its derivatives, propyl gallate, sulfite derivatives, and others known to those of ordinary skill in the art.
[000135] Other preseivatives that can be incorporated into the present compositions include, by way of example, p-chloro-in-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride, cetylpyridinium chloride, chlorohexidine diacetate or gluconate, ethanol, and propylene glycol.
[000136] It will be appreciated that because the adhesive compositions of the invention are useful in a variety of contexts, the desirability or need for certain additives may differ depending on the intended use. The applications in which the adhesive coinpositions of the invention are useful include, for example: drug delivery systems; wound dressings;
conductive hydrogels; pressure-relieving cushions for application to the skin including heel cushions, elbow pads, knee pads, shin pads, forearin pads, wrist pads, finger pads, corn pads, callus pads, blister pads, bunion pads, and toe pads, all of which can include active agents;
intraoral applications such as tooth whitening strips, breath freshening films, and oral care products to treat sore throat, sores within the mouth, gingivitis, periodontal and oral infections, periodontal lesions, or dental caries or decay; adhesives for affixing medical devices, diagnostic systems and other devices to a body surface; sealants for ostomy devices, prostheses, and face masks; sound, vibration, and iinpact absorbing materials;
carriers in cosmetic and cosmeceutical gel products; and many other uses known to or readily ascertainable by those of ordinary skill in the art, or as yet undiscovered.
MANUFACTURING METHODOLOGIES:
[000137] The properties of the compositions of the invention are readily controlled by adjusting one or more parameters during fabrication. For example, the adhesive strength of the composition can be increased, decreased, or eliminated during manufacture, by varying the type and/or quantity of different components, or by changing the mode of manufacture. It should also be noted that compositions prepared using a conventional melt extrusion process generally, although not necessarily, exhibit somewhat different properties relative to coinpositions prepared using a solution cast technique; for example, melt extrusion is typically more useful for preparing adhesive compositions that having lower taclc than corresponding adhesive compositions prepared using solution casting.
[000138] The compositions described herein are generally melt extrudable, and thus may be prepared using a simple blending and extruding process. The components of the coinposition are weighed out and then adinixed, for example using a Brabender or Baker Perkins Blender, generally although not necessarily at an elevated teinperature, e.g., about 90 to 170 C, typically 100 to 140 C. Solvents or water may be added if desired.
The resulting composition can be extruded using a single or twin extruder, or pelletized.
Alternatively, the individual components can be melted one at a time, and then mixed prior to extrusion. The coinposition can be extruded to a desired thickness directly onto a suitable substrate or backing member. The composition can be also extruded first, and then be pressed against a backing member or laminated to a backing meinber. A releasable liner may also be included.
The thickness of the resulting film, for most purposes, will be in the range of about 0.050 to 0.80 mm, more usually in the range of about 0.37 to 0.47 mm.
[000139] Alternatively, the coinpositions may be prepared by solution casting, by admixing the components in a suitable solvent, e.g., a volatile solvent such as ethyl acetate, or lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred, at a concentration typically in the range of about 35 to 60 % w/v. The solution is cast onto a substrate, backing member or releasable liner, as above. Both adinixture and casting are preferably carried out at ambient teinperature. The material coated with the filin is then baked at a teinperature in the range of about 80 to 100 C, optimally about 90 C, for time period in the range of about one to four hours, optimally about two hours.
[000140) In selecting the coinponents for incorporation into an adhesive composition of the invention, the film-forming hydrophilic polymer is selected first. Then, a complementary multifunctional polymer, with recurring functional groups capable of noncovalent bonding to the recurring polar groups within at least one linear segment of the hydrophilic polymer is selected. The complementary multifunctional polymer serves as a "ladder-like"
noncovalent crosslinker in that noncovalent bonding to the film-forming polymer results in the formation of a ladder-like interpolymer complex. The plasticizer is then selected, which, as noted elsewhere herein, is a bifunctional linear oligomer capable of forming a bridge between a polar group on one film-fonning polymer chain and a polar group on a second film-forming polymer chain, thereby forming a "carcass-like" crosslinked complex. The ainount of the film-forming polymer is greater than the ainount of the complementary multifunctional -)olymer and is also greater than the amount of the bifunctional linear oligomer.
0001411 Optional additives, including phaimacologically active agents and )smeceutical agents, can be combined with the polymers and oligomer during adhesive eparation. Alter-nately, an additive can be added after the components are mixed and the nposition prepared. One method of loading the composition with an active agent, for mple, involves providing a layer of the composition on a substrate, coating the layer with a solution of the active agent, placing a release liner on top of the active agent layer, and allowing the active agent to become absorbed by the composition.
[000142] Any natural or synthetic flavorants, such as those described in Chemicals Used in Food Processing, Pub. No. 1274, National Academy of Sciences, pages 63-258, can be included in the compositions of the invention. Suitable flavorants include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils (oil of cloves) and oleoresins, as known in the art, as well as combinations thereof.
The amount of flavorant employed is normally a matter of preference, subject to such factors as flavor type, individual flavor, and strength desired.
EXPERIMENTAL:
[000143] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to manufacture the adhesive compositions of the invention, and are not intended to limit the scope of that which the inventors regard as the invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., ainounts, temperatures, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, teinperature is in degrees Celsius ( C), and pressure is at or near atmospheric.
[000144] The abbreviations used in the examples are as follows:
AA: adipic acid (Aldrich) ATBC: acetyltributyl citrate (Rohm Ainerica Inc.) ATEC: acetyltriethyl citrate (Rohm America Inc.) Cab-O-Sil M5: synthetic silicone dioxide supplied with Cabot Corporation in the form of finely micronized powder.
Carbopol 974: chemically crosslinked polyacrylic acid (Noveon, Inc.) Eudragit E100: N-dimethylaminoethyl methacrylate copolyiner (Rohm America Inc.) Eudragit L 100-55: methacrylic acid copolymer (Rohm America Inc.) Eudragit L 100: methacrylic acid copolymer (Rohin America Inc.) Eudragit S 100: methacrylic acid copolyiner (Rohin Ainerica Inc.) Gantrez ES-425: monobutyl ether of maleic acid - methylvinyl ether copolymer (ISP) Gantrez S-97: maleic acid - methylvinyl ether copolymer (ISP) HPC: hydroxypropylcellulose HPMCP: hydroxypropyl methylcellulose phthalate Kollidon CLM: physically crosslinked polyvinylpyrrolidone supplied by BASF in the forin of finely micronized powder.
Oppanol B-15: polyisobutylene (PIB) Mw 75,000 g/mol (BASF) PVP K90: Kollidon 90F polyvinylpyrrolidone (BASF) PVP K30: Kollidon 30F polyvinylpyrrolidone (BASF) PEG 400: polyethylene glycol 400 Sylvagum RE 85K: glycerol ester of tall oil rosin (Arizona Chemical) TBC: tributyl citrate (Rohm Ainerica Inc.) TEC: triethyl citrate (Rohm America Inc.) Preparation and properties of adhesive compositions based on the ladder-like interpolymer complexes [000145] In the present example, Eudragit E-100 is used as the fihn-forming polymer, which is a copolymer of 2-dimethylaminoethyl methacrylate (DMAEMA), butyl methacrylate, and methyl methacrylate (2:1:1). The monomer units of DMAEMA are capable of forming electrostatic bonds with carboxyl groups in the ladder-like crosslinker, Eudragit L 100-55 and Eudragit S- 100 (copolymer of inethacrylic acid with methyl methacrylate, 1:2). In this way, these blends represent triple blends of two Eudragit grade polymers (E-100 and L 100-55, or S-100) with appropriate plasticizers of hydrophobic units in Eudragit, such as tributyl citrate (TBC), triethyl citrate (TEC), acetyltributyl citrate(ATBC) and acetyltriethyl citrate (ATEC) (see Scheme in FIG. 4).
Blend composition, wt. %
Film-forming Ladder-like Carcass- Sol polymer: crosslinker: Eudragit like Fraction, Swell Sample Eudragit E-100 L 100-55 or S-100 crosslinker % Ratio la 68 L 100-55 PEG-400 25.5 2.75 lb 68 L 100-55 TBC 15.06 2.45 1 c 68 L 100-55 TEC 18.62 2.64 ld 68 S-100 TEC 19.67 1.15 le 62.5 L 100-55 TEC 27.86 3.31 12.5 25 if 62.5 S-100 TEC 26.88 4.43 12.5 25 [000146] Preparation of films. Required amounts of TEC, Eudragit E100 and Eudragit L100-55 as indicated in Table Ex-1 were dissolved in ethanol under vigorous stirring.
Ethanol/Eudragit E100 weight ratio was 7/3 in all cases. The mixture was stirred over 2 hours to obtain homogeneous solution. The solution was stored over 5 hours to let air bubbles dissipate. Polymer films were prepared by solution casting onto a PET
backing with following drying at ambient temperature over 3 days. Films of 0.20 0.04 mm thickness were obtained.
[000147] Mechanical and adhesive properties of the Eudragit E100/Eudragit L100-55/TEC films were tested with Tensile and Probe Tack Tests as indicated above.
The values of maximum stress and maximum work of adhesive debonding for the tested films are documented in the Table Ex-1, whereas relevant tensile test and probe tack stress-strain curves are presented in FIGS. 5-7.
Table Example 1 Com osition wdebonding Maximum Eudragit E-100, Eudragit L 100-55, TEC, J/m2 stress, MPa grains grams gralns Ex 1-1 68.2 6.8 25 3 0.24 Ex 1-2 59.1 5.9 35 31 0.44 Ex 1-3 50 5 45 40 0.44 Ex 1-4 45.5 4.5 50 41 0.29 Ex 1-5 36.4 3.6 60 22 0.16 - 2g -[000148] Pressure sensitive adhesives based on Eudragit E-100 - Eudragit L-100-blends with plasticizer were first described in US Patent 6,063,399 by Assmus et al.
Although in this patent no indications were made that this formulation belongs to a broader class of interpolymer complex adhesives, we consider the Example 9 of present invention as a reference. As has been noted by Assmus et al., adhesive properties of the blends are the function of their compositions. In order to obtain the tools manipulating the adhesion and to offer a range of other adhesives that were not yet disclosed in literature, in this example we have to gain an insight into the functions of every blend component in the control of adhesion.
[000149] Characteristics of tensile stress-strain curves make possible the evaluation of cohesive strength in terms of ultimate tensile stress under fracture of adhesive film, whereas free volume may be assessed qualitatively in terms of maxiinuin elongation under rupture.
The area under stress-strain curve represents the work of viscoelastic polymer deformation up to break, and this value correlates to the work of adhesive debonding (see Feldstein M.M.
"Molecular Fundamentals of Pf-essuf=e-Sensitive Adhesion" in Benedek I.
"Developnzent and Manufacture of Pt essur=e-Set2sitive Produets", Marcel Dekker, N.Y., 2005, Chapter 4, pp.
179-215). As follows from the tensile stress-strain curves in FIG. 5, mixing the film-forming polymer with ladder-like crosslinker in a ratio of [FFP]:[LLC]=10:1 leads to dramatic increase of cohesive strength (the value of ultimate stress increases by 6.6 times), whereas the free voluine drops appreciably (the value of inaximmn elongation decreases by a factor of 4.3).
[000150] Adhesive properties of binary Eudragit E-100 and Eudragit L-100-55 blends with appropriate plasticizers were the subjects of US Patents 5,133,970 by Petereit & Roth and 5,296,512 by Beier et al., respectively. As the results of probe tack testing have shown (FIG. 6), at comparatively low plasticizer concentration (25 wt. %) the blend of Eudragit E-100 and Eudragit L-100-55 copolymers exhibits low tack and adhesive mechanism of debonding without fibrillation. With the rise of plasticizer content, the peak stress grows rapidly achieving the inaxiinum at 35 - 45 wt. % of TEC. Respectively, and maximum elongation at probe detachinent increases. However, if a peak value of stress passes through maximum at 35-45 wt. % of plasticizer concentration, the total ainount of dissipated energy has maximum at 45 - 50 wt. % of TEC, when fibrillation process is inuch more elaborated and the blend demonstrates appreciable elongational flow. Following increase in the plasticizer concentration leads to cohesively weak compositions, which leave a remainder of adhesive on probe surface upon debonding.
[000151] Technology of polymer blends enables easy manipulating the specific balance between the cohesive strength and fluidity of adhesive composite by the increase in the content of ladder-like crosslinker. As follows from the stress-strain curves presented in FIG.
7, binary blend of the film-forming polymer (Eudragit E-100) with 35 wt. % of plasticizer TEC that contains no crosslinker is highly tacky fluid and debonds cohesively at high values of relative elongation leaving the reinainder of the adhesive at the surface of probe. Mixing the film-forming polyiner with complementary ladder-like crosslinker in a ratio of [FFP]: [LLC]= 10: 1 leads to immediate change of debonding mechanism from cohesive to adhesive, while the tack (maxiinuin stress) is mainly controlled by the film-fonning polymer.
Improvement of adhesion of the ladder-like plasticized interpolymer complex by incorporation of tackifiers [000152] US Patent 6,063,399 by Assmus et al. does not describe all the tools necessary to enhance the adhesion of triple Eudragit E-100 - Eudragit L-100-55 - TEC
blends. One of such tools is mixing the Eudragit E-100 - Eudragit L-100-55 - TEC blends with tackifiers.
Owing to optimum hydrophilic-hydrophobic balance, the amphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 complexes turned out to be miscible with tackifiers, which are extensively used in adhesive technology to improve tack. As follows from the data shown in Table and FIG. 8, adding the tackifier Sylvagum RE 85K (glycerol ester of tall oil rosin) iinproves essentially the adhesive perfonnance of blended adhesive.
While plasticizers contribute mainly to the increase of material capability to develop large deformations under detaching stress, the tackifier enhances appreciably its cohesive strength by the increase in 6,,,ax value.
Ex. No. FFP LLC Plasticizer Tackifter Wdeb, aI aX, J/m2 MPa 2a Eudragit None Acetyltributyl SYLVAGUM 104 0.6 E-100, Citrate, 35 RE85K, Resin, 59,1 5,9 2b Eudragit Eudragit L Triethyl citrate, SYLVAGUM 32 0.6 E-100, 100-55, 5,7 30 RE85K, Resin, 57.3 7 2c Eudragit Eudragit L Triethyl citrate, SYLVAGUM 20 0.66 E-100, 100-55, 6,2 25 RE85K, Resin, 61,8 7 2d Eudragit Eudragit L Triethyl citrate, SYLVAGUM
E-100, 100-55, 7,1 15 RE85K, Resin, 70,9 7 [000153] The data presented by Examples 2e - 2g and illustrated in FIG. 9 demonstrate the effect of tackifier concentration (SYLVAGUM RE85K Resin) on adhesive properties of FFP, Eudragit E-100, plasticized with 25 wt % of ATBC in the absence of any LLC. Adding the tackifier results in the increase of tack that goes through a inaximum at 25 %
SYLVAGUM concentration.
Ex. No. FFP Plasticizer Tackifier Wdeba 6max, J/mZ MPa 2e Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 10 0.48 100, 25 Resin, 2f Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 26 0.8 100, 60 25 Resin, 2g Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 43 0.97 100, 50 25 Resin, [000154] Exainples 2h - 2i exhibit how dramatic is the gain in adhesion if using the tackifier SYLVAGUM is accompanied with the increase of plasticizer concentration.
Ex. FFP Plasticizer Tackifier Wdeb, 6max, No. J/m2 MPa 2h Eudragit E- Acetyltributyl SYLVAGUM 11 0.4 100, Citrate, 25 RE85K, 68.2 Resin, 6.8 2i Eudragit E- Acetyltributyl SYLVAGUM 104 0.6 100, 59.1 Citrate, 35 RE85K, Resin, 5.9 [000155] Examples 2k - 2m demonstrate how the adhesion of Eudragit E-100 -Eudragit L-100 55 blends (10:1) may be optimized by the combined effect of the plasticizer and the tackifier:
Ex. FFP LLC Plasticizer Tackifier Wdeb, 6max, No. J/m2 MPa 2k Eudragit E- Eudragit L- Triethyl SYLVAGUM 32 0.6 100, 100-55 Citrate, 30 RE85K, 57.3 5.7 Resin, 21 Eudragit E- Eudragit L- Triethyl SYLVAGUM 20 0.66 100, 61.8 100-55 Citrate, 25 RE85K, 6.2 Resin, 2m Eudragit E- Eudragit L- Triethyl SYLVAGUM 120 1.23 100, 52.4 100-55 Citrate, 25 RE85K, 2.6 Resin, 5.9 [000156] As is seen from the data presented in FIG. 10, SYLVAGUM Resin is not a single tackifier that is miscible with Eudragit E-100 - Eudragit L-100-55 ladder-like electrostatic complex, plasticized with TEC. An alternative tackifier, which is miscible with this blend, is Oppanol B15, a PIB of average molecular weight 75,000 ghnol.
Adhesive compositions based on the carcass-like complex of Eudragit E-100 polybase and its combination with the ladder-like electrostatic crosslinking [000157] The film forming polyiner, exemplified in this description with Eudragit E-100 polybase, may be converted into the forin of pressure sensitive adhesive not only by plasticizing with TEC, but also by adding into this blend higher carboxylic acids having 8 to 20 carbon atoms and dicarboxylic acids having 2 to 8 carbon atoms (US Pat.
5,113,970 to Petereit and Roth). As follows from the data presented in Table Ex.3 (see examples 3a and 3b), the blends of Eudragit E-100 with TEC and adipic acid (AA, dicarboxylic acid having 6 carbon atoms) are good skin contact adhesives. Forming two electrostatic bonds through both tenninal carboxyl groups at AA short chain, the AA acts as the carcass-like crosslinker of trialkylamino groups in Eudragit E-100 polybase. Additional incorporation of AA into the plasticized ladder-like Eudragit E-100 - Eudragit L-100-55 complex gives the blends outlined by Ex. 3c - 3f (FIG. 11), which are good bioadhesives demonstrating the tack to highly moistened biological substrates such as teeth and oral mucosa. As is evident from the probe tack curves presented in FIG. 11, the less the content of the LLC (Eudragit L-100-55), the higher the adhesion. Because the junctions of carcass-like network consist of single electrostatic bonds in contrast to the ladder-like network, where the junctions are composed of a sequence of multiple bonds (see scherne in FIG. 4), the carcass-like network can be more easily ruptured and reformed than the ladder-like network. For this reason the adhesives involving the carcass-like type of non-covalent crosslinking are inuch more easily soluble in water than the structures based on the ladder-like complex.
Table Example 3 Properties of coinpositions involving adipic acid (AA) as a carcass-like crosslinker of Eudragit E- 100 polybase.
PROPERTIES INVESTIGATED
Exam- Ratios, SF, % SR Adhesion to ple No. Components % wt wadlu 6max~
pHffs 6 teeth cheek gums arm J/m2 MPa Eu E-100 67 3a Adipic acid 8 FD* YES NO NO YES 200 1,25 Eu E-100 60 3b Adipic acid 15 FD YES NO YES YES 150 0,9 Eu E-100 61 3c Eu L-100-55 6 73,6 3,6 YES YES YES NO 23 0,8 Adipic acid 8 Eu E-100 54,5 3d Eu L-100-55 5,5 FD YES YES YES NO 19 0,6 Adipic acid 15 Eu E-100 63,8 3e Eu L-100-55 3,2 FD YES NO NO NO 64 1,26 Adipic acid 8 Eu E-100 57 3f Eu L-100-55 3 FD YES NO NO NO 59 0,99 Adipic acid 15 *) Fully dissolving [0001581 Other appropriate carcass-like crosslinkers of Eudragit E-100 FFP
have been found to be PEG-dicarboxylic acid and diacids having 2 to 6 carbon atoms between the carboxyl groups.
Enhancement of adhesion by partial ionization of film-forming Eudragit E-100 polymer and ladder-like crosslinker (Eudragit L-100-55) [000159] Another and highly effective tool to enhance the adhesion of Eudragit Eudragit L-100-55 - TEC blends, which also is not explored by the above mentioned US
Patent 6,063,399 by Assmus et al., is outlined by salutary impact of partial ionization of polyelectrolyte macromolecules within the interpolymer complex. The ainphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 blends involve two complementary polyelectrolytes: polyacid and polybase. The film-forming polymer, Eudragit E-100, represents the latter. Accordingly, the adhesion of Eudragit E-100 - Eudragit adhesives can be affected by partial ionization of both polyacid and polybase macromolecules.
[000160] FIG. 12 and 13 illustrate the procedure of partial ionization of the Eudragit E-100 polybase and Eudragit L-100-55 polybase with corresponding ainounts of neutralizing agents, HCI and NaOH, respectively. In order to determine the ainounts of acid and alkali needed for partial ionization of relevant polyelectrolyte to desirable extent, titration curve first must be measured. Taking into account that the jump in pH corresponds to 100 %
ionization of the polyelectrolyte, the ainount of neutralizing agent needed for 20 %
ionization of the polyelectrolyte constitutes a fifth fraction of total (equivalent) amount of the acid or alkali.
[000161] As is evident from the data presented in Table Ex.4, the tack is essentially improved with treatment of Eudragit L-100-55 by NaOH solution. The tack improvement becomes comparatively negligible as ionization degree exceeds 5%.
Table Example 4 Ex. FFP LLC Plasticizer pH modifier Wdeb, 6niax, No. J/m2 MPa 4a Eudragit E-100, Eudragit L 100- Triethyl NaOH 18.5 0.73 61,8 55,6,2 citrate, 25 5%
ionization 4b Eudragit E-100, Eudragit L 100- Triethyl NaOH 20 0.77 61,8 55,6,2 citrate, 25 10%
ionization 4c Eudragit E-100, Eudragit L 100- Triethyl NaOH 54 0.83 59.1 55, 5.9 citrate, 35 5%
ionization 4d Eudragit E-100, Eudragit L 100- Triethyl NaOH 57 0.97 59.1 55, 5.9 citrate, 35 10%
ionization 4e Eudragit E-100, Eudragit L 100- Triethyl HCl 23 0.82 61,8 55, 6,2 citrate, 25 5%
ionization 4f Eudragit E-100, Eudragit L 100- Triethyl HCl 68 1.3 61,8 55, 6,2 citrate, 25 10%
ionization 4g Eudragit E-100, Eudragit L 100- Triethyl HCl 50 0.82 59.1 55, 5.9 citrate, 35 5%
ionization 4h Eudragit E-100, Eudragit L 100- Triethyl HCl 77 0.93 59.1 55, 5.9 citrate, 35 10%
ionization [000162] As is seen from the stress-strain curves in FIG. 14, for comparatively ductile adhesives (exemplified here by the composition containing 35 wt. % of plasticizer), which reveal fibrillation (a plateau on the stress-strain curves), partial ionization of film-forming polybase Eudragit E-100 by HCl solution enhances the cohesive strength drainatically and the adhesive debonds without fibrillation. The maximum elongation in the-point of debonding first decreases with 5 % ionization and then increases again (at 10 %
ionization), implying that under comparatively small degree of polymer chain ionization the enhancement of cohesive strength is a predominant factor, whereas further increase in the ionization degree is accompanied with forination of large free volume. The enhanceinent of cohesive strength tends to a maximuin above 10 % of the ionization of film-forming polymer.
[000163] By coinparing the probe tack data presented in FIG. 14, 15 and in the Table Ex. 4, it may be seen that qualitatively the mechanisins of tack enhanceinent by ionization of the ladder-like crosslinker and the film-fonning polymer are similar. However, as follows from the data shown in FIG. 15, in quantitative terms the effect of ionization of the film-forming polybase on adhesion is much stronger than that observed for the ladder-like crosslinking polyacid.
[000164] If both the film-forming polymer and the ladder-like crosslinker are preliminarily ionized by treating respectively with HCl and NaOH solutions, then the ionic bonding between cationic groups of Eudragit E-100 copolymer and anionic groups of Eudragit L-100-55 copolymer contributes to the adhesive behavior of the interpolyiner complex along with hydrogen bonds forined between uncharged groups. As follows from the data shown in FIG. 16, in this case the adhesive properties of the complex are intermediate between those featured for the complex involving partial ionization of either the film-forming polymer or the ladder-like crosslinker. Effects of macroinolecular ionization on the tack of adhesive coinposites involving polyelectrolytes have never been earlier reported.
10001651 Partial 10 % ionization of the ladder-like crosslinker (Eudragit L-100-55) in interpolymer complex with film-forming Eudragit E-100 polymer does not affect the swelling and dissolution of the adhesive. However, the 10 % ionization of the film-forming polymer with HCl solution results in appreciable increase of swell ratio from 3.5 to 22.5, while the ainount of soluble fraction has comparatively insignificant effect on the value of sol fraction.
[000166] If the polybase and polyacid in the ladder-like Eudragit E-100 -Eudragit L-100-55 complex are interchanged in such a way that the polyacid (Eudragit L-100-55) serves as the film-forming polymer and the polybase (Eudragit E-100) is the ladder-like crosslinker, adhesive materials wherein the treatment with NaOH has a greater effect on adhesion and sorption are obtained.
Improvement of adhesion of PVP-PEG-Eudragit L-100-55 blends by means of partial ionization of the ladder-like crosslinker [000167] The hydrogen bonded interpolymer complexes combining the ladder-like and carcass-like types of noncovalent crosslinking, shown in schematic form in FIG. 3, share the properties of pressure-sensitive adhesives and bioadhesives (see U.S. Patent Application Serial No. 10/936,887 to Feldstein et al. for "Method of Preparing Polymeric Adhesive Coinpositions Utilizing the Mechanism of Interaction Between The Polymer Components,"
filed September 8, 2004). The effect of partial ionization of Eudragit L100-55 on adhesive properties of PVP/PEG/Eudragit L100-55 is demonstrated by present exainple.
[000168] Preparation of films. 30 g of PEG400 was dissolved in 280 g of water/ethanol (1:1) mixture. Required amount of sodium hydroxide was dissolved (as indicated in Table Ex-5.). Under vigorous stirring 12 g of Eudragit L100-55 powder was added followed by adding 58 g of PVP (K90) powder. The mixture was stirred over 2 hours to obtain homogeneous solution. The solution was stored over 5 hours to let air bubbles dissipate.
Polymer films were prepared by solution casting onto a PET backing with following drying at ambient temperature over 3 days. Films of 0,20 0,04 mm in thickness were obtained.
Water content in the films was measured gravimetrically by weight loss at 120 C. Films with hydration degree 12 0,5 wt% were obtained.
Table Example 5 PVP, PEG 400, Eudragit L100- NaOH, Eudragit L100-grams grams 55, grams grams 55 ionization,%
Ex 5-1 58 30 12 0 0 Ex 5-2 58 30 12 0,129 5 Ex 5-3 58 30 12 0,258 10 Ex 5-4 58 30 12 0,516 20 [000169] As is obvious from the stress-strain curves in FIG. 17, partial ionization of the ladder-like crosslinker in the blends with PVP-PEG carcass-like complex improves the adhesion appreciably but does not change the mechanism of adhesive defonnation under debonding process. The latter remains adhesive (no remainder of adhesive material at a probe surface upon debonding). Improvement of tack and adhesion tends to a maximum at 10 %
ionization of the ladder-like crosslinker. Such mechanism of tack improvement has been also established for the first time.
Others adhesive compositions based on plasticized ladder-like interpolymer complexes [000170] Eudragit E-100 is a typical and coinparatively well-studied but not unique representative of polybases suitable for the fonnulation of adhesives based on the ladder-like interpolymer complexes with polyacids. Others appropriate polybases include homopolymers and copolyiners of vinyl amine or chitosan ainong polyelectrolytes, and PVP or PNIPAM
ainong non-polyelectrolytes. As an exainple, following Table outlines the adhesive properties of the blends of high molecular weight PVP K-90 (film-forming polymer) with Eudragit L-100-55 as ladder-like crosslinker, plasticized with TEC. The inverted composition wherein the Eudragit L-100-55 serves as the film-forming polyiner and the PVP
as the ladder-like crosslinker was also prepared and characterized. These compositions differ from that described in Examples 1-3 by the lack of carcass-like crosslinker and, consequently, represent others examples of the adhesives based on ladder-like interpolymer complexes shown schematically in FIG. 4. The compositions were prepared by casting-drying method from ethanol solutions.
Ex. FFP LLC Plasticizer Wdb, 6'max~
No. J/mZ MPa 6a PVP K-90 Eudragit L 100- Triethyl 24 0.77 60.2 55, 9.8 citrate, 30 6b PVP K-90 Eudragit L 100- Triethyl 55 0.97 50.1 55,9,9 citrate, 40 6c Eudragit L 100- PVP K-90 Triethyl 44 0.80 55, 10.9 citrate, 30 61,1 [000171] In following coinposition the Eudragit E-100 was selected as film-forming polymer (polybase) and Gantrez S-97 as the ladder-like crosslinker (polyacid).
The latter is a copolymer of maleic acid with methylvinyl ether (1:1). TEC was used as plasticizer. Under vigorous stirring the powder of Gantrez S-97 polymer was slowly added into the 30% ethyl alcohol solution of Eudragit E-100, that was previously mixed with TEC
(plasticizer), until a homogeneous dispersion was obtained. The semitransparent, homogeneous film was obtained using simple casting and drying procedure of the previously obtained dispersion under ainbient temperature. Prepared films contained 25 wt % of TEC, while Eudragit E-100 - Gantrez S-97 ratio was varied. FIG. 18 compares the probe tack stress-strain curves for the Eudragit E- 100 - Gantrez S-97 ladder-like complex with the curve featured for Eudragit E-100 - Eudragit L-100-55 composition plasticized with equivalent ainount of TEC.
[000172] As follows from the curves demonstrated in FIG. 18, replaceinent of the Eudragit L-100-55 ladder-like crosslinker in the complex with Eudragit E-100 fihn-forming polyiner for much more hydrophilic Gantrez S-97 copolyiner iinproves the tack significantly.
[000173] While the water-absorbing capacity (measured in tenns of Swell Ratio, SR, which is a ratio of the weight of gel in swollen state to the diy weight of gel fraction) for ainphiphilic adhesives based on plasticized ladder-like Eudragit E-100 -Eudragit L-100-55 complexes is comparatively low, ranging from 3 to 6 depending on coinposition, it is dramatically affected by the nature of the ladder-like crosslinker. As the data in FIG. 19 have shown, replacement of comparatively hydrophobic Eudragit L-100-55 by much more hydrophilic Gantrez S-971eads to the increase of Swell Ratio from 4.4 to 89.2.
In this way, moderately absorbing adhesive compositions based on the ladder-like complexes may be easily modified to give super-absorbing adhesives. The super-absorbing adhesives, outlined by this invention, represent a new class of pharmaceutical materials.
[000174] Other suitable ladder-like crosslinkers for Eudragit L-100-55 polymer are alginic acids and carboxyl-containing cellulose derivatives such as HPMCP.
Their mixing with Eudragit L-100-55 in solutions can be significantly facilitated by partial ionization of relevant polymers.
[000175] Eudragit E-100 is not unique polybase that can be used as FFP in the blends with Eudragit L-100-55 polybase. Other suitable candidates as FFP in plasticized ladder-like complexes are the Eudragit RS and Eudragit RL. The Eudragit RS is a copolymer of triinethylammonioethyhnethacrylate chloride (0.1) with ethylacrylate (1) and methyl inethacrylate (2), available from Rohm Pharma Polymers. The Eudragit RL is a copolyiner of triinethylaminonioethyl methacrylate chloride with ethylacrylate and methyl methacrylate (0.2:1:2), available from Rohm Pharina Polymers as well. Although both TL and RS polymer contain ionic groups, they are insoluble in water due to high concentration of hydrophobic polymer units. The Eudragit RL and RS polymers are capable to forin ionic bonds with polymer units bearing negative charge (carboxylate anions). Appropriate ladder-like crosslinker for such polymers is ionized Eudragit L-100-55.
[000176] Next Table demonstrates the composition of adhesive blend prepared using Eudragit RL and Eudragit RS polyiners:
Composition % wt.
Eudragit RL 49.1 Eudragit RS 16.4 TEC 28.0 Eudragit L100-55 6.5 Fully ionized [000177] Under vigorous stirring the appropriate ainount of Eudragit RL was dissolved in the ethanol solution of Eudragit RS. Under stirring the required alnount of the plasticizer tributyl citrate (TBC) was added into the ethanol solution of two base polymers Eudragit RL
and Eudragit RS. Fully ionized Eudragit L100-55 was then dissolved in the blend of Eudragit RL/Eudragit RS/ TBC. The homogeneous film was obtained using casting and drying procedure of the previously obtained solution. Prepared composition feature the values of Sol fraction of 4.3 % and Swell ratio of 2.5. The homogeneous film is initially nontacky but adheres strongly to teeth surface providing good adhesive contact that is stable during 4 hours.
[000178] Another appropriate polybase forming the ladder-like complexes with polyacids is chitosan.
Effect of the nature of plasticizers on adhesive properties and water-absorbing capacity of Eudragit E-100 - Eudragit L-100-55 complex [000179] FIG. 20 and 21 illustrate the influence of hydrophilicity of plasticizers on the adhesive and water absorption properties of the compositions based on the interpolymer complex between Eudragit E-100 polybase Eudragit L-100-55 polyacid. As is evident from the probe tack profiles presented in FIG. 20, more hydrophilic plasticizers (TEC and ATEC) demonstrate more ductile inechanisin of deforination under debonding stress, developing higher values of maximum elongation compared to more hydrophobic TBC and TBC, which behave like solid adhesives and deform without fibrillation. The adhesion, ineasured in terms of the work of debonding, decreases in a row ATEC = TEC > ATBC > TBC.
[000180] Correspondingly, the swell ratio of the blends of Eudragit E100 -Eudragit L100-55 with plasticizers TEC, ATEC, TBC, ATBC, decreases with the decrease in their hydrophilicity in the row TEC >ATEC>TBC>ATBC. It is worthy of note that the nature of the plasticizers affects the water absorbing capacity to a smaller extent than the adhesion.
Hydrophilization of amphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 complexes [000181] As has been shown above, adhesive blends based on plasticized Eudragit E-100 - Eudragit L-100-55 complexes are miscible with such hydrophobic plasticizers and tackifiers as PIB (Oppanol B-15) (see FIG. 10). Because the inonoiner units in Eudragit E-100 - Eudragit L-100-55 complexes combine polar hydrophilic and non-polar lipophylic entities, these adhesives belong to the class of amphiphilic materials and are also miscible with hydrophilic and even hygroscopic polymers and fillers. Hydrophilization of ainphiphilic Eudragit E-100 - Eudragit L-100-55 adhesives represents an important tool to enhance their water-absorbing capacity and modify the adhesion.
[000182] The data presented in Table Ex. 8.1 and shown in FIG. 22 and 23 demonstrate the effect of mixing with hydrophilic PVP and with its adhesive blends with PEG-400 on adhesion and water absorbing capacity of Eudragit E-100 - Eudragit L-100-55 interpolyiner complex, plasticized with 25 wt. % of TEC. Under vigorous stirring, necessary amount of Eudragit L100-55 was dissolved in the ethanol solution of Eudragit E100. Then the plasticizer (TEC) was dissolved in the ethanol solution of two parent polymers. Under stirring the appropriate amount of low molecular weight PVP or low molecular weight PVP
blend with PEG-400 was dissolved in the ethanol solution of E100/L100-55 blend with TEC.
The fihns were obtained by a casting drying procedure as described above.
Table Example 8.1 Compositions and properties of Eudragit E-100 - Eudragit L-100 -55 blends with plasticizer TEC and hydrophilizing agents, PVP and PVP-PEG
Ex. FFP LLC Plasticizer Additive Sol SR Wdeb, 6max, No. J/m2 MPa 8a Eudragit E- Eudragit Triethyl PVP K 30, 53,4 9,5 none none 100, L 100-55, citrate 15 58,0 5,8 21,2 8b Eudragit E- Eudragit Triethyl PVP K 30, 51,7 8,1 none none 100, 54,1 L 100-55, citrate, 15 5,4 25,5 8c Eudragit E- Eudragit Triethyl PVP PEG 63,8 10,9 20 0,73 100, L 100-55, citrate, K 30 400 52,2 5,2 19,2 15 8,4 8d Eudragit E- Eudragit Triethyl PVP PEG 60,5 7,1 59,7 0,98 100, 48,7 L 100-55, citrate, K30 400 4,9 23,0 15 8,4 [000183] The films of Eudragit E100/Eudragit L100-55/TEC blends with PVP K-30 were semitransparent indicating of their heterogeneous structure. These films had poor or no initial tack in contrast to the blends with PVP-PEG carcass-like coinplex (FIG. 23). These latter films were homogeneous and transparent.
[000184] As is evident froin the data presented in Table Ex. 8.1 and FIG. 22, mixing with both PVP and PVP-PEG blends leads to an appreciable increase in water absorbing capacity of the adhesive materials.
[000185] The data in Tables 8.2 - 8.5 illustrate other approaches towards adhesive materials of controlled water-absorbing capacity based on ladder-like interpolymer complexes.
EUDRAGIT E100/TEC/CARBOPOL:
[000186] Preparation of films. Required amount of Eudragit E100 was dissolved in ethyl acetate (3 parts of Eudragit E100 were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.2) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar the required amount of Carbopo1974 (as indicated in the Table 8.2) was suspended in ethyl acetate (2 parts of Carbopol 974 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Carbopol 974 is a chemically crosslinked polyacrylic acid. Different grades of Carbopol polymers are supplied by Noveon, Inc. in the form of finely lnicronized powder. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ambient temperature over 3 days. Films of 0.15 0.04 min in thickness were obtained.
Table Example 8.2 Example Eudragit E100 TEC Carbopo1974 Swell ratio 1 65 25 10 4.6 2 55 25 20 12.8 3 45 25 30 20.4 4 40 30 30 23.7 [000187] In the examples 8.2 and 8.3 the Carbopol serves both as a ladder-like crosslinker and hydrophilizing agent.
Eudragit RS/RL/TEC/Carbopol [000188] Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.3) were dissolved in ethyl acetate (3 parts of the sum of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required ainount of TEC (as indicated in the Table 8.3) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar required ainount of Carbopo1974 (as indicated in the Table 8.3) was suspended in ethyl acetate (2 parts of Carbopol 974 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ambient teinperature over 3 days.
Films of 0,20 0,04 mm thickness were obtained.
Table Example 8.3 Ex. Eudragit Eudragit TEC Carbopol 974 Swell ratio RS RL
1 45 15 30 10 2.9 2 37,5 12,5 30 20 5.3 3 37,5 12,5 20 30 6.8 4 30 10 20 40 13.4 [000189] In the exainple 8.4 the Kollidon CLM serves as a ladder-like crosslinker and hydrophilizing agent.
EUDRAGIT RS/RL/TEC/KOLLinON CLM
[0001901 Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.4) were dissolved in ethyl acetate (3 parts of the sum of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.4) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar required ainount of Kollidon CLM (as indicated in the Table 8.4) was suspended in ethyl acetate (2 parts of Kollidon CLM were suspended in 5 parts of ethyl acetate) to obtain Solution II. Kollidon CLM is a physically crosslinked polyvinylpyrrolidone supplied by BASF in the form of finely micronized powder.
Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 inin. Polymer films were prepared by solution casting onto a PET backing with following drying at ainbient teinperature over 3 days. Films of 0.20 0.04 min thickness were obtained.
Table Example 8.4 Example Eudragit RS Eudragit RL TEC Kollidon Swell ratio CLM
1 45 15 30 10 2.3 2 41,25 13,75 30 15 3.1 3 45 15 20 20 4.0 4 37,5 12,5 20 30 4.8 [000191] In example 8.5 the Cab-O-Sil M5 serves as a hydrophilizing agent.
EUn2tAGIT RS/RL/TEC/CAS-O-SIL M
[000192] Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.5) were dissolved in ethyl acetate (3 parts of the suin of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.5) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar the required ainount of Cab-O-Sil M5 (as indicated in the Table 8.5) was suspended in ethyl acetate (2 parts of Cab-O-Sil M5 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Cab-O-Sil M5 is a synthetic silicone dioxide supplied with Cabot Corporation in the form of finely micronized powder. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ainbient temperature over 3 days. Films of 0.20 0.04 min thickness were obtained.
Table Example 8.5 Example Eudragit RS Eudragit RL TEC Cab-O-Sil Swell ratio 1 49,5 16,5 30 4 2.2 2 46,5 15,5 30 8 2.8 3 43,5 14,5 30 12 3.8 [000193] The value of Swell Ratio featured for parent Eudragit RL/RS - TEC
blend is around 2Ø As the data in Tables Ex. 8.3 - 8.5 have shown, the hydrophilization of the blends with crosslinked water absorbents such as Carbopol 974, Kollidon CLM and Cab-O-Sil M5 results only in a comparatively insignificant increase in Swell Ratio. This is most likely due to very low water permeability of hydrophobic film based on Eudragit RL/RS
polymers.
However, the materials described in Examples 8-3 - 8.5 may-be useful as carriers of hydrogen peroxide solution in tooth whitening strips. For this purpose, the hydrophilic filler (Carbopol 974, Kollidon CLM or Cab-O-Sil M5) should be impregnated with the hydrogen peroxide solution before incorporation into the Eudragit RL/RS film. This film provides good tack and adhesion toward hydrated tooth surface.
Performance properties of adhesive compositions based on interpolymer complexes compared to the properties of conventional pressure sensitive adhesives and bioadhesives [000194] The properties of the triple blend hydrogels of the invention (PVP-PEG-Eudragit L 100-55), were compared with those of the PVP-PEG binary blends, described in U.S. Patent 6,576,712, and with those of conventional pressure sensitive adhesives ("PSA";
DURO-TAe 34-4230, National Starch and Chemicals) and classical bioadhesives (covalently crosslinked polyacrylic acid polymers Carbopol 974P and Noveon AA1, both from B.F. Goodrich, Co.).
Adhesives based on interpolymer complexes compared to hydrophobic PSAs and bioadhesives PSA Bioadhe- water soluble hydrophilic amphi-Attribute sives US Pat. Exainples philic 6,576,712 1-8 Examples PEEL
ADHESION, N/m 300- 370-550 140-710 - in dry state 600 - in hydrated None 50 - 70 10 - 30 state None 10 - 60 300 - 550 100 - 300 SOLUBILITY IN Insoluble Insoluble, Soluble Insoluble, Insoluble, WATER Swellable Swellable Swellable Water sorption Less 1% 98 % Non limited 96 % 17 - 85 %
capacity Fihn-forming Yes No Yes Yes Yes capability Elasticity 1.0 - 5.0 0.09 - 0.9 1.3 - 5.0 0.4 - 40 1.0 - 7.3 modulus, Pa x105 MAXIMUM 22 More than 22 2.7 1.71 Ultimate tensile 16 0.01 12 30.4 5 stren th, MPa Logarithm 4.1 2.6 3.7 - 4.9 5.0 Not Yield stress, Available MPa [000195] PSAs, exemplified above by the SIS block-copolymer based DURO-TAIe 34-4230 adhesive, represent a special class of viscoelastic polymers. They are capable of forining a strong adhesive bond with various substrates under application of a slight external pressure over a short time (1-2 seconds). It is noteworthy that the typical PSAs for huinan use are mainly based on hydrophobic elastomers with low glass transition teinperatures, ranging from -120 to -30 C, which are usually increased by addition of tackifying resins. The coimnon property of the PSAs is a loss of adhesion as the surface of a substrate is moistened.
For this reason, conventional PSAs cannot be used for application to highly hydrated and soft biological tissues such as oral mucosa. For this purpose, hydrophilic bioadhesives are usually einployed, which are generally nontacky in the dry state, but adhere to wet substrates.
The adhesive strength of such bioadhesives, however is usually much lower than that of the PSAs.
[000196] As is seen from this data, the adhesives of various hydrophilic-hydrophobic balances outlined by present invention and obtained by non-covalent crosslinking of film-forming hydrophilic polyiners share the properties of both pressure sensitive adhesives and bioadhesives. Indeed, while their adhesive strength is typical of the PSAs, it has increased adhesion towards moistened substrate like bioadhesives. Varying the hydrogel composition and degree of ionization of ionogenic polymers can easily provide the further control of adhesive, water sorption and mechanical properties of the products based on non-covalently crosslinked hydrogels.
[000197] FIG. 24 compares the peel adhesion towards dry and moistened huinan forearin skin in vivo for conventional acrylic PSA and three grades of adhesives based on interpolymer complexes. According to these data, the adhesive properties of polymer composites described in the present application and in U.S. Patent 6,576,712 share the properties of PSAs and bioadhesives by combining high adhesion featured for conventional PSAs with capability to adhere to moistened skin and biological tissues typical of bioadhesives.
[000198] Stress-strain curves obtained in the course of Probe Tack Test are much inore informative on the mechanisms of adhesive debonding than the peel force traces presented in FIG. 21. In FIG. 25 the adhesive behaviors of water-soluble PVP-PEG adhesives (described in US Patent 6,576,712 by Feldstein et al.), PVP-PEG-Eudragit L-100-55 adhesive hydrogels (Exainples 1-4) and the amphiphilic Eudragit E-100 - Eudragit L-100-55 adhesives plasticized by TEC and filled with tackifier Rosin (Example 10) have been compared with the properties of two different grades of conventional PSAs: SIS-based DURO-TAK
PSA and acrylic PSA (3M).
[000199] Being expressed in terms of maximum stress under debonding, the tack of adhesives based on interpolymer complexes is comparable with that typical of conventional PSAs. However, a distinctive feature of the adhesive blends described in this application is the lower values of maxiinum elongation that result from non-covalent crosslinking of the chains of fihn-forming polymer. Because the carcass-like crosslinking is significantly looser than the ladder-like crosslinking, it is no wonder that the water-soluble PVP-PEG adhesive demonstrates higher stretching at probe detachment than the adhesives involving the ladder-like type of crosslinking. In this connection it is pertinent to note that the main tools to increase fluidity and maximum elongation of the adhesives provided by the ladder-like crosslinking it is the dilution of network density due to mixing with plasticizers, in the course of swelling in water and also the decrease in concentration of the ladder-like crosslinker.
Preparation of adhesive films by direct mixing of polymeric components followed by extrusion [000200] The behavior of the hydrophilic and amphiphilic adhesives described in this invention is typical of covalently crosslinked polymers. In contrast to covalently crosslinked systems, however, the adhesives based on interpolymer coinplexes can be easily prepared using a simpler blending process, and, furthertnore, provide film-forming properties that are unattainable using crosslinked polymers.
[000201] While above presented formulations were prepared by casting from solutions followed by drying, the adhesive films of the present invention can be also produced by direct mixing the components in dry state followed by extrusion. The mixing was provided using Therino Haake Mixer, whereas the extrusion was performed with Skania Single-Screw Extruder. The procedures of mixing and extrusion of the major formulations described in this invention are presented below.
I Preparation of the compositions outlined by Example 1 [000202] The following blend was prepared:
Eudragit E 100 68.2 weight %
Eudragit L 100-55 6.8 %
TEC 25.0%
[000203] Procedures of mixing and extrusion are indicated in Tables 10.1 &
10.2:
Table Example 10.1.
Time, min. Tinixture, oC N, rpm Torque N.m Operation 0-2 100 30 0-25 Loading of Eudragit E100 I 1 110 30 3 The beginning of loading premix "G"*
with a rate of -I ml/min 26 10-5 30 0- 0.8 Decrease of tem erature 38 91 30 0.7-0.8 The finishing of loading of premix "G"
47 74 30 3.0 Closing the mixer chamber 62 66 60 3.0-4.5 Increase of stirring rate 68 67 30 3-4 Elevation of temperature to 80 120 0 - Stop *) Preinix "G" is Eudragit L-100-55 plasticized with TEC.
Table Example 10.2.
Tzones Trouer N, rpm Extrusion Reducing Pressure, speed, step Bar mm/c 90/90/95 100 18 7.3 14 31-35 [000204] The following examples illustrate the applicability of interpolyiner complex adhesives for a range of pharmaceutical products.
Wound Dressings [000205] The following samples illustrate how the hydrogel compositions of this invention may be used for silver-containing antimicrobial wound dressings.
Wound dressings were prepared from the following ingredients using either a melt extrusion or casting/drying processes:
Composition, wt. %
Film-forining Ladder-like Carcass-like Silver salt Sample polymer crosslinker crosslinker (1 %) l la Eudragit E-100, Eudragit L 100-55, Triethyl Silver 67.2 6.7 citrate, 25.0 sulfate l lb Eudragit L 100- PVP, 9.9 PEG-400, Silver 55, 49.5 39.6 sulfate 11c Eudragit E-100, Eudragit S-100, 6.7 Triethyl Silver 66.9 citrate, 24.9 sulfate l ld Eudragit E-100, Eudragit L 100-55, Triethyl Silver 67.2 6.7 citrate, 25.0 phosphate [000206] All of the hydrogel samples were insoluble in water and exudate, but were swellable, thus absorbing a great ainount of exudate. Sample l lb was initially tacky and maintained a good adhesion toward dry and moderately exudating wounds, but could be removed from the skin without pain by washing with a large ainount of water.
Samples 11 a and 11 c possessed a slight initial tack but became nontacky in a swollen state. Accordingly, sample l lb is useful for treatment of pressure, diabetic, arterial and venous ulcers, whereas Sainples 6a and 6c are more suited for covering large, wet and infected wounds and burns.
[000207] A potentiometric method with Ag ion selective electrode was used to study silver release from anti-microbial d'ressings. Aqueous solutions of silver nitrate in the concentration range 2.5* 10-6 - 10"3 M were used to calibrate the Ag ion selective electrode.
Circular samples (with diaineter= 1 inch, area=5 cin) of anti-microbial films were die-cut and laminated to glass plates by means of a double-sided scotch. The glass plate with the Ag release side upwards was placed into a beaker. 50 ml of distilled water was poured into the beaker. The obtained system was covered with a petri dish and placed into an oven-therinostat at 25 0.2 C. After specified time points the receptor solution in the beaker over the sample was stirred and silver concentration was measured with the Ag ion selective electrode. After measurement the receptor solution was removed and replaced with 50 ml of distilled water.
Cumulative Ag release was calculated and expressed in g per cm2 of the anti-microbial dressing.
[0002081 FIG. 26 demonstrates how the release kinetics of silver sulfate, as the active agent, from the matrices in vitro were affected by the change in matrix composition. All three hydrogel compositions provided different drug release profiles: Sample 11 a delivered the highest amount of silver sulfate; Sainple 1 lb provided a fast release of the active agent during the onset period, followed by a rapid decrease of release rate within steady state stage;
and Sample 11 c provided zero-order release kinetics. Since various silver salts are characterized with different values of solubility product, it would be expected that different salts of silver, being incorporated into the saine hydrogel matrix, may deinonstrate different release kinetics.
[0002091 FIG. 27 illustrates the effect of silver salts on the release profile of Ag ion from the formulation outlined by Exainple 11 d. In this case the matrix based on Eudragit E-100 - Eudragit L- 100-55 ladder-like complex was loaded with silver phosphate instead of silver sulfate. Since solubility of silver phosphate in the matrix is about three orders of magnitude lower than that of silver sulfate, the adhesive matrix loaded with silver phosphate provides prolonged release kinetics of anti-microbial agent.
Slowly dissolving matrices with therapeutic agents [000210] The following compositions were prepared by dissolution in ethanol of components listed in the Table presented below, casting the solution and drying at temperature of 50 C.
[000211] The sainples use an acrylate polymer (Eudragit E100) as the film-forming polymer. Sample 12a uses two ladder-like crosslinkers, an acrylate polymer (Eudragit L 100-55) and a poly(N-vinyl lactam) (PVP 90), while Sample 12b only includes one ladder-like crosslinker, Eudragit L 100-55. Similarly, Sample 12a uses two carcass-like crosslinkers, an alkyl citrate (triethyl citrate) and a polyalkylene glycol (PEG 400), while Sample 12b only includes one carcass-like crosslinker, triethyl citrate.
Component Sample 17a (wt%) Sample 17b (wt%) Eudra it E100 58.29% 60.30%
Triethyl citrate 26.10% 27.00%
Eudragit L 100-55 2.61% 2.70%
PVP 90 2.00% 0 PEG 400 1% 0 Lidocaine base 10% 10%
Total 100% 100%
Liquid Film-Forming Bandages [000212] Samples 13a-13d represent liquid compositions suitable for application to skin as liquid bandages. Sample 13a is a liquid formulation for tooth whitening which contains the insoluble film-forming polymer (Eudragit RS) and plasticizer for this polymer tributylcitrate (TBC). Eudragit RS is a copolymer of trimethylammonioethyhnethacrylate chloride (0.1) with ethylaciylate (1) and methylmethacrylate (2), available from Rohin Pharma Polymers. Sainples 13b-13d contain no ladder-like crosslinker for the hydrophilic polymer, Eudragit L 100-55. Actually, the ladder-like crosslinker makes the polymer film insoluble. However, for the compositions containing Eudragit RS as a film-forming polyiner, the ladder-like crosslinker of PVP was not a necessary coinponent, because the blend is not soluble.
[000213] Sample 13e is a film-fonning liquid formulation suitable for the treatment of cold sores and canker sores. It contains Eudragit E-100 as a soluble fihn-fonning polymer instead of PVP. Correspondingly, PEG-400 is omitted from the formulation, because TBC is a good plasticizer for both Eudragit RS and E-100.
[000214] Liquid bandage and cold sore compositions for skin applications (Samples l0a-l0e) may also contain active agents such as local anesthetics. Suitable local anesthetics include dibucaine hydrochloride; dibucaine; lidocaine hydrochloride;
lidocaine; benzocaine;
p-butylaininobenzoic acid 2-(diethylamino) ethyl ester hydrochloride; procaine hydrochloride; tetracaine hydrochloride; chloroprocaine hydrochloride;
oxyprocaine hydrochloride; mepivacaine; cocaine hydrochloride; and piperocaine hydrochloride.
[000215] Samples 13c and 13e contain also a skin softening agent such as glycerol monooleate (Peceol, Gattefosse, France).
Composition, wt%
Soluble film- Ladder- Carcass-Insoluble forming like like film- Plasticizer polymer crosslinker crosslinker Sainple forming for (A) (B) for (B) for (B) Additives Solvent polymer (A) 13a Eudragit TBC, PVP K- Eudragit L PEG, 3.00 Sodium Ethanol, (Liquid RS, 2.50 90, 3.00 100-55, Citrate, 38.20 Bandage) 29.00 2.20 2.50 13b Eudragit TBC, PVP K- - PEG, - Ethanol, (Liquid RS, 11.70 90, 0.18 52.65 Bandage) 35.11 0.36 13c Eudragit TBC, PVP K- - PEG, GMO, Ethanol, (Liquid RS, 6.69 90, 0.21 3.00; 1,2- 14.29 30.09 Bandage) 20.06 Propylene Glycol, 28.57 13d Eudragit TBC, PVP K- - PEG, 1.14 - Ethanol, (Liquid RS, 7.95 4.55 17, 1.14 35.00 Bandage) 13e Eudragit TBC, Eudragit - - GMO, Ethanol, (Cold RS, 11.00 E-100, 10.00 44.00 Sore) 33.00, 11.00
Film-forming Ladder-like Carcass- Sol polymer: crosslinker: Eudragit like Fraction, Swell Sample Eudragit E-100 L 100-55 or S-100 crosslinker % Ratio la 68 L 100-55 PEG-400 25.5 2.75 lb 68 L 100-55 TBC 15.06 2.45 1 c 68 L 100-55 TEC 18.62 2.64 ld 68 S-100 TEC 19.67 1.15 le 62.5 L 100-55 TEC 27.86 3.31 12.5 25 if 62.5 S-100 TEC 26.88 4.43 12.5 25 [000146] Preparation of films. Required amounts of TEC, Eudragit E100 and Eudragit L100-55 as indicated in Table Ex-1 were dissolved in ethanol under vigorous stirring.
Ethanol/Eudragit E100 weight ratio was 7/3 in all cases. The mixture was stirred over 2 hours to obtain homogeneous solution. The solution was stored over 5 hours to let air bubbles dissipate. Polymer films were prepared by solution casting onto a PET
backing with following drying at ambient temperature over 3 days. Films of 0.20 0.04 mm thickness were obtained.
[000147] Mechanical and adhesive properties of the Eudragit E100/Eudragit L100-55/TEC films were tested with Tensile and Probe Tack Tests as indicated above.
The values of maximum stress and maximum work of adhesive debonding for the tested films are documented in the Table Ex-1, whereas relevant tensile test and probe tack stress-strain curves are presented in FIGS. 5-7.
Table Example 1 Com osition wdebonding Maximum Eudragit E-100, Eudragit L 100-55, TEC, J/m2 stress, MPa grains grams gralns Ex 1-1 68.2 6.8 25 3 0.24 Ex 1-2 59.1 5.9 35 31 0.44 Ex 1-3 50 5 45 40 0.44 Ex 1-4 45.5 4.5 50 41 0.29 Ex 1-5 36.4 3.6 60 22 0.16 - 2g -[000148] Pressure sensitive adhesives based on Eudragit E-100 - Eudragit L-100-blends with plasticizer were first described in US Patent 6,063,399 by Assmus et al.
Although in this patent no indications were made that this formulation belongs to a broader class of interpolymer complex adhesives, we consider the Example 9 of present invention as a reference. As has been noted by Assmus et al., adhesive properties of the blends are the function of their compositions. In order to obtain the tools manipulating the adhesion and to offer a range of other adhesives that were not yet disclosed in literature, in this example we have to gain an insight into the functions of every blend component in the control of adhesion.
[000149] Characteristics of tensile stress-strain curves make possible the evaluation of cohesive strength in terms of ultimate tensile stress under fracture of adhesive film, whereas free volume may be assessed qualitatively in terms of maxiinuin elongation under rupture.
The area under stress-strain curve represents the work of viscoelastic polymer deformation up to break, and this value correlates to the work of adhesive debonding (see Feldstein M.M.
"Molecular Fundamentals of Pf-essuf=e-Sensitive Adhesion" in Benedek I.
"Developnzent and Manufacture of Pt essur=e-Set2sitive Produets", Marcel Dekker, N.Y., 2005, Chapter 4, pp.
179-215). As follows from the tensile stress-strain curves in FIG. 5, mixing the film-forming polymer with ladder-like crosslinker in a ratio of [FFP]:[LLC]=10:1 leads to dramatic increase of cohesive strength (the value of ultimate stress increases by 6.6 times), whereas the free voluine drops appreciably (the value of inaximmn elongation decreases by a factor of 4.3).
[000150] Adhesive properties of binary Eudragit E-100 and Eudragit L-100-55 blends with appropriate plasticizers were the subjects of US Patents 5,133,970 by Petereit & Roth and 5,296,512 by Beier et al., respectively. As the results of probe tack testing have shown (FIG. 6), at comparatively low plasticizer concentration (25 wt. %) the blend of Eudragit E-100 and Eudragit L-100-55 copolymers exhibits low tack and adhesive mechanism of debonding without fibrillation. With the rise of plasticizer content, the peak stress grows rapidly achieving the inaxiinum at 35 - 45 wt. % of TEC. Respectively, and maximum elongation at probe detachinent increases. However, if a peak value of stress passes through maximum at 35-45 wt. % of plasticizer concentration, the total ainount of dissipated energy has maximum at 45 - 50 wt. % of TEC, when fibrillation process is inuch more elaborated and the blend demonstrates appreciable elongational flow. Following increase in the plasticizer concentration leads to cohesively weak compositions, which leave a remainder of adhesive on probe surface upon debonding.
[000151] Technology of polymer blends enables easy manipulating the specific balance between the cohesive strength and fluidity of adhesive composite by the increase in the content of ladder-like crosslinker. As follows from the stress-strain curves presented in FIG.
7, binary blend of the film-forming polymer (Eudragit E-100) with 35 wt. % of plasticizer TEC that contains no crosslinker is highly tacky fluid and debonds cohesively at high values of relative elongation leaving the reinainder of the adhesive at the surface of probe. Mixing the film-forming polyiner with complementary ladder-like crosslinker in a ratio of [FFP]: [LLC]= 10: 1 leads to immediate change of debonding mechanism from cohesive to adhesive, while the tack (maxiinuin stress) is mainly controlled by the film-fonning polymer.
Improvement of adhesion of the ladder-like plasticized interpolymer complex by incorporation of tackifiers [000152] US Patent 6,063,399 by Assmus et al. does not describe all the tools necessary to enhance the adhesion of triple Eudragit E-100 - Eudragit L-100-55 - TEC
blends. One of such tools is mixing the Eudragit E-100 - Eudragit L-100-55 - TEC blends with tackifiers.
Owing to optimum hydrophilic-hydrophobic balance, the amphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 complexes turned out to be miscible with tackifiers, which are extensively used in adhesive technology to improve tack. As follows from the data shown in Table and FIG. 8, adding the tackifier Sylvagum RE 85K (glycerol ester of tall oil rosin) iinproves essentially the adhesive perfonnance of blended adhesive.
While plasticizers contribute mainly to the increase of material capability to develop large deformations under detaching stress, the tackifier enhances appreciably its cohesive strength by the increase in 6,,,ax value.
Ex. No. FFP LLC Plasticizer Tackifter Wdeb, aI aX, J/m2 MPa 2a Eudragit None Acetyltributyl SYLVAGUM 104 0.6 E-100, Citrate, 35 RE85K, Resin, 59,1 5,9 2b Eudragit Eudragit L Triethyl citrate, SYLVAGUM 32 0.6 E-100, 100-55, 5,7 30 RE85K, Resin, 57.3 7 2c Eudragit Eudragit L Triethyl citrate, SYLVAGUM 20 0.66 E-100, 100-55, 6,2 25 RE85K, Resin, 61,8 7 2d Eudragit Eudragit L Triethyl citrate, SYLVAGUM
E-100, 100-55, 7,1 15 RE85K, Resin, 70,9 7 [000153] The data presented by Examples 2e - 2g and illustrated in FIG. 9 demonstrate the effect of tackifier concentration (SYLVAGUM RE85K Resin) on adhesive properties of FFP, Eudragit E-100, plasticized with 25 wt % of ATBC in the absence of any LLC. Adding the tackifier results in the increase of tack that goes through a inaximum at 25 %
SYLVAGUM concentration.
Ex. No. FFP Plasticizer Tackifier Wdeba 6max, J/mZ MPa 2e Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 10 0.48 100, 25 Resin, 2f Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 26 0.8 100, 60 25 Resin, 2g Eudragit E- Acetyltributyl Citrate, SYLVAGUM RE85K, 43 0.97 100, 50 25 Resin, [000154] Exainples 2h - 2i exhibit how dramatic is the gain in adhesion if using the tackifier SYLVAGUM is accompanied with the increase of plasticizer concentration.
Ex. FFP Plasticizer Tackifier Wdeb, 6max, No. J/m2 MPa 2h Eudragit E- Acetyltributyl SYLVAGUM 11 0.4 100, Citrate, 25 RE85K, 68.2 Resin, 6.8 2i Eudragit E- Acetyltributyl SYLVAGUM 104 0.6 100, 59.1 Citrate, 35 RE85K, Resin, 5.9 [000155] Examples 2k - 2m demonstrate how the adhesion of Eudragit E-100 -Eudragit L-100 55 blends (10:1) may be optimized by the combined effect of the plasticizer and the tackifier:
Ex. FFP LLC Plasticizer Tackifier Wdeb, 6max, No. J/m2 MPa 2k Eudragit E- Eudragit L- Triethyl SYLVAGUM 32 0.6 100, 100-55 Citrate, 30 RE85K, 57.3 5.7 Resin, 21 Eudragit E- Eudragit L- Triethyl SYLVAGUM 20 0.66 100, 61.8 100-55 Citrate, 25 RE85K, 6.2 Resin, 2m Eudragit E- Eudragit L- Triethyl SYLVAGUM 120 1.23 100, 52.4 100-55 Citrate, 25 RE85K, 2.6 Resin, 5.9 [000156] As is seen from the data presented in FIG. 10, SYLVAGUM Resin is not a single tackifier that is miscible with Eudragit E-100 - Eudragit L-100-55 ladder-like electrostatic complex, plasticized with TEC. An alternative tackifier, which is miscible with this blend, is Oppanol B15, a PIB of average molecular weight 75,000 ghnol.
Adhesive compositions based on the carcass-like complex of Eudragit E-100 polybase and its combination with the ladder-like electrostatic crosslinking [000157] The film forming polyiner, exemplified in this description with Eudragit E-100 polybase, may be converted into the forin of pressure sensitive adhesive not only by plasticizing with TEC, but also by adding into this blend higher carboxylic acids having 8 to 20 carbon atoms and dicarboxylic acids having 2 to 8 carbon atoms (US Pat.
5,113,970 to Petereit and Roth). As follows from the data presented in Table Ex.3 (see examples 3a and 3b), the blends of Eudragit E-100 with TEC and adipic acid (AA, dicarboxylic acid having 6 carbon atoms) are good skin contact adhesives. Forming two electrostatic bonds through both tenninal carboxyl groups at AA short chain, the AA acts as the carcass-like crosslinker of trialkylamino groups in Eudragit E-100 polybase. Additional incorporation of AA into the plasticized ladder-like Eudragit E-100 - Eudragit L-100-55 complex gives the blends outlined by Ex. 3c - 3f (FIG. 11), which are good bioadhesives demonstrating the tack to highly moistened biological substrates such as teeth and oral mucosa. As is evident from the probe tack curves presented in FIG. 11, the less the content of the LLC (Eudragit L-100-55), the higher the adhesion. Because the junctions of carcass-like network consist of single electrostatic bonds in contrast to the ladder-like network, where the junctions are composed of a sequence of multiple bonds (see scherne in FIG. 4), the carcass-like network can be more easily ruptured and reformed than the ladder-like network. For this reason the adhesives involving the carcass-like type of non-covalent crosslinking are inuch more easily soluble in water than the structures based on the ladder-like complex.
Table Example 3 Properties of coinpositions involving adipic acid (AA) as a carcass-like crosslinker of Eudragit E- 100 polybase.
PROPERTIES INVESTIGATED
Exam- Ratios, SF, % SR Adhesion to ple No. Components % wt wadlu 6max~
pHffs 6 teeth cheek gums arm J/m2 MPa Eu E-100 67 3a Adipic acid 8 FD* YES NO NO YES 200 1,25 Eu E-100 60 3b Adipic acid 15 FD YES NO YES YES 150 0,9 Eu E-100 61 3c Eu L-100-55 6 73,6 3,6 YES YES YES NO 23 0,8 Adipic acid 8 Eu E-100 54,5 3d Eu L-100-55 5,5 FD YES YES YES NO 19 0,6 Adipic acid 15 Eu E-100 63,8 3e Eu L-100-55 3,2 FD YES NO NO NO 64 1,26 Adipic acid 8 Eu E-100 57 3f Eu L-100-55 3 FD YES NO NO NO 59 0,99 Adipic acid 15 *) Fully dissolving [0001581 Other appropriate carcass-like crosslinkers of Eudragit E-100 FFP
have been found to be PEG-dicarboxylic acid and diacids having 2 to 6 carbon atoms between the carboxyl groups.
Enhancement of adhesion by partial ionization of film-forming Eudragit E-100 polymer and ladder-like crosslinker (Eudragit L-100-55) [000159] Another and highly effective tool to enhance the adhesion of Eudragit Eudragit L-100-55 - TEC blends, which also is not explored by the above mentioned US
Patent 6,063,399 by Assmus et al., is outlined by salutary impact of partial ionization of polyelectrolyte macromolecules within the interpolymer complex. The ainphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 blends involve two complementary polyelectrolytes: polyacid and polybase. The film-forming polymer, Eudragit E-100, represents the latter. Accordingly, the adhesion of Eudragit E-100 - Eudragit adhesives can be affected by partial ionization of both polyacid and polybase macromolecules.
[000160] FIG. 12 and 13 illustrate the procedure of partial ionization of the Eudragit E-100 polybase and Eudragit L-100-55 polybase with corresponding ainounts of neutralizing agents, HCI and NaOH, respectively. In order to determine the ainounts of acid and alkali needed for partial ionization of relevant polyelectrolyte to desirable extent, titration curve first must be measured. Taking into account that the jump in pH corresponds to 100 %
ionization of the polyelectrolyte, the ainount of neutralizing agent needed for 20 %
ionization of the polyelectrolyte constitutes a fifth fraction of total (equivalent) amount of the acid or alkali.
[000161] As is evident from the data presented in Table Ex.4, the tack is essentially improved with treatment of Eudragit L-100-55 by NaOH solution. The tack improvement becomes comparatively negligible as ionization degree exceeds 5%.
Table Example 4 Ex. FFP LLC Plasticizer pH modifier Wdeb, 6niax, No. J/m2 MPa 4a Eudragit E-100, Eudragit L 100- Triethyl NaOH 18.5 0.73 61,8 55,6,2 citrate, 25 5%
ionization 4b Eudragit E-100, Eudragit L 100- Triethyl NaOH 20 0.77 61,8 55,6,2 citrate, 25 10%
ionization 4c Eudragit E-100, Eudragit L 100- Triethyl NaOH 54 0.83 59.1 55, 5.9 citrate, 35 5%
ionization 4d Eudragit E-100, Eudragit L 100- Triethyl NaOH 57 0.97 59.1 55, 5.9 citrate, 35 10%
ionization 4e Eudragit E-100, Eudragit L 100- Triethyl HCl 23 0.82 61,8 55, 6,2 citrate, 25 5%
ionization 4f Eudragit E-100, Eudragit L 100- Triethyl HCl 68 1.3 61,8 55, 6,2 citrate, 25 10%
ionization 4g Eudragit E-100, Eudragit L 100- Triethyl HCl 50 0.82 59.1 55, 5.9 citrate, 35 5%
ionization 4h Eudragit E-100, Eudragit L 100- Triethyl HCl 77 0.93 59.1 55, 5.9 citrate, 35 10%
ionization [000162] As is seen from the stress-strain curves in FIG. 14, for comparatively ductile adhesives (exemplified here by the composition containing 35 wt. % of plasticizer), which reveal fibrillation (a plateau on the stress-strain curves), partial ionization of film-forming polybase Eudragit E-100 by HCl solution enhances the cohesive strength drainatically and the adhesive debonds without fibrillation. The maximum elongation in the-point of debonding first decreases with 5 % ionization and then increases again (at 10 %
ionization), implying that under comparatively small degree of polymer chain ionization the enhancement of cohesive strength is a predominant factor, whereas further increase in the ionization degree is accompanied with forination of large free volume. The enhanceinent of cohesive strength tends to a maximuin above 10 % of the ionization of film-forming polymer.
[000163] By coinparing the probe tack data presented in FIG. 14, 15 and in the Table Ex. 4, it may be seen that qualitatively the mechanisins of tack enhanceinent by ionization of the ladder-like crosslinker and the film-fonning polymer are similar. However, as follows from the data shown in FIG. 15, in quantitative terms the effect of ionization of the film-forming polybase on adhesion is much stronger than that observed for the ladder-like crosslinking polyacid.
[000164] If both the film-forming polymer and the ladder-like crosslinker are preliminarily ionized by treating respectively with HCl and NaOH solutions, then the ionic bonding between cationic groups of Eudragit E-100 copolymer and anionic groups of Eudragit L-100-55 copolymer contributes to the adhesive behavior of the interpolyiner complex along with hydrogen bonds forined between uncharged groups. As follows from the data shown in FIG. 16, in this case the adhesive properties of the complex are intermediate between those featured for the complex involving partial ionization of either the film-forming polymer or the ladder-like crosslinker. Effects of macroinolecular ionization on the tack of adhesive coinposites involving polyelectrolytes have never been earlier reported.
10001651 Partial 10 % ionization of the ladder-like crosslinker (Eudragit L-100-55) in interpolymer complex with film-forming Eudragit E-100 polymer does not affect the swelling and dissolution of the adhesive. However, the 10 % ionization of the film-forming polymer with HCl solution results in appreciable increase of swell ratio from 3.5 to 22.5, while the ainount of soluble fraction has comparatively insignificant effect on the value of sol fraction.
[000166] If the polybase and polyacid in the ladder-like Eudragit E-100 -Eudragit L-100-55 complex are interchanged in such a way that the polyacid (Eudragit L-100-55) serves as the film-forming polymer and the polybase (Eudragit E-100) is the ladder-like crosslinker, adhesive materials wherein the treatment with NaOH has a greater effect on adhesion and sorption are obtained.
Improvement of adhesion of PVP-PEG-Eudragit L-100-55 blends by means of partial ionization of the ladder-like crosslinker [000167] The hydrogen bonded interpolymer complexes combining the ladder-like and carcass-like types of noncovalent crosslinking, shown in schematic form in FIG. 3, share the properties of pressure-sensitive adhesives and bioadhesives (see U.S. Patent Application Serial No. 10/936,887 to Feldstein et al. for "Method of Preparing Polymeric Adhesive Coinpositions Utilizing the Mechanism of Interaction Between The Polymer Components,"
filed September 8, 2004). The effect of partial ionization of Eudragit L100-55 on adhesive properties of PVP/PEG/Eudragit L100-55 is demonstrated by present exainple.
[000168] Preparation of films. 30 g of PEG400 was dissolved in 280 g of water/ethanol (1:1) mixture. Required amount of sodium hydroxide was dissolved (as indicated in Table Ex-5.). Under vigorous stirring 12 g of Eudragit L100-55 powder was added followed by adding 58 g of PVP (K90) powder. The mixture was stirred over 2 hours to obtain homogeneous solution. The solution was stored over 5 hours to let air bubbles dissipate.
Polymer films were prepared by solution casting onto a PET backing with following drying at ambient temperature over 3 days. Films of 0,20 0,04 mm in thickness were obtained.
Water content in the films was measured gravimetrically by weight loss at 120 C. Films with hydration degree 12 0,5 wt% were obtained.
Table Example 5 PVP, PEG 400, Eudragit L100- NaOH, Eudragit L100-grams grams 55, grams grams 55 ionization,%
Ex 5-1 58 30 12 0 0 Ex 5-2 58 30 12 0,129 5 Ex 5-3 58 30 12 0,258 10 Ex 5-4 58 30 12 0,516 20 [000169] As is obvious from the stress-strain curves in FIG. 17, partial ionization of the ladder-like crosslinker in the blends with PVP-PEG carcass-like complex improves the adhesion appreciably but does not change the mechanism of adhesive defonnation under debonding process. The latter remains adhesive (no remainder of adhesive material at a probe surface upon debonding). Improvement of tack and adhesion tends to a maximum at 10 %
ionization of the ladder-like crosslinker. Such mechanism of tack improvement has been also established for the first time.
Others adhesive compositions based on plasticized ladder-like interpolymer complexes [000170] Eudragit E-100 is a typical and coinparatively well-studied but not unique representative of polybases suitable for the fonnulation of adhesives based on the ladder-like interpolymer complexes with polyacids. Others appropriate polybases include homopolymers and copolyiners of vinyl amine or chitosan ainong polyelectrolytes, and PVP or PNIPAM
ainong non-polyelectrolytes. As an exainple, following Table outlines the adhesive properties of the blends of high molecular weight PVP K-90 (film-forming polymer) with Eudragit L-100-55 as ladder-like crosslinker, plasticized with TEC. The inverted composition wherein the Eudragit L-100-55 serves as the film-forming polyiner and the PVP
as the ladder-like crosslinker was also prepared and characterized. These compositions differ from that described in Examples 1-3 by the lack of carcass-like crosslinker and, consequently, represent others examples of the adhesives based on ladder-like interpolymer complexes shown schematically in FIG. 4. The compositions were prepared by casting-drying method from ethanol solutions.
Ex. FFP LLC Plasticizer Wdb, 6'max~
No. J/mZ MPa 6a PVP K-90 Eudragit L 100- Triethyl 24 0.77 60.2 55, 9.8 citrate, 30 6b PVP K-90 Eudragit L 100- Triethyl 55 0.97 50.1 55,9,9 citrate, 40 6c Eudragit L 100- PVP K-90 Triethyl 44 0.80 55, 10.9 citrate, 30 61,1 [000171] In following coinposition the Eudragit E-100 was selected as film-forming polymer (polybase) and Gantrez S-97 as the ladder-like crosslinker (polyacid).
The latter is a copolymer of maleic acid with methylvinyl ether (1:1). TEC was used as plasticizer. Under vigorous stirring the powder of Gantrez S-97 polymer was slowly added into the 30% ethyl alcohol solution of Eudragit E-100, that was previously mixed with TEC
(plasticizer), until a homogeneous dispersion was obtained. The semitransparent, homogeneous film was obtained using simple casting and drying procedure of the previously obtained dispersion under ainbient temperature. Prepared films contained 25 wt % of TEC, while Eudragit E-100 - Gantrez S-97 ratio was varied. FIG. 18 compares the probe tack stress-strain curves for the Eudragit E- 100 - Gantrez S-97 ladder-like complex with the curve featured for Eudragit E-100 - Eudragit L-100-55 composition plasticized with equivalent ainount of TEC.
[000172] As follows from the curves demonstrated in FIG. 18, replaceinent of the Eudragit L-100-55 ladder-like crosslinker in the complex with Eudragit E-100 fihn-forming polyiner for much more hydrophilic Gantrez S-97 copolyiner iinproves the tack significantly.
[000173] While the water-absorbing capacity (measured in tenns of Swell Ratio, SR, which is a ratio of the weight of gel in swollen state to the diy weight of gel fraction) for ainphiphilic adhesives based on plasticized ladder-like Eudragit E-100 -Eudragit L-100-55 complexes is comparatively low, ranging from 3 to 6 depending on coinposition, it is dramatically affected by the nature of the ladder-like crosslinker. As the data in FIG. 19 have shown, replacement of comparatively hydrophobic Eudragit L-100-55 by much more hydrophilic Gantrez S-971eads to the increase of Swell Ratio from 4.4 to 89.2.
In this way, moderately absorbing adhesive compositions based on the ladder-like complexes may be easily modified to give super-absorbing adhesives. The super-absorbing adhesives, outlined by this invention, represent a new class of pharmaceutical materials.
[000174] Other suitable ladder-like crosslinkers for Eudragit L-100-55 polymer are alginic acids and carboxyl-containing cellulose derivatives such as HPMCP.
Their mixing with Eudragit L-100-55 in solutions can be significantly facilitated by partial ionization of relevant polymers.
[000175] Eudragit E-100 is not unique polybase that can be used as FFP in the blends with Eudragit L-100-55 polybase. Other suitable candidates as FFP in plasticized ladder-like complexes are the Eudragit RS and Eudragit RL. The Eudragit RS is a copolymer of triinethylammonioethyhnethacrylate chloride (0.1) with ethylacrylate (1) and methyl inethacrylate (2), available from Rohm Pharma Polymers. The Eudragit RL is a copolyiner of triinethylaminonioethyl methacrylate chloride with ethylacrylate and methyl methacrylate (0.2:1:2), available from Rohm Pharina Polymers as well. Although both TL and RS polymer contain ionic groups, they are insoluble in water due to high concentration of hydrophobic polymer units. The Eudragit RL and RS polymers are capable to forin ionic bonds with polymer units bearing negative charge (carboxylate anions). Appropriate ladder-like crosslinker for such polymers is ionized Eudragit L-100-55.
[000176] Next Table demonstrates the composition of adhesive blend prepared using Eudragit RL and Eudragit RS polyiners:
Composition % wt.
Eudragit RL 49.1 Eudragit RS 16.4 TEC 28.0 Eudragit L100-55 6.5 Fully ionized [000177] Under vigorous stirring the appropriate ainount of Eudragit RL was dissolved in the ethanol solution of Eudragit RS. Under stirring the required alnount of the plasticizer tributyl citrate (TBC) was added into the ethanol solution of two base polymers Eudragit RL
and Eudragit RS. Fully ionized Eudragit L100-55 was then dissolved in the blend of Eudragit RL/Eudragit RS/ TBC. The homogeneous film was obtained using casting and drying procedure of the previously obtained solution. Prepared composition feature the values of Sol fraction of 4.3 % and Swell ratio of 2.5. The homogeneous film is initially nontacky but adheres strongly to teeth surface providing good adhesive contact that is stable during 4 hours.
[000178] Another appropriate polybase forming the ladder-like complexes with polyacids is chitosan.
Effect of the nature of plasticizers on adhesive properties and water-absorbing capacity of Eudragit E-100 - Eudragit L-100-55 complex [000179] FIG. 20 and 21 illustrate the influence of hydrophilicity of plasticizers on the adhesive and water absorption properties of the compositions based on the interpolymer complex between Eudragit E-100 polybase Eudragit L-100-55 polyacid. As is evident from the probe tack profiles presented in FIG. 20, more hydrophilic plasticizers (TEC and ATEC) demonstrate more ductile inechanisin of deforination under debonding stress, developing higher values of maximum elongation compared to more hydrophobic TBC and TBC, which behave like solid adhesives and deform without fibrillation. The adhesion, ineasured in terms of the work of debonding, decreases in a row ATEC = TEC > ATBC > TBC.
[000180] Correspondingly, the swell ratio of the blends of Eudragit E100 -Eudragit L100-55 with plasticizers TEC, ATEC, TBC, ATBC, decreases with the decrease in their hydrophilicity in the row TEC >ATEC>TBC>ATBC. It is worthy of note that the nature of the plasticizers affects the water absorbing capacity to a smaller extent than the adhesion.
Hydrophilization of amphiphilic adhesives based on Eudragit E-100 - Eudragit L-100-55 complexes [000181] As has been shown above, adhesive blends based on plasticized Eudragit E-100 - Eudragit L-100-55 complexes are miscible with such hydrophobic plasticizers and tackifiers as PIB (Oppanol B-15) (see FIG. 10). Because the inonoiner units in Eudragit E-100 - Eudragit L-100-55 complexes combine polar hydrophilic and non-polar lipophylic entities, these adhesives belong to the class of amphiphilic materials and are also miscible with hydrophilic and even hygroscopic polymers and fillers. Hydrophilization of ainphiphilic Eudragit E-100 - Eudragit L-100-55 adhesives represents an important tool to enhance their water-absorbing capacity and modify the adhesion.
[000182] The data presented in Table Ex. 8.1 and shown in FIG. 22 and 23 demonstrate the effect of mixing with hydrophilic PVP and with its adhesive blends with PEG-400 on adhesion and water absorbing capacity of Eudragit E-100 - Eudragit L-100-55 interpolyiner complex, plasticized with 25 wt. % of TEC. Under vigorous stirring, necessary amount of Eudragit L100-55 was dissolved in the ethanol solution of Eudragit E100. Then the plasticizer (TEC) was dissolved in the ethanol solution of two parent polymers. Under stirring the appropriate amount of low molecular weight PVP or low molecular weight PVP
blend with PEG-400 was dissolved in the ethanol solution of E100/L100-55 blend with TEC.
The fihns were obtained by a casting drying procedure as described above.
Table Example 8.1 Compositions and properties of Eudragit E-100 - Eudragit L-100 -55 blends with plasticizer TEC and hydrophilizing agents, PVP and PVP-PEG
Ex. FFP LLC Plasticizer Additive Sol SR Wdeb, 6max, No. J/m2 MPa 8a Eudragit E- Eudragit Triethyl PVP K 30, 53,4 9,5 none none 100, L 100-55, citrate 15 58,0 5,8 21,2 8b Eudragit E- Eudragit Triethyl PVP K 30, 51,7 8,1 none none 100, 54,1 L 100-55, citrate, 15 5,4 25,5 8c Eudragit E- Eudragit Triethyl PVP PEG 63,8 10,9 20 0,73 100, L 100-55, citrate, K 30 400 52,2 5,2 19,2 15 8,4 8d Eudragit E- Eudragit Triethyl PVP PEG 60,5 7,1 59,7 0,98 100, 48,7 L 100-55, citrate, K30 400 4,9 23,0 15 8,4 [000183] The films of Eudragit E100/Eudragit L100-55/TEC blends with PVP K-30 were semitransparent indicating of their heterogeneous structure. These films had poor or no initial tack in contrast to the blends with PVP-PEG carcass-like coinplex (FIG. 23). These latter films were homogeneous and transparent.
[000184] As is evident froin the data presented in Table Ex. 8.1 and FIG. 22, mixing with both PVP and PVP-PEG blends leads to an appreciable increase in water absorbing capacity of the adhesive materials.
[000185] The data in Tables 8.2 - 8.5 illustrate other approaches towards adhesive materials of controlled water-absorbing capacity based on ladder-like interpolymer complexes.
EUDRAGIT E100/TEC/CARBOPOL:
[000186] Preparation of films. Required amount of Eudragit E100 was dissolved in ethyl acetate (3 parts of Eudragit E100 were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.2) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar the required amount of Carbopo1974 (as indicated in the Table 8.2) was suspended in ethyl acetate (2 parts of Carbopol 974 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Carbopol 974 is a chemically crosslinked polyacrylic acid. Different grades of Carbopol polymers are supplied by Noveon, Inc. in the form of finely lnicronized powder. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ambient temperature over 3 days. Films of 0.15 0.04 min in thickness were obtained.
Table Example 8.2 Example Eudragit E100 TEC Carbopo1974 Swell ratio 1 65 25 10 4.6 2 55 25 20 12.8 3 45 25 30 20.4 4 40 30 30 23.7 [000187] In the examples 8.2 and 8.3 the Carbopol serves both as a ladder-like crosslinker and hydrophilizing agent.
Eudragit RS/RL/TEC/Carbopol [000188] Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.3) were dissolved in ethyl acetate (3 parts of the sum of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required ainount of TEC (as indicated in the Table 8.3) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar required ainount of Carbopo1974 (as indicated in the Table 8.3) was suspended in ethyl acetate (2 parts of Carbopol 974 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ambient teinperature over 3 days.
Films of 0,20 0,04 mm thickness were obtained.
Table Example 8.3 Ex. Eudragit Eudragit TEC Carbopol 974 Swell ratio RS RL
1 45 15 30 10 2.9 2 37,5 12,5 30 20 5.3 3 37,5 12,5 20 30 6.8 4 30 10 20 40 13.4 [000189] In the exainple 8.4 the Kollidon CLM serves as a ladder-like crosslinker and hydrophilizing agent.
EUDRAGIT RS/RL/TEC/KOLLinON CLM
[0001901 Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.4) were dissolved in ethyl acetate (3 parts of the sum of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.4) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar required ainount of Kollidon CLM (as indicated in the Table 8.4) was suspended in ethyl acetate (2 parts of Kollidon CLM were suspended in 5 parts of ethyl acetate) to obtain Solution II. Kollidon CLM is a physically crosslinked polyvinylpyrrolidone supplied by BASF in the form of finely micronized powder.
Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 inin. Polymer films were prepared by solution casting onto a PET backing with following drying at ainbient teinperature over 3 days. Films of 0.20 0.04 min thickness were obtained.
Table Example 8.4 Example Eudragit RS Eudragit RL TEC Kollidon Swell ratio CLM
1 45 15 30 10 2.3 2 41,25 13,75 30 15 3.1 3 45 15 20 20 4.0 4 37,5 12,5 20 30 4.8 [000191] In example 8.5 the Cab-O-Sil M5 serves as a hydrophilizing agent.
EUn2tAGIT RS/RL/TEC/CAS-O-SIL M
[000192] Preparation of films. Required amounts of Eudragit RS, Eudragit RL
(as indicated in the Table 8.5) were dissolved in ethyl acetate (3 parts of the suin of Eudragit RS
and Eudragit RL were dissolved in 7 parts of ethyl acetate). Required amount of TEC (as indicated in the Table 8.5) was added under vigorous stirring to obtain homogeneous solution (Solution I). In a separate jar the required ainount of Cab-O-Sil M5 (as indicated in the Table 8.5) was suspended in ethyl acetate (2 parts of Cab-O-Sil M5 were suspended in 5 parts of ethyl acetate) to obtain Solution II. Cab-O-Sil M5 is a synthetic silicone dioxide supplied with Cabot Corporation in the form of finely micronized powder. Under vigorous stirring Solution II was added into Solution I, and the mixture was stirred over 20 min. Polymer films were prepared by solution casting onto a PET backing with following drying at ainbient temperature over 3 days. Films of 0.20 0.04 min thickness were obtained.
Table Example 8.5 Example Eudragit RS Eudragit RL TEC Cab-O-Sil Swell ratio 1 49,5 16,5 30 4 2.2 2 46,5 15,5 30 8 2.8 3 43,5 14,5 30 12 3.8 [000193] The value of Swell Ratio featured for parent Eudragit RL/RS - TEC
blend is around 2Ø As the data in Tables Ex. 8.3 - 8.5 have shown, the hydrophilization of the blends with crosslinked water absorbents such as Carbopol 974, Kollidon CLM and Cab-O-Sil M5 results only in a comparatively insignificant increase in Swell Ratio. This is most likely due to very low water permeability of hydrophobic film based on Eudragit RL/RS
polymers.
However, the materials described in Examples 8-3 - 8.5 may-be useful as carriers of hydrogen peroxide solution in tooth whitening strips. For this purpose, the hydrophilic filler (Carbopol 974, Kollidon CLM or Cab-O-Sil M5) should be impregnated with the hydrogen peroxide solution before incorporation into the Eudragit RL/RS film. This film provides good tack and adhesion toward hydrated tooth surface.
Performance properties of adhesive compositions based on interpolymer complexes compared to the properties of conventional pressure sensitive adhesives and bioadhesives [000194] The properties of the triple blend hydrogels of the invention (PVP-PEG-Eudragit L 100-55), were compared with those of the PVP-PEG binary blends, described in U.S. Patent 6,576,712, and with those of conventional pressure sensitive adhesives ("PSA";
DURO-TAe 34-4230, National Starch and Chemicals) and classical bioadhesives (covalently crosslinked polyacrylic acid polymers Carbopol 974P and Noveon AA1, both from B.F. Goodrich, Co.).
Adhesives based on interpolymer complexes compared to hydrophobic PSAs and bioadhesives PSA Bioadhe- water soluble hydrophilic amphi-Attribute sives US Pat. Exainples philic 6,576,712 1-8 Examples PEEL
ADHESION, N/m 300- 370-550 140-710 - in dry state 600 - in hydrated None 50 - 70 10 - 30 state None 10 - 60 300 - 550 100 - 300 SOLUBILITY IN Insoluble Insoluble, Soluble Insoluble, Insoluble, WATER Swellable Swellable Swellable Water sorption Less 1% 98 % Non limited 96 % 17 - 85 %
capacity Fihn-forming Yes No Yes Yes Yes capability Elasticity 1.0 - 5.0 0.09 - 0.9 1.3 - 5.0 0.4 - 40 1.0 - 7.3 modulus, Pa x105 MAXIMUM 22 More than 22 2.7 1.71 Ultimate tensile 16 0.01 12 30.4 5 stren th, MPa Logarithm 4.1 2.6 3.7 - 4.9 5.0 Not Yield stress, Available MPa [000195] PSAs, exemplified above by the SIS block-copolymer based DURO-TAIe 34-4230 adhesive, represent a special class of viscoelastic polymers. They are capable of forining a strong adhesive bond with various substrates under application of a slight external pressure over a short time (1-2 seconds). It is noteworthy that the typical PSAs for huinan use are mainly based on hydrophobic elastomers with low glass transition teinperatures, ranging from -120 to -30 C, which are usually increased by addition of tackifying resins. The coimnon property of the PSAs is a loss of adhesion as the surface of a substrate is moistened.
For this reason, conventional PSAs cannot be used for application to highly hydrated and soft biological tissues such as oral mucosa. For this purpose, hydrophilic bioadhesives are usually einployed, which are generally nontacky in the dry state, but adhere to wet substrates.
The adhesive strength of such bioadhesives, however is usually much lower than that of the PSAs.
[000196] As is seen from this data, the adhesives of various hydrophilic-hydrophobic balances outlined by present invention and obtained by non-covalent crosslinking of film-forming hydrophilic polyiners share the properties of both pressure sensitive adhesives and bioadhesives. Indeed, while their adhesive strength is typical of the PSAs, it has increased adhesion towards moistened substrate like bioadhesives. Varying the hydrogel composition and degree of ionization of ionogenic polymers can easily provide the further control of adhesive, water sorption and mechanical properties of the products based on non-covalently crosslinked hydrogels.
[000197] FIG. 24 compares the peel adhesion towards dry and moistened huinan forearin skin in vivo for conventional acrylic PSA and three grades of adhesives based on interpolymer complexes. According to these data, the adhesive properties of polymer composites described in the present application and in U.S. Patent 6,576,712 share the properties of PSAs and bioadhesives by combining high adhesion featured for conventional PSAs with capability to adhere to moistened skin and biological tissues typical of bioadhesives.
[000198] Stress-strain curves obtained in the course of Probe Tack Test are much inore informative on the mechanisms of adhesive debonding than the peel force traces presented in FIG. 21. In FIG. 25 the adhesive behaviors of water-soluble PVP-PEG adhesives (described in US Patent 6,576,712 by Feldstein et al.), PVP-PEG-Eudragit L-100-55 adhesive hydrogels (Exainples 1-4) and the amphiphilic Eudragit E-100 - Eudragit L-100-55 adhesives plasticized by TEC and filled with tackifier Rosin (Example 10) have been compared with the properties of two different grades of conventional PSAs: SIS-based DURO-TAK
PSA and acrylic PSA (3M).
[000199] Being expressed in terms of maximum stress under debonding, the tack of adhesives based on interpolymer complexes is comparable with that typical of conventional PSAs. However, a distinctive feature of the adhesive blends described in this application is the lower values of maxiinum elongation that result from non-covalent crosslinking of the chains of fihn-forming polymer. Because the carcass-like crosslinking is significantly looser than the ladder-like crosslinking, it is no wonder that the water-soluble PVP-PEG adhesive demonstrates higher stretching at probe detachment than the adhesives involving the ladder-like type of crosslinking. In this connection it is pertinent to note that the main tools to increase fluidity and maximum elongation of the adhesives provided by the ladder-like crosslinking it is the dilution of network density due to mixing with plasticizers, in the course of swelling in water and also the decrease in concentration of the ladder-like crosslinker.
Preparation of adhesive films by direct mixing of polymeric components followed by extrusion [000200] The behavior of the hydrophilic and amphiphilic adhesives described in this invention is typical of covalently crosslinked polymers. In contrast to covalently crosslinked systems, however, the adhesives based on interpolymer coinplexes can be easily prepared using a simpler blending process, and, furthertnore, provide film-forming properties that are unattainable using crosslinked polymers.
[000201] While above presented formulations were prepared by casting from solutions followed by drying, the adhesive films of the present invention can be also produced by direct mixing the components in dry state followed by extrusion. The mixing was provided using Therino Haake Mixer, whereas the extrusion was performed with Skania Single-Screw Extruder. The procedures of mixing and extrusion of the major formulations described in this invention are presented below.
I Preparation of the compositions outlined by Example 1 [000202] The following blend was prepared:
Eudragit E 100 68.2 weight %
Eudragit L 100-55 6.8 %
TEC 25.0%
[000203] Procedures of mixing and extrusion are indicated in Tables 10.1 &
10.2:
Table Example 10.1.
Time, min. Tinixture, oC N, rpm Torque N.m Operation 0-2 100 30 0-25 Loading of Eudragit E100 I 1 110 30 3 The beginning of loading premix "G"*
with a rate of -I ml/min 26 10-5 30 0- 0.8 Decrease of tem erature 38 91 30 0.7-0.8 The finishing of loading of premix "G"
47 74 30 3.0 Closing the mixer chamber 62 66 60 3.0-4.5 Increase of stirring rate 68 67 30 3-4 Elevation of temperature to 80 120 0 - Stop *) Preinix "G" is Eudragit L-100-55 plasticized with TEC.
Table Example 10.2.
Tzones Trouer N, rpm Extrusion Reducing Pressure, speed, step Bar mm/c 90/90/95 100 18 7.3 14 31-35 [000204] The following examples illustrate the applicability of interpolyiner complex adhesives for a range of pharmaceutical products.
Wound Dressings [000205] The following samples illustrate how the hydrogel compositions of this invention may be used for silver-containing antimicrobial wound dressings.
Wound dressings were prepared from the following ingredients using either a melt extrusion or casting/drying processes:
Composition, wt. %
Film-forining Ladder-like Carcass-like Silver salt Sample polymer crosslinker crosslinker (1 %) l la Eudragit E-100, Eudragit L 100-55, Triethyl Silver 67.2 6.7 citrate, 25.0 sulfate l lb Eudragit L 100- PVP, 9.9 PEG-400, Silver 55, 49.5 39.6 sulfate 11c Eudragit E-100, Eudragit S-100, 6.7 Triethyl Silver 66.9 citrate, 24.9 sulfate l ld Eudragit E-100, Eudragit L 100-55, Triethyl Silver 67.2 6.7 citrate, 25.0 phosphate [000206] All of the hydrogel samples were insoluble in water and exudate, but were swellable, thus absorbing a great ainount of exudate. Sample l lb was initially tacky and maintained a good adhesion toward dry and moderately exudating wounds, but could be removed from the skin without pain by washing with a large ainount of water.
Samples 11 a and 11 c possessed a slight initial tack but became nontacky in a swollen state. Accordingly, sample l lb is useful for treatment of pressure, diabetic, arterial and venous ulcers, whereas Sainples 6a and 6c are more suited for covering large, wet and infected wounds and burns.
[000207] A potentiometric method with Ag ion selective electrode was used to study silver release from anti-microbial d'ressings. Aqueous solutions of silver nitrate in the concentration range 2.5* 10-6 - 10"3 M were used to calibrate the Ag ion selective electrode.
Circular samples (with diaineter= 1 inch, area=5 cin) of anti-microbial films were die-cut and laminated to glass plates by means of a double-sided scotch. The glass plate with the Ag release side upwards was placed into a beaker. 50 ml of distilled water was poured into the beaker. The obtained system was covered with a petri dish and placed into an oven-therinostat at 25 0.2 C. After specified time points the receptor solution in the beaker over the sample was stirred and silver concentration was measured with the Ag ion selective electrode. After measurement the receptor solution was removed and replaced with 50 ml of distilled water.
Cumulative Ag release was calculated and expressed in g per cm2 of the anti-microbial dressing.
[0002081 FIG. 26 demonstrates how the release kinetics of silver sulfate, as the active agent, from the matrices in vitro were affected by the change in matrix composition. All three hydrogel compositions provided different drug release profiles: Sample 11 a delivered the highest amount of silver sulfate; Sainple 1 lb provided a fast release of the active agent during the onset period, followed by a rapid decrease of release rate within steady state stage;
and Sample 11 c provided zero-order release kinetics. Since various silver salts are characterized with different values of solubility product, it would be expected that different salts of silver, being incorporated into the saine hydrogel matrix, may deinonstrate different release kinetics.
[0002091 FIG. 27 illustrates the effect of silver salts on the release profile of Ag ion from the formulation outlined by Exainple 11 d. In this case the matrix based on Eudragit E-100 - Eudragit L- 100-55 ladder-like complex was loaded with silver phosphate instead of silver sulfate. Since solubility of silver phosphate in the matrix is about three orders of magnitude lower than that of silver sulfate, the adhesive matrix loaded with silver phosphate provides prolonged release kinetics of anti-microbial agent.
Slowly dissolving matrices with therapeutic agents [000210] The following compositions were prepared by dissolution in ethanol of components listed in the Table presented below, casting the solution and drying at temperature of 50 C.
[000211] The sainples use an acrylate polymer (Eudragit E100) as the film-forming polymer. Sample 12a uses two ladder-like crosslinkers, an acrylate polymer (Eudragit L 100-55) and a poly(N-vinyl lactam) (PVP 90), while Sample 12b only includes one ladder-like crosslinker, Eudragit L 100-55. Similarly, Sample 12a uses two carcass-like crosslinkers, an alkyl citrate (triethyl citrate) and a polyalkylene glycol (PEG 400), while Sample 12b only includes one carcass-like crosslinker, triethyl citrate.
Component Sample 17a (wt%) Sample 17b (wt%) Eudra it E100 58.29% 60.30%
Triethyl citrate 26.10% 27.00%
Eudragit L 100-55 2.61% 2.70%
PVP 90 2.00% 0 PEG 400 1% 0 Lidocaine base 10% 10%
Total 100% 100%
Liquid Film-Forming Bandages [000212] Samples 13a-13d represent liquid compositions suitable for application to skin as liquid bandages. Sample 13a is a liquid formulation for tooth whitening which contains the insoluble film-forming polymer (Eudragit RS) and plasticizer for this polymer tributylcitrate (TBC). Eudragit RS is a copolymer of trimethylammonioethyhnethacrylate chloride (0.1) with ethylaciylate (1) and methylmethacrylate (2), available from Rohin Pharma Polymers. Sainples 13b-13d contain no ladder-like crosslinker for the hydrophilic polymer, Eudragit L 100-55. Actually, the ladder-like crosslinker makes the polymer film insoluble. However, for the compositions containing Eudragit RS as a film-forming polyiner, the ladder-like crosslinker of PVP was not a necessary coinponent, because the blend is not soluble.
[000213] Sample 13e is a film-fonning liquid formulation suitable for the treatment of cold sores and canker sores. It contains Eudragit E-100 as a soluble fihn-fonning polymer instead of PVP. Correspondingly, PEG-400 is omitted from the formulation, because TBC is a good plasticizer for both Eudragit RS and E-100.
[000214] Liquid bandage and cold sore compositions for skin applications (Samples l0a-l0e) may also contain active agents such as local anesthetics. Suitable local anesthetics include dibucaine hydrochloride; dibucaine; lidocaine hydrochloride;
lidocaine; benzocaine;
p-butylaininobenzoic acid 2-(diethylamino) ethyl ester hydrochloride; procaine hydrochloride; tetracaine hydrochloride; chloroprocaine hydrochloride;
oxyprocaine hydrochloride; mepivacaine; cocaine hydrochloride; and piperocaine hydrochloride.
[000215] Samples 13c and 13e contain also a skin softening agent such as glycerol monooleate (Peceol, Gattefosse, France).
Composition, wt%
Soluble film- Ladder- Carcass-Insoluble forming like like film- Plasticizer polymer crosslinker crosslinker Sainple forming for (A) (B) for (B) for (B) Additives Solvent polymer (A) 13a Eudragit TBC, PVP K- Eudragit L PEG, 3.00 Sodium Ethanol, (Liquid RS, 2.50 90, 3.00 100-55, Citrate, 38.20 Bandage) 29.00 2.20 2.50 13b Eudragit TBC, PVP K- - PEG, - Ethanol, (Liquid RS, 11.70 90, 0.18 52.65 Bandage) 35.11 0.36 13c Eudragit TBC, PVP K- - PEG, GMO, Ethanol, (Liquid RS, 6.69 90, 0.21 3.00; 1,2- 14.29 30.09 Bandage) 20.06 Propylene Glycol, 28.57 13d Eudragit TBC, PVP K- - PEG, 1.14 - Ethanol, (Liquid RS, 7.95 4.55 17, 1.14 35.00 Bandage) 13e Eudragit TBC, Eudragit - - GMO, Ethanol, (Cold RS, 11.00 E-100, 10.00 44.00 Sore) 33.00, 11.00
Claims (84)
1. A method for preparing a water-insoluble, water-absorbent adhesive composition, comprising combining, under conditions effective to form a substantially homogeneous admixture:
(a) a film-forming, hydrophilic polymer comprising at least one linear segment containing a plurality of recurring polar groups;
(b) a complementary multifunctional polymer containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the complementary multifunctional polymer; and (c) a plasticizer capable of plasticizing the film-forming polymer, wherein the weight fraction of the film-forming polymer in the admixture is greater than the weight fraction of either the complementary multifunctional polymer or the plasticizer.
(a) a film-forming, hydrophilic polymer comprising at least one linear segment containing a plurality of recurring polar groups;
(b) a complementary multifunctional polymer containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the complementary multifunctional polymer; and (c) a plasticizer capable of plasticizing the film-forming polymer, wherein the weight fraction of the film-forming polymer in the admixture is greater than the weight fraction of either the complementary multifunctional polymer or the plasticizer.
2. The method of claim 1, wherein the plasticizer is selected from the group consisting of dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates, mixed alkyl-aryl phthalates, alkyl phosphates, aryl phosphates, alkyl citrates, citrate esters, alkyl adipates, dialkyl tartrates, dialkyl sebacates, dialkyl succinates, alkyl glycolates, alkyl glycerolates, glycol esters, glycerol esters, and mixtures thereof.
3. The method of claim 2, wherein the plasticizer is selected from dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate, dicapryl phthalate, tributyl phosphate, trioctyl phosphate, tricresyl phosphate, triphenyl phosphate, trimethyl citrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, trihexyl citrate, dioctyl adipate, diethyl adipate, di(2-methylethyl)adipate, dihexyl adipate, diethyl tartrate, dibutyl tartrate, diethyl sebacate, dipropyl sebacate, dinonyl sebacate, diethyl succinate, dibutyl succinate, glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, and mixtures thereof.
4. The method of claim 3, wherein the plasticizer is selected from tributyl phosphate, trioctyl phosphate, triphenyl phosphate, trimethyl citrate, triethyl citrate, and tributyl citrate.
5. The method of claim 1, wherein the plasticizer is a bifunctional, linear oligomer having a functional group at each terminus, each of said terminal functional groups capable of noncovalently binding to one of the polar groups so that a bridged interpolymer complex is formed in which the bifunctional linear oligomer links two of said linear segments to each other.
6. The method of claim 1, further comprising extruding the admixture onto a substrate.
7. The method of claim 1, further comprising combining a solvent with components (a), (b), and (c) in an amount effective to provide a solution, casting the solution onto a substrate, and heating the solution-coated substrate to volatilize the solvent and provide the substantially homogeneous adhesive admixture on the substrate.
8. The method of claim 1, wherein:
the film-forming, hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the admixture;
the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the admixture; and the bifunctional, linear oligomer represents approximately 1 wt.% to approximately 50 wt.% of the admixture.
the film-forming, hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the admixture;
the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the admixture; and the bifunctional, linear oligomer represents approximately 1 wt.% to approximately 50 wt.% of the admixture.
9. The method of claim 1, wherein the recurring functional groups, the terminal functional groups, or both the recurring functional groups and the terminal functional groups bind to the recurring polar groups through a mechanism selected from hydrogen bonding, electrostatic bonding, and ionic bonding.
10. The method of claim 9, wherein the recurring functional groups and the recurring polar groups are ionogenic.
11. The method of claim 10, wherein prior to forming the admixture, zero to approximately 30% of the ionogenic groups are ionized.
12. The method of claim 11, wherein prior to forming the admixture, approximately 5% to approximately 10% of the ionogenic groups are ionized.
13. The method of claim 10, wherein the recurring functional groups bind to the recurring polar groups via electrostatic bonding.
14. The method of claim 10, wherein the recurring functional groups bind to the recurring polar groups via ionic bonding.
15. The method of claim 1, wherein the recurring polar groups are pendant groups.
16. The method of claim 1, wherein the recurring polar groups comprise backbone heteroatoms.
17. The method of claim 1, wherein the recurring functional groups are pendant groups.
18. The method of claim 1, wherein the recurring functional groups comprise backbone heteroatoms.
19. The method of claim 1, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 20,000 to 3,000,000.
20. The method of claim 19, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 100,000 to 2,000,000.
21. The method of claim 20, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 100,000 to 1,500,000.
22. The method of claim 1, wherein the molecular weight of the complementary multifunctional polymer is in the range of approximately 10,000 to 1,000,000.
23. The method of claim 22, wherein the molecular weight of the complementary multifunctional polymer is in the range of approximately 100,000 to 1,000,000.
24. The method of claim 1, wherein:
the recurring polar groups and the recurring functional groups are selected from hydroxyl, sulfhydryl, hydrocarbyloxy, acyl, acyloxy, hydrocarbyloxycarbonyl, carboxy, carboxylato, carbamoyl, cyano, isocyano, cyanato, isocyanato, formyl, amino, secondary amino, tertiary amino, pendant cyclic amino, quaternary ammonium groups, amido, alkylamido, arylamido, nitro, sulfo, sulfonato, hydrocarbylsulfanyl, phosphono, phosphonato, phosphinato, phospho, backbone nitrogen atoms, backbone oxygen atoms, and backbone sulfur atoms.
the recurring polar groups and the recurring functional groups are selected from hydroxyl, sulfhydryl, hydrocarbyloxy, acyl, acyloxy, hydrocarbyloxycarbonyl, carboxy, carboxylato, carbamoyl, cyano, isocyano, cyanato, isocyanato, formyl, amino, secondary amino, tertiary amino, pendant cyclic amino, quaternary ammonium groups, amido, alkylamido, arylamido, nitro, sulfo, sulfonato, hydrocarbylsulfanyl, phosphono, phosphonato, phosphinato, phospho, backbone nitrogen atoms, backbone oxygen atoms, and backbone sulfur atoms.
25. The method of claim 24, wherein the recurring polar groups and the recurring functional groups are selected from hydroxyl, acyloxy, alkoxy, alkoxycarbonyl, carboxy, carboxylato, amino, alkylamino, dialkylamino, pendant cyclic amino, quaternary ammonium, sulfo, sulfonato, phosphono, and phosphonato.
26. The method of claim 1, wherein:
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing.
27. The method of claim 26, wherein:
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of an of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of an of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing.
28. The method of claim 1, wherein:
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing;
and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing;
and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing.
29. The method of claim 28, wherein:
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of any of the foregoing.
30. The method of claim 1, wherein the film-forming hydrophilic polymer is an acrylic acid or methacrylic acid polymer or copolymer, the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylate), poly(dialkyl aminoalkyl methacrylate), and poly(trimethylammonioethyl methacrylate) copolymers, and the plasticizer is a C2-C8 dicarboxylic acid.
31. The method of claim 30, wherein the film-forming hydrophilic polymer is a methacrylic acid - methacrylate copolymer, the complementary multifunctional polymer is a copolymer of dimethylaminoethyl methacrylate and a neutral methacrylate, and the plasticizer is adipic acid.
32. The method of claim 5, wherein the bifunctional, linear oligomer has a molecular weight in the range of approximately 45 to approximately 800 g/mol.
33. The method of claim 32, wherein the bifunctional, linear oligomer has a molecular weight in the range of approximately 45 to approximately 600 g/mol.
34. The method of claim 5, wherein the terminal functional groups are selected from hydroxyl, carboxy, and amino groups.
35. The method of claim 34, wherein the terminal functional groups are selected from hydroxyl and carboxy groups.
36. The method of claim 35, wherein the terminal functional groups are hydroxyl groups.
37. The method of claim 1, further comprising combining at least one optional additive with the film-forming hydrophilic polymer, the complementary multifunctional polymer, and the bifunctional, linear oligomer in the formation of the admixture.
38. The method of claim 37, wherein the at least one additive includes an active agent.
39. The method of claim 38, wherein the additive is a pharmacologically active agent.
40. The method of claim 39, wherein the pharmacologically active agent is a drug.
41. The method of claim 38, wherein the additive is a cosmeceutically active agent.
42. The method of claim 41, wherein the cosmeceutically active agent is a tooth whitening agent.
43. The method of claim 37, wherein the at least one additive is selected from fillers, pH regulating agents, ionizing agents, tackifiers, electrolytes, antimicrobial agents, antioxidants, preservatives, colorants, and combinations thereof.
44. A water-insoluble, water-absorbent adhesive composition, comprising a blend of:
(a) a film-forming, hydrophilic polymer comprising at least one linear segment containing a plurality of recurring polar groups;
(b) a complementary multifunctional polymer containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the complementary multifunctional polymer; and (c) a plasticizer capable of plasticizing the film-forming polymer, wherein the weight fraction of the film-forming polymer in the blend is greater than the weight fraction of either the complementary multifunctional polymer or the plasticizer.
(a) a film-forming, hydrophilic polymer comprising at least one linear segment containing a plurality of recurring polar groups;
(b) a complementary multifunctional polymer containing a plurality of recurring functional groups along the polymer backbone, said recurring functional groups capable of noncovalently binding to the recurring polar groups so that a ladder-like interpolymer complex is formed between the at least one linear segment and the complementary multifunctional polymer; and (c) a plasticizer capable of plasticizing the film-forming polymer, wherein the weight fraction of the film-forming polymer in the blend is greater than the weight fraction of either the complementary multifunctional polymer or the plasticizer.
45. The composition of claim 44, wherein the plasticizer is selected from the group consisting of dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates, mixed alkyl-aryl phthalates, alkyl phosphates, aryl phosphates, alkyl citrates, citrate esters, alkyl adipates, dialkyl tartrates, dialkyl sebacates, dialkyl succinates, alkyl glycolates, alkyl glycerolates, glycol esters, glycerol esters, and mixtures thereof.
46. The composition of claim 45, wherein the plasticizer is selected from dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate, dicapryl phthalate, tributyl phosphate, trioctyl phosphate, tricresyl phosphate, triphenyl phosphate, trimethyl citrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, trihexyl citrate, dioctyl adipate, diethyl adipate, di(2-methylethyl)adipate, dihexyl adipate, diethyl tartrate, dibutyl tartrate, diethyl sebacate, dipropyl sebacate, dinonyl sebacate, diethyl succinate, dibutyl succinate, glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, and mixtures thereof.
47. The composition of claim 46, wherein the plasticizer is selected from tributyl phosphate, trioctyl phosphate, triphenyl phosphate, trimethyl citrate, triethyl citrate, and tributyl citrate.
48. The composition of claim 44, wherein the plasticizer is a bifunctional, linear oligomer having a functional group at each terminus, each of said terminal functional groups capable of noncovalently binding to one of the polar groups so that a bridged interpolymer complex is formed in which the bifunctional linear oligomer links two of said linear segments to each other.
49. The composition of claim 44, wherein:
the film-forming, hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the blend;
the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the blend; and the bifunctional, linear oligomer represents approximately 1 wt.% to approximately 50 wt.% of the blend.
the film-forming, hydrophilic polymer represents approximately 20 wt.% to approximately 95 wt.% of the blend;
the complementary multifunctional polymer represents approximately 0.5 wt.% to approximately 40 wt.% of the blend; and the bifunctional, linear oligomer represents approximately 1 wt.% to approximately 50 wt.% of the blend.
50. The composition of claim 44, wherein the recurring functional groups, the terminal functional groups, or both the recurring functional groups and the terminal functional groups bind to the recurring polar groups through a mechanism selected from hydrogen bonding, electrostatic bonding, and ionic bonding.
51. The composition of claim 50, wherein the recurring functional groups and the recurring polar groups are ionogenic.
52. The composition of claim 51, wherein zero to approximately 30% of the ionogenic groups are ionized.
53. The composition of claim 52, wherein approximately 5% to approximately 10%
of the ionogenic groups are ionized.
of the ionogenic groups are ionized.
54. The composition of claim 51, wherein the recurring functional groups bind to the recurring polar groups via electrostatic bonding.
55. The composition of claim 51, wherein the recurring functional groups bind to the recurring polar groups via ionic bonding.
56. The composition of claim 44, wherein the recurring polar groups are pendant groups.
57. The composition of claim 44, wherein the recurring polar groups comprise backbone heteroatoms.
58. The composition of claim 44, wherein the recurring functional groups are pendant groups.
59. The composition of claim 44, wherein the recurring functional groups comprise backbone heteroatoms.
60. The composition of claim 44, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 20,000 to 3,000,000.
61. The composition of claim 60, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 100,000 to 2,000,000.
62. The composition of claim 61, wherein the molecular weight of the film-forming hydrophilic polymer is in the range of approximately 100,000 to 1,500,000.
63. The composition of claim 44, wherein the molecular weight of the complementary multifunctional polymer is in the range of approximately 10,000 to 1,000,000.
64. The composition of claim 63, wherein the molecular weight of the complementary multifunctional polymer is in the range of approximately 100,000 to 1,000,000.
65. The composition of claim 44, wherein:
the recurring polar groups and the recurring functional groups are selected from hydroxyl, sulfhydryl, hydrocarbyloxy, acyl, acyloxy, hydrocarbyloxycarbonyl, carboxy, carboxylato, carbamoyl, cyano, isocyano, cyanato, isocyanato, formyl, amino, secondary amino, tertiary amino, pendant cyclic amino, quaternary ammonium groups, amido, alkylamido, arylamido, nitro, sulfo, sulfonato, hydrocarbylsulfanyl, phosphono, phosphonato, phosphinato, phospho, backbone nitrogen atoms, backbone oxygen atoms, and backbone sulfur atoms.
the recurring polar groups and the recurring functional groups are selected from hydroxyl, sulfhydryl, hydrocarbyloxy, acyl, acyloxy, hydrocarbyloxycarbonyl, carboxy, carboxylato, carbamoyl, cyano, isocyano, cyanato, isocyanato, formyl, amino, secondary amino, tertiary amino, pendant cyclic amino, quaternary ammonium groups, amido, alkylamido, arylamido, nitro, sulfo, sulfonato, hydrocarbylsulfanyl, phosphono, phosphonato, phosphinato, phospho, backbone nitrogen atoms, backbone oxygen atoms, and backbone sulfur atoms.
66. The composition of claim 65, wherein the recurring polar groups and the recurring functional groups are selected from hydroxyl, acyloxy, alkoxy, alkoxycarbonyl, carboxy, carboxylato, amino, alkylamino, dialkylamino, pendant cyclic amino, quaternary ammonium, sulfo, sulfonato, phosphono, and phosphonato.
67. The composition of claim 44, wherein:
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing.
68. The composition of claim 67, wherein:
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of an of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of an of the foregoing; and the complementary multifunctional polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing.
69. The composition of claim 44, wherein:
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing;
and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(sulfonic acid), poly(vinyl alcohol), poly(vinyl phenol), poly(ethylene oxide), poly(hydroxyalkyl methacrylates), cellulose derivatives, alginic acid, copolymers thereof, and combinations of any of the foregoing;
and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(vinyl amine), poly(alkylene imine), poly(N-vinyl acrylamide), poly(N-vinyl alkylacrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), chitosan, copolymers thereof, and combinations of any of the foregoing.
70. The composition of claim 69, wherein:
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of any of the foregoing.
the film-forming hydrophilic polymer is selected from poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), poly(hydroxyalkyl methacrylates), cellulose derivatives, copolymers thereof, and combinations of any of the foregoing; and the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of any of the foregoing.
71. The composition of claim 44, wherein the film-forming hydrophilic polymer is an acrylic acid or methacrylic acid polymer or copolymer, the complementary multifunctional polymer is selected from poly(dialkyl aminoalkyl acrylate), poly(dialkyl aminoalkyl methacrylate), and poly(trimethylaminonioethyl methacrylate) copolymers, and the plasticizer is a C2-C8 dicarboxylic acid.
72. The composition of claim 71, wherein the film-forming hydrophilic polymer is a methacrylic acid - methacrylate copolymer, the complementary multifunctional polymer is a copolymer of dimethylaminoethyl methacrylate and a neutral methacrylate, and the plasticizer is adipic acid.
73. The composition of claim 48, wherein the bifunctional, linear oligomer has a molecular weight in the range of approximately 45 to approximately 800 g/mol.
74. The composition of claim 73, wherein the bifunctional, linear oligomer has a molecular weight in the range of approximately 45 to approximately 600 g/mol.
75. The composition of claim 48, wherein the terminal functional groups are selected from hydroxyl, carboxy, and amino groups.
76. The composition of claim 75, wherein the terminal functional groups are selected from hydroxyl and carboxy groups.
77. The composition of claim 76, wherein the terminal functional groups are hydroxyl groups.
78. The composition of claim 44, further comprising at least one additive with the film-forming hydrophilic polymer, the complementary multifunctional polymer, and the bifunctional, linear oligomer in the formation of the admixture.
79. The composition of claim 78, wherein the at least one additive includes an active agent.
80. The composition of claim 79, wherein the additive is a pharmacologically active agent.
81. The composition of claim 80, wherein the pharmacologically active agent is a drug.
82. The composition of claim 79, wherein the additive is a cosmeceutically active agent.
83. The composition of claim 82, wherein the cosmeceutically active agent is a tooth whitening agent.
84. The composition of claim 78, wherein the at least one additive is selected from fillers, pH regulating agents, ionizing agents, tackifiers, electrolytes, antimicrobial agents, antioxidants, preservatives, colorants, and combinations thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/028,702 | 2005-01-03 | ||
US11/028,702 US20050215727A1 (en) | 2001-05-01 | 2005-01-03 | Water-absorbent adhesive compositions and associated methods of manufacture and use |
PCT/US2006/000098 WO2006074173A2 (en) | 2005-01-03 | 2006-01-03 | Water-absorbent adhesive compositions and associated methods of manufacture and use |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2594183A1 true CA2594183A1 (en) | 2006-07-13 |
CA2594183C CA2594183C (en) | 2014-05-13 |
Family
ID=36648113
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2594183 Active CA2594183C (en) | 2005-01-03 | 2006-01-03 | Water-absorbent adhesive compositions and associated methods of manufacture and use |
Country Status (7)
Country | Link |
---|---|
US (5) | US20050215727A1 (en) |
EP (1) | EP1838358B1 (en) |
AU (1) | AU2006204127B2 (en) |
CA (1) | CA2594183C (en) |
ES (1) | ES2607785T3 (en) |
RU (1) | RU2416433C2 (en) |
WO (1) | WO2006074173A2 (en) |
Families Citing this family (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE44145E1 (en) | 2000-07-07 | 2013-04-09 | A.V. Topchiev Institute Of Petrochemical Synthesis | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
US20050215727A1 (en) | 2001-05-01 | 2005-09-29 | Corium | Water-absorbent adhesive compositions and associated methods of manufacture and use |
US8541021B2 (en) | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
RU2276998C2 (en) | 2001-05-01 | 2006-05-27 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Hydrogel compositions |
RU2286801C2 (en) | 2001-05-01 | 2006-11-10 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Water-absorbing biphase bioadhesive compositions |
US8206738B2 (en) | 2001-05-01 | 2012-06-26 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
US20050113510A1 (en) | 2001-05-01 | 2005-05-26 | Feldstein Mikhail M. | Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components |
US8840918B2 (en) | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
US8524200B2 (en) | 2002-09-11 | 2013-09-03 | The Procter & Gamble Company | Tooth whitening products |
CN102764247B (en) | 2004-01-30 | 2016-04-20 | 考里安国际公司 | The rapidly dissolving film of active agent delivery |
AU2005271259B2 (en) | 2004-08-05 | 2012-01-19 | A.V. Topchiev Institute Of Petrochemical Synthesis | Adhesive composition |
CA2822648A1 (en) * | 2004-12-21 | 2006-06-29 | Corium International, Inc. | Sustained release tooth whitening formulations and systems |
US20070178262A1 (en) * | 2006-01-27 | 2007-08-02 | The Procter & Gamble Company | Storage wrap material |
MX2009001221A (en) * | 2006-07-31 | 2009-02-11 | Smithkline Beecham Corp | Denture adhesive composition. |
JP5481199B2 (en) * | 2006-12-27 | 2014-04-23 | ザ ジョンズ ホプキンス ユニバーシティー | Compositions and methods for treating inflammation and autoimmune diseases |
US7989173B2 (en) | 2006-12-27 | 2011-08-02 | The Johns Hopkins University | Detection and diagnosis of inflammatory disorders |
DE102008040572A1 (en) * | 2008-07-21 | 2010-01-28 | Biotronik Vi Patent Ag | Implant with coating |
US20100137775A1 (en) * | 2008-11-25 | 2010-06-03 | Spiracur Inc. | Device for delivery of reduced pressure to body surfaces |
WO2010083035A2 (en) | 2009-01-14 | 2010-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
AU2012202981B2 (en) * | 2009-09-30 | 2014-01-23 | Cilag Gmbh International | Adhesive Composition for Use in an Immunosensor |
US8221994B2 (en) * | 2009-09-30 | 2012-07-17 | Cilag Gmbh International | Adhesive composition for use in an immunosensor |
JP2011095657A (en) * | 2009-11-02 | 2011-05-12 | Seiko Epson Corp | Image forming apparatus and image forming method |
ES2719595T3 (en) | 2010-05-04 | 2019-07-11 | Corium Int Inc | Method and device for transdermal administration of parathyroid hormone using a microprojection matrix |
US20130008342A1 (en) * | 2011-07-05 | 2013-01-10 | Elmer's Products, Inc. | Glue stick formulated with naturally occurring polymers |
US10470936B2 (en) | 2012-02-29 | 2019-11-12 | Hollister Incorporated | Buffered adhesive compositions for skin-adhering medical products |
AU2013226154B2 (en) * | 2012-02-29 | 2015-07-09 | Hollister Incorporated | Buffered adhesive compositions for skin-adhering products and methods of making same |
US9422463B2 (en) * | 2012-02-29 | 2016-08-23 | Hollister, Inc. | Buffered adhesive compositions for skin-adhering medical products |
CN104780929A (en) | 2012-09-11 | 2015-07-15 | Slh最佳保健有限责任公司 | Dental cleaning composition |
WO2015038580A1 (en) * | 2013-09-11 | 2015-03-19 | 3M Innovative Properties Company | Oral compositions, dental structures and methods of delivering oral compositions |
EP3043869B1 (en) | 2013-09-11 | 2018-10-24 | 3M Innovative Properties Company | Oral compositions |
EP3824883B1 (en) * | 2013-09-11 | 2023-08-02 | MEDRx Co., Ltd. | Novel composition for plaster base material in tape preparation |
CA2947748A1 (en) * | 2014-05-05 | 2015-11-12 | Lubrizol Advanced Materials, Inc. | Homogenous film compositions |
WO2016055075A1 (en) * | 2014-10-09 | 2016-04-14 | Coloplast A/S | Composition comprising a polymer and a switch initiator |
JP2017537214A (en) * | 2014-12-08 | 2017-12-14 | スリーエム イノベイティブ プロパティズ カンパニー | Compositions based on acrylic block copolymer blends |
RU2611880C2 (en) * | 2015-06-01 | 2017-03-01 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Башкирский государственный университет" | Electroconductive polymer composition for 3d-printing |
US9808416B2 (en) | 2015-12-09 | 2017-11-07 | Colgate-Palmolive Company | Oral care compositions and methods |
GB201603721D0 (en) * | 2016-03-03 | 2016-04-20 | Ascenticus Pharma Ltd | Dental compositions |
TWI577395B (en) * | 2016-06-14 | 2017-04-11 | Chen ming-hong | Nano - silver colloidal wound dressing film and its preparation method |
US10821066B2 (en) | 2017-01-12 | 2020-11-03 | Colgate-Palmolive Company | Oral care composition for long-lasting peroxide delivery |
ES2887977T3 (en) | 2017-01-23 | 2021-12-29 | Afyx Therapeutics As | Method for the manufacture of a two-layer product based on electrospun fibers |
MX2019008155A (en) | 2017-01-23 | 2019-11-07 | Afyx Therapeutics As | Method for preparing electrospun fibers with a high content of a bioadhesive substance. |
RU2725879C2 (en) * | 2018-07-26 | 2020-07-07 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Казанский Государственный медицинский университет" Министерства здравоохранения Российской Федерации | Interpolymer carrier for oral systems of controlled delivery of active pharmaceutical ingredients |
US11571563B2 (en) * | 2019-09-11 | 2023-02-07 | Bose Corporation | Electrically conductive ear tips |
CN114456421B (en) * | 2020-05-29 | 2023-04-28 | 深圳硅基传感科技有限公司 | Method for preparing polymer film with three-dimensional network structure |
JP2022124000A (en) * | 2021-02-15 | 2022-08-25 | セイコーエプソン株式会社 | Liquid absorbing sheet |
JP2024517376A (en) * | 2021-04-06 | 2024-04-22 | ディディピー スペシャルティ エレクトロニック マテリアルズ ユーエス 9 エルエルシー | Film-forming composition |
US11821200B2 (en) * | 2022-02-28 | 2023-11-21 | Schul International Co., Llc | Interface transition and environmental barrier |
CN115025293A (en) * | 2022-06-09 | 2022-09-09 | 振德医疗用品股份有限公司 | Smearing type operation film and preparation method thereof |
US11951082B2 (en) | 2022-08-22 | 2024-04-09 | Ford Therapeutics, Llc | Composition of chlorhexidine |
Family Cites Families (334)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2561071A (en) | 1949-09-21 | 1951-07-17 | Prisk Howard Conley | Holder for subcutaneous administration of medicaments |
US2579403A (en) | 1950-06-01 | 1951-12-18 | Slomowitz Julius | Medical bandage |
BE585940A (en) | 1959-12-23 | |||
DE1617282A1 (en) | 1965-11-30 | 1975-02-06 | Astra Pharma Prod | DEVICE FOR LOCAL ANESTHETIZATION BY LOCAL APPLICATION AND METHOD FOR MANUFACTURING THIS DEVICE |
US3689439A (en) | 1968-06-12 | 1972-09-05 | Gaf Corp | Process for preparing a crosslinked porous polyvinyl pyrrolidone granule |
US3639524A (en) * | 1969-07-28 | 1972-02-01 | Maurice Seiderman | Hydrophilic gel polymer insoluble in water from polyvinylpyrrolidone with n-vinyl-2-pyrrolidone and methacrylic modifier |
DE1964156C3 (en) | 1969-12-22 | 1978-08-24 | Basf Ag, 6700 Ludwigshafen | Thermoplastic molding compounds with high impact strength |
US3852228A (en) | 1971-01-07 | 1974-12-03 | D Brothers | Thixotropic coating composition |
US3996934A (en) | 1971-08-09 | 1976-12-14 | Alza Corporation | Medical bandage |
US3993551A (en) | 1973-09-10 | 1976-11-23 | Union Carbide Corporation | Process for cocrosslinking water soluble polymers and products thereof |
US3957605A (en) * | 1973-09-10 | 1976-05-18 | Union Carbide Corporation | Process for radiation cocrosslinking water soluble polymers and products thereof |
AU513753B2 (en) * | 1974-07-08 | 1980-12-18 | Johnson & Johnson | Antimicrobial composition |
US4093673A (en) * | 1974-11-14 | 1978-06-06 | Ppg Industries, Inc. | Coating compositions composed of hydroxyfunctional polymers or copolymers and alkoxysilanes |
US4077407A (en) | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
GB1576522A (en) * | 1977-05-24 | 1980-10-08 | Colorplast International A S | Sealing material for ostomy devices |
SE7713618L (en) | 1977-12-01 | 1979-06-02 | Astra Laekemedel Ab | LOCAL ANESTHETIC MIXTURE |
US4277580A (en) | 1978-05-22 | 1981-07-07 | Texaco Inc. | Terpolymer of N-vinyl pyrrolidone in alkoxylated form |
US4291015A (en) * | 1979-08-14 | 1981-09-22 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing a vasodilator |
JPS5770816A (en) | 1980-10-17 | 1982-05-01 | Ono Pharmaceut Co Ltd | Multilayered film preparation of prostagladin of prolonged action |
US4325851A (en) * | 1980-10-24 | 1982-04-20 | Herman Colon | Water-activatable hot-melt adhesives |
US4346709A (en) | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
DK147035C (en) * | 1980-12-05 | 1984-09-03 | Coloplast As | Skin Barrier |
US4369229A (en) | 1981-01-29 | 1983-01-18 | The Kendall Company | Composite hydrogel-forming article and method of making same |
US4699146A (en) | 1982-02-25 | 1987-10-13 | Valleylab, Inc. | Hydrophilic, elastomeric, pressure-sensitive adhesive |
US4750482A (en) * | 1982-02-25 | 1988-06-14 | Pfizer Inc. | Hydrophilic, elastomeric, pressure-sensitive adhesive |
JPS58162681U (en) | 1982-04-22 | 1983-10-29 | ソニー株式会社 | Electrical equipment operating device |
LU84210A1 (en) * | 1982-06-17 | 1984-03-07 | Oreal | COMPOSITION BASED ON CATIONIC POLYMERS, ANIONIC POLYMERS AND WAXES FOR USE IN COSMETICS |
JPS593241A (en) | 1982-06-29 | 1984-01-09 | Shimadzu Corp | Spectrophotometer |
FR2533577B1 (en) * | 1982-09-27 | 1986-02-28 | Norton Sa | ADHESIVE THERMOPLASTIC COMPOSITIONS |
JPS59196817A (en) | 1983-04-21 | 1984-11-08 | Sekisui Chem Co Ltd | Application drug |
US4557934A (en) | 1983-06-21 | 1985-12-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
US5224928A (en) | 1983-08-18 | 1993-07-06 | Drug Delivery Systems Inc. | Mounting system for transdermal drug applicator |
US5364628A (en) * | 1985-05-31 | 1994-11-15 | Sandoz Ltd. | Pharmaceutical compositions |
US4904247A (en) * | 1984-08-31 | 1990-02-27 | Kendall Company | Pressure-sensitive hydrophilic laminate structures for use in wound dressing, transdermal and topical drug delivery |
US4624665A (en) | 1984-10-01 | 1986-11-25 | Biotek, Inc. | Method of transdermal drug delivery |
US4568343A (en) * | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
US4593053A (en) * | 1984-12-07 | 1986-06-03 | Medtronic, Inc. | Hydrophilic pressure sensitive biomedical adhesive composition |
DE8509793U1 (en) | 1985-04-02 | 1985-05-15 | Allpack Industrielle Lohnverpackung GmbH & Co KG, 7050 Waiblingen | Pharmaco adhesive plaster |
CA1280398C (en) | 1986-02-05 | 1991-02-19 | Hideharu Shirai | Water-absorbent resin and process for producing the same |
US4743249A (en) * | 1986-02-14 | 1988-05-10 | Ciba-Geigy Corp. | Dermal and transdermal patches having a discontinuous pattern adhesive layer |
DE3609545A1 (en) | 1986-03-21 | 1987-09-24 | Basf Ag | METHOD FOR THE DISCONTINUOUS PRODUCTION OF CROSSLINKED, FINE-PARTICLE POLYMERISATS |
ATE71287T1 (en) | 1986-06-13 | 1992-01-15 | Alza Corp | ACTIVATION OF A TRANSDERMAL DRUG DELIVERY SYSTEM BY MOISTURE. |
US4713243A (en) | 1986-06-16 | 1987-12-15 | Johnson & Johnson Products, Inc. | Bioadhesive extruded film for intra-oral drug delivery and process |
US5344656A (en) | 1986-09-12 | 1994-09-06 | Alza Corporation | Subsaturated transdermal therapeutic system having improved release characteristics |
US4908027A (en) | 1986-09-12 | 1990-03-13 | Alza Corporation | Subsaturated transdermal therapeutic system having improved release characteristics |
DK154747C (en) * | 1986-10-17 | 1989-05-08 | Coloplast As | BANDAGE WITH A SKIN-FRIENDLY, WATER-ABSORBING CLOTH DISC WHICH IS ON THE SURFACE IS STRONGLY ASSOCIATED WITH A NON-CLASSIC COVERAGE AND ON THE OTHER WITH A REMOVABLE PROTECTIVE COVER |
US4863970A (en) | 1986-11-14 | 1989-09-05 | Theratech, Inc. | Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols |
US5686489A (en) | 1986-12-23 | 1997-11-11 | Tristrata Technology, Inc. | Alpha hydroxyacid esters for skin aging |
US6051609A (en) * | 1997-09-09 | 2000-04-18 | Tristrata Technology, Inc. | Additives enhancing the effect of therapeutic agents |
US5023084A (en) * | 1986-12-29 | 1991-06-11 | Rutgers, The State University Of New Jersey | Transdermal estrogen/progestin dosage unit, system and process |
US4906169A (en) * | 1986-12-29 | 1990-03-06 | Rutgers, The State University Of New Jersey | Transdermal estrogen/progestin dosage unit, system and process |
US4945084A (en) | 1987-07-08 | 1990-07-31 | Norman Oksman | Method and composition for topically treating anorectal or other dermal wounds |
US5196405A (en) * | 1987-07-08 | 1993-03-23 | Norman H. Oskman | Compositions and methods of treating hemorrhoids and wounds |
JPS6447831A (en) | 1987-08-12 | 1989-02-22 | Takeshi Masumoto | High strength and heat resistant aluminum-based alloy and its production |
EP0303445A1 (en) | 1987-08-13 | 1989-02-15 | Walton S.A. | Clebopride transdermal patch |
US4877628A (en) | 1987-09-03 | 1989-10-31 | International Flavors & Fragrances Inc. | Process for preparing a coated food product |
US5422119A (en) * | 1987-09-24 | 1995-06-06 | Jencap Research Ltd. | Transdermal hormone replacement therapy |
SU1705319A1 (en) | 1987-10-23 | 1992-01-15 | Всесоюзный Научно-Исследовательский Институт Биотехнологии | Polymer diffuse matrix composition for transdermal drug introduction |
US4849224A (en) | 1987-11-12 | 1989-07-18 | Theratech Inc. | Device for administering an active agent to the skin or mucosa |
US4983395A (en) * | 1987-11-12 | 1991-01-08 | Theratech Inc. | Device for administering an active agent to the skin or mucosa |
US4863738A (en) | 1987-11-23 | 1989-09-05 | Alza Corporation | Skin permeation enhancer compositions using glycerol monooleate |
GB8804164D0 (en) | 1988-02-23 | 1988-03-23 | Tucker J M | Bandage for administering physiologically active compound |
US5474783A (en) | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US4994267A (en) | 1988-03-04 | 1991-02-19 | Noven Pharmaceuticals, Inc. | Transdermal acrylic multipolymer drug delivery system |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5234957A (en) | 1991-02-27 | 1993-08-10 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5719197A (en) * | 1988-03-04 | 1998-02-17 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5300291A (en) * | 1988-03-04 | 1994-04-05 | Noven Pharmaceuticals, Inc. | Method and device for the release of drugs to the skin |
US5446070A (en) | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5438076A (en) * | 1988-05-03 | 1995-08-01 | Perio Products, Ltd. | Liquid polymer composition, and method of use |
US5641504A (en) * | 1988-06-09 | 1997-06-24 | Alza Corporation | Skin permeation enhancer compositions using glycerol monolinoleate |
DE3827561C1 (en) * | 1988-08-13 | 1989-12-28 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
US5073381A (en) | 1988-08-15 | 1991-12-17 | University Of Akron | Amphiphilic networks |
US5599373A (en) | 1988-09-30 | 1997-02-04 | F.P.S.- Finances Products Services, S.R.L. | Sulfur-based chemical soil-corrective in the form of pellets for agricultural use |
US4927408A (en) * | 1988-10-03 | 1990-05-22 | Alza Corporation | Electrotransport transdermal system |
US5496266A (en) | 1990-04-30 | 1996-03-05 | Alza Corporation | Device and method of iontophoretic drug delivery |
EP0364211B1 (en) | 1988-10-11 | 1994-12-21 | Shire Holdings Ltd. | A percutaneous pharmaceutical preparation |
JPH01151524A (en) | 1988-11-10 | 1989-06-14 | Yamanouchi Pharmaceut Co Ltd | 'satotsu-ko' poultice and preparation thereof |
CA2003808C (en) | 1988-11-28 | 1999-11-09 | Eugene Joseph Sehm | Crosslinked polyacrylic acid |
US4953053A (en) | 1989-01-31 | 1990-08-28 | Harnischfeger Corporation | Method and apparatus for detecting mechanical overload of a hoist |
JPH06100467B2 (en) | 1989-02-06 | 1994-12-12 | 株式会社シ−エックスア−ル | Proximity sensor |
US5240995A (en) | 1989-02-09 | 1993-08-31 | Alza Corporation | Electrotransport adhesive |
US4973468A (en) | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
US5053227A (en) | 1989-03-22 | 1991-10-01 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
DE3910543A1 (en) | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH INCREASED ACTIVE FLUID AND METHOD FOR THE PRODUCTION THEREOF |
US5788983A (en) | 1989-04-03 | 1998-08-04 | Rutgers, The State University Of New Jersey | Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes |
DE3913734C2 (en) * | 1989-04-26 | 1998-08-20 | Roehm Gmbh | Use of an aqueous skin pressure sensitive adhesive solution for producing an adhesive layer which can be easily washed off with water |
DE3924393A1 (en) * | 1989-07-24 | 1991-01-31 | Roehm Gmbh | WATER-SOLUBLE PRESSURE-SENSITIVE SKIN ADHESIVE, THE USE THEREOF AND MEANS THEREFORE |
JPH0366612A (en) | 1989-08-04 | 1991-03-22 | Sato Seiyaku Kk | Ointment in mouth |
US5102662A (en) * | 1989-12-08 | 1992-04-07 | Dow Corning Corporation | Insect repellent plastic |
US5270358A (en) | 1989-12-28 | 1993-12-14 | Minnesota Mining And Manufacturing Company | Composite of a disperesed gel in an adhesive matrix |
US5057500A (en) | 1990-02-12 | 1991-10-15 | Dermatologic Research Corporation | Treatment of pruritis with esters and amides |
JPH03247334A (en) | 1990-02-26 | 1991-11-05 | Sumitomo Rubber Ind Ltd | Cold insulant |
JPH03275619A (en) | 1990-03-23 | 1991-12-06 | Nitsusui Seiyaku Kk | External agent composition |
US5125894A (en) * | 1990-03-30 | 1992-06-30 | Alza Corporation | Method and apparatus for controlled environment electrotransport |
US5173302A (en) | 1990-09-28 | 1992-12-22 | Medtronic, Inc. | Hydrophilic pressure sensitive adhesive for topical administration of hydrophobic drugs |
JPH06502419A (en) | 1990-10-29 | 1994-03-17 | アルザ・コーポレーション | Transdermal contraceptive preparations, methods and devices |
US5326685A (en) | 1991-02-13 | 1994-07-05 | Gaglio Thomas J | Viscous fluid dispensing apparatus |
JP3132837B2 (en) | 1991-02-21 | 2001-02-05 | 積水化学工業株式会社 | Medical adhesive |
US5332576A (en) | 1991-02-27 | 1994-07-26 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
IL97930A (en) | 1991-04-23 | 1996-06-18 | Perio Prod Ltd | Sustained-release toothbleaching preparations containing a peroxy agent |
EP0516026A1 (en) | 1991-05-28 | 1992-12-02 | Takeda Chemical Industries, Ltd. | Hydrogel and method of producing same |
US5232702A (en) | 1991-07-22 | 1993-08-03 | Dow Corning Corporation | Silicone pressure sensitive adhesive compositons for transdermal drug delivery devices and related medical devices |
GB9117256D0 (en) | 1991-08-09 | 1991-09-25 | Smith & Nephew | Adhesive products |
US5827247A (en) | 1991-08-20 | 1998-10-27 | Bioderm | External incontinence device and vapor-absorptive adhesive compositions |
US5234690A (en) | 1991-08-23 | 1993-08-10 | Cygnus Therapeutic Systems | Transdermal drug delivery device using an unfilled microporous membrane to achieve delayed onset |
US5310563A (en) * | 1991-10-25 | 1994-05-10 | Colgate-Palmolive Company | Dental material and method for applying preventative and therapeutic agents |
DE4238263A1 (en) * | 1991-11-15 | 1993-05-19 | Minnesota Mining & Mfg | Adhesive comprising hydrogel and crosslinked polyvinyl:lactam - is used in electrodes for biomedical application providing low impedance and good mechanical properties when water and/or moisture is absorbed from skin |
WO1993009713A1 (en) * | 1991-11-15 | 1993-05-27 | Minnesota Mining And Manufacturing Company | Biomedical electrode provided with two-phase composites conductive, pressure-sensitive adhesive |
US5276079A (en) * | 1991-11-15 | 1994-01-04 | Minnesota Mining And Manufacturing Company | Pressure-sensitive poly(n-vinyl lactam) adhesive composition and method for producing and using same |
US5279816A (en) | 1991-11-22 | 1994-01-18 | Colgate-Palmolive Co. | Oral composition having improved tooth whitening effect |
DK5492A (en) * | 1992-01-17 | 1993-07-18 | Coloplast As | A dressing |
US5183901A (en) | 1992-01-24 | 1993-02-02 | Isp Investments Inc. | Urea-hydrogen peroxide-polyvinylpyrrolidone |
US5206385A (en) | 1992-01-24 | 1993-04-27 | Isp Investments Inc. | Urea-hydrogen peroxide-polyvinylpyrrolidone process |
US5322689A (en) * | 1992-03-10 | 1994-06-21 | The Procter & Gamble Company | Topical aromatic releasing compositions |
IL101387A (en) | 1992-03-26 | 1999-11-30 | Pharmos Ltd | Emulsion with enhanced topical and/or transdermal systemic effect utilizing submicron oil droplets |
IL105748A0 (en) * | 1992-05-22 | 1993-09-22 | Int Research & Dev Corp | Topical antiperspirant composition |
US5985860A (en) | 1992-06-03 | 1999-11-16 | Toppo; Frank | System for transdermal delivery of pain relieving substances |
DE4219368C2 (en) | 1992-06-12 | 1994-07-28 | Lohmann Gmbh & Co Kg | Electrically conductive transparent pressure sensitive adhesive films, process for their production and use for the production of biomedical electrodes |
KR950702436A (en) * | 1992-07-28 | 1995-07-29 | 자코부스 코르넬리스 라세르 | PHARMACEUTICAL COMPOSITION FOR TOPICAL USE CONTAINING A CROSSLINKED CATIONIC POLYMER AND AN ALKOXYLATED ETHER |
GR1002418B (en) | 1992-07-29 | 1996-08-21 | Johnson & Johnson Consumer Products Inc. | Bioactive treatment compositions and methods of use. |
DK170792B1 (en) | 1992-08-27 | 1996-01-22 | Coloplast As | Skin plate product for dosing one or more medications |
US6162456A (en) | 1992-09-24 | 2000-12-19 | Ortho-Mcneil Pharmaceutical, Inc. | Adhesive transdermal drug delivery matrix of a physical blend of hydrophilic and hydrophobic polymers |
CA2104046C (en) * | 1992-10-05 | 1998-09-15 | Yen-Lane Chen | Adhesive compositions, wound dressings and methods |
US5462743A (en) | 1992-10-30 | 1995-10-31 | Medipro Sciences Limited | Substance transfer system for topical application |
US5575654A (en) | 1992-11-24 | 1996-11-19 | Fontenot; Mark G. | Apparatus and method for lightening teeth |
US5489624A (en) | 1992-12-01 | 1996-02-06 | Minnesota Mining And Manufacturing Company | Hydrophilic pressure sensitive adhesives |
ES2078203T3 (en) * | 1992-12-15 | 1997-04-01 | Grain Systems Inc | FEEDER FOR BIRDS. |
WO1994015609A1 (en) | 1992-12-31 | 1994-07-21 | Sunkyong Industries Co., Ltd. | Enhanced pharmaceutical compositions for skin penetration |
US5510339A (en) * | 1993-02-02 | 1996-04-23 | Mayo Foundation For Medical Education And Research | Method for the treatment of bronchial asthma by administration of topical anesthetics |
GB2274995B (en) | 1993-02-15 | 1996-10-09 | John Mccune Anderson | Biomedical electrode device |
US5785976A (en) | 1993-03-05 | 1998-07-28 | Pharmacia & Upjohn Ab | Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof |
DE4310012A1 (en) * | 1993-03-27 | 1994-09-29 | Roehm Gmbh | Dermal therapeutic system made of a meltable poly (meth) acrylate mixture |
US6313202B1 (en) * | 1993-05-28 | 2001-11-06 | Eastman Chemical Company | Cellulose ester blends |
US5773490A (en) * | 1993-06-24 | 1998-06-30 | Takiron Co., Ltd. | Pressure sensitive adhesive for transdermal absorption formulations |
US5853755A (en) | 1993-07-28 | 1998-12-29 | Pharmaderm Laboratories Ltd. | Biphasic multilamellar lipid vesicles |
US5354823A (en) | 1993-08-09 | 1994-10-11 | Isp Investments Inc. | Films and extrusions of cured crosslinked vinyl lactam polymer and method of preparation |
US5744155A (en) * | 1993-08-13 | 1998-04-28 | Friedman; Doron | Bioadhesive emulsion preparations for enhanced drug delivery |
EP0717761A4 (en) * | 1993-08-19 | 1998-01-07 | Cygnus Therapeutic Systems | Water-soluble pressure-sensitive mucoadhesive and devices provided therewith for emplacement in a mucosa-lined body cavity |
US5723145A (en) * | 1993-09-30 | 1998-03-03 | Takiron Co., Ltd. | Transdermal absorption preparation |
US5885211A (en) | 1993-11-15 | 1999-03-23 | Spectrix, Inc. | Microporation of human skin for monitoring the concentration of an analyte |
US5508367A (en) * | 1993-11-29 | 1996-04-16 | Adhesives Research, Inc. | Water-soluble pressure sensitive adhesive |
IT1270754B (en) | 1993-11-30 | 1997-05-07 | Olimpio Stocchiero | IMPROVED DEVICE FOR DISCHARGING OUTSIDE THE GASES PRODUCED INSIDE ACCUMULATORS |
DE4341444C2 (en) * | 1993-12-04 | 1996-03-14 | Lohmann Therapie Syst Lts | Active substance-containing plaster and process for its production |
US5962011A (en) | 1993-12-06 | 1999-10-05 | Schering-Plough Healthcare Products, Inc. | Device for delivery of dermatological ingredients |
US5641507A (en) * | 1993-12-06 | 1997-06-24 | Devillez; Richard L. | Delivery system for dermatological and cosmetic ingredients |
CA2176824A1 (en) | 1993-12-27 | 1995-07-06 | Hiroshi Kuroda | Percutaneously absorbable preparation |
TW369558B (en) | 1994-01-28 | 1999-09-11 | Minnesota Mining & Mfg | Polymerized microemulsion pressure sensitive adhesive compositions and methods of preparing and using same |
US5527271A (en) * | 1994-03-30 | 1996-06-18 | Bristol-Myers Squibb Co. | Thermoplastic hydrogel impregnated composite material |
US5851549A (en) | 1994-05-25 | 1998-12-22 | Becton Dickinson And Company | Patch, with system and apparatus for manufacture |
US5492943A (en) * | 1994-06-20 | 1996-02-20 | Hollister Incorporated | Adhesive skin barrier composition for ostomy appliance |
US5726250A (en) * | 1994-07-11 | 1998-03-10 | Adhesives Research, Inc. | Covalently crosslinked water-absorbent graft copolymer |
SE9402453D0 (en) * | 1994-07-12 | 1994-07-12 | Astra Ab | New pharmaceutical preparation |
US5543148A (en) | 1994-07-12 | 1996-08-06 | Combe, Incorporated | Stick delivery system for topical application of a treatment agent |
US5585398A (en) | 1994-07-15 | 1996-12-17 | Ernst; Amy A. | Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use |
WO1996010389A1 (en) | 1994-09-30 | 1996-04-11 | Mika Pharma Gesellschaft Für Die Entwicklung Und Vermarktung Pharmazeutischer Produkte Mbh | Pharmaceutical composition |
DE4440337A1 (en) * | 1994-11-11 | 1996-05-15 | Dds Drug Delivery Services Ges | Pharmaceutical nanosuspensions for drug application as systems with increased saturation solubility and dissolution rate |
US6093328A (en) | 1994-12-08 | 2000-07-25 | Santina; Peter F. | Method for removing toxic substances in water |
EP0799029A1 (en) | 1994-12-21 | 1997-10-08 | Theratech, Inc. | Transdermal delivery system with adhesive overlay and peel seal disc |
US6696459B1 (en) | 1994-12-22 | 2004-02-24 | Ligand Pharmaceuticals Inc. | Steroid receptor modulator compounds and methods |
US5563153A (en) | 1995-02-22 | 1996-10-08 | University Of Kansas Medical Center | Sterile topical anesthetic gel |
US5990179A (en) | 1995-04-28 | 1999-11-23 | Alza Corporation | Composition and method of enhancing electrotransport agent delivery |
CN1188189C (en) | 1995-06-07 | 2005-02-09 | 奥瑟-麦内尔制药公司 | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with estrogen |
US6316022B1 (en) | 1995-06-07 | 2001-11-13 | Noven Pharmaceuticals, Inc. | Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures |
US5948416A (en) | 1995-06-29 | 1999-09-07 | The Procter & Gamble Company | Stable topical compositions |
US5780050A (en) | 1995-07-20 | 1998-07-14 | Theratech, Inc. | Drug delivery compositions for improved stability of steroids |
DE19526864A1 (en) | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
CA2184316A1 (en) | 1995-09-12 | 1997-03-13 | Wei-Chi Liao | Buccal delivery system for therapeutic agents |
JP3819956B2 (en) | 1995-09-22 | 2006-09-13 | 関西ペイント株式会社 | Composition for hydrophilic treatment and method for hydrophilic treatment |
DE69637989D1 (en) | 1995-09-25 | 2009-09-17 | Discus Dental Llc | Tooth whitening compositions |
US5827213A (en) | 1995-10-19 | 1998-10-27 | Ole R. Jensen | Heel and elbow dressing |
US5985990A (en) | 1995-12-29 | 1999-11-16 | 3M Innovative Properties Company | Use of pendant free-radically polymerizable moieties with polar polymers to prepare hydrophilic pressure sensitive adhesive compositions |
CN1061843C (en) * | 1996-01-19 | 2001-02-14 | 黄力子 | Film for whitening teeth |
US6280745B1 (en) * | 1997-12-23 | 2001-08-28 | Alliance Pharmaceutical Corp. | Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions |
US5718886A (en) * | 1996-03-11 | 1998-02-17 | Laclede Professional Products, Inc. | Stabilized anhydrous tooth whitening gel |
US5645855A (en) | 1996-03-13 | 1997-07-08 | Ridge Scientific Enterprises, Inc. | Adhesive compositions including polyvinylpyrrolidone acrylic acid polymers, and polyamines |
US5846558A (en) | 1996-03-19 | 1998-12-08 | Minnesota Mining And Manufacturing Company | Ionically conductive adhesives prepared from zwitterionic materials and medical devices using such adhesives |
EP0889723B1 (en) | 1996-03-25 | 2002-06-05 | LTS LOHMANN Therapie-Systeme AG | Transdermal therapeutic system with small application-area thickness and great flexibility, and production process |
US5762956A (en) * | 1996-04-24 | 1998-06-09 | Rutgers, The State University Of New Jersey | Transdermal contraceptive delivery system and process |
US5863662A (en) * | 1996-05-14 | 1999-01-26 | Isp Investments Inc. | Terpolymer for ink jet recording |
US5725876A (en) * | 1996-05-17 | 1998-03-10 | Noven Pharmaceuticals Inc., | Compositions and methods for using low-swell clays in nicotine containing dermal compositions |
JP3628809B2 (en) | 1996-06-10 | 2005-03-16 | アルケア株式会社 | Drug sustained-release medical preparation and method for producing the same |
GR1002807B (en) | 1996-06-20 | 1997-11-13 | Lavipharm A.E. | Device for topical treatment of acne and method of manufacture. |
US5911980A (en) * | 1996-06-27 | 1999-06-15 | Macrochem Corporation | Lipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin |
JPH1017448A (en) | 1996-06-28 | 1998-01-20 | Lion Corp | Plaster for oral cavity |
US6007837A (en) | 1996-07-03 | 1999-12-28 | Alza Corporation | Drug delivery devices and process of manufacture |
US6201164B1 (en) * | 1996-07-11 | 2001-03-13 | Coloplast A/S | Hydrocolloid wound gel |
DE19640365A1 (en) | 1996-09-30 | 1998-04-02 | Basf Ag | Polymer-hydrogen peroxide complexes |
US5958984A (en) | 1996-10-10 | 1999-09-28 | Devillez; Richard L. | Method and composition for skin treatment |
US5800832A (en) | 1996-10-18 | 1998-09-01 | Virotex Corporation | Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces |
EP0934078B1 (en) | 1996-10-24 | 2002-12-18 | Alza Corporation | Permeation enhancers for transdermal drug delivery compositions, devices, and methods |
KR19980033113A (en) | 1996-10-25 | 1998-07-25 | 야스다케 히지 | Aqueous solutions of local anesthetics, how to improve the solubility of local anesthetics, local anesthetics with reduced neurotoxicity and methods of reducing the neurotoxicity of local anesthetics |
US20010006677A1 (en) | 1996-10-29 | 2001-07-05 | Mcginity James W. | Effervescence polymeric film drug delivery system |
DE19646392A1 (en) * | 1996-11-11 | 1998-05-14 | Lohmann Therapie Syst Lts | Preparation for use in the oral cavity with a layer containing pressure-sensitive adhesive, pharmaceuticals or cosmetics for dosed delivery |
DE19652268C2 (en) | 1996-12-16 | 2000-06-29 | Lohmann Therapie Syst Lts | Medicinal preparation for the release of apomorphine in the oral cavity |
DE19653605C2 (en) * | 1996-12-20 | 2002-11-28 | Roehm Gmbh | Adhesives and binders for dermal or transdermal therapy systems and their use for producing a transdermal therapy system |
DE19653606A1 (en) | 1996-12-20 | 1998-06-25 | Roehm Gmbh | Adhesive and binder made from (meth) acrylate polymer, organic acid and plasticizer |
US5858332A (en) * | 1997-01-10 | 1999-01-12 | Ultradent Products, Inc. | Dental bleaching compositions with high concentrations of hydrogen peroxide |
US5785527A (en) | 1997-01-10 | 1998-07-28 | Ultradent Products, Inc. | Stable light or heat activated dental bleaching compositions |
US5837713A (en) | 1997-02-26 | 1998-11-17 | Mayo Foundation For Medical Education And Research | Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids |
US5879701A (en) | 1997-02-28 | 1999-03-09 | Cygnus, Inc. | Transdermal delivery of basic drugs using nonpolar adhesive systems and acidic solubilizing agents |
US5843472A (en) | 1997-02-28 | 1998-12-01 | Cygnus, Inc. | Transdermal drug delivery sytem for the administration of tamsulosin, and related compositions and methods of use |
US6306370B1 (en) | 1997-05-30 | 2001-10-23 | Ultradent Products, Inc. | Compositions and methods for whitening and desensitizing teeth |
US5894017A (en) | 1997-06-06 | 1999-04-13 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US5879691A (en) * | 1997-06-06 | 1999-03-09 | The Procter & Gamble Company | Delivery system for a tooth whitener using a strip of material having low flexural stiffness |
DE69823364T2 (en) | 1997-06-06 | 2005-02-17 | The Procter & Gamble Co., Cincinnati | DEVICE FOR THE ADMINISTRATION OF TOOTH-BLEACHERS USING A STRIP WITH LOW BENDING STRENGTH |
US6096328A (en) | 1997-06-06 | 2000-08-01 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US5989569A (en) | 1997-06-06 | 1999-11-23 | The Procter & Gamble Company | Delivery system for a tooth whitener using a permanently deformable strip of material |
US6045811A (en) * | 1997-06-06 | 2000-04-04 | The Procter & Gamble Company | Delivery system for an oral care substance using a permanently deformable strip of material |
US20020018754A1 (en) | 1999-03-15 | 2002-02-14 | Paul Albert Sagel | Shapes for tooth whitening strips |
JPH1115358A (en) | 1997-06-25 | 1999-01-22 | Denso Corp | Hologram |
US6197331B1 (en) * | 1997-07-24 | 2001-03-06 | Perio Products Ltd. | Pharmaceutical oral patch for controlled release of pharmaceutical agents in the oral cavity |
US6055453A (en) * | 1997-08-01 | 2000-04-25 | Genetronics, Inc. | Apparatus for addressing needle array electrodes for electroporation therapy |
US5921251A (en) | 1997-08-07 | 1999-07-13 | Ceramatec, Inc. | Brush that delivers beneficial agents |
US5948433A (en) | 1997-08-21 | 1999-09-07 | Bertek, Inc. | Transdermal patch |
US5902598A (en) * | 1997-08-28 | 1999-05-11 | Control Delivery Systems, Inc. | Sustained release drug delivery devices |
DE69813838T2 (en) | 1997-08-29 | 2004-02-19 | Avery Dennison Corp., Pasadena | BIOLOGICAL LIQUID ABSORBING PRESSURE SENSITIVE ADHESIVES |
IT1294748B1 (en) * | 1997-09-17 | 1999-04-12 | Permatec Tech Ag | FORMULATION FOR A TRANSDERMAL DEVICE |
RU2234337C2 (en) * | 1997-09-26 | 2004-08-20 | Ноувен Фамэсьютикэлз, Инк. | Bioadhesive composition (variants), method for its preparing, device for delivery of active agent through mucosa, method for prolonged topical administration of one or more active agents to patient (variants) and method for reducing time required for sticking composition to mucosa tissue |
US5945457A (en) * | 1997-10-01 | 1999-08-31 | A.V. Topchiev Institute Of Petrochemical Synthesis, Russian Academy Of Science | Process for preparing biologically compatible polymers and their use in medical devices |
CA2317066A1 (en) | 1997-10-03 | 1999-04-15 | Lavipharm Laboratories, Inc. | A prolamine-plant polar lipid composition, its method of preparation and applications thereof |
DE19745208A1 (en) | 1997-10-13 | 1999-04-15 | Labtec Gmbh | Pharmaceutical film that dissolves in mouth |
US6212671B1 (en) * | 1997-10-20 | 2001-04-03 | Mitsubishi Electric System Lsi Design Corporation | Mask pattern data producing apparatus, mask pattern data producing method and semiconductor integrated circuit device |
US5997886A (en) | 1997-11-05 | 1999-12-07 | The Procter & Gamble Company | Personal care compositions |
US6221341B1 (en) | 1997-11-19 | 2001-04-24 | Oraceutical Llc | Tooth whitening compositions |
US6072100A (en) | 1998-01-28 | 2000-06-06 | Johnson & Johnson Consumer Products, Inc. | Extrudable compositions for topical or transdermal drug delivery |
US5900249A (en) * | 1998-02-09 | 1999-05-04 | Smith; David J. | Multicomponent pain relief topical medication |
US6193993B1 (en) * | 1998-03-03 | 2001-02-27 | Eisai Co., Ltd. | Suppository containing an antidementia medicament |
US6022316A (en) | 1998-03-06 | 2000-02-08 | Spectrx, Inc. | Apparatus and method for electroporation of microporated tissue for enhancing flux rates for monitoring and delivery applications |
NZ506202A (en) | 1998-03-19 | 2003-10-31 | Bristol Myers Squibb Co | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
ES2141050B1 (en) | 1998-03-20 | 2001-01-01 | Biocosmetics Sl | DENTAL WHITENING COMPOSITION. |
DE69914479T2 (en) | 1998-04-21 | 2005-01-20 | Coloplast A/S | Pressure sensitive adhesive composition |
US5993836A (en) | 1998-04-28 | 1999-11-30 | Castillo; James G. | Topical anesthetic formulation |
DE69923675T2 (en) | 1998-04-29 | 2006-05-11 | Virotex Corp., Fort Collins | PHARMACEUTICAL CARRIER DEVICE SUITABLE FOR THE ADMINISTRATION OF SLEEPING SURFACES |
KR100274400B1 (en) | 1998-05-09 | 2000-12-15 | 구자홍 | Manufacturing method, recording / reproducing method and apparatus thereof of optical recording medium having differential free space |
DE19821788C1 (en) | 1998-05-15 | 1999-12-02 | Sanol Arznei Schwarz Gmbh | Transdermal therapeutic system (TTS) containing pergolide |
US6124362A (en) | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
FR2783412B1 (en) | 1998-09-18 | 2000-12-15 | Lhd Lab Hygiene Dietetique | NON-ADHERENT STERILE COMPRESS |
US6437070B1 (en) * | 1998-09-22 | 2002-08-20 | Rohm And Haas Company | Acrylic polymer compositions with crystalline side chains and processes for their preparation |
US6596298B2 (en) | 1998-09-25 | 2003-07-22 | Warner-Lambert Company | Fast dissolving orally comsumable films |
CA2520986C (en) | 1998-09-25 | 2007-11-13 | Warner-Lambert Company | Physiological compatible film |
US6611706B2 (en) | 1998-11-09 | 2003-08-26 | Transpharma Ltd. | Monopolar and bipolar current application for transdermal drug delivery and analyte extraction |
US6708060B1 (en) * | 1998-11-09 | 2004-03-16 | Transpharma Ltd. | Handheld apparatus and method for transdermal drug delivery and analyte extraction |
US6148232A (en) * | 1998-11-09 | 2000-11-14 | Elecsys Ltd. | Transdermal drug delivery and analyte extraction |
US6309625B1 (en) * | 1998-11-12 | 2001-10-30 | Ultradent Products, Inc. | One-part dental compositions and methods for bleaching and desensitizing teeth |
US6312666B1 (en) * | 1998-11-12 | 2001-11-06 | 3M Innovative Properties Company | Methods of whitening teeth |
DE19853046A1 (en) | 1998-11-18 | 2000-05-25 | Basf Ag | Water-soluble or water-dispersible graft copolymers based on a polyvinyllactam, their preparation and use |
US6275728B1 (en) | 1998-12-22 | 2001-08-14 | Alza Corporation | Thin polymer film drug reservoirs |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US7504114B1 (en) | 1999-04-13 | 2009-03-17 | Hisamitsu Pharmaceuticals | Preparations for percutaneous absorption |
DE19922662C1 (en) | 1999-05-18 | 2000-12-28 | Sanol Arznei Schwarz Gmbh | Transdermal therapeutic system (TTS) containing tolterodine |
US6962691B1 (en) | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
US6312612B1 (en) | 1999-06-09 | 2001-11-06 | The Procter & Gamble Company | Apparatus and method for manufacturing an intracutaneous microneedle array |
AU768471B2 (en) | 1999-07-02 | 2003-12-11 | Procter & Gamble Company, The | Delivery system for oral care compositions comprising organosiloxane reins using a removable backing strip |
ES2286028T3 (en) | 1999-07-27 | 2007-12-01 | Hisamitsu Pharmaceutical Co. Inc. | PATCHES FOR EXTERNAL USE. |
US6322774B1 (en) | 1999-12-20 | 2001-11-27 | Ultradent Products, Inc. | Dental bleaching compositions containing sucralose |
DE19949202A1 (en) | 1999-10-13 | 2001-05-03 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the delivery of acetylsalicylic acid and / or salicylic acid |
US6264981B1 (en) | 1999-10-27 | 2001-07-24 | Anesta Corporation | Oral transmucosal drug dosage using solid solution |
US7384650B2 (en) * | 1999-11-24 | 2008-06-10 | Agile Therapeutics, Inc. | Skin permeation enhancement composition for transdermal hormone delivery system |
US6673363B2 (en) * | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
US20030104041A1 (en) | 1999-12-16 | 2003-06-05 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
WO2001052823A2 (en) | 2000-01-20 | 2001-07-26 | Noven Pharmaceuticals, Inc. | Compositions to effect the release profile in the transdermal administration of drugs |
JP2001213768A (en) | 2000-02-01 | 2001-08-07 | Okayama Taiho Pharmaceutical Co Ltd | Poultice |
US6806308B2 (en) * | 2000-03-06 | 2004-10-19 | Chemico Systems, Inc. | Method for protecting paint on an article, a composition useful therefor, and a method for making the composition |
US6689344B2 (en) * | 2000-03-17 | 2004-02-10 | Lg Household & Healthcare Ltd. | Patches for teeth whitening |
US7785572B2 (en) | 2000-03-17 | 2010-08-31 | Lg Household And Health Care Ltd. | Method and device for teeth whitening using a dry type adhesive |
US8652446B2 (en) | 2000-03-17 | 2014-02-18 | Lg Household & Healthcare Ltd. | Apparatus and method for whitening teeth |
KR20020045224A (en) | 2000-12-08 | 2002-06-19 | 성재갑 | Peroxide Stabilized Patches for Teeth Whitening |
CA2402021C (en) * | 2000-03-17 | 2005-04-12 | Lg Household & Health Care Ltd. | Patches for teeth whitening |
US6558654B2 (en) * | 2000-04-11 | 2003-05-06 | Mclaughlin Gerald | Composition and method for whitening teeth |
AU6124401A (en) | 2000-05-09 | 2001-11-20 | Nitromed Inc | Infrared thermography and methods of use |
KR100452972B1 (en) | 2000-05-16 | 2004-10-14 | 주식회사 삼양사 | Hydrogel composition for transdermal drug |
US6517350B2 (en) * | 2000-05-26 | 2003-02-11 | Dentovations Inc. | Method for whitening teeth |
PL360092A1 (en) | 2000-06-28 | 2004-09-06 | The Procter & Gamble Company | Structures and compositions increasing the stability of peroxide actives |
CA2415076C (en) * | 2000-07-07 | 2010-04-13 | Mikhail M. Feldstein | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
JP2002029949A (en) | 2000-07-19 | 2002-01-29 | Lion Corp | Composition for oral cavity |
US6667410B2 (en) | 2000-09-18 | 2003-12-23 | Board Of Regents, The University Of Texas System | Conversion of α,β-unsaturated ketones and α,β-unsaturated esters into α-hydroxy ketones and α-hydroxy esters using Mn(III) catalyst, phenylsilane and dioxygen |
US6488913B2 (en) | 2000-09-20 | 2002-12-03 | Scientific Pharmaceuticals, Inc | Two-part composition for high efficacy teeth whitening comprising a mixture of peroxides and/or percarbonates of metals |
JP2002145746A (en) | 2000-11-02 | 2002-05-22 | Haruyuki Kawahara | Tooth bleaching agent |
US20020131990A1 (en) | 2000-11-30 | 2002-09-19 | Barkalow David G. | Pullulan free edible film compositions and methods of making the same |
US7078359B2 (en) | 2000-12-22 | 2006-07-18 | Aspen Aerogels, Inc. | Aerogel composite with fibrous batting |
US6419906B1 (en) * | 2001-03-12 | 2002-07-16 | Colgate Palmolive Company | Strip for whitening tooth surfaces |
NZ530439A (en) * | 2001-04-20 | 2004-11-26 | Lavipharm Lab Inc | Intraoral delivery of nicotine for smoking cessation |
US20050215727A1 (en) | 2001-05-01 | 2005-09-29 | Corium | Water-absorbent adhesive compositions and associated methods of manufacture and use |
RU2276998C2 (en) | 2001-05-01 | 2006-05-27 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Hydrogel compositions |
RU2286801C2 (en) | 2001-05-01 | 2006-11-10 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Water-absorbing biphase bioadhesive compositions |
US8840918B2 (en) | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
US8206738B2 (en) | 2001-05-01 | 2012-06-26 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
US20030235549A1 (en) | 2001-05-01 | 2003-12-25 | Parminder Singh | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
US20050113510A1 (en) | 2001-05-01 | 2005-05-26 | Feldstein Mikhail M. | Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components |
US8541021B2 (en) | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
CA2446060A1 (en) | 2001-05-07 | 2002-11-14 | Corium International | Compositions and delivery systems for administration of a local anesthetic agent |
US6591124B2 (en) | 2001-05-11 | 2003-07-08 | The Procter & Gamble Company | Portable interstitial fluid monitoring system |
ES2375105T3 (en) | 2001-06-18 | 2012-02-24 | Noven Pharmaceuticals, Inc. | IMPROVED ADMINISTRATION OF MEDICINES IN TRANSDERMAL SYSTEMS. |
US6946142B2 (en) | 2001-06-23 | 2005-09-20 | Lg Household & Healthcare Ltd. | Multi-layer patches for teeth whitening |
KR100455228B1 (en) | 2001-06-23 | 2004-11-09 | 주식회사 엘지생활건강 | Semi-transparent patches for teeth whitening |
KR100471918B1 (en) | 2001-06-26 | 2005-03-08 | 주식회사 엘지생활건강 | Patches for teeth whitening |
US6884833B2 (en) * | 2001-06-29 | 2005-04-26 | 3M Innovative Properties Company | Devices, compositions, and methods incorporating adhesives whose performance is enhanced by organophilic clay constituents |
KR100816250B1 (en) | 2001-07-04 | 2008-03-21 | 주식회사 엘지생활건강 | Manufacturing process of patches for teeth whitening |
KR100471919B1 (en) | 2001-07-04 | 2005-03-08 | 주식회사 엘지생활건강 | Flexible patches for teeth whitening |
WO2003011259A1 (en) | 2001-07-30 | 2003-02-13 | Wm. Wrigley Jr. Company | Improved edible film formulations containing maltodextrin |
US6656493B2 (en) | 2001-07-30 | 2003-12-02 | Wm. Wrigley Jr. Company | Edible film formulations containing maltodextrin |
US6585997B2 (en) | 2001-08-16 | 2003-07-01 | Access Pharmaceuticals, Inc. | Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds |
US6732383B2 (en) | 2001-12-03 | 2004-05-11 | The Burton Corporation | Goggle with side arm for wearing with a helmet |
US6759030B2 (en) | 2002-03-21 | 2004-07-06 | Carl M. Kosti | Bleach stable toothpaste |
US6750291B2 (en) | 2002-04-12 | 2004-06-15 | Pacific Corporation | Film-forming agent for drug delivery and preparation for percutaneous administration containing the same |
WO2003089046A1 (en) | 2002-04-16 | 2003-10-30 | Cyto Pulse Sciences, Inc. | Method of treating biological materials with translating electrical fields and electrode polarity reversal |
US7217853B2 (en) * | 2002-05-24 | 2007-05-15 | Corium International, Inc. | Composition for cushions, wound dressings and other skin-contacting products |
MXPA04011808A (en) | 2002-05-31 | 2005-09-12 | Univ Mississippi | Transmucosal delivery of cannabinoids. |
CN100591386C (en) | 2002-06-25 | 2010-02-24 | 权圣润 | Rapidly dissolving micro-perforator for drug delivery and other applications |
US8956160B2 (en) * | 2002-07-02 | 2015-02-17 | Ranir, Llc | Device and method for delivering an oral care agent |
DE10236349A1 (en) * | 2002-08-08 | 2004-02-19 | Basf Coatings Ag | Coil coating composition, useful in automobile manufacture, comprises a binding agent comprising at least one polyester and a cross-linking agent comprising at least two amine group-containing resins of different reactivity |
AU2003275311A1 (en) | 2002-09-16 | 2004-04-30 | Sung-Yun Kwon | Solid micro-perforators and methods of use |
FR2846663B1 (en) | 2002-11-05 | 2006-08-11 | Rhodia Elect & Catalysis | LIGHT-EMITTING MATERIAL, PARTICULARLY FOR GREENHOUSE WALLS, COMPRISING AS A BARIUM AND MAGNESIUM SILICATE ADDITIVE |
JP4157527B2 (en) | 2002-11-21 | 2008-10-01 | エル・ジー ハウスホールド アンド ヘルスケア リミティッド | Ginger safe dry type patch |
US6805874B1 (en) | 2002-12-03 | 2004-10-19 | Permamed Ag | Method and skin cleansing compositions for dermatological basic treatment |
CA2453013C (en) | 2002-12-13 | 2011-02-15 | Gary W. Cleary | Dermal, transdermal, mucosal or transmucosal ingredient delivery devices |
US7112713B2 (en) | 2003-03-12 | 2006-09-26 | Gelsus Research And Consulting, Inc. | Dressing based on the Teorell-Meyer gradient |
US20040181183A1 (en) | 2003-03-12 | 2004-09-16 | Sceusa Nicholas A. | Bandage based on the teorell-meyer gradient |
RU2326893C2 (en) | 2003-04-16 | 2008-06-20 | Кориум Интернэшнл | Covalent and non-covalent linking of hydrophilic polymers and adhesive compositions with them |
WO2004103328A1 (en) * | 2003-04-30 | 2004-12-02 | Icure Pharmaceutical Corporation | Patch for tooth whitening |
DE10330816A1 (en) | 2003-07-08 | 2005-01-27 | Still Gmbh | Industrial truck with an electric drive, a fuel cell system and a heater for an operator station |
CN102764247B (en) | 2004-01-30 | 2016-04-20 | 考里安国际公司 | The rapidly dissolving film of active agent delivery |
US7649029B2 (en) * | 2004-05-17 | 2010-01-19 | 3M Innovative Properties Company | Dental compositions containing nanozirconia fillers |
AU2005271259B2 (en) * | 2004-08-05 | 2012-01-19 | A.V. Topchiev Institute Of Petrochemical Synthesis | Adhesive composition |
ES2317138T3 (en) | 2004-11-22 | 2009-04-16 | Hisamitsu Pharmaceutical Co., Inc. | TRANSDERMAL PATCH THAT INCLUDES AN AGENT OF DIMINUTION OF THE FUSION POINT. |
CA2822648A1 (en) | 2004-12-21 | 2006-06-29 | Corium International, Inc. | Sustained release tooth whitening formulations and systems |
CA2596529C (en) | 2005-01-27 | 2014-08-19 | Corium International, Inc. | Hydrophilic biocompatible adhesive formulations and uses |
WO2006124639A1 (en) | 2005-05-11 | 2006-11-23 | Corium International, Inc. | Permeabilization of biological membranes |
WO2007119656A1 (en) | 2006-04-11 | 2007-10-25 | Nichiban Co., Ltd. | Tamsulosin-containing percutaneous absorption type preparation |
EP2196197A1 (en) | 2008-12-15 | 2010-06-16 | Bouty S.P.A. | Antiviral patch |
WO2010083035A2 (en) | 2009-01-14 | 2010-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
WO2015042165A1 (en) | 2013-09-17 | 2015-03-26 | Corium International, Inc. | Topical adhesive composition, and device, for improving aesthetic appearance of skin |
-
2005
- 2005-01-03 US US11/028,702 patent/US20050215727A1/en not_active Abandoned
-
2006
- 2006-01-03 CA CA 2594183 patent/CA2594183C/en active Active
- 2006-01-03 AU AU2006204127A patent/AU2006204127B2/en not_active Ceased
- 2006-01-03 RU RU2007129752A patent/RU2416433C2/en not_active Application Discontinuation
- 2006-01-03 EP EP06717322.9A patent/EP1838358B1/en active Active
- 2006-01-03 ES ES06717322.9T patent/ES2607785T3/en active Active
- 2006-01-03 WO PCT/US2006/000098 patent/WO2006074173A2/en active Application Filing
-
2010
- 2010-07-12 US US12/834,645 patent/US20100278757A1/en not_active Abandoned
-
2011
- 2011-10-07 US US13/269,465 patent/US8273405B2/en not_active Expired - Lifetime
-
2012
- 2012-08-24 US US13/594,746 patent/US8617647B2/en not_active Expired - Lifetime
-
2013
- 2013-12-23 US US14/139,530 patent/US9127140B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
AU2006204127A1 (en) | 2006-07-13 |
CA2594183C (en) | 2014-05-13 |
US8273405B2 (en) | 2012-09-25 |
US20140322143A1 (en) | 2014-10-30 |
US9127140B2 (en) | 2015-09-08 |
US20120321569A1 (en) | 2012-12-20 |
RU2416433C2 (en) | 2011-04-20 |
EP1838358A2 (en) | 2007-10-03 |
US8617647B2 (en) | 2013-12-31 |
WO2006074173A2 (en) | 2006-07-13 |
WO2006074173A3 (en) | 2007-01-11 |
RU2007129752A (en) | 2009-02-10 |
AU2006204127B2 (en) | 2010-12-23 |
US20050215727A1 (en) | 2005-09-29 |
EP1838358B1 (en) | 2016-11-30 |
US20120027695A1 (en) | 2012-02-02 |
US20100278757A1 (en) | 2010-11-04 |
ES2607785T3 (en) | 2017-04-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2594183C (en) | Water-absorbent adhesive compositions and associated methods of manufacture and use | |
US20040242770A1 (en) | Covalent and non-covalent crosslinking of hydrophilic polymers and adhesive compositions prepared therewith | |
CA2447302C (en) | Two-phase, water-absorbent bioadhesive composition | |
AU2005282263B2 (en) | Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components | |
AU2005271259B2 (en) | Adhesive composition | |
US20060182788A1 (en) | Hydrophilic biocompatible adhesive formulations and uses | |
WO2015088368A1 (en) | Hydrophilic thermo-switchable pressure-sensitive adhesive composition | |
AU2015200099A1 (en) | Adhesive composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |