U.S. patent application number 10/936887 was filed with the patent office on 2005-05-26 for method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components.
Invention is credited to Bairamov, Danir F., Chalykh, Anatoly E., Cleary, Gary W., Feldstein, Mikhail M., Kulichikhin, Valery G., Plate, Nicolai A., Singh, Parminder.
Application Number | 20050113510 10/936887 |
Document ID | / |
Family ID | 35833529 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113510 |
Kind Code |
A1 |
Feldstein, Mikhail M. ; et
al. |
May 26, 2005 |
Method of preparing polymeric adhesive compositions utilizing the
mechanism of interaction between the polymer components
Abstract
A method of selecting components for use in water-absorbing
pressure-sensitive adhesive compositions is provided. The method
involves selecting a film-forming polymer, a ladder-like
non-covalent crosslinker that is capable of forming a ladder-like
interpolymer complex with the film-forming polymer selected, and
selecting a carcass-like non-covalent crosslinker that is capable
of forming a carcass-like complex with at least one of the
film-forming polymer selected or the ladder-like non-covalent
crosslinker selected. The adhesive hydrogels provide high adhesion
in a swollen state and bridge the gap between conventional pressure
sensitive adhesives and bioadhesives. Methods for preparing and
using the resulting compositions are also disclosed.
Inventors: |
Feldstein, Mikhail M.;
(Moscow, RU) ; Bairamov, Danir F.; (Moscow,
RU) ; Plate, Nicolai A.; (Moscow, RU) ;
Kulichikhin, Valery G.; (Moscow, RU) ; Chalykh,
Anatoly E.; (Moscow, RU) ; Cleary, Gary W.;
(Los Altos Hills, CA) ; Singh, Parminder; (San
Francisco, CA) |
Correspondence
Address: |
REED INTELLECTUAL PROPERTY LAW GROUP
800 MENLO AVENUE, SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
35833529 |
Appl. No.: |
10/936887 |
Filed: |
September 8, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10936887 |
Sep 8, 2004 |
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10359548 |
Feb 5, 2003 |
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10359548 |
Feb 5, 2003 |
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10137664 |
May 1, 2002 |
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60288008 |
May 1, 2001 |
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Current U.S.
Class: |
524/556 ;
424/443; 525/330.3; 525/384; 525/385 |
Current CPC
Class: |
A61L 15/585 20130101;
C08L 2312/00 20130101; A61C 19/066 20130101; A61K 8/817 20130101;
A61K 8/22 20130101; A61Q 11/00 20130101; A61K 6/69 20200101; C08L
53/00 20130101; A61K 8/8176 20130101; A61K 8/0208 20130101; A61K
9/7007 20130101; A61K 2800/5422 20130101; A61L 15/60 20130101; A61L
15/60 20130101; A61K 8/042 20130101; A61K 2800/5424 20130101; A61K
8/8152 20130101; A61K 2800/262 20130101; A61K 2800/54 20130101;
A61K 8/86 20130101; A61K 8/731 20130101 |
Class at
Publication: |
524/556 ;
424/443; 525/384; 525/385; 525/330.3 |
International
Class: |
C08F 020/10 |
Claims
We claim:
1. An adhesive composition comprising: a film-forming polymer
selected from water-swellable water-insoluble polymers and
water-soluble polymers; a ladder-like non-covalent crosslinker that
contains complementary reactive functional groups in the repeating
units of the backbone, and is capable of forming a ladder-like
interpolymer complex with the film-forming polymer; and a
carcass-like non-covalent crosslinker that contains complementary
reactive functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
or the ladder-like non-covalent crosslinker; wherein the amount of
the film-forming polymer is greater than the amount of the
ladder-like non-covalent crosslinker or the amount of the
carcass-like non-covalent crosslinker.
2. The composition of claim 1, which comprises about 20-95 wt % of
the film-forming polymer.
3. The composition of claim 1, which comprises about 0.5-40 wt % of
the ladder-like crosslinker.
4. The composition of claim 1, which comprises about 0.5-60 wt % of
the carcass-like crosslinker.
5. The composition of claim 1, wherein the water-swellable
water-insoluble polymer is selected from cellulose derivatives, and
acrylate-based polymers and copolymers.
6. The composition of claim 5, wherein the cellulose derivative is
a cellulose ester polymer containing unesterified cellulose monomer
units, cellulose acetate monomer units, and either cellulose
butyrate monomer units or cellulose propionate monomer units.
7. The composition of claim 5, wherein the cellulose derivative is
a polymer containing hydroxyalkyl cellulose monomer units or
carboxyalkyl cellulose monomer units.
8. The composition of claim 5, wherein the acrylate-based polymer
or copolymer is selected from polymers and copolymers of acrylic
acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, and ethyl methacrylate.
9. The composition of claim 1, wherein the water-soluble polymer is
selected from water-soluble cellulose derived polymers, homopolymer
and copolymers of vinyl alcohols, homopolymer and copolymers of
vinyl phenols, homopolymer and copolymers of ethylene oxides,
homopolymer and copolymers of maleic acid, collagen, gelatin,
alginates, starches, and naturally occurring polysaccharides.
10. The composition of claim 9, wherein the water-soluble cellulose
derived polymer is selected from hydroxypropylcellulose,
hydroxyethylcellulose, methylcellulose, hydroxypropyl
methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, hydratecellulose, and
hydroxypropylmethylcellulose.
11. The composition of claim 9, wherein the naturally occurring
polysaccharide is selected from agars, alginates, derivatives of
alginic acid, carrageenans, chitin, chitosan, glucomannan, gellan
gum, gelatin, gum guar, gum Arabic, gum ghatti, gum karaya, gum
tragacanth, locust bean gum, pectins, pullulan, starches and starch
derivatives, tamarind gum, and xanthans.
12. The composition of claim 1, wherein the ladder-like
non-covalent crosslinker is selected from hydrophilic polymers,
water-swellable water-insoluble polymers, water-soluble polymers,
copolymers of hydrophilic and hydrophobic monomers, and
combinations thereof.
13. The composition of claim 12, wherein the hydrophilic polymer is
selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl
aminoalkyl methacrylates), polyamines, polyvinyl amines,
poly(alkylene imines), polyacrylic acids, polymethacrylic acids,
polymaleic acids, polysulfonic acids, poly(N-vinyl lactams),
polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols,
poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),
poly(N-vinyl acrylamides), poly(N-alkylacrylamides), polar
derivatives of cellulose containing hydroxyl and carboxyl groups,
alginic acid, chitosan, gelatin, combinations and copolymers
thereof.
14. The composition of claim 12, wherein the water-swellable
water-insoluble polymer is selected from cellulose derivatives,
acrylate-based polymers and copolymers, and combinations
thereof.
15. The composition of claim 14, wherein the cellulose derivative
is a cellulose ester polymer containing unesterified cellulose
monomer units, cellulose acetate monomer units, and either
cellulose butyrate monomer units or cellulose propionate monomer
units.
16. The composition of claim 14, wherein the cellulose derivative
is a polymer containing hydroxyalkyl cellulose monomer units or
carboxyalkyl cellulose monomer units.
17. The composition of claim 14, wherein the acrylate-based polymer
or copolymer is selected from polymers and copolymers of acrylic
acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, and ethyl methacrylate.
18. The composition of claim 12, wherein the water-soluble polymer
is selected from water-soluble cellulose derived polymers,
homopolymer and copolymers of vinyl alcohols, homopolymer and
copolymers of vinyl phenols, homopolymer and copolymers of ethylene
oxides, homopolymer and copolymers of maleic acid, collagen,
gelatin, alginates, starches, naturally occurring polysaccharides,
and combinations thereof.
19. The composition of claim 1, wherein the carcass-like
non-covalent crosslinker is selected from monomeric and oligomeric
alkylene glycols comprising about 1-20 alkylene oxide units in
their chains, polyalcohols, alkane diols, carbonic diacids, ether
alcohols, poly(alkylene glycol diacids), and combinations
thereof.
20. The composition of claim 1, further comprising at least one
active agent.
21. The composition of claim 1, further comprising at least one
additive selected from absorbent fillers, preservatives, pH
regulators, plasticizers, softeners, thickeners, antioxidants,
pigments, dyes, conductive species, refractive particles,
stabilizers, toughening agents, tackifiers or adhesive agents,
detackifiers, flavorants and sweeteners, antioxidants, and
permeation enhancers.
22. The composition of claim 1, wherein the film-forming polymer is
an acrylate polymer, the ladder-like crosslinker is a poly(N-vinyl
lactam), and the carcass-like crosslinker is an oligomeric alkylene
glycol comprising about 1-20 alkylene oxide units in its chain.
23. The composition of claim 1, further comprising a second
ladder-like non-covalent crosslinker that contains complementary
reactive functional groups in the repeating units of the backbone,
and is capable of forming a ladder-like interpolymer complex with
the film-forming polymer or the first ladder-like non-covalent
crosslinker; and wherein the carcass-like non-covalent crosslinker
is capable of forming a carcass-like complex with at least one of
the film-forming polymer, the first ladder-like non-covalent
crosslinker or the second ladder-like non-covalent crosslinker.
24. The composition of claim 23, wherein the second ladder-like
non-covalent crosslinker is capable of forming a ladder-like
interpolymer complex with the first ladder-like non-covalent
crosslinker and the carcass-like non-covalent crosslinker is
capable of forming a carcass-like complex with the second
ladder-like non-covalent crosslinker.
25. The composition of claim 24, wherein the film-forming polymer
and the first ladder-like crosslinker are acrylate polymers, the
second ladder-like crosslinker is a poly(N-vinyl lactam), and the
carcass-like crosslinker is an oligomeric alkylene glycol
comprising about 1-20 alkylene oxide units in its chain.
26. A method of selecting polymer components for use in an adhesive
composition, comprising: (a) selecting a film-forming polymer; (b)
selecting a ladder-like non-covalent crosslinker that contains
complementary reactive functional groups in the repeating units of
the backbone, and is capable of forming a ladder-like interpolymer
complex with the film-forming polymer selected; and (c) selecting a
carcass-like non-covalent crosslinker that contains complementary
reactive functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
selected or the ladder-like non-covalent crosslinker selected; and
wherein the amount of the film-forming polymer is greater than the
amount of the ladder-like non-covalent crosslinker or the amount of
the carcass-like non-covalent crosslinker.
27. The method of claim 26, wherein the amount of the film-forming
polymer is about 20-95 wt % of the composition, the amount of the
ladder-like crosslinker is about 0.5-40 wt % of the composition,
and the amount of the carcass-like crosslinker is about 0.5-60 wt %
of the composition.
28. The method of claim 26, wherein the film-forming polymer is
selected from hydrophilic polymers, water-swellable water-insoluble
polymers, water-soluble polymers, and copolymers of hydrophilic and
hydrophobic monomers.
29. The method of claim 28, wherein the hydrophilic polymer is
selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl
aminoalkyl methacrylates), polyamines, polyvinyl amines,
poly(alkylene imines), polyacrylic acids, polymethacrylic acids,
polymaleic acids, polysulfonic acids, poly(N-vinyl lactams),
polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols,
poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),
poly(N-vinyl acrylamides), poly(N-alkylacrylamides), polar
derivatives of cellulose containing hydroxyl and carboxyl groups,
alginic acid, chitosan, gelatin, and copolymers thereof.
30. The method of claim 28, wherein the water-swellable
water-insoluble polymer is selected from cellulose derivatives, and
acrylate-based polymers and copolymers.
31. The method of claim 30, wherein the cellulose derivative is a
cellulose ester polymer containing unesterified cellulose monomer
units, cellulose acetate monomer units, and either cellulose
butyrate monomer units or cellulose propionate monomer units.
32. The method of claim 30, wherein the cellulose derivative is a
polymer containing hydroxyalkyl cellulose monomer units or
carboxyalkyl cellulose monomer units.
33. The method of claim 30, wherein the acrylate-based polymer or
copolymer is selected from polymers and copolymers of acrylic acid,
methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, and ethyl methacrylate.
34. The method of claim 28, wherein the water-soluble polymer is
selected from water-soluble cellulose derived polymers, homopolymer
and copolymers of vinyl alcohols, homopolymer and copolymers of
vinyl phenols, homopolymer and copolymers of ethylene oxides,
homopolymer and copolymers of maleic acid, collagen, gelatin,
alginates, starches, and naturally occurring polysaccharides.
35. The method of claim 26, wherein the ladder-like non-covalent
crosslinker is selected from hydrophilic polymers, water-swellable
water-insoluble polymers, water-soluble polymers, copolymers of
hydrophilic and hydrophobic monomers, and combinations thereof.
36. The method of claim 34, wherein the hydrophilic polymer is
selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl
aminoalkyl methacrylates), polyamines, polyvinyl amines,
poly(alkylene imines), polyacrylic acids, polymethacrylic acids,
polymaleic acids, polysulfonic acids, poly(N-vinyl lactams),
polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols,
poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),
poly(N-vinyl acrylamides), poly(N-alkylacrylamides), polar
derivatives of cellulose containing hydroxyl and carboxyl groups,
alginic acid, chitosan, gelatin, combinations and copolymers
thereof.
37. The method of claim 35, wherein the water-swellable
water-insoluble polymer is selected from cellulose derivatives,
acrylate-based polymers and copolymers, and combinations
thereof.
38. The method of claim 37, wherein the cellulose derivative is a
cellulose ester polymer containing unesterified cellulose monomer
units, cellulose acetate monomer units, and either cellulose
butyrate monomer units or cellulose propionate monomer units.
39. The method of claim 37, wherein the cellulose derivative is a
polymer containing hydroxyalkyl cellulose monomer units or
carboxyalkyl cellulose monomer units.
40. The method of claim 37, wherein the acrylate-based polymer or
copolymer is selected from polymers and copolymers of acrylic acid,
methacrylic acid, methyl acrylate, ethyl acrylate, methyl
methacrylate, and ethyl methacrylate.
41. The method of claim 35, wherein the water-soluble polymer is
selected from water-soluble cellulose derived polymers, homopolymer
and copolymers of vinyl alcohols, homopolymer and copolymers of
vinyl phenols, homopolymer and copolymers of ethylene oxides,
homopolymer and copolymers of maleic acid, collagen, gelatin,
alginates, starches, naturally occurring polysaccharides, and
combinations thereof.
42. The method of claim 35, which further comprises selecting one
or more additional ladder-like non-covalent crosslinkers.
43. The method of claim 26, wherein the carcass-like non-covalent
crosslinker is selected from monomeric and oligomeric alkylene
glycols comprising about 1-20 alkylene oxide units in their chains,
polyalcohols, alkane diols, carbonic diacids, ether alcohols,
poly(alkylene glycol diacids), and combinations thereof.
44. The method of claim 43, which further comprises selecting one
or more additional carcass-like non-covalent crosslinkers.
45. A method of manufacturing an adhesive composition, comprising:
(a) (i) selecting a film-forming polymer; (ii) selecting a
ladder-like non-covalent crosslinker that contains complementary
reactive functional groups in the repeating units of the backbone,
and is capable of forming a ladder-like interpolymer complex with
the film-forming polymer selected; and (iii) selecting a
carcass-like non-covalent crosslinker that contains complementary
reactive functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
selected or the ladder-like non-covalent crosslinker selected; and
wherein the amount of the film-forming polymer is greater than the
amount of the ladder-like non-covalent crosslinker or the amount of
the carcass-like non-covalent crosslinker; (b) mixing the
film-forming polymer, ladder-like non-covalent crosslinker and
carcass-like non-covalent crosslinker; and (c) forming an adhesive
composition by melt extrusion or solution casting.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation in part of U.S. patent
application Ser. No. 10/359,548, filed Feb. 5, 2003; which is a
continuation in part of U.S. patent application Ser. No.
10/137,664, filed May 1, 2002; which claims priority under 35
U.S.C. .sctn. 119(e)(1) to provisional U.S. patent application Ser.
No. 60/288,008, filed May 1, 2001.
TECHNICAL FIELD
[0002] This invention relates to polymer compositions. More
particularly, the invention relates to hydrogel and bioadhesive
compositions, methods of selecting materials for manufacturing the
compositions, and methods of using these compositions in
therapeutic applications such as drug delivery systems (e.g.,
topical, transdermal, transmucosal, iontophoretic), medical skin
coverings, wound dressings and wound healing products, and
biomedical electrodes, as well as in cosmeceutical applications
such as tooth whitening products.
BACKGROUND
[0003] Various types of bandages and wound dressings are known and
used to protect wounds and burns. Typically, wound dressings are
fabricated with an absorbent material so that wound exudate is
removed and the wound dried, facilitating healing. Wound dressings
may also contain one or more pharmacologically active agents such
as antibiotics, local anesthetics, or the like. Commonly used wound
dressings include fibrous materials such as gauze and cotton pads,
which are advantageous in that they are absorbent but problematic
in that fibers may adhere to the wound or newly forming tissue,
causing wound injury upon removal. Other wound dressings have been
prepared with foams and sponges, but the absorbance of these
materials is often limited. Furthermore, such wound dressings
require the use of adhesive tape, as they are not themselves
adhesive.
[0004] Hydrophilic pressure-sensitive adhesives ("PSAs") are used
in a variety of pharmaceutical and cosmetic products, such as
topical and transdermal drug delivery systems, wound dressings,
face masks, bioadhesive films designed for buccal and mucosal
administration, teeth whitening strips, and so on. A general
distinctive feature of hydrophilic PSAs is that they typically
adhere to wet biological substrates, while conventional hydrophobic
(rubber-based) PSAs typically lose their adhesive properties when
moistened.
[0005] The adhesive properties of PSAs will vary depending upon how
and where the products are to be used. For transdermal drug
delivery and topical applications, an adhesive patch, for instance,
should provide high tack immediately upon use, and such tack should
be maintained during the entire application period (from one day to
one week). For buccal patches and teeth strips, it is often
desirable to use elastic polymer films, which exhibit no adhesion
towards dry surfaces, but are highly tacky when applied to
hydrated, soft mucosal surfaces and/or moistened solid tissue
surfaces such as teeth. For wound dressings and other various
purposes, in order to avoid skin damage upon patch removal, either
water-soluble adhesives or insoluble hydrogel adhesives, which lose
their adhesion under swelling in a large amount of water, are
preferred. Face masks and some tooth whitening products best
utilize hydrophilic polymer compositions in the form of aqueous or
ethanol-water solutions, which become dry after placement on a
surface, thereby forming an insoluble, polymer film that adheres to
the underlying tissue surface, but does not adhere to other
surfaces.
[0006] In order to effectively tailor the adhesive properties of
polymer materials useful in pharmaceutical and cosmetic products, a
design method has been developed based on molecular insight into
mechanisms underlying the adhesive properties. As has been recently
established, at a molecular level, the pressure-sensitive adhesion
is due to coupling of two apparently incompatible types of
molecular structures. This reveals that there is a fine balance
between strong cohesive interaction energy and enhanced free
volume. See, for example, Feldstein et al. (1999) Polym. Mater.
Sci. Eng., 81:465-466; Feldstein et al., General approach to the
molecular design of hydrophilic pressure-sensitive adhesives,
Proceed. 25.sup.th Annual Meeting Adhesion Soc. and 2.sup.nd World
Congress on Adhesion and Relative Phenomena, February 2002,
Orlando, Fla., vol.1 (Oral Presentations), p. 292-294; and Chalykh
et al. (2002) J. Adhesion 78(8):667-694.
[0007] The "free volume" property of the molecular structure of PSA
polymers results in high tack at a macroscopic level and a
liquid-like fluidity of the PSA material, which allows for a
fast-forming adhesive bond. The "cohesive interaction energy" or
"cohesion energy" property defines the cohesive toughness of the
PSA polymer and provides the dissipation of detaching energy in the
course of adhesive joint failure. Based on this finding, a general
method for obtaining novel hydrophilic adhesives is described in
U.S. Pat. No. 6,576,712 to Feldstein et al., which involves
physically mixing non-adhesive, hydrophilic, high-molecular-weight
polymers with appropriate short-chain plasticizers.
[0008] In various PSAs, different molecular structures provide
proper amounts of cohesion energy and free volume, thereby defining
the adhesive properties of the polymer materials. For instance, in
acrylic PSAs, strong cohesive interaction energy is a result of
mutual hydrophobic attraction of the alkyl radicals in side chains,
whereas large free volume is due to either electrostatic repulsion
of negatively charged carboxyl groups or a large volume of isoalkyl
radicals in the side chains. In synthetic rubbers, a large free
volume is obtained by adding high volume, low-density molecules of
tackifying resins. In hydrophilic adhesives, when high molecular
weight polyvinyl lactams (i.e. poly(N-vinyl-2-pyrrolidone) ("PVP")
or polyvinyl caprolactame ("PVCap")) are blended with the
short-chain polyethylene glycol ("PEG"), as described in U.S. Pat.
No. 6,576,712, high cohesive strength results from hydrogen bonding
between, for example, PVP carbonyl groups and complementary
terminal hydroxyls of PEG, while the large free volume is due to
the location of reactive groups at both ends of the PEG chains,
which are of appreciable length and flexibility.
[0009] A proper balance between high cohesion energy and large free
volume, which is responsible for adhesive properties of polymer
materials, is achieved by evaluating the various PSA properties.
For instance, the ratio between cohesion energy and free volume
defines the value of glass transition temperature, Tg, and
elasticity modulus, E, of a polymer. Higher cohesion energy and
lower free volume, results in higher values for both Tg and E. It
is well recognized that all PSAs demonstrate a Tg in the range of
about -55 to -30.degree. C. and an E.apprxeq.1-10.sup.5 Pa.
[0010] In U.S. Pat. No. 6,576,712, the hydrophilic polymers and
plasticizer are capable of hydrogen bonding or electrostatic
bonding to each other and are present in a ratio that optimizes key
characteristics of the adhesive composition, such as adhesive
strength, cohesive strength and hydrophilicity. The plasticizer has
complementary reactive functional groups at both ends and when both
terminal groups interact with complementary functional groups in
the hydrophilic polymer, the plasticizer acts as a non-covalent
crosslinker between the longer chains of hydrophilic polymer. In
doing so, the plasticizer combines the plasticization effect with
enhanced cohesive toughness of the PSA polymer blend. This
molecular design method for tailoring new hydrophilic PSAs
describes the adhesive capability of long-chain, high Tg
hydrophilic polymers, as well as the ratio of hydrophilic polymer
to plasticizer (cohesive enhancer), which provides the best
adhesion.
[0011] When dry, the adhesives described in U.S. Pat. No.
6,576,712, e.g. the blends of high molecular weight PVP with
oligomeric PEG ranging in molecular weight from 200 to 600 g/mol,
provide rather low adhesion toward dry surfaces. Adhesion increases
when the surface of a substrate is moistened or the adhesive
absorbs water. The maximum adhesion is observed when the adhesive
contains 5-10% of absorbed water. This is usually the case when the
adhesive is exposed to an atmosphere having 50% relative humidity.
Additionally, under direct contact with water, the adhesive
dissolves. However, these adhesives not contain covalent
crosslinks, and are thus not suitable for applications that require
swellable yet water-insoluble adhesives. In particular, these prior
art adhesives are less useful when increased adhesion is desired
upon much more appreciable hydration levels (e.g., 15% of absorbed
water and higher).
[0012] Therefore, while the prior art discloses polymers and
hydrogel compositions that can be tailored with respect to cohesive
strength, adhesive strength, tack, elasticity, and water
swellability, it remains desirable to develop a molecular design
method for preparing novel hydrophilic PSAs that focuses on
balancing cohesive interaction energy and free volume at a
molecular level.
[0013] In order to resolve these problems, this invention is
directed to a method of obtaining water-insoluble, film-forming
compositions by blending soluble polymers. While this has been
attempted in the past, e.g., U.S. Pat. No. 5,597,873 to Chambers et
al. and U.S. Pat. No. 5,306,504 to Lorenz et al. (mixing
carboxyl-containing polymers with polyhydric alcohols and
polyamines) and U.S. Pat. No. 4,771,105 to Shirai et al. and U.S.
Pat. No. 5,726,250 to Zajaczkowski (crosslinking of polyacrylic
acid "PAA" or the copolymers of acrylic acid with the salts of di-
and trivalent metals (Ca.sup.2+, Al.sup.3+), all of these
procedures are directed to the production of non-adhesive water
absorbents by mixing techniques.
SUMMARY OF THE INVENTION
[0014] One aspect of the invention pertains to an adhesive
composition comprising: a film-forming polymer selected from
water-swellable water-insoluble polymers and water-soluble
polymers; a ladder-like non-covalent crosslinker that contains
complementary reactive functional groups in the repeating units of
the backbone, and is capable of forming a ladder-like interpolymer
complex with the film-forming polymer; and a carcass-like
non-covalent crosslinker that contains complementary reactive
functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
or the ladder-like non-covalent crosslinker; wherein the amount of
the film-forming polymer is greater than the amount of the
ladder-like non-covalent crosslinker or the amount of the
carcass-like non-covalent crosslinker.
[0015] Another aspect of the invention relates to a method of
selecting polymer components for use in an adhesive composition,
comprising: (a) selecting a film-forming polymer; (b) selecting a
ladder-like non-covalent crosslinker that contains complementary
reactive functional groups in the repeating units of the backbone,
and is capable of forming a ladder-like interpolymer complex with
the film-forming polymer selected; and (c) selecting a carcass-like
non-covalent crosslinker that contains complementary reactive
functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
selected or the ladder-like non-covalent crosslinker selected; and
wherein the amount of the film-forming polymer is greater than the
amount of the ladder-like non-covalent crosslinker or the amount of
the carcass-like non-covalent crosslinker.
[0016] Yet another aspect of the invention relates to a method of
manufacturing an adhesive composition, comprising: (a) (i)
selecting a film-forming polymer; (ii) selecting a ladder-like
non-covalent crosslinker that contains complementary reactive
functional groups in the repeating units of the backbone, and is
capable of forming a ladder-like interpolymer complex with the
film-forming polymer selected; and (iii) selecting a carcass-like
non-covalent crosslinker that contains complementary reactive
functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
selected or the ladder-like non-covalent crosslinker selected; and
wherein the amount of the film-forming polymer is greater than the
amount of the ladder-like non-covalent crosslinker or the amount of
the carcass-like non-covalent crosslinker; (b) mixing the
film-forming polymer, ladder-like non-covalent crosslinker and
carcass-like non-covalent crosslinker; and (c) forming an adhesive
composition by melt extrusion or solution casting.
[0017] The adhesive compositions produced by the methods of the
invention provide a number of significant advantages relative to
the prior art. In particular, these compositions provide one or
more of the following advantages over the art: provide ease of
handling; are readily modified during manufacture so that
properties such as adhesion, absorption, translucence, and swelling
can be controlled and optimized; can be formulated so that tack
increases or decreases in the presence of moisture so that the
composition is not sticky until moistened; minimize leakage of the
active agent, when included, from the composition onto a mucosal
surface (e.g., into the user's mouth); can be fabricated in
translucent from, enabling the user to view the extent of whitening
without removing the hydrogel composition from the teeth or mucosal
surface; minimize damage to gums or mucous membranes in the mouth;
can be worn comfortably and unobtrusively; are easily removed from
the skin, teeth or mucosal surface, and leave no residue; are
amenable to extended duration of wear or action; and can provide
sustained and controlled release of a variety of active agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a schematic representation of a carcass-like
PVP-PEG network complex. 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. The carcass-like structure of the complex results from
the location of reactive functional groups at both ends of PEG
short chains.
[0019] FIG. 2 is a schematic representation of a ladder-like PVP
complex with a complementary proton-donating polymer as the
ladder-like non-covalent crosslinker. When the complementary
polymer contains reactive functional groups in repeating units of
the backbone, the resulting complex has a so-called "ladder-like"
structure.
[0020] FIG. 3 demonstrates a schematic representation of an
interpolymer complex combining carcass-like and ladder-like types
of crosslinking. "FFP" represents a film-forming polymer, "CCL"
represents a carcass-like non-covalent crosslinker, and "LLC"
represents a ladder-like non-covalent crosslinker.
[0021] FIG. 4 demonstrates Sol Fraction and Swell Ratio (at a pH of
4.6) for the triple blends of PVP (50 wt %) with PEG and Eudragit L
100-55 as a function of the concentration of H-bonding, ladder-like
crosslinker, Eudragit L 100-55.
[0022] FIG. 5 shows the dependence of Sol Fraction and Swell Ratio
(at a pH of 4.6) for the triple blends of PVP with PEG and Eudragit
L 100-55 (PVP:Eudragit ratio of 5:1) to the concentration of
H-bonding, carcass-like crosslinker, PEG.
[0023] FIG. 6 demonstrates the effect of non-covalent, ladder-like
crosslinker, Eudragit L 100-55, on tensile stress-strain curves up
to break the films of PVP-PEG-Eudragit L 100-55 blends under
uniaxial extension with drawing rate of 20 mm/min. The
concentration of the carcass-like crosslinker PEG was fixed at 50
wt %.
[0024] FIG. 7 illustrates the effect of the non-covalent,
carcass-like crosslinker, PEG, on stress-strain curves up to break
the films of PVP-PEG-Eudragit L 100-55 blends under uniaxial
extension with drawing rate of 20 mm/min. The PVP:Eudragit L 100-55
ratio is 5:1.
[0025] FIG. 8 illustrates the impact of absorbed water upon
adhesive properties of the PVP-PEG-Eudragit L 100-55 blends, where
the composition contains 58 wt % PVP, 30 wt % PEG, and 12 wt % of
the Eudragit L 100-55. The amounts of absorbed water (in wt %) are
indicated.
[0026] FIG. 9 is a plot of the maximum stress and maximum of
elongation under adhesive debonding versus the weight fraction of
absorbed water for the PVP-PEG-Eudragit L 100-55 hydrogel.
[0027] FIG. 10 displays the work of adhesive debonding as a
function of absorbed water for PVP-PEG-Eudragit L 100-55
hydrogel.
[0028] FIG. 11 illustrates the in vivo release profile of hydrogen
peroxide from tooth whitening strips based on a Carbopol
bioadhesive and on the PVP-PEG-Eudragit L 100-55 hydrogel.
DETAILED DESCRIPTION OF THE INVENTION
[0029] I. Definitions and Nomenclature
[0030] Before describing the present invention in detail, it is to
be understood that unless otherwise indicated this invention is not
limited to specific hydrogel materials or manufacturing processes,
as such may vary. It is also to be understood that the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting. It must be noted that, as
used in this specification and the appended claims, 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
polymer but also a combination or mixture of two or more different
hydrophilic polymers, reference to "a plasticizer" includes a
combination or mixture of two or more different plasticizers as
well as a single plasticizer, and the like.
[0031] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0032] The definitions of "hydrophobic" and "hydrophilic" polymers
are based on the amount of water vapor absorbed by polymers at 100%
relative humidity (rh). According to this classification,
hydrophobic polymers absorb only up to 1 wt % of water at 100%
relative humidity, while moderately hydrophilic polymers absorb
1-10 wt % of water, hydrophilic polymers are capable of absorbing
more than 10 wt % of water, and hygroscopic polymers absorb more
than 20 wt % of water. A "water-swellable" polymer is one that
absorbs an amount of water greater than at least 25 wt % of its own
weight, preferably at least 50 wt %, upon immersion in an aqueous
medium.
[0033] The term "crosslinked" herein refers to a composition
containing intramolecular and/or intermolecular crosslinks, whether
arising through covalent or non-covalent bonding. "Non-covalent"
bonding includes both hydrogen bonding and electrostatic (ionic)
bonding.
[0034] The term "polymer" includes homopolymers, linear and
branched polymer structures, and also encompasses crosslinked
polymers as well as copolymers (which may or may not be
crosslinked), thus including block copolymers, alternating
copolymers, random copolymers, and the like. Those compounds
referred to herein as "oligomers" are polymers having a molecular
weight below about 1000 Da, preferably below about 800 Da.
[0035] The term "water-insoluble" refers to a polymer, compound or
composition whose solubility in water is less than 5 wt %,
preferably less than 3 wt %, more preferably less than 1 wt %
(measured in water at 20.degree. C.).
[0036] The term "hydrogel" 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 environment, dry hydrogels swell to the extent allowed
by the degree of cross-linking.
[0037] The term "hydrogel composition" refers to a composition that
either contains a hydrogel or is entirely composed of a hydrogel.
As such, "hydrogel compositions" encompass not only hydrogels per
se but also compositions that comprise a hydrogel and one or more
non-hydrogel components or compositions, e.g., hydrocolloids, which
contain a hydrophilic component (which may contain or be a
hydrogel) distributed in a hydrophobic phase.
[0038] The terms "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" means a hydrogel composition that has a
tack value that is less than about 25 g-cm/sec, "slightly tacky"
means a hydrogel composition that has a tack value in the range of
about 25 g-cm/sec to about 100 g-cm/sec, and "tack" means a
hydrogel composition that has a tack value of at least 100
g-cm/sec.
[0039] The term "pressure sensitive adhesive" (PSA) relates to the
polymer materials, which form a strong adhesive bond to any surface
with application of very slight external pressure over a short
period of time (e.g., 1-5 seconds).
[0040] The term "bioadhesive" means a hydrogel that exhibits a
pressure-sensitive character of adhesion toward highly hydrated
biological surfaces such as mucosal tissue.
[0041] The term "complex" or "interpolymer complex" refers to the
association of macromolecules of two or more complementary polymers
that forms as a result of favorable interactions between their
macromolecules. In general, the interpolymer complex between the
film forming polymer, the ladder-like crosslinker and the
carcass-like crosslinker is formed by hydrogen bonding,
electrostatic bonding, ionic bonding, or a combination thereof.
[0042] The term "ladder-like" defines the complex or the mechanism
of complexation leading to the associate of complementary
macromolecules, wherein specific interaction occurs between the
complementary functional groups in the repeating units of polymeric
backbones. Due to entropic reasons, functional groups are linked
together not separately but in a cooperative manner, thus forming
sequences of relatively short and tough bonds. The schematic
structure of this complex shown in FIG. 2 resembles a ladder.
[0043] The term "carcass-like" defines the complex or the mechanism
of complexation leading to the association of complementary
macromolecule and oligomeric chains, wherein specific interaction
occurs between the complementary functional groups in the repeating
units of the backbone of the longer polymer chain and the reactive
groups at the both ends of the shorter oligomeric chain. In
contrast to the ladder-like complex, the term "carcass-like"
emphasizes that the crosslinks between the longer polymer chains
are of appreciable length and the density of network formed by this
way is much lower, as shown schematically in FIG. 1.
[0044] Both the ladder-like and carcass-like complexes are
crosslinked due to specific interactions between reactive groups in
complementary macromolecules and thus represent "networks". In the
context of present invention the term "network" is used
interchangeably with the term "complex", but refers more
specifically to the i structure of the interpolymer complex, as
shown schematically in FIG. 3.
[0045] The terms "active agent," "pharmacologically active agent"
and "drug" are used interchangeably herein to refer to a chemical
material or compound that induces a desired pharmacological or
physiological effect, and includes agents that are therapeutically
effective, prophylactically effective, or cosmeceutically
effective. The terms also encompass pharmaceutically acceptable,
pharmacologically active derivatives and analogs of those active
agents specifically mentioned herein, including, but not limited
to, salts, esters, amides, prodrugs, active metabolites, inclusion
complexes, analogs, and the like. When the terms "active agent,"
"pharmacologically active agent" and "drug" are used, it is to be
understood that both the active agent per se as well as
pharmaceutically acceptable, pharmacologically active salts,
esters, amides, prodrugs, active metabolites, inclusion complexes,
analogs, etc., are included.
[0046] The term "effective amount" or "a cosmeceutically effective
amount" of a cosmeceutically active agent is meant a nontoxic but
sufficient amount of a cosmeceutically active agent to provide the
desired cosmetic effect. The term "effective amount" or "a
therapeutically effective amount" of a drug or pharmacologically
active agent is intended to mean a nontoxic but sufficient amount
of the drug or agent to provide the desired therapeutic effect. The
amount that is "effective" will vary from subject to subject,
depending on the age and general condition of the individual, the
particular active agent or agents, and the like. Thus, it is not
always possible to specify an exact "effective amount." However, an
appropriate "effective" amount in any individual case may be
determined by one of ordinary skill in the art using routine
experimentation. Furthermore, the exact "effective" amount of an
active agent incorporated into a composition or dosage form of the
invention is not critical, so long as the concentration is within a
range sufficient to permit ready application of the formulation so
as to deliver an amount of the active agent that is within a
therapeutically effective range.
[0047] The term "transdermal" drug delivery means administration of
an active agent to the skin or mucosa of an individual so that the
drug passes through the skin tissue and into the individual's blood
stream. Unless otherwise indicated, the term "transdermal" is
intended to include "transmucosal" drug administration, i.e.,
administration of a drug to the mucosal (e.g., sublingual, buccal,
vaginal, rectal, urethral) surface of an individual so that the
drug passes through the mucosal tissue and into the individual's
blood stream.
[0048] The term "topical administration" is used in its
conventional sense to mean delivery of an active agent to a body
surface, such as, the skin or mucosa, as in, for example, topical
drug administration in the prevention or treatment of various skin
disorders, the application of cosmetics (including moisturizers,
masks, sunscreens, etc.), and the like. Topical administration, in
contrast to transdermal administration, provides a local rather
than a systemic effect.
[0049] The term "surface" or "body surface" is used to refer to any
surface located on the human body or within a body orifice. Thus, a
"body surface" includes, by way of example, teeth, skin or mucosal
tissue, including the interior surface of body cavities that have a
mucosal lining. Unless otherwise indicated, the term "skin" as used
herein should be interpreted as including mucosal tissue and vice
versa. Similarly, when the term "transdermal" is used herein, as in
"transdermal drug administration" and "transdermal drug delivery
systems," it is to be understood that unless explicitly indicated
to the contrary, both "transmucosal" and "topical" administration
and systems are intended as well.
[0050] II. Adhesive Compositions-Main Components
[0051] It is desirable to obtain water-swellable, hydrophilic
adhesive compositions (adhesive hydrogels) that are capable to form
homogeneous films either upon casting a solution to backing layer
followed by drying, or under external pressure or by means of
extrusion. Preferably, such compositions are also water-insoluble.
The film-forming capability is optimal when the blend is free of
covalent crosslinks. Blending specific polymers provides a
convenient way to obtain composite materials with specifically
tailored properties, since the properties of the blend are
typically intermediate between those of the unblended components
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 hamper
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.
[0052] Preparation of polymer composite materials whose properties
are new and untypical of the individual components requires a high
degree of skill. This challenge may be resolved if the individual
blend components are capable of strong favorable interactions with
each other. Typically, such interaction is due to hydrogen,
electrostatic or ionic bonding. In this instance mixing of two or
more soluble polymers provides a ladder-like complex, schematically
shown in FIG. 2 that is swellable, but insoluble or partly
soluble.
[0053] In order to resolve these problems, this invention is
directed to a method of obtaining water-insoluble, film-forming
compositions by blending soluble polymers, more specifically by
blending hydrophilic polymers with complementary macromolecules
that are capable of hydrogen bonding, electrostatic or ionic
bonding.
[0054] At least one component of the blend is a film-forming
polymer, at least one component of the blend is a ladder-like
non-covalent crosslinker of the film-forming polymer, and at least
one component of the blend is a carcass-like non-covalent
crosslinker of the film-forming polymer. Key to the invention is
that the film-forming polymer is present in a higher concentration
than either of the cross-linkers. This concentration is what
determines the film-forming characteristics. Therefore, while there
may be materials that are suitable for use as either the
film-forming polymer or as the ladder-like non-covalent
crosslinker, their function and role in the composition will be
determined by the amount of material present in the
composition.
[0055] For example, poly-acids 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 polyamines are suited for
use as both the film-forming polymer or as the ladder-like
non-covalent crosslinker. In a composition having a greater amount
of an acrylate or another proton donating polymer relative to the
amount of a poly(N-vinyl lactam), the acrylate polymer serves as
the film-forming polymer and the poly(N-vinyl lactam) or polyamine
or another proton-accepting polymer serves as the ladder-like
crosslinker. Similarly, in a composition having a greater amount of
a poly(N-vinyl lactam) or polyamine relative to the amount of an
acrylate polymer, the poly(N-vinyl lactam) or polyamine serves as
the film-forming polymer and the acrylate polymer serves as the
ladder-like crosslinker.
[0056] Thus, one embodiment of the invention is a method of
selecting polymer components for use in an adhesive composition.
The method first involves selecting a film-forming polymer. Then, a
ladder-like non-covalent crosslinker is selected that (1) contains
complementary reactive functional groups in the repeating units of
the backbone, and (2) is capable of forming a ladder-like
interpolymer complex with the film-forming polymer selected.
Finally, a carcass-like non-covalent crosslinker is selected that
(1) contains complementary reactive functional groups at its ends,
and (2) is capable of forming a carcass-like complex with at least
one of the film-forming polymer selected or the ladder-like
non-covalent crosslinker selected. The carcass-like non-covalent
crosslinker is preferably compatible or at least partially
compatible with both the film-forming polymer and the ladder-like
non-covalent crosslinker. The method involves not only the
aforementioned material selections, but also involves selecting the
quantities of materials used. In particular, the amount of the
film-forming polymer is greater than the amount of the ladder-like
non-covalent crosslinker or the amount of the carcass-like
non-covalent crosslinker. The method may also comprise the steps of
selecting one or more additional ladder-like non-covalent
crosslinkers and/or selecting one or more additional carcass-like
non-covalent crosslinkers. Such additional crosslinkers will be
selected based upon the same or similar criteria as the first
crosslinkers, i.e., complementarity and ability to form the desired
complex.
[0057] Typically the composition will contain one film forming
polymer, but may contain more than one ladder-like crosslinker
and/or more than one carcass-like crosslinker.
[0058] The adhesion profile of the water-insoluble, film-forming
compositions of the invention can be tailored based on materials,
the composition ratio and the extent of water in the blend. The
ladder-like crosslinker and its ratio to the amount of film-forming
polymer is selected so as to provide the desired adhesion profile
with respect to hydration. Generally, the compositions that are
relatively slightly crosslinked through comparatively loose
hydrogen bonds and demonstrating a large free volume, provide
initial tack in the dry state. As the degree of crosslinking and
cohesive strength of the network in the interpolymer complex moves
above some critical value, the energy of cohesion dominates under
free volume and such compositions are usually non-tacky in the dry
state. However, as the free volume is increased in this blend, the
adhesion immediately appears. Since water is a good plasticizer for
hydrophilic polymers, absorption of water can lead to the
improvement of adhesion. Since electrostatic bonds are appreciably
stronger than the hydrogen ones, the cohesion in the blends of
polymers bearing carboxyl groups is usually higher than in
materials made of polymers having hydroxyl groups. Adhesion in such
blends appears under higher concentration of absorbed water.
Flexible polymers provide higher cohesion than the polymers with
rigid chains. As an example, for the blends of PVP as film-forming
polymer, when the ladder-like crosslinker is a rigid-chain
cellulose ester bearing OH groups or cellulose, 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 carboxylic groups, a composition is provided that
is generally substantially nontacky prior to contact with water,
but becomes tacky upon contact with a moist surface.
[0059] A. Film-Forming Polymers
[0060] The film-forming polymers are present in the adhesive
composition in a higher concentration than the amount of the
ladder-like crosslinker or the amount of the carcass-like
crosslinker and provides film-forming properties. Typically, the
amount of the film-forming polymer will range from about 20-95 wt %
of the composition, while the amount of the ladder-like crosslinker
will range from about 0.5-40 wt % and the amount of the
carcass-like crosslinker will range from about 0.5-60 wt %. The
balance of the composition can be made up of components such as
plasticizers and tackifiers, water or other solvents, active
agents, pH regulators, and so forth, as are described below.
[0061] Typically, the film-forming polymers are relatively high
molecular weight polymers and will have a molecular weight within
the range of about 20,000 to 3,000,000, preferably within the range
of 100,000 to 2,000,000, more typically in the range of
approximately 500,000 to 1,500,000.
[0062] The film-forming polymer is capable of forming hydrogen or
electrostatic bonds with the functional repeating units of the
ladder-like crosslinker and the terminal functional groups of the
carcass-like crosslinker. Suitable film-forming polymers include,
by way of illustration and not limitation, hydrophilic polymers,
water-swellable water-insoluble polymers, water-soluble polymers,
copolymers of hydrophilic and hydrophobic monomers, and
combinations thereof.
[0063] 1. Hydrophilic Polymers
[0064] Exemplary synthetic hydrophilic polymers include, by way of
illustration and not limitation, poly(dialkyl aminoalkyl
acrylates), poly(dialkyl aminoalkyl methacrylates), polyamines,
polyvinyl amines, poly(alkylene imines), substituted and
unsubstituted acrylic and methacrylic acid polymers such as
polyacrylic acids (PAAs) and polymethacrylic acids (PMAs),
polymaleic acids, polysulfonic acids, poly(N-vinyl lactams),
polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols,
poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),
poly(N-vinyl acrylamides), poly(N-alkylacrylamides), homopolymers,
copolymers, and combinations thereof, as well as copolymers with
other types of hydrophilic monomers (e.g. vinyl acetate).
[0065] Exemplary natural hydrophilic polymers include, by way of
illustration and not limitation, polar derivatives of cellulose
containing hydroxyl and carboxyl groups, such as
carboxymethylcellulose and hydroxypropylmethylcellulose phthalate,
alginic acid, chitosan and gelatin.
[0066] Preferred hydrophilic polymer film-forming polymers are
synthetic polymers, and include poly(dialkyl aminoalkyl acrylates);
poly(dialkyl aminoalkyl methacrylates); polyacrylic acids;
polymethacrylic acids; polymaleic acids; polyvinylamines;
poly(N-vinyl lactams) such as poly(N-vinyl pyrrolidone) (e.g.,
poly(N-vinyl-2-pyrrolidone)), poly(N-vinyl-2-valerolactam), and
poly(N-vinyl caprolactam) (e.g., poly(N-vinyl-2-caprolactam));
polyalkylene oxides such as polyethylene oxide (PEO) and
polypropylene oxide; polyvinyl alcohols; polyvinyl phenols; and
poly(hydroxyalkyl acrylates) such as poly(hydroxyethyl
methacrylate) (PolyHEMA), poly(hydroxyethyl acrylate), and
copolymers thereof.
[0067] Other suitable hydrophilic polymers include repeating units
derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a
maleic acid monomer, a dialkyl aminoalkyl acrylate or a dialkyl
aminoalkyl methacrylate monomer, ethylene oxide monomer, a vinyl
ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide
monomer, and/or a hydroxy vinyl monomer. Such polymers include, by
way of example, polyvinylamines, polyacrylic acids, polymethacrylic
acids, polymaleic acids, poly(N-vinyl lactams), poly(N-vinyl
acrylamides), poly(N-alkylacrylamides), polyethylene oxides,
polyvinyl alcohols, and polyvinyl phenol.
[0068] Poly(N-vinyl lactams) useful herein are preferably
noncrosslinked homopolymers or copolymers of N-vinyl lactam monomer
units, with N-vinyl lactam monomer units representing the majority
of the total monomeric units of a poly(N-vinyl lactams) copolymer.
Preferred poly(N-vinyl lactams) for use in conjunction with the
invention are prepared by polymerization of one or more of the
following N-vinyl lactam monomers: N-vinyl-2-pyrrolidone;
N-vinyl-2-valerolactam; and N-vinyl-2-caprolactam. Nonlimiting
examples of non-N-vinyl lactam comonomers useful with N-vinyl
lactam monomeric units include N,N-dimethylacrylamide, acrylic
acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide,
2-acrylamido-2-methyl-1-propane sulfonic acid or its salt, and
vinyl acetate.
[0069] Poly (N-alkylacrylamides) include, by way of example,
poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM).
[0070] Polymers of carboxy vinyl monomers are typically formed from
acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid,
itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic
acid or fumaric acid, maleic anhydride, or mixtures thereof, with
preferred hydrophilic polymers within this class including
polyacrylic acid and polymethacrylic acid, with polyacrylic acid
most preferred.
[0071] Preferred hydrophilic polymers herein are the following:
poly(N-vinyl lactams), particularly poly(N-vinyl pyrrolidone) (PVP)
and poly(N-vinyl caprolactam) (PVCap); poly(N-vinyl acetamides),
particularly polyacetamide per se; polymers of carboxy vinyl
monomers, particularly polyacrylic acid and polymethacrylic acid;
polymaleic acids; and copolymers and blends thereof. PVP and PVCap
are particularly preferred.
[0072] 2. Water-Swellable Water-Insoluble Polymers
[0073] Exemplary water-swellable water-insoluble polymers include,
by way of illustration and not limitation, cellulose derivatives
such as cellulose esters, and acrylate-based polymers or
copolymers, as well as combinations thereof. The water-swellable
water-insoluble polymer is capable of at least some degree of
swelling when immersed in an aqueous liquid but is insoluble in
water. The polymer may be comprised of a cellulose ester, for
example, cellulose acetate, cellulose acetate propionate (CAP),
cellulose acetate butyrate (CAB), cellulose propionate (CP),
cellulose butyrate (CB), cellulose propionate butyrate (CPB),
cellulose diacetate (CDA), cellulose triacetate (CTA), or the like.
These cellulose esters are described in U.S. Pat. Nos. 1,698,049,
1,683,347, 1,880,808, 1,880,560, 1,984,147, 2,129,052, and
3,617,201, and may be prepared using techniques known in the art or
obtained commercially. Commercially available cellulose esters
suitable herein include CA 320, CA 398, CAB 381, CAB 551, CAB 553,
CAP 482, CAP 504, all available from Eastman Chemical Company,
Kingsport, Term. Such cellulose esters typically have a number
average molecular weight of between about 10,000 and about
75,000.
[0074] Generally, the cellulose ester comprises a mixture of
cellulose and cellulose ester monomer units; for example,
commercially available cellulose acetate butyrate contains
cellulose acetate monomer units as well as cellulose butyrate
monomer units and unesterified cellulose monomer units, while
cellulose acetate proprionate contains monomer units such as
cellulose proprionate. Preferred cellulose esters herein are
cellulose acetate propionate compositions and cellulose acetate
butyrate compositions having the butyryl, propionyl, acetyl, and
unesterified (OH) cellulose content as indicated below:
1 Acetyl MW T.sub.g T.sub.m (%) OH (%) (g/mole) (.degree. C.)
(.degree. C.) Cellulose Acetate 17-52% 2.0-29.5 1.1-4.8
12,000-70,000 96-141 130-240 Butyrate Butyrate Cellulose Acetate
42.5-47.7% 0.6-1.5 1.7-5.0 15,000-75,000 142-159 188-210 Propionate
Propionate
[0075] The preferred molecular weight, glass transition temperature
(T.sub.g) and melting temperature (T.sub.m) are also indicated.
Also, suitable cellulosic polymers typically have an inherent
viscosity (I.V.) of about 0.2 to about 3.0 deciliters/gram,
preferably about 1 to about 1.6 deciliters/gram, as measured at a
temperature of 25.degree. C. for a 0.5 gram sample in 100 ml of a
60/40 by weight solution of phenol/tetrachloroethane. When prepared
using a solvent casting technique, the water-swellable
water-insoluble polymer should be selected to provide greater
cohesive strength and thus facilitate film forming (generally, for
example, cellulose acetate propionate tends to improve cohesive
strength to a greater degree than cellulose acetate butyrate).
[0076] Other cellulose derivatives include cellulosic polymers
containing hydroxyalkyl cellulose or carboxyalkyl cellulose monomer
units.
[0077] Other preferred water-swellable water-insoluble polymers are
acrylate-based polymers or copolymers, generally formed from
acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate,
methyl methacrylate, ethyl methacrylate, and/or other vinyl
monomers. Several of these are also classified as hydrophilic
polymers, above. Suitable acrylate polymers are those copolymers
available under the tradename "Eudragit" from Rohm Pharma
(Germany). The Eudragit.RTM. series E, L, S, RL, RS and NE
copolymers are available solubilized in organic solvent, in an
aqueous dispersion, or as a dry powder. Preferred acrylate polymers
are copolymers of methacrylic acid and methyl methacrylate, such as
the Eudragit L and Eudragit S series polymers. Particularly
preferred such copolymers 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 Eudragit L 100-55 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 7.0. This copolymer is soluble
at pH 7.0 and above. Eudragit L 100 may 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 6.0.
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 suitable acrylate polymers are those
methacrylic acid/ethyl acrylate copolymers available under the
tradename "Kollicoat" from BASF AG (Germany). For example,
Kollicoat MAE has the same molecular structure as Eudragit L
100-55.
[0078] When the water-swellable water-insoluble polymer is an
acrylic acid or acrylate polymer, a hydrogel is provided that can
be reversibly dried, i.e., after removal of water and any other
solvents, the dried hydrogel may be reconstituted to its original
state by addition of water. In addition, hydrophilic hydrogels
prepared with an acrylic acid/acrylate water-swellable polymer are
generally substantially nontacky prior to contact with water, but
become tacky upon contact with a moist surface, such as is found in
the interior of the mouth, such as on the surface of the teeth.
This property of being nontacky prior to contact with water enables
positioning or repositioning on a chosen surface before, or as the
hydrogel becomes tacky. For example, once hydrated, the hydrogel
becomes tacky and can adhere to a surface such as a tooth or
mucosal surface.
[0079] In addition, acrylate-containing compositions can generally
provide swelling in the range of about 400% to 1500% upon immersion
of the composition in water or other aqueous liquid, at a pH of
less than 5.5-6.0, although the ratio of the acrylate polymer to
the other materials can be selected such that the rate and extent
of swelling in an aqueous environment has a predetermined
pH-dependence. This feature also provides for retroactive
incorporation of whitening agents or other active agents, such as
loading the composition with peroxide, peroxy acids, chlorites,
stabilizers, flavoring agents, etc.
[0080] By contrast, incorporating a cellulose ester as the
water-swellable water-insoluble polymer renders the composition
tacky prior to application to a moist surface, but nontacky upon
absorption of water. It will be appreciated that such a composition
may be desirable when a decrease in tack is desired for ultimate
removal of the product from the teeth.
[0081] 3. Water-Soluble Polymers
[0082] Exemplary water-soluble polymers include, by way of
illustration and not limitation, water-soluble cellulose derived
polymers; homopolymer and copolymers of vinyl alcohols; homopolymer
and copolymers of vinyl phenols; homopolymer and copolymers of
ethylene oxides; homopolymer and copolymers of maleic acid;
collagen; gelatin; alginates; starches; and naturally occurring
polysaccharides; and combinations thereof. The polymers
include.
[0083] Exemplary water-soluble cellulose derived polymers include
hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose,
hydroxypropyl methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, hydratecellulose (cellophane), and
hydroxypropylmethylcellulose, and combinations thereof.
[0084] Exemplary naturally occurring polysaccharides include agars
of various origin such as gum agar; alginates such as alginic acid,
salts of alginic acid (e.g., calcium alginate, potassium alginate,
sodium alginate), and derivatives of alginic acid (e.g. propylene
glycol alginate, Kelcoloid.RTM., Monsanto); carrageenans including
kappa-, iota- and lambda carrageenans; chitin; chitosan;
glucomannan; gellan gum (Kelcogel.RTM., Monsanto); gelatin; gum
guar (TIC Gums); gum arabic; gum ghatti; gum karaya; gum
tragacanth; locust bean gum; pectins such as pectin and
amylopectin; pullulan; starches and starch derivatives such as
potato starch acetate, Clearam.RTM. CH10, Roquette; tamarind gum;
xanthans such as xanthan gum; and combinations thereof.
[0085] Exemplary water-soluble maleic acid polymers include those
available under the tradename Gantrez.RTM. from International
Specialty Products. Gantrez.RTM. products are a family of synthetic
copolymers of methylvinyl ether and maleic anhydride. Gantrez AN
are copolymers of methylvinyl ether and maleic anhydride. Gantrez S
series represent the copolymers of methylvinyl ether and maleic
acid, such as Gantrez S-97. Gantrez ES is the half ester form of
maleic acid and represent a range of methylvinyl ether and maleic
acid copolymers with different alkyl chain lengths and molecular
weights. Thus Gantrez ES-225 and Gantrez ES-425 are monoethyl and
monobutyl esters of the copolymers of methylvinyl ether and maleic
acid.
[0086] B. Ladder-Like Non-Covalent Crosslinkers
[0087] The ladder-like non-covalent crosslinker of the film-forming
polymer is preferably a long chain polymer containing complementary
reactive functional groups in the repeating units of the backbone,
and is capable of forming a ladder-like interpolymer complex with
the hydrophilic, high molecular weight film-forming polymer. This
complex can be water-soluble or water-insoluble, but is preferably
water-insoluble.
[0088] One function of the ladder-like crosslinker is to provide
insolubility and limited swelling to the blend. In essence, the
ladder-like crosslinker can serve as a gel-forming agent. Suitable
complementary reactive functional groups for the ladder-like
crosslinker, include hydroxyl, carboxyl, phenolic, sulfo, and amino
groups, all of which are capable of non-covalently crosslinking the
hydrophilic polymer blend. Typically, these polymers will have a
length within the range of about 10,000 to 1,000,000 g/mol,
optimally 100,000-300,000 g/mol. It may be desirable to select a
ladder-like crosslinker that has a lower molecular weight than that
of the film-forming polymer.
[0089] Exemplary long chain polymers suitable for use as the
ladder-like crosslinker include, by way of illustration and not
limitation, hydrophilic polymers, water-swellable water-insoluble
polymers, and water-soluble polymers, as described above for use as
film-forming polymers.
[0090] As noted above, the same materials may be used as either the
film-forming polymer or as the ladder-like non-covalent crosslinker
since both the film-forming polymer and the ladder-like
non-covalent crosslinker represent the same class of polymers,
which bear reactive groups, capable of hydrogen, electrostatic or
ionic bonding, in the repeating units of polymer backbones. Their
function and role in the composition will be determined by the
amount of material present in the composition, where the material
present in the greatest quantity functions as the film-forming
polymer, i.e., the difference between the film-forming polymer and
its ladder-like crosslinker is an issue of their concentration. The
predominant component is typically referred to as the film-forming
polymer, while the minor component is referred to as the
ladder-like non-covalent crosslinker. Thus, for the purposes of
present invention, it is not critical what polymer serves as the
major film-forming polymer, and what serves as the ladder-like
non-covalent crosslinker.
[0091] Nevertheless, the complementarity of the film-forming
polymer and the ladder-like non-covalent crosslinker is an
important aspect of the invention. A list of exemplary
complementary functional groups and the types of bonding for the
film-forming polymer and the ladder-like non-covalent crosslinker
is presented below. A distinctive feature of hydrogen bonding
between proton donating and proton accepting complementary groups
is that both the reactive groups and the product of their
interaction bear no electric charge. Electrostatic bonding is the
interaction of proton donating and proton accepting groups, which
are initially uncharged, with the formation of ionic bond. And
lastly, ionic bonding is the interaction of oppositely charged
groups with the formation of ionic bond.
2 Type of Complementary groups Bonding --COOH, --PhOH, --NH.sub.2,
--NHR, --NR.sub.2 Electrostatic --SO.sub.3H --OH, --C--O--C--,
Hydrogen --CONH.sub.2, --CONHR, --CONR.sub.2 --COO.sup.-
--NH.sub.3.sup.+, --NH.sub.2R.sup.+, --NHR.sub.2.sup.+, Ionic
--NR.sub.3.sup.+ --OH --COOH, --SO.sub.3H, --CONH.sub.2, Hydrogen
--CONHR, --CONR.sub.2
[0092] --R and -Ph represent alkyl or phenyl radicals,
respectively.
[0093] The composition may also contain a second ladder-like
non-covalent crosslinker. Like the first ladder-like crosslinker,
the second ladder-like crosslinker also contains complementary
reactive functional groups in the repeating units of the backbone.
However, the second ladder-like crosslinker is capable of forming a
ladder-like interpolymer complex with the film-forming polymer or
the first ladder-like crosslinker.
[0094] C. Carcass-Like Non-Covalent Crosslinkers
[0095] The carcass-like non-covalent crosslinker preferably
contains complementary reactive functional groups at its ends, and
is capable of forming a carcass-like complex with at least one of
the film-forming polymer or the ladder-like non-covalent
crosslinker. Typically, the carcass-like non-covalent crosslinker
is a hydrophilic oligomer with reactive groups at both ends of its
short chain.
[0096] One function of the carcass-like crosslinker is to impart
the adhesive properties to the hydrophilic polymer blend. Suitable
complementary reactive functional groups for the carcass-like
crosslinker, include hydroxyl, carboxyl and amino groups, all of
which are capable of non-covalently crosslinking the hydrophilic
polymer blend.
[0097] Preferably, the carcass-like non-covalent crosslinker is
terminated with hydroxyl groups, amino or carboxyl groups.
Generally, the carcass-like non-covalent crosslinker will have a
molecular weight in the range from about 45 to about 800,
preferably in the range of about 45 to about 600.
[0098] Exemplary carcass-like crosslinkers include, by way of
illustration and not limitation, monomeric and oligomeric alkylene
glycols comprising about 1-20 alkylene oxide units in their chains
such as polyalkylene glycols (e.g., ethylene glycol, 1,2-propylene
glycol (PG) and polyethylene glycol), including carboxyl-terminated
oligomeric alkylene glycols such as carboxyl-terminated
polyalkylene glycols, and amino-terminated oligomeric alkylene
glycols such as amino-terminated polyalkylene glycols; polyalcohols
such as low molecular weight polyhydric alcohols (e.g. glycerol or
sorbitol); alkane diols from butane diol to octane diol; carbonic
diacids; ether alcohols (e.g., glycol ethers); and poly(alkylene
glycol diacids), and combinations thereof.
[0099] Preferred carcass-like crosslinkers are oligo-alkylene
glycols such as polyethylene glycol (PEG), carboxyl-terminated
oligo-alkylene glycols such as carboxyl-terminated poly(ethylene
glycols), and polyhydric alcohols. Particularly preferred
crosslinkers are low molecular weight polyalkylene glycols
(molecular weight 200-600) such as polyethylene glycol 400.
[0100] The carcass-like crosslinker may also serve as a low
molecular weight plasticizer, for example, when the carcass-like
crosslinker is a compound such as polyethylene glycol 400. Such
carcass-like crosslinker plasticizers would preferably be miscible
with the other components and be able to decrease the glass
transition temperature (Tg) and elasticity modulus of the
composition. Alternatively, a different compound can be included as
a low molecular weight plasticizer.
[0101] The carcass-like non-covalent crosslinker typically has a
glass transition temperature T.sub.g in the range of about
-100.degree. C. to about -30.degree. C. and a melting temperature
T.sub.m lower than about 20.degree. C. The carcass-like
non-covalent crosslinker may be also amorphous. The difference
between the T.sub.g values of the film-forming polymer and the
ladder-like non-covalent crosslinker the T.sub.g value of the
carcass-like non-covalent crosslinker is preferably greater than
about 50.degree. C., more preferably greater than about 100.degree.
C., and most preferably in the range of about 150.degree. C. to
about 300.degree. C. The film-forming polymer, ladder-like
non-covalent crosslinker and carcass-like non-covalent crosslinker
should be compatible, i.e. capable of forming a homogeneous
blend.
[0102] As discussed in U.S. Patent Publication No. 2002/0037977 to
Feldstein et al., the ratio of the carcass-like non-covalent
crosslinker to the other components of the composition can affect
both adhesive strength and the cohesive strength. For example, the
carcass-like non-covalent crosslinker decreases the glass
transition of the film-forming polymer/carcass-like non-covalent
crosslinker blend to a greater degree than predicted by the Fox
equation, which is given by equation (1) 1 1 T g predicted = w pol
T g pol + w pl T g pl ( 1 )
[0103] where T.sub.g predicted is the predicted glass transition
temperature of the blend, w.sub.pol is the weight fraction of the
film-forming polymer in the blend, w.sub.pl is the weight fraction
of the carcass-like non-covalent crosslinker in the blend, T.sub.g
pol is the glass transition temperature of the film-forming
polymer, and T.sub.g pl is the glass transition temperature of the
carcass-like non-covalent crosslinker. As also explained in that
patent application, an adhesive composition having optimized
adhesive and cohesive strength can be prepared by selecting the
film-forming polymer and carcass-like non-covalent crosslinker, and
their relative amounts to give a predetermined deviation from
T.sub.g predicted. Generally, to maximize adhesion, the
predetermined deviation from T.sub.g predicted will be the maximum
negative deviation, while to minimize adhesion, any negative
deviation from T.sub.g predicted is minimized.
[0104] As noted above, the composition may also contain a second
ladder-like non-covalent crosslinker that is capable of forming a
ladder-like interpolymer complex with the film-forming polymer or
the first ladder-like crosslinker. When a second ladder-like
crosslinker is included, the carcass-like non-covalent crosslinker
can also be capable of forming a carcass-like complex with the
second ladder-like crosslinker.
[0105] For example, an acrylate polymer (Eudragit E 100) can be
selected as the film-forming polymer. The first ladder-like
crosslinker can be Eudragit L-100-55, which forms a ladder-like
interpolymer complex with the Eudragit E 100 film-forming polymer.
The second ladder-like crosslinker can be PVP, which forms a
ladder-like interpolymer complex with the Eudragit L-100-55 first
ladder-like crosslinker. The carcass-like crosslinker can be PEG,
which forms a carcass-like complex with the second ladder-like
crosslinker PVP.
[0106] D. Exemplary Adhesive Compositions
[0107] 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 polymers 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, polymethacrylic acids, polymaleic acids, homo-
and co-polymers thereof, as well as sulfonic acid and alginic
acid.
[0108] 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.
[0109] 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
complexes were first described by Kabanov et al. (1979) Vysokomol.
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.
[0110] Due to the decrease in free volume 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.
[0111] There are certain preferred combinations of components in
the adhesive composition. For example, 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 polyacrylic acid, polymethacrylic acid, polymaleic
acid, polyvinyl alcohol, poly(hydroxyalkyl acrylate),
poly(hydroxyalkyl methacrylate) such as poly(hydroxyethyl
methacrylate), methacrylic acid copolymer, or any other
carboxyl-containing Eudragit.
[0112] Similarly, when the film-forming polymer is a poly(dialkyl
aminoalkyl acrylate) or poly(dialkyl aminoalkyl methacrylate), then
the ladder-like crosslinker is typically a hydroxyl containing
polymer such as polyacrylic acid, polymethacrylic acid, or
polymaleic acid. When the film-forming polymer is a polyvinyl
alcohol, polyvinyl phenol, or poly(hydroxyalkyl acrylate) such as
poly(hydroxyethyl methacrylate), the ladder-like crosslinker is
preferably a poly(N-vinyl lactam) such as poly(N-vinyl pyrrolidone)
or poly(N-vinyl caprolactam), as well as a homopolymer or copolymer
of polyacrylic, polymethacrylic or polymaleic acid. When the
film-forming polymer is polyethylene oxide, then appropriate
ladder-like crosslinkers are polyacids such as homopolymers and
copolymers of acrylic, methacrylic and maleic acids. Copolymers of
poly(N-dialkylamino alkyl acrylate) with alkyl acrylate,
methacrylate or ethacrylate monomers, a copolymer of
poly(N-dialkylamino alkyl methacrylate) and alkyl acrylate,
methacrylate or ethacrylate monomers can be used instead of the
corresponding homopolymers both as film-forming polymers or
ladder-like crosslinkers.
[0113] 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.
[0114] Other examples of suitable blends are shown below:
3 film-forming carcass-like polymer ladder-like crosslinker
crosslinker PVCap Eudragit series L and S PEG and carboxyl such as
L 100 and L 100-55, terminated PEG PAA, PMA, PVA, polyvinyl phenol,
and PolyHEMA PNIPAM Eudragit series L and S PEG and carboxyl such
as L 100, L 100-55, terminated PEG S 100, PAA, PMA, alginic acid,
PVA, and PolyHEMA PEO Eudragit series L and S Propylene glycol,
such as L 100, L 100-55, Glycerol, PEG, PEG- and S 100; PAA, PMA,
diacid alginic acid, Gantrez ES-225, Gantrez ES-425, polyvinyl
phenol PAA, PMA Eudragit series E, L, R PEG and S such as E-100*
and L 100-55, and polyvinyl amine Eudragit E-100* PAA, PMA,
Eudragit series Carboxyl terminated L such as L 100 and L PEG,
carbonic di- and 100-55, and alginic acid polyvalent acids**
*Eudragit E-100 is a copolymer of 2-dimethylaminoethyl
methacrylate, butyl methacrylate and methyl methacrylate 2:1:1,
commercially available from Rohm Pharma Polymers **As described in
U.S. Pat. No. 6,576,712
[0115] To illustrate the approach 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.
[0116] The properties of adhesive polymer 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
polymer 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.
[0117] Another exemplary composition comprises: a film-forming
polymer selected from water-swellable water-insoluble polymers and
water-soluble polymers; a ladder-like non-covalent crosslinker that
contains complementary reactive functional groups in the repeating
units of the backbone, and is capable of forming a ladder-like
interpolymer complex with the film-forming polymer; and a
carcass-like non-covalent crosslinker that contains complementary
reactive functional groups at its ends, and is capable of forming a
carcass-like complex with at least one of the film-forming polymer
or the ladder-like non-covalent crosslinker. The amount of the
film-forming polymer is greater than the amount of either of the
crosslinkers.
[0118] III. Adhesive Compositions-Optional Components
[0119] The adhesive compositions of the present invention are
useful in any number of additional contexts, wherein adhesion of a
product to a body surface is called for or desirable. These
applications include, for example, drug delivery systems; wound
dressings; conductive hydrogels; pressure-relieving cushions for
application to a foot including heel cushions, elbow pads, knee
pads, shin pads, forearm pads, wrist pads, finger pads, corn pads,
callus pads, blister pads, bunion pads, and toe pads, all of which
can include active agents for the treatment of dicubitis, veinous
and diabetic foot ulcers, and the like; intraoral applications such
as teeth whitening strips, breath freshener films for treating
halitosis, and oral care products to treat sore throat, mouth
ulcer/canker sore, gingivitis, periodontal and oral infections,
periodontal lesions, dental caries or decay, and other periodontal
diseases; transmucosal applications; adhesives for affixing medical
devices, diagnostic systems and other devices to be affixed to a
body surface; sealants for ostomy devices, prostheses, and face
masks; sound, vibration or impact absorbing materials; carriers in
cosmetic and cosmeceutical gel products; as well as many other uses
known to or readily ascertainable by those of ordinary skill in the
art, or as yet undiscovered.
[0120] Depending upon the particular intended use, there are
numerous components that can be incorporated in the composition or
combined with the composition to form a medical patch, bandage or
device. These are detailed below.
[0121] A. Active Agents
[0122] Any of the presently described compositions may be modified
so as to contain an active agent, and thereby act as an active
agent delivery system when applied to a body surface in active
agent-transmitting relation thereto. The release of active agents
loaded into the compositions typically involves both absorption of
water and desorption of the agent via a swelling-controlled
diffusion mechanism. Active agent-containing compositions may be
employed, by way of example, in transdermal drug delivery systems,
in wound dressings, in topical pharmaceutical formulations, in
implanted drug delivery systems, in oral dosage forms, in teeth
whitening strips, and the like.
[0123] Such agents would be present in a cosmeceutically or
therapeutically effective amount. Suitable active agents that may
be incorporated into the present compositions and delivered
topically or systemically (e.g., with a transdermal, oral, or other
dosage form suitable for systemic administration of a drug)
include, but are not limited to: adrenergic agents; adrenocortical
steroids; adrenocortical suppressants; alcohol deterrents;
aldosterone antagonists; amino acids; ammonia detoxicants; anabolic
agents; analeptic agents; analgesic agents; androgenic agents;
anesthetic agents; anorectic compounds; anorexic agents;
antagonists; anterior pituitary activators and anterior pituitary
suppressants; anti-acne agents; anti-adrenergic agents;
anti-allergic agents; anti-amebic agents; anti-androgen agents;
anti-anemic agents; anti-anginal agents; anti-anxiety agents;
anti-arthritic agents; anti-asthmatic agents and other respiratory
drugs; anti-atherosclerotic agents; anti-bacterial agents;
anti-cancer agents, including antineoplastic drugs, and anti-cancer
supplementary potentiating agents; anticholinergics;
anticholelithogenic agents; anti-coagulants; anti-coccidal agents;
anti-convulsants; anti-depressants; anti-diabetic agents;
anti-diarrheals; anti-diuretics; antidotes; anti-dyskinetics
agents; anti-emetic agents; anti-epileptic agents; anti-estrogen
agents; anti-fibrinolytic agents; anti-fungal agents; anti-glaucoma
agents; antihelminthics; anti-hemophilic agents; anti-hemophilic
Factor; anti-hemorrhagic agents; antihistamines;
anti-hyperlipidemic agents; anti-hyperlipoproteinemic agents;
antihypertensive agents; anti-hypotensives; anti-infective agents
such as antibiotics and antiviral agents; anti-inflammatory agents,
both steroidal and non-steroidal; anti-keratinizing agents;
anti-malarial agents; antimicrobial agents; anti-migraine agents;
anti-mitotic agents; anti-mycotic agents; antinauseants;
antineoplastic agents; anti-neutropenic agents; anti-obsessional
agents; anti-parasitic agents; antiparkinsonism drugs;
anti-pneumocystic agents; anti-proliferative agents; anti-prostatic
hypertrophy drugs; anti-protozoal agents; antipruritics;
anti-psoriatic agents; antipsychotics; antipyretics;
antispasmodics; anti-rheumatic agents; anti-schistosomal agents;
anti-seborrheic agents; anti-spasmodic agents; anti-tartar and
anti-calculus agents; anti-thrombotic agents; anti-tubercular
agents; antitussive agents; anti-ulcerative agents; anti-urolithic
agents; antiviral agents; anxiolytics; appetite suppressants;
attention deficit disorder (ADD) and attention deficit
hyperactivity disorder (ADHD) drugs; bacteriostatic and
bactericidal agents; benign prostatic hyperplasia therapy agents;
blood glucose regulators; bone resorption inhibitors;
bronchodilators; carbonic anhydrase inhibitors; cardiovascular
preparations including anti-anginal agents, anti-arrhythmic agents,
beta-blockers, calcium channel blockers, cardiac depressants,
cardiovascular agents, cardioprotectants, and cardiotonic agents;
central nervous system (CNS) agents; central nervous system
stimulants; choleretic agents; cholinergic agents; cholinergic
agonists; cholinesterase deactivators; coccidiostat agents;
cognition adjuvants and cognition enhancers; cough and cold
preparations, including decongestants; depressants; diagnostic
aids; diuretics; dopaminergic agents; ectoparasiticides; emetic
agents; enzymes which inhibit the formation of plaque, calculus or
dental caries; enzyme inhibitors; estrogens; fibrinolytic agents;
fluoride anticavity/antidecay agents; free oxygen radical
scavengers; gastrointestinal motility agents; genetic materials;
glucocorticoids; gonad-stimulating principles; hair growth
stimulants; hemostatic agents; herbal remedies; histamine H2
receptor antagonists; hormones; hormonolytics; hypnotics;
hypocholesterolemic agents; hypoglycemic agents; hypolipidemic
agents; hypotensive agents; HMGCoA reductase inhibitors; immunizing
agents; immunomodulators; immunoregulators; immunostimulants;
immunosuppressants; impotence therapy adjuncts; inhibitors;
keratolytic agents; leukotriene inhibitors; LHRH agonists; liver
disorder treatments; luteolysin agents; memory adjuvants; mental
performance enhancers; metal chelators such as
ethylenediaminetetraacetic acid, tetrasodium salt; mitotic
inhibitors; mood regulators; mucolytics; mucosal protective agents;
muscle relaxants; mydriatic agents; narcotic antagonists; nasal
decongestants; neuroleptic agents; neuromuscular blocking agents;
neuroprotective agents; nicotine; NMDA antagonists; non-hormonal
sterol derivatives; nutritional agents, such as vitamins, essential
amino acids and fatty acids; ophthalmic drugs such as antiglaucoma
agents; oxytocic agents; pain relieving agents; parasympatholytics;
peptide drugs; plasminogen activators; platelet activating factor
antagonists; platelet aggregation inhibitors; post-stroke and
post-head trauma treatments; potentiators; progestins;
prostaglandins; prostate growth inhibitors; proteolytic enzymes as
wound cleansing agents; prothyrotropin agents; psychostimulants;
psychotropic agents; radioactive agents; regulators; relaxants;
repartitioning agents; scabicides; sclerosing agents; sedatives;
sedative-hypnotic agents; selective adenosine A1 antagonists;
serotonin antagonists; serotonin inhibitors; serotonin receptor
antagonists; steroids, including progestogens, estrogens,
corticosteroids, androgens and anabolic agents; smoking cessation
agents; stimulants; suppressants; sympathomimetics; synergists;
thyroid hormones; thyroid inhibitors; thyromimetic agents;
tranquilizers; tooth desensitizing agents; tooth whitening agents
such as peroxides, metal chlorites, perborates, percarbonates,
peroxyacids, and combinations thereof; unstable angina agents;
uricosuric agents; vasoconstrictors; vasodilators including general
coronary, peripheral and cerebral; vulnerary agents; wound healing
agents; xanthine oxidase inhibitors; and the like.
[0124] Specific active agents with which the present adhesive
compositions are useful include, without limitation, anabasine,
capsaicin, oxybutynin, isosorbide dinitrate, aminostigmine,
nitroglycerine, verapamil, propranolol, silabolin, foridone,
clonidine, cytisine, phenazepam, nifedipine, fluacizin, and
salbutamol.
[0125] The composition can also include any cosmetically active
agent. As used herein, a "cosmetically active agent" includes any
substance that can be released from the composition to effect a
desired change in the appearance of the skin, teeth or surrounding
tissue, or which imparts a socially desirable characteristic to the
user, such as fresh breath. For example, a cosmetically active
agent can be a breath freshener or an agent which effects whitening
or bleaching of the teeth. Recognizing that in some cultures or in
certain segments of Western society coloration of the teeth may be
significant or desirable, the cosmetically active agent can also be
any agent which imparts a color or tint to the teeth.
[0126] B. Other Ingredients
[0127] The compositions made by the methods described herein, may
also comprise conventional additives such as absorbent fillers,
preservatives, pH regulators, plasticizers, softeners, thickeners,
antioxidants, pigments, dyes, conductive species, refractive
particles, stabilizers, toughening agents, tackifiers or adhesive
agents, detackifiers, flavorants and sweeteners, antioxidants, and
permeation enhancers. In those embodiments where adhesion is to be
reduced or eliminated, conventional detackifying agents may be
used. These additives, and the amounts thereof, are selected in
such a way that they do not significantly interfere with the
desired chemical and physical properties of the hydrogel
composition.
[0128] 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, clay, lactose, guar gum, kaolin, mannitol,
colloidal silica, alumina, zinc oxide, titanium oxide, magnesium
silicate, magnesium aluminum silicate, hydrophobic starch, calcium
sulfate, calcium stearate, calcium phosphate, calcium phosphate
dihydrate, and woven, non-woven paper, and cotton materials. Other
suitable fillers are inert, i.e., substantially non-adsorbent, and
include, for example, polyethylenes, polypropylenes, polyurethane
polyether amide copolymers, polyesters and polyester copolymers,
nylon, and rayon. One preferred filler is colloidal silica, e.g.,
Cab-O-Sil.RTM. (available from Cabot Corporation, Boston
Mass.).
[0129] Preservatives include, by way of example, p-chloro-m-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.
[0130] Compounds useful as pH regulators include, but are not
limited to, glycerol buffers, citrate buffers, borate buffers,
phosphate buffers, and citric acid-phosphate buffers, which may be
included so as to ensure that the pH of the composition is
compatible with that of an individual's body surface. In addition,
when the composition is to be applied to a tooth surface, the
addition of a pH regulator can insure that the pH of the
composition is compatible with that of the environment of the mouth
and will not leach minerals from the surface of the teeth; in order
to optimize whitening without demineralization of the teeth,
calcium and/or fluoride salts can be included in the
composition.
[0131] 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 citrate 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; lower
diols such as 1,2- and 1,3-propylene glycol; low molecular weight
poly(alkylene oxides) such as polypropylene glycol and polyethylene
glycol; polyhydric alcohols such as glycerol; sorbitol; tartaric
acid esters such as dibutyl tartrate; and mixtures thereof.
[0132] Since the carcass-like non-covalent crosslinker may itself
act as a plasticizer, it is not generally necessary to incorporate
an added plasticizer. However, inclusion of an additional low
molecular weight plasticizer in the composition may, in some cases,
be advantageous. For example, both the adhesive and the water
absorbing properties of the adhesive composition can be easily
controlling by adding appropriate amounts of a plasticizer. The
mechanism of plasticization results in the increase of free volume.
By increasing the free volume, the plasticizer modifies the balance
between cohesion energy and the free volume, which is a factor
controlling the adhesion. Since the film-forming polymer,
ladder-like crosslinker and carcass-like crosslinker are preferably
hydrophilic materials, suitable plasticizers are also preferably
hydrophilic in nature.
[0133] Preferred thickeners 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.
[0134] Pigments and dyes of the type commonly used with a food,
drugs, or cosmetics in connection with the human body, especially
color additives permitted for use in foods which are classified as
"certifiable" or "exempt from certification," can be used to color
the composition. These colorizing compounds can be derived from
natural sources such as vegetables, minerals or animals, or can be
man-made counterparts of natural derivatives.
[0135] Colorizing compounds presently certified under the Food Drug
& Cosmetic Act for use in food and ingested drugs include dyes
such as FD&C Red No. 3 (sodium salt of tetraiodofluorescein);
Food Red 17 (disodium salt of
6-hydroxy-5-{(2-methoxy-5-methyl-4-sulphophenyl)azo}-2-naphthalen-
esulfonic acid); Food Yellow 13 (sodium salt of a mixture of the
mono and disulfonic acids of quinophthalone or
2-(2-quinolyl)indanedione); FD&C Yellow No. 5 (sodium salt of
4-p-sulfophenylazo-1-p-sulfophenyl-5-hydroxy- pyrazole-3 carboxylic
acid); FD&C Yellow No. 6 (sodium salt of
p-sulfophenylazo-B-napthol-6-monosulfonate); FD&C Green No. 3
(disodium salt of
4-{[4-(N-ethyl-p-sulfobenzylamino)-phenyl]-(4-hydroxy-2-sulfonium-
-phenyl)-methylene}-[1-(N-ethyl-N-p-sulfobenzyl)-3,5-cyclohexadienimine]);
FD&C Blue No. 1 (disodium salt of
dibenzyldiethyl-diaminotriphenylcarbino- l trisulfonic acid
anhydrite); FD&C Blue No. 2 (sodium salt of disulfonic acid of
indigotin); FD&C Red No. 40; Orange B; and Citrus Red No. 2;
and combinations thereof in various proportions.
[0136] Colorizing compounds exempt from FDA certification include
annatto extract; beta-apo-8'-carotenal; beta-carotene; beet powder;
canthaxanthin; caramel color; carrot oil; cochineal extract
(carmine); toasted, partially defatted, cooked cottonseed flour;
ferrous gluconate; fruit juice; grape color extract; grape skin
extract (enocianina); paprika; paprika oleoresin; riboflavin;
saffron; turmeric; turmeric oleoresin; vegetable juice; and
combinations thereof in various proportions.
[0137] The form of the colorizing compound for use in the
composition preferably includes dye form additives, but may also
include lake forms which are compatible with the materials used in
the hydrogel compositions. Water soluble dyes, provided in the form
of powders, granules, liquids or other special-purpose forms, can
be used in accordance with the present method. Preferably, the
"lake", or water insoluble form of the dye, is used. For example,
if a suspension of a colorizing compound is to be used, a lake form
additive can be employed. Suitable water insoluble dye lakes
prepared by extending calcium or aluminum salts of FD&C dyes on
alumina include FD&C Green #1 lake, FD&C Blue #2 lake,
FD&C R&D #30 lake and FD&C # Yellow 15 lake.
[0138] Other suitable colorizing compounds include non-toxic, water
insoluble inorganic pigments such as titanium dioxide; chromium
oxide greens; ultramarine blues and pinks; and ferric oxides. Such
pigments preferably have a particle size in the range of about 5 to
about 1000 microns, more preferably about 250 to about 500 microns.
The concentration of the colorizing compound in the composition is
preferably from about 0.05 to 10 wt %, and is more preferably from
about 0.1 to 5 wt %. More than one colorizing compound can be
present so that multiple colors are imparted therein. These
multiple colors can be patterned into stripes, dots, swirls, or any
other design which a consumer may find pleasing. The colorizing
compound can also be used with other appearance-enhancing
substances such as glitter particles.
[0139] The compositions can be rendered electrically conductive for
use with biomedical electrodes and in other electrotherapy
contexts, i.e., to attach an electrode or other electrically
conductive member to the body surface, by the inclusion of
conductive species. For example, the composition, formulated so as
to exhibit pressure-sensitive adhesion, 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
hydrogel composition so as to enhance conductivity and contain a
conductive species. In order to enhance conductivity, adding of
poly-2-acrylamido-2-methyl propane sulfonic acid or its use as the
film-forming polymer or the ladder-like crosslinker can be helpful.
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 thereof. Examples of ionically conductive
electrolytes include, but are not limited to, ammonium sulfate,
ammonium acetate, monoethanolamine acetate, diethanolamine acetate,
sodium lactate, sodium citrate, magnesium acetate, magnesium
sulfate, sodium acetate, calcium chloride, magnesium chloride,
calcium sulfate, lithium chloride, lithium perchlorate, sodium
citrate, sodium chloride, and potassium 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
compositions of the current invention, typically the electrolyte is
present at a concentration in the range of about 0.1-15 wt % of the
composition.
[0140] Refractive particles are particles that refract and reflect
light striking the adhesive and the color of the reflected light
changes as the angle at which the composition is viewed is changed.
Exemplary refractive particles are those made from embossed,
aluminized polyester.
[0141] Suitable stabilizers include, parabens such as methyl
paraben and propyl paraben.
[0142] Tackifiers or adhesive agents can also be included to
improve the adhesive and tack properties of the composition, which
is particularly beneficial to maintain adhesiveness when the
composition is used in a manner such that it is subjected to a
large amount of mechanical stress. The mechanism underlying tack
improvement results from the large size and hydrophobic character
of tackifier molecules. When mixed with interpolymer complex
composition, the tackifier can increase the free volume causing
only a slight impact upon the energy of cohesion. Suitable
tackifiers may be solid or liquid. Exemplary materials include
tacky rubbers such as polyisobutylene, polybutadiene, butyl rubber,
polystyrene-isoprene copolymers, polystyrene-butadiene copolymers,
and neoprene (polychloroprene). Preferred adhesive agents include
low molecular weight polyisobutylene and butyl rubber. Other
examples of suitable tackifiers herein are those that are
conventionally used with pressure sensitive adhesives, e.g.,
rosins, rosin esters (for example Sylvagum.RTM. RE 85K (formerly
Zonester.RTM. 85K Resin) available from Arizona Chemical),
polyterpenes, and hydrogenated aromatic resins in which a very
substantial portion, if not all, of the benzene rings are converted
to cyclohexane rings (for example, the Regalrez family of resins
manufactured by Hercules, such as Regalrez 1018, 1033, 1065, 1078
and 1126, and Regalite R-100, the Arkon family of resins from
Arakawa Chemical, such as Arkon P-85, P-100, P-115 and P-125) and
hydrogenated polycyclic resins (typically dicyclopentadiene resins,
such as Escorez 5300, 5320, 5340 and 5380 manufactured by Exxon
Chemical Co.).
[0143] In those embodiments wherein adhesion is to be reduced or
eliminated, conventional detackifying agents may also be used.
Suitable detackifiers include, crosslinked poly vinyl pyrrolidone,
silica gel, bentonites, and so forth.
[0144] For compositions that are to be used in the oral cavity, any
natural or synthetic flavorant or food additive, such as those
described in Chemicals Used in Food Processing, Pub. No. 1274,
National Academy of Sciences, pages 63-258 (the entire disclosure
of which is herein incorporated by reference) can be included in
the compositions of the invention. Suitable flavorants include
wintergreen, peppermint, spearmint, menthol, fruit flavors,
vanilla, cinnamon, spices, flavor oils 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.
Preferably, the composition comprises from about 0.1-5 wt %
flavorant. Sweeteners can also be included, such as sucrose,
fructose, aspartame, xylitol and saccharine. Preferably, the
composition comprises sweeteners in an amount from about 0.001-5.0
wt %.
[0145] Heat, light, impurities, and other factors can all result in
oxidation of the hydrogel composition. Thus, antioxidants can be
included in the composition to protect against light-induced
oxidation, chemically induced-oxidation, and thermally-induced
oxidative degradation during processing and/or storage. Oxidative
degradation, as will be appreciated by those in the art, involves
generation of peroxy radicals, which in turn react with organic
materials to form hydroperoxides. Primary antioxidants are peroxy
free radical scavengers, while secondary antioxidants induce
decomposition of hydroperoxides, and thus protect a material from
degradation by hydroperoxides. Most primary antioxidants are
sterically hindered phenols, and preferred such compounds for use
herein are tetrakis [methylene
(3,5-di-tert-butyl-4-hydroxyhydrocinnamate- )] methane (e.g.,
Irganox.RTM. 1010 available from Ciba-Geigy Corp., Hawthorne, N.Y.)
and 1,3,5-trimethyl-2,4,6-tris [3,5-di-t-butyl-4-hydroxy- -benzyl]
benzene (e.g., Ethanox.RTM. 330 available from Ethyl Corp.). A
particularly preferred secondary antioxidant that may replace or
supplement a primary antioxidant is
tris(2,4-di-tert-butylphenyl)phosphit- e (e.g., Irgafos.RTM. 168
available from Ciba-Geigy Corp.). Other antioxidants, including but
not limited to multi-functional antioxidants, are also useful.
Multifunctional antioxidants serve as both a primary and a
secondary antioxidant. Irganox.RTM. 1520 D, manufactured by
Ciba-Geigy is one example of a multifunctional antioxidant. Vitamin
E antioxidants, such as that sold by Ciba-Geigy as Irganox.RTM.
E17, are also useful in the present compositions. Other suitable
antioxidants include, without limitation, ascorbic acid, ascorbic
palmitate, tocopherol acetate, propyl gallate, butylhydroxyanisole
(BHA), butylated hydroxytoluene (BHT),
bis(1,2,2,6,6-pentamethyl-4-piperidinyl)-(3,5-di-tert-butyl-4-hydroxybenz-
yl)butylpropanedioate, (available as Tinuvin.RTM. 144 from
Ciba-Geigy Corp.) and a combination of octadecyl
3,5-di-tert-butyl-4-hydroxyhydrocin- namate (also known as
octadecyl 3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)pr- opionate)
(Naugard.RTM. 76 available from Uniroyal Chemical Co., Middlebury,
Conn.) and bis(1,2,2,6,6-pentamethyl-4-piperidinylsebacate)
(Tinuvin.RTM. 765 available from Ciba-Geigy Corp.). Preferably, the
antioxidant is present in an amount up to about 2 wt % of the
hydrogel composition; typically, the amount of antioxidant is in
the range of about 0.05 wt % to 1.5 wt %.
[0146] One or more permeation enhancers can be included in the
compositions described herein. With some active agents, it may be
desirable to administer the agent along with a suitable permeation
enhancer in order to achieve a therapeutically effective flux
through the skin or mucosa. Selection of suitable permeation
enhancers will depend upon the agent being delivered, as well as
the enhancer's compatibility with the other components of the
composition.
[0147] Exemplary permeation enhancers include, by way of
illustration and not limitation, sulfoxides such as
dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C.sub.10MSO);
ethers such as diethylene glycol monoethyl ether (available
commercially as Transcutol.RTM.) and diethylene glycol monomethyl
ether; surfactants such as sodium laurate, sodium lauryl sulfate,
cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer
(231, 182, 184), Tween.RTM. (20, 40, 60, 80) and lecithin (U.S.
Pat. No. 4,783,450 to Fawzi et al.); the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (Azone.RTM. available from
Nelson Research & Development Co., Irvine, Calif.; see U.S.
Pat. No. 4,557,934 to Cooper, and U.S. Pat. Nos. 3,989,816,
4,316,893, and 4,405,616 to Rajadhyaksha); alcohols such as
ethanol, propanol, octanol, decanol, benzyl alcohol, and the like;
fatty acids such as lauric acid, oleic acid and valeric acid; fatty
acid esters such as isopropyl myristate, isopropyl palmitate,
methylpropionate, and ethyl oleate; polyols and esters thereof such
as propylene glycol, ethylene glycol, glycerol, butanediol,
polyethylene glycol, and polyethylene glycol monolaurate (PEGML;
see, e.g., U.S. Pat. No. 4,568,343 to Leeper et al.); amides and
other nitrogenous compounds such as urea, dimethylacetamide,
dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone,
ethanolamine, diethanolamine and triethanolamine; terpenes;
alkanones; and organic acids, particularly salicylic acid and
salicylates, citric acid and succinic acid; and mixtures
thereof.
[0148] A substrate can also be affixed to the composition. The
substrate can be any surface that the composition is adhered to
during manufacture, and can be a permanent substrate (e.g., a
backing member) or a temporary substrate (e.g., a manufacturing
tool or equipment surface or a release liner). Exemplary substrates
include flexible, resilient materials such as fabric, and open-cell
foams such as polyurethane, polystyrene, and polyethylene foams;
polyesters; polyethylene; polypropylene; polyurethanes; polyether
amides; and non-polymeric materials such as waxes (e.g.,
microcrystalline or paraffin waxes) a or wax/foam laminate. The
substrate is typically in the range of about 15 microns to about
250 microns in thickness. The substrate can also be embedded or
decorated with decorative items such as beads, rhinestones, or the
like, as long as these items do not interfere with the
visco-elastic properties of the substrate required for proper
deformation of the composition onto the body surface. The substrate
can also display letters, words, or images designed to be pleasing
or attractive to a consumer. The substrate can also be translucent
so that the composition is unobtrusive when worn. However, the
substrate or the composition can optionally be colored, so that the
composition is easily seen when worn. Preferably, if coloring is
desired, the color will be present in the substrate. For example,
the substrate can be colored with bright or vibrant colors which a
consumer may find pleasing. The substrate can therefore comprise a
colorizing compound, such as, for example, a dye, pigment or
substance that can impart color when added to the material forming
the substrate.
[0149] The composition may also be attached to a release liner,
which is a disposable element that serves to protect the system
prior to application. The release liner should be formed from a
material impermeable to any active agents, as well as the
composition itself, and that is easily stripped from the adhesive
composition. Release liners are typically treated with silicone or
fluorocarbons, and are commonly made from polyesters and
polyethylene terephthalate.
[0150] The compositions of the invention are also suitable for use
in a delivery system or patch, for example a transdermal drug
delivery device. Exemplary systems would contain a drug reservoir,
an outwardly facing backing layer, and a means for affixing the
system to a body surface. In manufacturing such systems, the
composition may be cast or extruded onto a backing layer or release
liner, and serves as the skin-contacting face of the system. The
composition may also be used as an active agent reservoir within
the interior of such a system, with a conventional skin contact
adhesive laminated thereto to affix the system to a patient's body
surface.
[0151] Systems for the topical, transdermal, or transmucosal
administration of an active agent typically may contain on of more
of the following: a reservoir containing an effective amount of an
active agent; an adhesive means for maintaining the system in
active agent transmitting relationship to a body surface; a backing
layer; a rate-controlling membrane; and a disposable release liner
that covers the otherwise exposed adhesive, protecting the adhesive
surface during storage and prior to use. In many such devices, the
reservoir can also serve as the adhesive means, and the
compositions of the invention can be used as the reservoir and/or
the adhesive means.
[0152] IV. Methods of Making
[0153] The properties of the composition of the invention are
readily controlled by adjusting one or more parameters during
fabrication. For example, the adhesive strength of the composition
can be controlled during manufacture in order to increase,
decrease, or eliminate adhesion. This can be accomplished by
varying type and/or amount of different components, or by changing
the mode of manufacture. Also, with respect to the fabrication
process, compositions prepared using a conventional melt extrusion
process have generally, although not necessarily, somewhat
different performance properties than compositions prepared using a
solution cast technique. Furthermore, the degree to which the
composition will swell upon contact with water can be varied by
material selection. The compositions may vary in appearance from
clear, transparent to translucent to opaque. In addition, certain
compositions may be rendered translucent by changing the relative
quantities of the components, or by changing the fabrication method
(translucent hydrogels are more readily obtained using solution
casting than melt extrusion). In this manner, the translucent
composition allows the user to observe the therapeutic (wound
healing) or cosmetic (e.g., whitening) process while it is
occurring and determine when the desired effect has been
obtained.
[0154] The compositions described herein are generally melt
extrudable, and thus may be prepared using a simple blending and
extruding process. The components of the composition are weighed
out and then admixed, for example using a Brabender or Baker
Perkins Blender, generally although not necessarily at an elevated
temperature, e.g., about 90 to 170.degree. C., typically 100 to
140.degree. 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
composition 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 member. 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.
[0155] Alternatively, the compositions 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 admixture and casting are preferably carried
out at ambient temperature. The material coated with the film is
then baked at a temperature in the range of about 80 to 100.degree.
C., optimally about 90.degree. C., for time period in the range of
about one to four hours, optimally about two hours. Accordingly,
one embodiment of the invention is a method for preparing a
composition of the invention, which involves the following steps:
preparing a solution of the components in a solvent; depositing a
layer of the solution on a substrate to provide a coating thereon;
and heating the coated substrate to a temperature in the range of
about 80 to 100.degree. C. for a time period in the range of about
1 to 4 hours, thereby providing an adhesive composition on a
substrate.
[0156] Thus, one embodiment of the invention is a method of
manufacturing an adhesive composition. First, the materials are
selected, then mixed to form an adhesive composition by melt
extrusion or solution casting. Material selection is as described
above. A film-forming polymer is selected first. Then, a
ladder-like non-covalent crosslinker is selected that (1) contains
complementary reactive functional groups in the repeating units of
the backbone, and (2) is capable of forming a ladder-like
interpolymer complex with the film-forming polymer selected.
Finally, a carcass-like non-covalent crosslinker is selected that
(1) contains complementary reactive functional groups at its ends,
and (2) is capable of forming a carcass-like complex with at least
one of the film-forming polymer selected or the ladder-like
non-covalent crosslinker selected; and wherein the amount of the
film-forming polymer is greater than the amount of the ladder-like
non-covalent crosslinker or the amount of the carcass-like
non-covalent crosslinker.
[0157] When tacky compositions are desired, solution casting is the
preferred process. For preparation of substantially nontacky
compositions, melt extrusion is preferred. Either melt extrusion or
solution casting techniques can be used to prepare translucent
compositions, although solution casting is typically preferred for
these embodiments.
[0158] Active agents can be added to the film-forming polymer,
ladder-like non-covalent crosslinker, and carcass-like non-covalent
crosslinker components, as they are all being mixed together. The
active agent can be added as a solid or as a solution to the
composition dissolved in solvent. The mixture is then cast as usual
onto a suitable substrate and allowed to dry, although a lower
drying temperature is desired when using this method of loading.
Compositions prepared in this manner can be dried at ambient
temperature for a time period ranging from about 1 hour to several
days.
[0159] Alternately, the active agent can be added after the
components are mixed and the composition prepared. One method of
loading the composition with the active agent comprises layering a
desired active agent, e.g., a tooth whitening agent, in aqueous
solution onto the surface of the composition placed on a suitable
substrate, or to place the active agent directly on the substrate.
The release liner is then assembled on top of the composition,
forming a sandwich structure, and the solution containing the
active agent is absorbed into the composition due to its
water-swellable properties. Thus, one embodiment of the invention
is a method of forming a drug-containing composition, which
involves the following steps: melt processing the components
through an extruder to form an extruded composition; extruding the
composition as a film of desired thickness onto a suitable erodible
backing member; and, when cooled, and loading the film with an
aqueous solution of the active agent, e.g., a peroxide.
Alternatively, the composition layered onto the substrate can be
submerged in a solution containing the desired concentration of
active agent, and the solution absorbed into the composition. By
measuring the rate of weight gain on absorbing the liquid, the
percent loading of the composition with the active agent can be
determined and controlled.
[0160] The invention also contemplates having a multiple layer
system. For example, it may be desirable to include additional
active agents that may not be compatible with the primary active
agent during storage. In this manner, one layer can be the primary
active agent-containing layer and the other layer(s) can contain
additional actives. These other layers can be made of the
composition of the invention, or any other biocompatible
formulation known in the art (e.g., polyisobutylene, dimethyl
siloxane, ethylene vinyl acetate, polyvinylacetate, cellulose
acetate, butyrate, propionate, ethyl cellulose and water insoluble
acrylates). In addition, depending on ordering of the layers, it
may be desired to have a tacky layer, e.g., the layer to be
positioned directly on the body surface, and a non-tacky layer,
e.g., the outer layer that is positioned nearest the clothing or
other area where contact is not desired. Another advantage of
having a multiple layer system is that the ratio of polymers used
in the outermost layer can be varied to achieve a non-tacky layers
so as to avoid having to include a separate backing layer in the
product.
[0161] A typical film thickness is from about 0.050 to 0.80 mm,
preferably 0.25 to 0.50 mm. The thickness of the film is not
critical, and can be varied according to the desired concentration
of any active agent incorporated into the film, the length of time
the composition is to be adhered to the body surface, the level of
comfort desired by the wearer, and so forth.
[0162] V. Methods of Use
[0163] In practice, the compositions can be used simply by removing
the product from its package, removing a release liner (when
included) and applying the composition to the desired body surface,
e.g., applied to the teeth that it is desired to whiten or placed
on any body surface for use as a wound dressing or drug delivery
system. The composition of the invention can be provided in a
variety of sizes and configurations.
[0164] A backing member can be included, and may be formulated to
be occlusive or impermeable to the active agent so as to reduce or
prevent leakage of the active agent, from the composition, while
the user wears the composition for the desired amount of time,
i.e., the composition will then deliver the drug uni-directionally,
e.g., only towards the body surface to which it is attached, such
as the mucosal tissue. Alternately, the backing member can be
formulated to have a predetermined permeability so as to provide
for bi-directional drug delivery, e.g., towards the mucosal surface
as well as towards the surrounding environment of the oral cavity.
The level of permeability, i.e., its selective nature, can also be
used to control the relative rates of delivery towards the
attachment surface and the surrounding environment.
[0165] The composition can be maintained in the desired location
for as little time as a few minutes, several hours, all day or
overnight, and then removed when the desired therapeutic or
cosmetic effect has been achieved. Alternately, when placed in a
moist environment such as to oral cavity, the composition can be
left in place and allowed to erode entirely. Accordingly, in one
embodiment of the invention, a method for whitening teeth may
simply comprise applying the composition to teeth in need of
whitening, while in another embodiment, the method may further
comprise removing the composition when the desired degree of
whitening has been achieved.
[0166] If desired, a translucent composition can be provided, and
is worn without being obtrusive or noticeable to others. The system
can also be designed without an active ingredient and finds utility
as a protective dressing for an oral surface, e.g., as a wound
dressing.
[0167] The composition can be worn for an extended period of time,
but will typically be worn for a predetermined period of time of
from about 10 minutes to about 24 hours, after which the
composition can be removed or will have eroded away. For tooth
whitening applications, a preferred time period is from about 10
minutes to about 8 hours (e.g., overnight), with 30 minutes to
about 1 hour also being a preferred embodiment. For other active
agents, a therapeutically or cosmeceutically effective time can be
readily determined based upon the active agent that is being used
as well as the condition being treated.
[0168] In one embodiment, the composition is a solid and is
attached to the backing member during manufacture. Accordingly, the
composition is applied in a single step. Alternately, the
composition can be a non-solid and manufactured and packaged
separate from the backing member. In that instance, the composition
is first applied by the user, followed by the user applying the
backing member to the outer surface of the composition. In either
embodiment, the user can form the composition on the body surface,
e.g., around the upper or lower teeth or other oral tissue, by
applying normal manual pressure to the backing member with the tips
of the fingers and thumbs, optionally by slightly moistening the
composition or the body surface prior to application. Assuming the
surface area of the average adult finger or thumb tip is
approximately one square centimeter, the normal pressure generated
by the finger and thumb tips is about 100,000 to about 150,000
Pascals (i.e., about 3 lbs. or 1.36 kg) per square centimeter. The
pressure is typically applied to the composition by each finger and
thumb tip for about one or two seconds. Once the pressure applied
to the backing member by the tips of the fingers and thumbs is
removed, the composition remains in the shape of, and adherent to,
the body surface onto which it was formed.
[0169] When the user is ready to remove the composition, the
composition can be removed simply by peeling it away from the body
surface. If desired, the composition can be re-adhered for
additional treatment time. Any residue left behind is minimal, and
can be removed using conventional washing, tooth or oral cavity
cleansing methods.
[0170] In one embodiment of the invention, the composition is a
solid and is a pressure sensitive adhesive and absorbs water.
[0171] The composition can also be applied as a non-solid
composition, for example applied as a liquid or gel. For example,
the user can extrude the composition from a tube onto a finger for
application to the teeth or other body surface, extrude the
composition from a tube directly onto the teeth, apply the
composition by means of a brush or other applicator, and so forth.
The erodible backing member can then be applied as separate step
after the liquid or gel is applied. After the evaporation of
solvent, the liquid or gel composition dries to form a matrix-type
polymer film or gel on the body surface. In one embodiment of this
liquid or gel film-former composition, the composition contains
sufficient water or other solvent to provide flowable property. In
another embodiment of this composition, the polymer components of
the liquid or gel composition are soluble in a water-ethanol
mixture both at ambient temperature and at refrigeration
temperatures of about 4.degree. C., and are miscible upon solvent
evaporation. In yet another embodiment of this liquid or gel
film-former composition, the polymeric composition has a Lower
Critical Solution Temperature of about 36.degree. C. in an
ethanol-water mixture. For use in the oral cavity, the resulting
film (after solvent evaporation) is preferably insoluble or slowly
soluble in saliva at body temperature so as to provide long lasting
contact between the composition and the dental enamel.
[0172] 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 make and use the compounds of the invention,
and are not intended to limit the scope of what the inventors
regard as their invention. Efforts have been made to ensure
accuracy with respect to numbers (e.g., amounts, temperatures,
etc.) but some errors and deviations should be accounted for.
Unless indicated otherwise, parts are parts by weight, temperature
is in degrees Celsius (.degree. C.), and pressure is at or near
atmospheric.
Abbreviations
[0173] DMAEMA 2-dimethylaminoethyl methacrylate
[0174] Eudragit E 100 methacrylic acid copolymer, (Rohm America
Inc.)
[0175] Eudragit L 100 methacrylic acid copolymer (Rohm America
Inc.)
[0176] Eudragit L 100-55 methacrylic acid copolymer (Rohm America
Inc.)
[0177] Eudragit S 100 methacrylic acid copolymer (Rohm America
Inc.)
[0178] Gantrez S-97 maleic acid-methylvinyl ether copolymer
(International Specialty Products)
[0179] HPC hydroxypropylcellulose, MW=1,150,000
[0180] HPMCP hydroxypropylmethylcellulose phthalate
[0181] PEO polyethylene oxide, MW=200,000 g/mol
[0182] PG 1,2-propylene glycol
[0183] PVA Poly(vinyl alcohol), MW=75,000
[0184] PVP 90 Kollidon.RTM. 90F polyvinylpyrrolidone (BASF)
[0185] PEG 400 polyethylene glycol 400
[0186] TBC tributyl citrate
[0187] TEC triethyl citrate
EXAMPLE 1
Preparation and Properties of Adhesive Compositions Based on the
Combination of the Ladder-Like and Carcass-Like Types of
Crosslinking of the Film-Forming Polymer
[0188] First, PVP 90 is selected as the film-forming polymer. In
this case, examples of complementary polymers that are able to
crosslink the PVP non-covalently by the formation of a
water-insoluble ladder-like interpolymeric complex with PVP are:
homopolymers or copolymers of polyacrylic acid (PAA),
polymethacrylic acid (PMA), homopolymers or copolymers of maleic
acid, homopolymers or copolymers of polyvinyl alcohol (PVA),
homopolymers or copolymers of polyvinyl phenol, alginic acid and
hydroxypropyl cellulose (HPC). One such non-covalent crosslinker of
PVP is a copolymer of methacrylic acid and ethyl acrylate (1:1),
commercially available from Rohm Pharma Polymers as Eudragit L
100-55. Blending the Eudragit L 100-55 with an adhesive PVP 90-PEG
400 mixture, results in the formation of an insoluble, homogeneous
single-phase mixture. Being insoluble in water, the triple
PVP-PEG-Eudragit blend was characterized in terms of Sol Fraction
(%) and Swell Ratio, as shown in the table below and in FIGS. 4 and
5).
[0189] Preparation of the films: 50 g of PEG 400 was dissolved in
200 g of ethanol. Under vigorous stirring, the Eudragit L 100-55
powder was added in the amounts indicated below. Under vigorous
stirring, the PVP 90 powder was added in amounts as indicated
below. The mixture was stirred over 2 hours to obtain a homogeneous
solution. The solution was stored over 2-5 hours to let air bubbles
dissipate. Polymer films were prepared by solution casting onto a
PET backing, followed by drying at ambient temperature over 3 days.
Films of 0.20.+-.0.03 mm were obtained. The water content in the
obtained films was measured gravimetrically by weight loss at
120.degree. C. The water content in the films was found to be in
the range 11.+-.1.5 wt %.
4 Composition (grams) Swell Ratio, Sol Swell Ratio, Sol Eudragit
PEG g/g, Fraction, %, g/g, Fraction, %, Sample PVP 90 L 100-55 400
pH = 4.6 pH = 4.6 pH = 5.6 pH = 5.6 1-1 46 4 50 45.1 60.9 60.4 60.2
1-2 41.67 8.33 50 19.0 57.0 28.1 58.5 1-3 38.46 11.54 50 14.5 58.5
20.7 59.6 1-4 35.71 14.29 50 9.9 59.5 14.3 59.7 1-5 14.29 35.71 50
2.3 52.4 2.6 43.1
[0190] The swelling properties of the films were tested
gravimetrically. The samples were placed into a 0.1 M buffer
solution, at least 200-fold amount of solution was taken with
respect to the sample weight. The samples were stored over 3 days
at 25.degree. C. The swollen samples were then accurately removed
and dried at 110.degree. C. The Swell Ratio and Sol Fraction were
calculated as follows: Swell Ratio=m.sub.d/m.sub.s; Sol Fraction,
%=100.multidot.(m.sub.0-m.sub.d)/m.sub.0, where m.sub.0 is initial
sample weight, m.sub.s is the weight of the swollen sample and
m.sub.d is the weight of the sample after drying.
[0191] According to the data shown above, the higher the pH in
water, the greater the swell ratio, whereas the fraction of soluble
blend was only slightly affected by pH. The higher the pH, the
greater the degree of ionization of Eudragit carboxyl groups and
the higher the swelling of the ladder-like complex in water. This
data implies that the solubility of the blend in water (expressed
in terms of sol fraction) is controlled by non-covalent
crosslinking with the Eudragit and depends on the crosslinker
content. Actually, with the increase of Eudragit concentration, the
sol fraction decreased correspondingly (FIG. 4). The value of sol
fraction was close to the content of PEG 400 in blends (FIG. 5),
while the PVP was mainly in an insoluble state due to the
ladder-like crosslinking with Eudragit.
[0192] Swell ratio is a measure of the degree of non-covalent
crosslinking of the film-forming polymer (PVP). The higher the
concentration of the ladder-like crosslinker, Eudragit L 100-55,
the lower the swell ratio and the denser the network of
PVP-Eudragit hydrogen bonds (FIG. 4). The carcass-like crosslinker,
PEG, caused the increase of both swell ratio and sol fraction (FIG.
5). By this way, the swelling and dissolution of PVP-PEG-Eudragit
triple blends can be readily changed by the change in blend
composition.
[0193] Varying the ratio of film-forming polymer (PVP 90) to the
ladder-like crosslinker (Eudragit L 100-55) and the content of the
carcass-like crosslinker (PEG 400), was found to be a feasible tool
to control the mechanical properties of adhesive hydrogels. Tensile
properties of the PVP-PEG-Eudragit hydrogels were typical of those
for cured rubbers (FIG. 6). Adding the ladder-like non-covalent
crosslinker, Eudragit, to the PVP-PEG adhesives described in U.S.
Pat. No. 6,576,712 to Feldstein et al., caused a sharp gain in
mechanical strength and the loss of ductility. The ultimate tensile
stress came through a maximum at 8% Eudragit content, while the
maximum elongation at break decreased smoothly with the rise of the
Eudragit concentration for single-phase blends. Two-phase
compositions exemplified by 36% Eudragit blend exhibited a slight
increase of ductility, accompanied with the loss of cohesive
strength. The carcass-like crosslinker, PEG, was a good plasticizer
for the PVP-PEG-Eudragit triple blends. The rise in PEG content
promoted the ductility of hydrogel films (FIG. 7).
EXAMPLE 2
Adhesive Properties of Hydrogels in Swollen State
[0194] This example demonstrates the adhesive properties of the
PVP-PEG-Eudragit L 100-55 blend as function of hydration degree.
Preparation of films: 30 g of PEG 400 was dissolved in 280 g of
ethanol. Under vigorous stirring, 12 g of Eudragit L 100-55 powder
was added. Under vigorous stirring, 58 g of PVP 90 powder was
added. The mixture was stirred over 2 hours to obtain a 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, followed by drying at ambient temperature over 1 day.
The films then were dried in an oven at 110.degree. C. overnight.
Films of a size of 0.20.+-.0.04 mm were obtained. The
PVP-PEG-Eudragit L 100-55 films of different hydration degree were
prepared by spraying controlled amounts of distilled water over
film surfaces. The films then were covered with a PET release
liner, sealed in aluminum pouches and stored over 7 days to insure
uniform distribution of water within the film samples. Water
content in the obtained films was measured gravimetrically by
weight loss at 120.degree. C. Films with a hydration degree ranging
from 11 to 40 wt % and higher were prepared as indicated in the
table below. The adhesive properties of hydrated PVP-PEG-Eudragit
films (FIG. 8-10) were tested in accordance with ASTM D 2979 method
using a TAXT2 Texture Analyzer Machine. A stainless steel probe
with average roughness 50 nm was used, a contact pressure was 0.8
MPa, contact time was 1 sec, debonding rate was 0.1 mm/sec.
5 Water Content, % W.sub.debonding, J/m.sup.2 Maximum stress, MPa
11% 1 0.12 15% 14 0.46 17% 16 0.44 20% 10 0.24 30% 9 0.20 35% 10
0.17 40% 11 0.15
[0195] The value of maximum stress in probe tack stress-strain
curves is traditionally considered as a measure of tack. The
maximum tack was documented at approximately 15-17% hydration
degree (FIGS. 8 and 9). However, the more accurate measure of
adhesion is the total amount of energy dissipated in the course of
debonding process (the work of debonding). The work of debonding is
shown in FIG. 10 as the function of water content in swollen
hydrogel. As follows from the data in FIG. 10, the adhesion towards
probe was high enough even at 40% hydration degree. At
comparatively low degrees of hydration of the blend, the type of
adhesive bond failure was always adhesive. As the content of
absorbed water exceeded 50%, the type of debonding became cohesive.
In this way, the PVP-PEG/Eudragit L 100-55 (12%) blends revealed
the properties that are typical of both pressure sensitive
adhesives (high adhesion) and bioadhesives (enhancement of adhesion
in the course of swelling in water). Such unique coupling the high
adhesion with the capability to increase a tack under hydration has
never been earlier reported.
EXAMPLE 3
Effect of Composition of Methacrylic Acid Copolymers on Performance
Properties of their Blends with a PVP-PEG Adhesive
[0196] In the following example PVP 90 was chosen as the
film-forming polymer, whereas copolymers of methylmethacrylate and
methacrylic acid (Eudragit L 100 and Eudragit S 100) served as the
ladder-like crosslinkers. PEG 400 was used as the carcass-like
crosslinker. Films were prepared and tested.
[0197] Eudragit L 100 differs from Eudragit L 100-55 by the
composition of hydrophobic monomer, while the content of monomer
units of methacrylic acid is the same (50%). In Eudragit L 100-55
the hydrophobic monomer units are represented by ethyl acrylate,
while Eudragit L 100 is a copolymer of methacrylic acid with methyl
methacrylate. In turn, Eudragit S 100 is distinguished from
Eudragit L 100 by the decreased content of the units of methacrylic
acid (33% instead of 50%), whereas methyl methacrylate is
hydrophobic monomer in both copolymers.
[0198] Preparation of films: 40 g of PEG 400 was dissolved in 280 g
of a water/ethanol (1:1) mixture. The required amount of sodium
hydroxide was dissolved (as indicated in the table below). Under
vigorous stirring, 12 g of Eudragit L 100-55 powder was added.
Under vigorous stirring, 58 g of PVP 90 powder was added. The
mixture was stirred over 2 hours to obtain a 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,
followed by drying at ambient temperature over 3 days. Films of
0,20.+-.0,04 mm thickness were obtained. Water content in the films
was measured gravimetrically by weight loss at 120.degree. C. Films
with a hydration degree of 10.+-.1.5 wt % were obtained.
[0199] The adhesive properties of these PVP-PEG-Eudragit films are
set forth below:
6 PVP 90, PEG 400, Eudragit Eudragit NaOH, W.sub.debonding, Maximum
Sample g g L 100, g S 100, g g J/m.sup.2 stress, MPa 4-1 60 40 10 0
0.108 9 0.26 4-2 60 40 0 10 0.054 11 0.37
[0200] The PVP-PEG blends with Eudragit L 100 as the ladder-like
crosslinker were found to be soluble in water, while the blends
containing Eudragit S 100 as the ladder-like crosslinker were water
swellable hydrogels.
EXAMPLE 4
Compositions Containing Methacrylic Acid Copolymers as the
Film-Forming Polymer and PVP as the Ladder-Like Crosslinker
[0201] While in the Examples 1-3, the film-forming polymer was PVP
and the ladder-like crosslinker was either Eudragit L 100-55, L
100, or S 100, this example represents an inverted composition,
where the Eudragit serves as the film-forming polymer and the
ladder-like crosslinker is PVP. Sol fraction corresponded closely
to the content of water-soluble carcass-like crosslinker, PEG,
indicating that the formation of the ladder-like interpolymer
complex resulted in an insoluble product.
7 Composition of Example 4, wt. % Eudragit L 100-55 PVP 90 PEG 400
Sol Fraction, % Swell Ratio 50 10 40 44.9 2.03
[0202] In this way, by varying the composition of PVP-PEG-Eudragit
L 100-55 blends, adhesive materials of various degrees of
hydrophilicity were obtained, where the values of the swell ratio
ranged between 2 to 60.
EXAMPLE 5
Gradually Dissolving and Swellable Adhesive Blends of PVP-PEG
Carcass-Like Complex with Non-Acrylic Carboxyl-Containing
Ladder-Like Crosslinkers
[0203] PVP 90 was selected as the film-forming polymer and PEG 400
was selected as carcass-like crosslinker and enhancer of adhesion.
Copolymers of maleic acid and cellulose derivatives bearing
carboxyl groups were then evaluated and determined to be suitable
ladder-like crosslinkers.
[0204] One of most illustrative examples of using the copolymers of
maleic acid with methylvinyl ether as the ladder-like crosslinker
in PVP-PEG complex is provided by the Gantrez S-97 copolymer. PVP
blends containing 40 wt % of PEG and 5, 10 and 15 wt % of Gantrez
were obtained by casting/drying in water-ethanol solutions (1:1).
All the blends were soluble in water, although the time required
for full dissolution of the films was in linear relationship to the
content of the ladder-like crosslinker (Gantrez). In contrast, the
less Gantrez content in the blends, the higher the adhesion.
[0205] Another typical example supporting the proposal that
different carboxyl-containing polymers are suitable ladder-like
crosslinkers of electron-donating hydrophilic polymers such as PVP
is provided by HPMCP. PEG 400 was used as the carcass-like
crosslinker of PVP 90.
[0206] Preparation of films: 40 g of PEG 400 was dissolved in 240 g
of ethanol/water mixture (80 wt parts ethanol:20 wt parts water).
Then under vigorous stirring, the required amounts of HPMCP and PVP
were dissolved. The mixture was stirred over 2 hours to obtain a
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, followed by drying at ambient
temperature over 3 days. Films of 0.20.+-.0.04 mm thickness were
obtained. The adhesive behavior of these swollen hydrogels followed
the pattern exhibited by PVP-PEG-Eudragit L 100-55 blends. Swelling
and dissolution properties of the films are presented below.
8 PVP 90, PEG 400, HPMCP, Swell Ratio, Sol Fraction, Sample g g g
g/g % 5-1 50 40 10 48.3 85.3 5-2 45 40 15 30.5 71.0
EXAMPLE 6
Using Hydroxyl-Containing Hydrophilic Polymers as the Ladder-Like
Crosslinkers of PVP in Adhesive Hydrogels
[0207] The list of appropriate ladder-like crosslinkers of the
electron-donating hydrophilic film-forming polymers, exemplified
here by PVP, is not exhausted by polyacids. Other suitable
hydrophilic polymers bear hydroxyl group in their repeating units.
This example demonstrates the suitability of PVA and
hydroxyl-containing cellulose derivatives such as HPC as
ladder-like crosslinkers of PVP.
[0208] Blends of PVP 90 with PVA, with PEG, PG or glycerol as the
carcass-linker crosslinker, can be prepared as follows. Under
vigorous stirring, the required amount of PVA was dissolved in
distilled water at 95.degree. C. (9 wt parts of water was taken to
dissolve 1 wt part of PVA). Then under vigorous stirring, the
required amounts of PG and PVP were dissolved. The mixture was
stirred over 2 hours at 85.degree. C. to obtain a homogeneous
solution. Polymer films were prepared by solution casting onto a
backing member, following by drying at ambient temperature over 3
days. Films of 0.20.+-.0.02 mm thickness were obtained. The
adhesive properties of the films were found to be similar to those
observed with PVP-PEG-Eudragit L 100-55 blends. The results of
sol-gel analysis are listed below.
9 PVP 90, PVA, PG, Swell Ratio, Sol Fraction, Sample g g g g/g %
6-1 50 10 40 35.0 74.0 6-2 45 15 40 26.0 69.0 6-3 40 20 40 14.6
66.0 6-4 35 25 40 14.0 61.5
[0209] Another appropriate ladder-like crosslinker of PVP is HPC.
High molecular weight PVP 90 (58.67 wt %), PEG 400 (29.33%) and HPC
were dissolved in ethyl alcohol under stirring. The resulting
solution was cast onto a release liner and dried at 50.degree. C.
An alternative method of blend production involves direct mixing of
the components followed by mixture extrusion as indicated below in
Example 11. The prepared blend possessed a soluble fraction of 62%
and swell ratio of 10.13. The adhesive behavior of the formulation
follows the pattern shown by PVP-PEG-Eudragit L 100-55 blends.
[0210] An adhesive blend containing 58.67 wt % of PVP 90, 29.33 wt
% of PEG 400, 9.6 wt % of HPC and 2.4 wt % of Eudragit L 100-55 was
prepared as indicated above. The properties of this composition
were found to be intermediate between those of PVP-PEG-Eudragit L
100-55 and PVP-PEG-HPC blends. The content of sol fraction was 48%
and swell ratio was 6.8.
EXAMPLE 7
PVP-Free Adhesive Hydrogels Based on the Interpolymer Complexes
Involving the Combination of the Ladder-Like and Carcass-Like
Crosslinking
[0211] Although PVP is one of most successful representatives of
the hydrophilic polymers suitable to serve as film-forming
components in the adhesives of the invention, others appropriate
film-forming polymers include PEO. PEO is a much weaker electron
donating polymer as compared to PVP. For this reason, the PEO is
capable of forming sufficiently strong hydrogen bonds with strong
proton-donating polymers such as polyacids.
[0212] A blend containing 68.2 wt % of PEO, 25 wt % of PG as the
carcass-like crosslinker and 6.8 wt % of Gantrez S-97 as the
ladder-like crosslinker, was prepared by casting/drying of a water
solution. The prepared film of 0.2 mm in thickness was cohesively
tough (ultimate tensile stress was 5.0 MPa) indicating that the PEO
is crosslinked due to H-bonding with the carboxyl groups of Gantrez
S-97. Upon film immersion into water, the film dissolved over 1-2
minutes. Appreciable tack was observed for moderately hydrated
films. The maximum tack (about 0.8 MPa) was observed with the film
containing 13 wt % of water.
EXAMPLE 8
Preparation and Properties of Adhesive Compositions Based on the
Ladder-Like Interpolymer Complexes
[0213] While the hydrophilic adhesives presented above are formed
due to hydrogen bonding between polymeric components, the samples
shown in the table below, illustrate the properties of hydrogels
prepared by coupling the H-bond and electrostatic crosslinking of
the film-forming polymer. Electrostatic interactions, as a rule,
are stronger than H-bonding. Eudragit E-100 was used as the
film-forming polymer, which is a copolymer of 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.
10 Blend composition, wt % Sol Eudragit Eudragit PEG Fraction,
Swell Sample E-100 L 100-55 400 % Ratio 8-1 68 7 25 25.5 2.75
EXAMPLE 9
Performance Properties of Adhesive Compositions Based on
Interpolymer Complexes Compared to Conventional Pressure Sensitive
Adhesives and Bioadhesives
[0214] The properties of the triple blend hydrogels of the
invention (PVP-PEG-Eudragit L 100-55), were compared with those of:
conventional pressure sensitive adhesives (PSA; DURO-TAK.RTM.
34-4230, National Starch and Chemicals); classical bioadhesives
(covalently crosslinked polyacrylic acid polymers Carbopol.RTM.
974P and Noveon.RTM. AA1, both from B.F. Goodrich, Co.); PVP-PEG
binary blends, described in U.S. Pat. No. 6,576,712 to Feldstein et
al.; and the hydrophilic adhesives of the invention (Examples
1-7)
11 Attribute PSA Bioadhesive PVP-PEG Hydrophilic Peel adhesion, N/m
in dry state 300-600 None 50-70 10-30 in hydrated state None 10-60
300-550 100-300 Solubility in water Insoluble Insoluble, Soluble
Insoluble, Swellable Swellable Water sorption capacity Less 1% 98%
Non limited 96% Film-forming capability Yes No Yes Yes Elastic
modulus, Pa .times. 10.sup.5 1.0-5.0 0.09-0.9 1.3-5.0 0.4-40
Maximum elongation 22 More than 30 22 2.7 Ultimate tensile
strength, MPa 16 0.01 12 30.4 Logarithm Yield stress, MPa 4.1 2.6
3.7-4.9 5.0
[0215] PSAs, exemplified above by the SIS block-copolymer based
DURO-TAK.RTM. 34-4230 adhesive, represent a special class of
viscoelastic polymers. They are capable of forming 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 human use are mainly based on hydrophobic
elastomers with low glass transition temperatures, ranging from
-120 to -30.degree. C., which are usually increased by addition of
tackifying resins. The common 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 employed, 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.
[0216] As is seen from this data, the adhesives of the present
invention share properties of both pressure sensitive adhesives and
bioadhesives. Indeed, while their adhesive strength was typical of
the PSAs, they exhibited increased adhesion towards moistened
substrate like bioadhesives. Varying the hydrogel composition can
easily provide the further control of adhesive, water sorption and
mechanical properties of the products based on non-covalently
crosslinked hydrogels (See FIGS. 3-7).
[0217] The peel adhesion towards dry and moistened human forearm
skin in vivo for conventional acrylic PSA and three grades of
adhesives based on interpolymer complexes of the invention, was
evaluated. The data established that the adhesive properties of the
water-soluble PVP-PEG adhesives described in U.S. Pat. No.
6,576,712 share the properties of PSAs and bioadhesives by
combining the high adhesion featured for conventional PSAs with the
ability to adhere to moistened skin and biological tissues typical
of bioadhesives. The adhesive behavior of the water-soluble PVP-PEG
adhesives and the PVP-PEG-Eudragit L 100-55 adhesives of the
invention were compared with the properties of two different grades
of conventional PSAs: SIS-based DURO-TAK.RTM. 34-4230 PSA and
acrylic PSA (3M).
[0218] Expressed in terms of maximum stress under debonding, the
tack of adhesives based on the interpolymer complexes was found to
be comparable with that of conventional PSAs. However, a
distinctive feature of the adhesive blends of the invention was the
lower values of maximum elongation that resulted from the
non-covalent crosslinking of the chains of film-forming polymer.
Because the carcass-like crosslinking is significantly looser than
the ladder-like crosslinking, the water-soluble PVP-PEG adhesive
demonstrated higher stretching at probe detachment than observed
with adhesives having the ladder-like type of crosslinking. In this
regard, it is pertinent to note that the main tools to increase
fluidity and maximum elongation of the adhesives provided by the
ladder-like crosslinking, is the dilution of network density due to
mixing with carcass-like crosslinkers that can function as
plasticizers, in the course of swelling in water and also the
decrease in concentration of the ladder-like crosslinker.
EXAMPLE 10
Preparation of Adhesive Films by Direct Mixing of Polymeric
Components Followed by Extrusion
[0219] The behavior of the hydrophilic and amphiphilic adhesives of
the invention is typical of covalently crosslinked polymers. In
contrast to covalently crosslinked systems, however, the adhesives
based on interpolymer complexes can be easily prepared using a
simpler blending process, and, furthermore, provide film-forming
properties that are unattainable using crosslinked polymers.
[0220] While the formulations described in the examples above were
prepared by casting from solutions followed by drying, the adhesive
films of the invention can be also produced by direct mixing of the
components in the dry state followed by extrusion. Direct mixing
was done using a Thermo Haake Mixer, whereas the extrusion
procedure was performed with a Skania Single-Screw Extruder. The
procedures of mixing and extrusion are described below.
Preparation of a PVP-PEG-Eudragit Composition
[0221] The blend composition was as follows: 58.7 wt % PVP 90; 9.33
wt % PEG 400; and 12.0 wt % Eudragit L 100-55.
[0222] Mixing Procedure: The total amounts of PEG and Eudragit were
mixed at room temperature. An amount of PVP was then added at room
temperature to reach convenient consistency, producing a premix.
This premix was loaded in the mixer under stirring at 30 rpm at
55.degree. C. The remaining PVP was then introduced by small
portions, with an increase in stirring intensity to 60 rpm. The
mixing regime is presented below.
12 Time, T.sub.mixture, n, Torque, min. .degree. C. rpm N-m
Operation 0-4 54 30 4.2-5.7 loading of premix 12 55 30 11.0-12.5
loading of remaining PVP 24 65 60 14.0-16.0 mixing 34 75 0 --
stop
[0223] Extrusion Procedure: The die with the slit thickness of 100
.mu.m and width of 6.5 cm was constructed to prepare the film with
the thickness of .about.5 mil. Two temperature regimes, I and II,
were used, as shown below.
13 N, Extrusion Reducing Pressure, Regime T.sub.zones T.sub.roller
rpm speed, mm/c step Bar I 100/100/105 100 20 4.82 14 72 II
118/120/119 100 20 6.73 14 68
[0224] The formulation layer was then extruded (without any filter)
between two PET anti-adhesion films and pull out with a linear
speed of .about.5-7 mm/c.
Preparation of a PVP-PEG-HPC Composition
[0225] The blend composition was as follows: 58.67 wt % PVP 90;
29.33 wt % PEG 400; and 12.0 wt % HPC. The mixing procedure was as
described above, and the mixing regime is presented below.
14 Time, T mixture, n, Torque, min. .degree. C. rpm N-m Operation 0
54 30 0 loading of premix 12 58 30 4.4 loading of remaining PVP 22
59 30 8-9 start of temperature elevation 32 110 30 2-3 introducing
the HPC 42 123 0 -- stop
[0226] The extrusion procedure was as described above, and the
regime is presented below
15 N, Extrusion Reducing Pressure, T.sub.zones T.sub.roller rpm
speed, mm/c step Bar 120/120/130 100 15 7.29 14 56
Preparation of a PVP-PEG-HPC-Eudragit Composition
[0227] The blend composition was as follows: 58.67 wt % PVP 90;
29.33 wt % PEG 400; 9.60 wt % HPC; and 2.40 wt % Eudragit L 100-55.
The mixing and extrusion procedures were as described above, and
the regimes are presented below.
16 Time, T mixture, n, Torque, min. .degree. C. rpm N-m Operation 0
55 30 2.6 loading of premix 3 58 30 6.6 loading of remaining PVP 12
58 30 7 start of temperature elevation 25 115 30 1.4 introducing
the HPC 36 120 30 3.5 introducing the Eudragit 55 119 0 -- stop
[0228]
17 N, Extrusion Reducing Pressure, T.sub.zones T.sub.roller rpm
speed, mm/c step Bar 110/110/115 100 20 7.29 14 67
EXAMPLE 11
Wound Dressings
[0229] The following samples illustrate how the hydrogel
compositions of this invention may be used for silver-containing
antimicrobial wound dressings. Wound dressing films were prepared
from the following ingredients:
18 Composition (wt %) Film-forming Ladder-like Carcass-like Silver
salt, Sample polymer crosslinker crosslinker 1.0 wt % 11-1 Eudragit
L 100-55 PVP (9.9) PEG 400 Silver sulfate (49.5) (39.6)
[0230] The antimicrobial dressing was insoluble in water and
exudate, but were swellable, thus absorbing a great amount of
exudate. The dressing 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 amount
of water. Accordingly, the dressing of this example is useful for
treatment of pressure, diabetic, arterial and venous ulcers.
[0231] The potentiometric method with an Ag ion selective electrode
was used to study silver release from the dressing. Aqueous
solutions of silver nitrate in the concentration range
2.5.times.10.sup.-6-10.sup.-3 M were used to calibrate the Ag ion
selective electrode. Circular samples (1" diameter; 5 cm.sup.2
area) of the film was die-cut and laminated to glass plates by
means of a double-sided tape. The glass plate with the Ag release
side upwards was placed into a beaker and 50 ml of distilled water
was poured into the beaker. The system was then covered with a
petri-dish and placed into an oven, set to 25.+-.0.2.degree. C.
After specified time points the receptor solution in the beaker
over the sample was stirred and the 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 .mu.g
per cm.sup.2 of the anti-microbial dressing. Sample 11-1 was found
to deliver a high amount of silver sulfate.
EXAMPLE 12
Tooth Whitening Strips
[0232] One embodiment of a composition for tooth whitening was
prepared from the following ingredients using a melt extrusion
process:
19 Component Sample 12-1 (wt %) PVP (Film-forming polymer) 44
Eudragit L 100-55 (Ladder-like crosslinker) 9 PEG (Carcass-like
crosslinker) 22 Hydrogen peroxide 6 Water, stabilizers, pH
regulators 19 Total 100
[0233] The ingredients were melt processed in a Brabender single
screw extruder as follows. The Eudragit L 100-55 was added to the
extruder first, followed by PVP and PEG, at a temperature of 100 to
150.degree. C. The composition was extruded to a thickness of 0.35
mm between two polyethylene terephthalate release liners. A
hydrogen peroxide solution was added to the extruded film. Being
applied to tooth surface, the initially nontacky film adhered
immediately to tooth enamel, swelled and dissolved slowly in
saliva, releasing the hydrogen peroxide.
[0234] FIG. 11 compares the in vivo release profiles of the
hydrogen peroxide from a tooth whitening strip based on
PVP-PEG-Eudragit L 100-55 composition and from Crest
Whitestrips.TM. (Proctor & Gamble Co., Cincinnati, Ohio;
referred to as the "Crest Product"). The Crest Product contained
5.3% hydrogen peroxide in a Carbopol 956 gel on a thin polyethylene
film. The Carbopol is a classic representative of bioadhesive
hydrogels made due to covalent crosslinking of polyacrylic acid.
The amount of hydrogen peroxide released in vivo was measured by
the remainder of hydrogen peroxide in the product removed from
teeth surface upon a predetermined period of wearing. The
composition of the present invention provided a prolonged hydrogen
peroxide release compared to the Crest Product. Indeed as compared
to the Carbopol-based matrix in the Crest Product, the bioadhesive
PVP-PEG-Eudragit L 100-55 film in present invention provided a
retarded the rate of dissolution. In turn, prolonged release of
hydrogen peroxide from the composition of present invention
provided improved the tooth whitening effect.
EXAMPLE 13
Liquid Tooth Whitening Formulations
[0235] Adhesive blends described in this invention can be applied
either in the form of adhesive films or as solutions in appropriate
solvents, which are capable of forming the film upon drying at
application site. To prepare a liquid teeth whitener, the following
components were mixed:
20 Composition (wt %) Film-forming Ladder-like Carcass-like Sample
polymer crosslinker crosslinker Solvent Active agent pH regulator
17-1 PVP 90 (12.00) Eudragit L PEG 400 (3.00) water (33.12) and
carbamide peroxide sodium citrate 100-55 (0.75) ethanol (33.00)
(18.00) (0.13) 17-2 PVP 90 (7.00) Eudragit L PEG 400 (1.00) ethanol
(35.00) carbamide peroxide sodium citrate 100-55 (4.00) (18.00)
(0.13) 17-3 PVP K-30 Eudragit L 100-55 PEG 400 (7.00) water (15.00)
and hydrogen peroxide sodium citrate (13.50) and (7.20) and ethanol
(40.50) (10.00) (0.20) PVP 90 (3.00) Eudragit RL (3.60)
[0236] Eudragit RL is a copolymer of trimethylammonioethyl
methacrylate chloride with ethylacrylate and methylmethacrylate
(0.2:1:2), available from Rohm Pharma Polymers. Being insoluble in
aqueous media, in the hydrogel composition, it serves to protect
the hydrogel film from fast dissolution.
[0237] When applied to teeth surface and allowed to dry for 30
seconds, the liquid compositions form a thin hydrogel film, staying
on the teeth for a period longer 30 minutes and provide a tooth
whitening effect.
EXAMPLE 14
Adhesive Matrices with Therapeutic Agents
[0238] The following compositions were prepared by dissolution in
ethanol of components listed below, casting the solution and drying
at temperature of 50.degree. C.
[0239] The sample uses an acrylate polymer (Eudragit E 100) as the
film-forming polymer. The Eudragit L-100-55 is the ladder-like
crosslinker of Eudragit E 100, and PVP is the ladder-like
crosslinker of the Eudragit L-100-55. PVP also helps to increase
blend hydrophilicity. PEG is the carcass-like crosslinker of PVP.
The sample also includes an alkyl citrate (TEC) as a
plasticizer.
21 Component Sample 14-1 (wt %) Eudragit E 100 58.29 TEC 26.10
Eudragit L 100-55 2.61 PVP 90 2.00 PEG 400 1 Lidocaine base 10
Total 100
EXAMPLE 15
Liquid Film-Forming Bandages
[0240] In this example, adhesives were formulated with a soluble
ladder-like crosslinker, along with a ladder-like and carcass-like
crosslinker for the soluble ladder-like crosslinker. The main
component was an insoluble film-forming polymer, and a plasticizer
was included.
[0241] Samples 15-1 to 15-4 represent liquid compositions suitable
for application to skin as liquid bandages. Sample 15-1 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
trimethylammonioethylmethacrylate chloride (0.1) with ethylacrylate
(1) and methylmethacrylate (2), available from Rohm Pharma
Polymers. Samples 15-2 to 15-4 contain no ladder-like crosslinker
for the PVP Ladder-like crosslinker.
[0242] Liquid bandage and cold sore compositions for skin
applications may also contain active agents such as local
anesthetics. Suitable local anesthetics include dibucaine
hydrochloride; dibucaine; lidocaine hydrochloride; lidocaine;
benzocaine; p-butylaminobenzoic acid 2-(diethylamino) ethyl ester
hydrochloride; procaine hydrochloride; tetracaine hydrochloride;
chloroprocaine hydrochloride; oxyprocaine hydrochloride;
mepivacaine; cocaine hydrochloride; and piperocaine
hydrochloride.
[0243] 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.
[0244] Sample 15-3 also contains a skin softening agent such as
glycerol monooleate (Peceol, Gattefoss, France).
22 Composition, wt % Ladder- Ladder- Carcass- Film- like like like
forming Plasticizer crosslinker crosslinker crosslinker Sample
polymer (A) for (A) (B) for (B) for (B) Additives Solvent 15-1
Eudragit RS, TBC, 2.50 PVP K-90, Eudragit L PEG, 3.00 Sodium
Ethanol, 29.00 3.00 100-55, Citrate, 38.20 2.20 2.50 15-2 Eudragit
RS, TBC, PVP K-90, -- PEG, -- Ethanol, 35.11 11.70 0.36 0.18 52.65
15-3 Eudragit RS, TBC, 6.69 PVP K-90 -- PEG, 3.00; GMO, Ethanol,
20.06 0.21 1,2- 14.29 30.09 Propylene Glycol, 28.57 15-4 Eudragit
RS, TCB, 4.55 PVP K-17, -- PEG, 1.14 -- Ethanol, 7.95 1.14
35.00
[0245] The practice of the present invention will employ, unless
otherwise indicated, conventional techniques of polymer chemistry,
adhesive manufacture, and hydrogel preparation, which are within
the skill of the art. Such techniques are fully explained in the
literature.
[0246] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments,
the description and examples that are presented above are intended
to illustrate and not limit the scope of the invention. Other
aspects, advantages and modifications will be apparent to those
skilled in the art to which the invention pertains. All patents,
patent applications, journal articles, and other references cited
herein are incorporated by reference in their entireties.
* * * * *