U.S. patent number RE32,991 [Application Number 07/223,896] was granted by the patent office on 1989-07-18 for drug dispensing wound dressing.
This patent grant is currently assigned to Thermedics, Inc.. Invention is credited to Donald J. Dempsey, Jonathan L. Rolfe, Michael Szycher.
United States Patent |
RE32,991 |
Szycher , et al. |
July 18, 1989 |
Drug dispensing wound dressing
Abstract
The disclosed wound dressings have a drug dispersed throughout a
polyurethane matrix that is the reaction product of: (A) An
isocyante terminated prepolymer formed by reaction of isophorone
diisocyanate and a marcoglycol and (B) a monomer containing
hydroxyl and vinyl groups. The reaction product is a vinyl
terminated polyurethane oligomer which is liquid at room
temperature and which may be readily admixed with a pharmacoactive
substance and a photosensitizer, formed into a film and cured by
exposure to UV light without release of heat. In the most preferred
embodiments the foregoing oligomer is codissolved in an organic
solvent with a polyurethane polymer which is the reaction product
of: dicyclohexyl methane diisocyanate; a polytetramethylene ether
polyol having a molecular weight in the range of 1000-3000 daltons;
and 1,4-butane diol. That solution is then admixed with the
pharmacoactive agent, formed into a film and cured.
Inventors: |
Szycher; Michael (Lynnfield,
MA), Dempsey; Donald J. (Newbury, MA), Rolfe; Jonathan
L. (North Easton, MA) |
Assignee: |
Thermedics, Inc. (Woburn,
MA)
|
Family
ID: |
26918234 |
Appl.
No.: |
07/223,896 |
Filed: |
July 25, 1988 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
670810 |
Nov 13, 1984 |
04614787 |
Sep 30, 1986 |
|
|
Current U.S.
Class: |
528/75; 252/381;
252/387; 252/397; 424/411; 427/389.9; 428/354; 512/4; 522/6;
522/44; 522/46; 523/102; 604/304; 604/372; 427/2.31; 442/286 |
Current CPC
Class: |
A61L
15/26 (20130101); A61L 15/44 (20130101); C08G
18/672 (20130101); C08G 18/755 (20130101); C08L
75/16 (20130101); A61L 15/26 (20130101); C08L
75/04 (20130101); C08G 18/672 (20130101); C08G
18/48 (20130101); C08L 75/16 (20130101); C08L
75/04 (20130101); A61F 2013/530007 (20130101); A61L
2300/402 (20130101); A61L 2300/404 (20130101); A61L
2300/41 (20130101); A61L 2300/418 (20130101); Y10T
442/3854 (20150401); Y10T 428/2848 (20150115) |
Current International
Class: |
A61L
15/26 (20060101); A61L 15/16 (20060101); A61L
15/44 (20060101); C08G 18/67 (20060101); C08G
18/00 (20060101); C08L 75/00 (20060101); C08G
18/75 (20060101); C08L 75/16 (20060101); A61F
13/15 (20060101); C08G 018/10 (); C08G 018/30 ();
A61F 013/00 (); A61L 001/00 (); A01N 025/10 (); B05D
003/02 (); B32B 007/00 (); C09J 007/02 () |
Field of
Search: |
;528/75 ;522/6,44,46
;604/304,372 ;424/28,32 ;252/381,387,397 ;427/2,389.9 ;428/254,354
;512/4 ;523/102 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
273966 |
|
0000 |
|
AU |
|
3239318A1 |
|
May 1983 |
|
DE |
|
2017113A |
|
Mar 1979 |
|
GB |
|
2123012A |
|
May 1983 |
|
GB |
|
Primary Examiner: Kight; John
Assistant Examiner: Nutter; Nathan M.
Attorney, Agent or Firm: Lorusso & Loud
Claims
What is claimed is:
1. A wound dressing comprising a drug-dispensing elastomeric film,
said film comprising:
A. A cured reaction product consiting essentially of:
(1) isophorone diisocyanate;
(2) a macroglycol; and
(3) a monomer containing hydroxyl and vinyl groups; and
B. a pharmacoactive agent dispersed through said cured reaction
product.
2. The cured wound dressing of claim 1 wherein the repeating
molecular units of said film are cross-linked through terminal
vinyl groups.
3. The wound dressing of claim 1 wherein said film has been cured
by incorporation of a photosensitizer and exposure to ultraviolet
light.
4. The wound dressing of claim 1 wherein said reaction product is
formed by:
(a) reacting said isophorone diisocyanate and said macroglycol
together in the presence of a catalyst to form an isocyanate
terminated prepolymer;
(b) reacting said prepolymer with said monomer containing hydroxyl
and vinyl groups to form an ultraviolet-curable, vinyl terminated
polyurethane oligomer;
(c) admixing said oligomer with the pharmacoactive agent to form an
UV-curable homogeneous blend;
(d) forming the UV-curable homogeneous mixture into a film; and
(e) curing said film by exposure to ultraviolet light.
5. The wound dressing of claim 4 wherein said macroglycol is
polypropylene glycol having a number average molecular weight of
500-5000 daltons and said monomer is hydroxyethyl methacrylate.
6. The wound dressing of claim 4 wherein said film contains 1-10
wt. % of said drug, based on the weight of said oligomer.
7. The wound dressing of claim 4 wherein said drug is selected from
the group consisted of coagulants, antibiotics, antifungals,
topical anesthetics, anti-inflammatories mixtures thereof.
8. The wound dressing of claim 4 further comprising a coating of a
pressure sensitive adhesive on one surface of said film.
9. The wound dressing of claim 4 wherein a photoinitiator is
admixed with said oligomer.
10. The wound dressing of claim 9 wherein said photoinitiator is
selected from the group consisting of diacetoxyacetobenzophenone,
benzophenone, diethoxyacetophenone 4-morpholine benzophenone,
4-aminobenzophenone and 4'-methoxyacetophenone.
11. The wound dressing of claim 4 wherin said film further
comprises at least one non-reactive thixotropic agent.
12. The wound dressing of claim 11 wherein said non-reactive
thixotropic agent is selected from the group consisting of
pyrogenic silica and bentonite clays.
13. The wound dressing of claim 4 wherein the vinyl terminated
oligomer is co-dissolved with a polyurethane polymer which is the
reaction product of:
(d) dicyclohexyl methane diisocyanate;
(e) a polytetramethylene ether polyol having a number average
molecular weight in the range of 1000-3000 Daltons; and
(f) 1,4-butane diol;
and the resulting solution is formed into said film.
14. The wound dressing of claim 13 wherein said film contains 80-99
parts by weight of said vinyl terminated oligomer and 1-20 parts by
weight of said polyurethane polymer.
15. The wound dressing of claim 13 further comprising a textile
fabric, said film being formed on said textile fabric.
16. The wound dressing of claim 15 wherein said textile fabric is
first coated with a polyurethane polymer that is the reaction
product of:
dicyclohexyl methane diisocyanate;
a polytetramethylene ether polyol having a number average molecular
weight in the range of 1000-3000 Daltons; and
1,4-butane diol
and then coated with said solvent solution.
17. The wound dressing of claim 16 further comprising a coating of
a pressure sensitive adhesive on one surface of said film.
18. The wound dressing of claim 13 wherin said film further
comprises at least one non-reactive thixotropic agent.
19. The wound dressing of claim 18 wherein said non-reactive
thixotropic agent is selected from the group consisting of
pyrogenic silica and bentonite clays.
20. A process for forming a drug-dispensing wound dressing
comprising:
(1) preparing a reaction product consisting essentially of
isophorone diisocyanate, a macroglycol and a monomer containing
hydroxyl and vinyl groups by reacting (a) isophorone diisocyanate
and
(b) a macroglycol in the presence of a catalyst to form an
isocyanate terminated prepolymer and
reacting said prepolymer with (c) a monomer containing hydroxyl and
vinyl groups to form an ultraviolet-curable, vinyl terminated
polyurethane liquid oligomer;
(2) admixing said vinyl terminated oligomer with a drug to form an
UV-curable mixture;
(3) forming the UV-curable mixture into a film; and
(4) curing said film by exposure to ultraviolet light.
21. The process of claim 20 wherein a photoinitiator is admixed
with said oligomer and wherein said curing is at approximately room
temperature.
22. The process of claim 20 wherein said macroglycol is
polypropylene glycol having a number average molecular weight of
500-5000 daltons and said monomer is hydroxyethyl methacrylate.
23. The process of claim 20 wherein said drug is added in an amount
1-10% by weight, based on the weight of said oligomer.
24. The process of claim 20 wherein said drug is selected from the
group consisting of coagulants, antibiotics, antifungals, topical
anesthetics, amti-inflammatories and mixtures thereof.
25. The process of claim 20 further comprising coating one surface
of said film with a pressure sensitive adhesive.
26. The process of claim 21 wherein said photoinitiator is selected
from the group consisting of diacetoxyacetobenzophenone,
benzophenone, diethoxyacetophenone, 4-morpholine benzophenone,
4-aminobenzophenone and 4'-methoxyacetophenone.
27. The process of claim 21 further comprising mixing said oligomer
with at least one non-reactive thixotropic agent.
28. The process of claim 27 wherein said non-reactive thixotropic
agent is selected from the group consisting of pyrogenic silica and
bentonite clays.
29. A process in accordance with claim 20 wherein said vinyl
terminated oligomer is dissolved in an organic solvent and the drug
is admixed in said solvent solution.
30. A process in accordance with claim 29 wherein the vinyl
terminated oligomer is co-dissolved with a polyurethane polymer
which is the reaction product of:
(d) dicyclohexyl methane diisocyanate;
(e) a polytetramethylene ether polyol having a number average
molecular weight in the range of 1000-3000 daltons; and
(f) 1,4-butane diol.
31. The process of claim 30 wherein 80-99 parts by weight of said
vinyl terminated oligomer are codissolved with 1-20 parts by weight
of said polyurethane polymer.
32. The process of claim 30 wherein said monomer is hydroxyethyl
methacrylate and said macroglycol is a polypropylene glycol having
a number average molecular weight of 500-3000 daltons.
33. The process of claim 30 further comprising providing a textile
fabric and coating said textile fabric with said solvent solution
to form said film.
34. The process of claim 33 wherin said textile fabric is first
coated with a polyurethane polymer that is the reaction product
of:
dicyclohexyl methane diisocyanate;
a polytetramethylene ether polyol having a number average molecular
weight in the range of 1000-3000 daltons; and
1. 4-butane diol
and then coated with said solvent solution.
35. A process in accordance with claim 20 wherein a sufficient
amount of (c) is added so that only compounds with number average
molecular weights of 1500-5000 are present. .Iadd.
36. A dispensing elastomeric film, said film comprising:
A. A cured reaction product consisting essentially of:
(1) isophorone diisocyanate;
(2) a macroglycol; and
(3) a monomer containing hydroxyl and vinyl groups; and
B. an agent to be dispensed through said cured reaction product.
.Iaddend. .Iadd.37. The cured dispensing elastomeric film of claim
36 wherein the repeating molecular units of said film are
cross-linked through terminal
vinyl groups. .Iaddend. .Iadd.38. The dispensing elastomeric film
of claim 36 wherein said film has been cured by incorporation of a
photosensitizer and exposure to ultraviolet light. .Iaddend.
.Iadd.39. The dispensing elastomeric film of claim 36 wherein said
reaction product is formed by:
(a) reacting said isophorone diisocyanate and said macroglycol
together in the presence of a catalyst to form an isocyanate
terminated prepolymer;
(b) reacting said prepolymer with said monomer containing hydroxyl
and vinyl groups to form an ultraviolet-curable, vinyl terminated
polyurethane oligomer;
(c) admixing said oligomer with the agent to be dispensed to form
an UV-curable homogeneous blend;
(d) forming the UV-curable homogeneous mixture into a film; and
(e) curing said film by exposure to ultraviolet light. .Iaddend.
.Iadd.40. The dispensing elastomeric film of claim 39 wherein said
macroglycol is polypropylene glycol having a number average
molecular weight of 500-5000 daltons and said monomer is
hydroxyethyl methacrylate. .Iaddend. .Iadd.41. The dispensing
elastomeric film of claim 39 wherein said film containing 1-10 wt.
% of said agent to be dispensed, based on the weight of said
oligomer. .Iaddend. .Iadd.42. The dispensing elastomeric film of
claim 39 further comprising a coating of a pressure sensitive
adhesive on one surface of said film. .Iaddend. .Iadd.43. The
dispensing elastomeric film of claim 39 wherein a photoinitiator is
admixed with said oligomer. .Iaddend. .Iadd.44. The dispensing
elastomeric film of claim 43 wherein said photoinitiator is
selected from the group consisting of diacetoxyacetobenzophenone,
benzophenone, diethoxyacetophenone 4-morpholine benzophenone,
aminobenzophenone and 4'-methoxyacetophenone. .Iaddend. .Iadd.45.
The dispensing elastomeric film of claim 39 wherein said film
further comprises at least one non-reactive thixotropic agent.
.Iaddend. .Iadd.46. The dispensing elastomeric film of claim 45
wherein said non-reactive thixotropic agent is selected from the
group consisting of pyrogenic silica and bentonite clays. .Iaddend.
.Iadd.47. The dispensing elastomeric film of claim 39 wherein the
vinyl terminator oligomer is co-dissolved with a polyurethane
polymer which is the reaction product of:
(d) dicyclohexyl methane diisocyanate;
(e) a polytetramethylene ether polyol having a number average
molecular weight in the range of 1000-3000 Daltons; and
(f) 1,4-butane diol;
and the resulting solution is formed into said film. .Iaddend.
.Iadd.48. The dispensing elastomeric film of claim 47 wherein said
film contains 80-99 parts by weight of said vinyl terminated
oligomer and 1-20 parts by weight of said polyurethane polymer.
.Iaddend. .Iadd.49. The dispensing elastomeric film of claim 47
further comprising a textile fabric, said film being formed on said
textile fabric. .Iaddend. .Iadd.50. The dispensing elastomeric film
of claim 49 wherein said textile fabric is first coated with a
polyurethane polymer that is the reaction product of:
dicyclohexyl methane diisocyanate;
a polytetramethylene ether polyol having a number average molecular
weight in the range of 1000-3000 Daltons; and
1,4-butane diol
and then coated with said solvent solution. .Iaddend. .Iadd.51. The
dispensing elastomeric film of claim 50 further comprising a
coating of a pressure sensitive adhesive on one surface of said
film. .Iaddend. .Iadd.52. The dispensing elastomeric film of claim
47 wherein said film further comprises at least one non-reactive
thixotropic agent. .Iaddend. .Iadd.53. The dispensing elastomeric
film of claim 52 wherein said non-reactive thixotropic agent is
selected from the group consisting of pyrogenic silica and
bentonite clays. .Iaddend. .Iadd.54. A process for forming and
dispensing elastomeric film comprising:
(1) preparing a reaction product consisting essentially of
isophorone diisocyanate, a macroglycol and a monomer containing
hydroxyl and vinyl groups by reacting (a) isophorone diisocyanate
and (b) a macroglycol in the presence of a catalyst to form an
isocyanate terminated prepolymer and reacting said prepolymer with
(c) a monomer containing hydroxyl and vinyl groups to form an
ultraviolet-curable, vinyl terminated polyurethane liquid
oligomer;
(2) admixing said vinyl terminated oligomer with an agent to be
dispensed to form an UV-curable mixture;
(3) forming the UV-curable mixture into a film; and
(4) curing said film by exposure to ultraviolet light. .Iaddend.
.Iadd.55. The process of claim 54 wherein a photoinitiator is
admixed with said oligomer and wherein said curing is at
approximately room temperature. .Iaddend. .Iadd.56. The process of
claim 54 wherein said macroglycol is polypropylene glycol having a
number average molecular weight of 500-5000 daltons and said
monomer is hydroxyethyl methacrylate. .Iaddend. .Iadd.57. The
process of claim 54 wherein said agent is added in an amount 1-10%
by weight, based on the weight of said oligomer. .Iaddend.
.Iadd.58. The process of claim 54 further comprising coating one
surface of said film
with a pressure sensitive adhesive. .Iaddend. .Iadd.59. The process
of claim 55 wherein said photoinitiator is selected from the group
consisting of diacetoxyacetobenzophenone, benzophenone,
4-aminobenzophenone and 4'-methoxyacetophenone. .Iaddend. .Iadd.60.
The process of claim 55 further comprising mixing said oligomer
with at least one non-reactive thixotropic agent. .Iaddend.
.Iadd.61. The process of claim 60 wherein said non-reactive
thixotropic agent is selected from the group consisting of
pyrogenic silica and bentonite clays. .Iaddend. .Iadd.62. A process
in accordance with claim 54 wherein said vinyl terminated oligomer
is dissolved in an organic solvent and the agent is admixed in said
solvent solution. .Iaddend. .Iadd.63. A process in accordance with
claim 62 wherein the vinyl terminated oligomer is co-dissolved with
a polyurethane polymer which is the reaction product of:
(d) dicyclohexyl methane diisocyanate;
(e) a polytetramethylene ether polyol having a number average
molecular weight in the range of 1000-3000 daltons; and
(f) 1,4-butane diol. .Iaddend. .Iadd.64. The process of claim 63
wherein 80-99 parts by weight of said vinyl terminated oligomer are
co-dissolved with 1-20 parts by weight of siad polyurethane
polymer. .Iaddend. .Iadd.65. The process of claim 63 wherein said
monomer is hydroxyethyl methacrylate and said macroglycol is a
polypropylene glycol having a number average molecular weight of
500-3000 daltons. .Iaddend. .Iadd.66. The process of claim 63
further comprising providing a textile fabric and coating said
textile fabric with said solvent solution to form said film.
.Iaddend. .Iadd.67. The process of claim 66 wherein said textile
fabric is first coated with a polyurethane polymer that is the
reaction product of:
dicyclohexyl methane diisocyanate;
a polytetramethylene ether polyol having a number average molecular
weight in the range of 1000-3000 daltons; and
1,4-butane diol
and then coated with said solvent solution. .Iaddend. .Iadd.68. A
process in accordance with claim 54 wherein a sufficient amount of
(c) is added so that only compounds with number average molecular
weights of 1500-5000 are present. .Iaddend.
Description
BACKGROUND OF THE INVENTION
There has long been a need for a wound dressing which is soft,
pliable and elastic, yet high in tensile strength and abrasion
resistance and which can release drugs at a controlled, sustained
level.
Presently available bandages made of materials such as cotton are
undesirable because they retain water, serve as growth mediums for
bacteria, and soak up tissue pieces and blood which clots, causing
adhesion to the wound and trauma during removal.
Other bandages are made with plastic coverings with an adhesion
coating to decrease the undesirable water absorption of cotton
wound dressings. Unfortunately, new problems were created due to
lack of oxygen transmission through the plastic coating. Indeed,
holes had to be punched through the plastic covering to allow the
transmission of some oxygen to the skin below. Hard plastic or
silicone coatings were also applied to the side of the bandage
adjacent to the wound to prevent adhesion. These coatings did not
significantly decrease the problem of the bandage sticking to the
wound, and blocked oxygen and water transmission.
In further attempts to overcome the adhesion and permeability
problems, polyurethane and other plastic dressings were tried. For
example, U.S. Pat. No. 3,975,567 to Lock discloses a pressure and
heat-treated polyurethane foam which is lyophilic.
Other polyurethanes which polymerize upon exposure to ultraviolet
light were also developed. The majority of these UV-curable
polyurethanes were designed for use as orthopedic casts, e.g., U.S.
Pat. No. 4,209,605. Other types of polymers have been used as
matrices for incorporation of biologically active agents and, in
the form of polymerized sheets or films, have been used as wound
dressings, such as the compounds disclosed by U.S. Pat. Nos.
4,321,117 (acrylic polymers) and 4,156,067 (polyurethane). None of
these compositions managed to combine the properties of softness,
oxygen and water vapor permeability, flexibility, thixotropy and
capability for incorporation of biologically active agents, with a
fast cure at room temperature to a tough, colorless film. The
ability to cure at room temperature without release of heat is
particularly important because many drugs are heat labile.
At present, the most commercially successful burn and superficial
skin wound dressing is a polyether-based polyurethane,
moisture-vapor permeable membrane compounded with silica gel. The
composition, known as "Op-Site".RTM., described in U.S. Pat. Nos.
4,340,043 and 4,460,369 assigned to Smith & Nephew Research
Ltd., is in the form of a thin film having a surface coated with a
polyvinylethylether adhesive. Although considerably more
comfortable, permeable, and effective as protection against
bacterial contamination than the prior art wound dressings, this
material still suffers from the inability to incorporate
biologically active agents such as coagulants and antibiotics into
the membrane, rather than into the adhesive, and from difficulty in
formation and application as a bandage which conforms to the
contour of the site of application. In connection with this latter
problem, two to three people are required for application.
It is therefore an object of the present invention to provide a
wound dressing which physically incorporates drugs such as
antibiotics, coagulants, and anti-inflammatories into the dressing
structure having appreciable tensile strength rather than into the
adhesive or thin coating on the dressing so that the drugs are
released in a controlled, sustained manner.
It is a further object of the present invention to provide a
material for use as a wound dressing which is strong yet flexible,
and which can be made to conform to the shape of the site of the
wound.
It is a still further object of the present invention to provide
such a material for use as a wound dressing which is nontoxic,
non-carcinogenic, and biocompatible.
It is a further object of the present invention to provide a
material which can be easily formed and applied to a wound by one
person in adverse circumstances.
Yet a further object of the invention is to provide a polymeric
material which is a liquid at room temperature and which has a
sufficiently low viscosity at room temperature (prior to cure) to
facilitate admixture with a drug to form a homogeneous blend.
Still a further object is to provide such a polymeric material
which cures at room temperature without release of heat
(non-exothermic).
The foregoing and other objects and features of the claimed
invention will be understood by those skilled in the art from a
reading of the description which follows.
SUMMARY OF THE INVENTION
A polyurethane has now been discovered which is compatible with a
wide range of pharmacoactive agents and which, in the form of an
oligomer (uncured) which is a liquid at room temperature, may be
admixed in liquid state with one or more pharmacoactive agents.
Because the cure is not exothermic to any appreciable degree,
curing may be conducted without cooling and with no increase in
temperature. The cured polyurethane elastomer is crystal clear,
soft and elastomeric. Applied to a wound in the form of a film, the
polyurethane serves to release the incorporated drug at a
controlled, sustained rate while protecting that portion of the
incorporated drug yet to be released. The polyurethane product is
hydrophilic in nature and solvent resistant.
More specifically, the wound dressings of the present invention
have a drug dispersed throughout a polyurethane matrix that is the
reaction product of:
A. an isocyanate terminated prepolymer formed by reaction of
isophorone diisocyanate and a macroglycol; and
B. a monomer containing hydroxyl and vinyl groups. This reaction
product is a vinyl terminated polyurethane oligomer which is liquid
at room temperature. This liquid oligomer may be readily admixed
with a pharmacoactive substance and a photosensitizer, formed into
a film and curved by exposure to UV light without release of
heat.
In the most preferred embodiments the foregoing oligomer is
codissolved in an organic solvent with a polyurethane polymer which
is the reaction product of: dicyclohexyl methane diisocyanate; a
polytetramethylene ether polyol having a molecular weight in the
range of 1000-3000; Daltons and 1,4-butane diol. The pharmacoactive
agent and photoinitiator are then admixed into the solution and a
film is formed and cured.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
At the outset, the invention is described in its broadest overall
aspects with a more detailed description following.
The drug dispensing composition of the present invention is formed
by reacting isophorone diisocyanate and a macroglycol together to
form an isocyanate terminated prepolymer and then reacting the
prepolymer with a chain terminator to form a vinyl terminated
polyurethane oligomer. The drug and, optionally, a photoinitiator
may be admixed with the foregoing compounds at any point prior to
curing to form a homogeneous admixture. The homogeneous admixture
is formed into a liquid film and cured to form the wound dressing
with one side of the cured film optionally provided with a pressure
sensitive adhesive.
The isophorone diisocyanate (IPDI) used in the present invention is
an aliphatic compound having the following formula: ##STR1## IPDI
is utilized in the present invention because it is a liquid at room
temperature, because it cures to a crystal clear product upon
exposure to ultraviolet light, rather than yellowing as is the case
with many prior art diisocyanates, and because it cures without any
temperature rise.
The macroglycol preferred for use in the present invention is a
polypropylene glycol (PPG), preferably having a molecular weight of
500-5000 daltons and, more preferably 1000-3000 daltons. PPG is
preferred because it reacts with the IPDI at a fast rate at room
temperature with no temperature rise. Other high molecular weight
glycols such as polyethylene glycol (PEG) may be employed, but PEG
is a solid at room temperature and a feasible rate of reaction
would require heating. As used herein, the term "macroglycol" has
reference to any glycol having a molecular weight in excess of 500
daltons.
The chain terminator used in formulating the products of the
invention should have both hydroxyl and vinyl functional groups and
is preferably an acrylic compound such as hydroxyethyl acrylate or
hydroxyethyl methacrylate. Hydroxyethyl methacrylate (HEMA) is most
preferred for use as the chain terminator.
A large variety of drugs, including heat labile drugs, may be
incorporated into the compositions of the present invention at any
point within the formulation/reaction sequence because the process
of the present invention does not involve any exothermic reaction
and, therefore, no cooling of any reaction mixture is required
prior to the addition of a drug having activity highly susceptible
to degradation by heat. However, it is preferred that the drug be
added to the uncured liquid, vinyl-terminated oligomer as the last
additive prior to curing and after aeration for removal of all
entrained gases. It is contemplated that any coagulant, antibiotic,
antifungal agent, topical anesthetic, anti-inflammatory agent or
mixture thereof might be incorporated into any one of the liquid
precursors of the cured product. In the examples which follow
thrombin is mentioned as a coagulant and gentamycin sulfate is
mentioned as a wide-spectrum antibiotic but those specifically
mentioned drugs are merely exemplary of the wide range of drugs
that would be useful here.
Photosensitizers useful herein include benzophenone, acteophenone,
azobenzene, acenaphthenequinone, o-methoxy benzophenone,
thioxanthen-9-one, xanthen-9-one, 7-H-Benz(de) anthracen-7-one,
1-naphthaldehyde 4,4'-bis(dimethylamino)benzophenone,
fluorene-9-one, 1'-acetonaphthone, 2'-acetonaphthone,
anthraquinone, 2-tert.-butyl anthraquinone,
4-morpholinobenzophenone, p-diacetylbenzene, 4-aminobenzophenone,
4'-methoxyacetophenone, diethoxyacetophenone, benzaldehyde, and the
like.
Specifically useful herein are acetophenone photosensitizers of the
structure: ##STR2## wherein R is alkyl of from 1 to about 8 carbon
atoms, or aryl of 6 ring carbon atoms and R' is hydrogen, alkyl of
from 2 to about 8 carbon atoms, aryl of from 6 to 14 carbon atoms,
or cyclo alkyl of 5 to 8 ring carbon atoms.
Diethoxyacetophenone is the preferred photosensitizer.
The diisocyanate, macroglycol and chain terminator are reacted in
approximately stoichiometric amounts, i.e., in the approximate
ratio of 2 moles (2.0 equiv.) isophorone diisocyanate to 1 mole
(1.0 equiv.) macroglycol to 2 moles (1.0 equiv.) chain terminator.
At the end of the reaction between the prepolymer and the chain
terminator free isocyanate is monitored by infrared
spectrophotometry and, if necessary, additional small amounts of
the chain terminator may be added to scavenge any remaining
isocyanate. It is important that the low molecular weight monomers
present in the composition be reacted prior to contact with the
skin so that only compounds with molecular weights of 1500-5000
Daltons are present. The high molecular weight compounds do not
leach out of the wound dressing into the underlying tissue and are
therefore non-toxic.
An antioxidant such as tetrakis [methylene
(3,5-di-tert-butyl-4-hydroxyhydrocinnamate)] may be added to
inhibit spontaneous oxygen-initiated curing. A polyurethane
catalyst such as dioctyl tin dilaurate, N-methyl morpholine,
trimethylamine, triethylamine, zinc octoate, and dibutyl tin
dilaurate is added to both the reaction medium in which the
prepolymer is formed and the reaction medium in which the
prepolymer is reacted with the chain terminator.
The performed wound dressings require a material which exhibits
thixotropic behavior: a very high apparent viscosity which
decreases rapidly under shear stress. Thixotropic behavior is
necessary to allow the uncured wound dressings to conform to body
geometry, and to prevent sagging when the dressing is applied to
vertical surfaces. Thixotropic behavior may be induced by varying
the molecular weight of the macroglycol (the higher the molecular
weight, the thicker the uncured dressing); by adding a non-reactive
thixotropic agent; or by a combination of the two methods. The
tensile strength and hardness of the polyurethane is also varied by
varying the molecular weight of the PPG. As the molecular weight is
decreased, the tensile strength and hardness are increased. As the
molecular weight is in creased, the tensile strength and hardness
are decreased.
Nonreactive thixotropic agents include pyrogenic silica such as
Cab-O-Sil M-5.RTM. and Cab-O-Sil N70TS.RTM. from the Cabot Company
and bentonitte clays. Generally speaking, addition of 1.0 part
Cab-O-Sil M-5.RTM. to 100 parts urethane oligomer increases the
apparent viscosity by a factor of 10,000.
To produce a thixotropic or shear-sensitive, high viscosity liquid,
ultraviolet radiation curable oligomer, the vinyl terminated
oligomer is dissolved together with TECOFLEX.RTM.EG-60D in an
organic solvent. Preferably, 80-99 parts by wt. of the
vinyl-terminated oligomer are used per 1-20 parts by wt of said
polyurethane polymer. The resulting solution is thixotropically
thickened by the addition of high surface area fumed silica
particles. The preferred thixotropic composition is formed from 88
grams of the oligomer of Example 3 dissolved with 12 grams
TECOFLEX.RTM.EG-60D in 2000 grams methylene chloride, 10 grams of
fumed silica Cab-O-sil M-5.RTM. is added. The resulting thixotropic
mixture is suitable for the production of continuous liquid films
and displays a viscosity of 370 cps at 23.degree. C. at 20 RPM on
spindle #2.
TECOFLEX.RTM. the tradename of Thermedics Inc. for a polyurethane
which is the reaction product of (1) dicyclohexyl methane
diisocyanate, (2) a polytetramethylene ether polyol having a
molecular weight in the range 1000-3000 Daltons and (3) 1,4-butane
diol and is further described in U.S. patent application Ser. No.
600,568 filed Apr. 17, 1984 in the name of Michael Szycher, the
teachings of which are incorporated herein by reference.
The presence of a thixotropic agent and the increased viscosity
does not affect cure rate since the silica particles are
transparent to UV radiation.
A film of the resulting mixture can be formed by drawing, rolling,
or spraying using techniques well known in the art. Optionally, the
film may be formed on a textile fabric. Curing may be accomplished
by exposure to ultraviolet radiation, typically between 219 and 425
nm for 20 seconds at 0.5 W/cm.sup.2. Curing transforms the liquid
oligomer into a solid elastomer.
The cured polyurethane product is crystal clear, soft and
elastomeric and serves to release the incorporated drug at a
controlled, sustained rate while protecting that portion of the
incorporated drug yet to be released. The product is hydrophilic in
nature and solvent resistant.
Any pressure-sensitive adhesive conventionally used for wound
dressings or bandages may be spread over one surface of the cured
film, e.g. a polyacrytate adhesive or a polyvinylethyl ether blend
adhesive. A release paper or plastic film is then applied over the
exposed surface of the adhesive.
The examples which follow serve to further illustrate the present
invention but should not be considered as limiting; rather, the
scope of the invention is defined by the claims which follow.
EXAMPLE 1
A four liter reactor equipped with continuous nitrogen blanketing
and a heating mantel is charged with 81.6 grams isophorone
diisocyanate, 245.2 g of 2,000 molecular weight polypropylene
glycol and 0.1% by weight dioctyl tin dilaurate.
Agitation is begun and the mixture is raised to and maintained at
60.degree. C. After three hours, 64 grams hydroxyethyl methacrylate
(HEMA) is added with an additional 0.1% by weight dioctyltin
dilurate.
The mixture is allowed to react exothermally to 110.degree. C. for
two hours.
At the end of this reaction, free isocyanate is monitored by
infrared spectrophotometry, and if necessary small amounts of
hydroxyethyl methacrylate may then be added (up to 2 gm) to
scavenge any remaining isocyanate.
0.1% by weight of IRGANOX 1010*, and 4% by weight diethoxy
acetophenone (DEAP, a photoinitiator) is then added and the mixture
agitated and deaerated.
A film of the resulting mixture can be formed by drawing, rolling,
or spraying by techniques well known in the art.
Curing may be accomplished by exposure to ultraviolet radiation,
typically between 219 and 380 nanometers for 20 seconds at 0.5
watts per square centimeter.
This results in a fully cured, solvent-resistant hydrophilic
transparent elastomer with the following physical properties:
tensile strength 600 P.S.I., elongation 150%, hardness (shore A)
55.
EXAMPLE 2
A four liter reactor equipped with continuous nitrogen blanketing
and a heating mantel is charged with 102 grams IPDI, 229.2 grams
1,000 molecular weight polypropylene glycol, and 0.1% by weight
dioctyltin dilaurate.
Agitation is begun and the mixture is raised to and maintained at
60.degree. C. After three hours, 59.60 grams of HEMA is added with
an additional 0.1% by weight dioctyltin dilaurate.
The mixtrue is allowed to react exothermally to 110.degree. C. for
two hours.
At the end of this reaction, free isocyanate is monitored by
infrared spectrophotometry, and if necessary small amounts of HEMA
are added to to scavenge any remaining isocyanate.
0.1% by weight of IRGANOX 1010.RTM. and 4% by weight diethoxy
acetophenone are then added and the mixture agitated and
deaerated.
A film of the resulting mixture can be formed by drawing, rolling,
or spraying by techniques well known in the art.
Curing may be accomplished by exposure to ultraviolet radiation,
typically between 219 and 380 nanometers for 20 seconds at 0.5
watts per square centimeter.
This results in a fully cured, solvent-resistant, hydrophilic,
transparent elastomer with the following physical properties:
tensile strength: 950 PSI, elongation 150%, hardness, (shore A)
55.
EXAMPLE 3
A four liter reactor equipped with continuous nitrogen blanketing
and a heating mantel is charged with 101.6 grams IPDI, 228.8 grams
1,000 molecular weight polypropylene glycol and 0.1% by weight
dioctyl tin dilaurate.
Agitation is begun and the mixture is raised to and maintained at
60.degree. C. for two hours. Thereafter, 55.3 g HEMA is added with
an additional 0.1% by weight dioctyltin dilaurate.
At the end of this reaction, free isocyanate is monitored by
infrared spectrophotometry, and if necessary small additions of
hydroxyethyl methacrylate may then be made (up to 2 gm) to scavenge
any remaining isocyanate. The result is the preferred oligomer.
0.1% by weight of IRGANOX 1010.RTM. and 4% by weight
diethoxyacetophenone are then added and the mixture agitated and
deaerated.
A film of the resulting mixture can be formed by drawing, rolling,
or spraying by techniques well known in the art.
Curing may be accomplished by exposure to ultraviolet radiation,
typically between 219 and 380 nanometers for 20 seconds at 0.5
watts per square centimeter.
This results in a fully cured, solvent-resistant, hydrophilic,
transparent elastomer with the following physical properties:
tensile strength: 950 PSI, elongation 32.5%, hardness (shore A)
60.
EXAMPLE 4
To produce a thixotropic (shear-sensitive high viscosity liquid),
UV Curable Oligomer, the preferred oligomer obtained in Example 3
is co-dissolved with TECOFLEX.RTM.EG-60D (the 65 Shore D product
mentioned at p. 7 in aforementioned U.S. Ser. No. 600,568) in
methylene chloride. The resulting solution is further stabilized by
the addition of high surface area fumed silica particles as
described below.
A preparation containing 94 grams of the oligomer from Example 2 is
co-dissolved with 6 grams of TECOFLEX EG-60D.RTM. in 2000 grams of
methylene chloride. To this solution, 10 grams of fumed silica
(CAB-O-Sil N70TS.RTM. are added. The result is a thixotropic
mixture, but it did not have sufficient viscosity to produce
continuous liquid films.
EXAMPLE 5
A preparation containing 88 grams of the oligomer from example 3,
admixed with the 0.1 wt. % IRGANOX.RTM. and 4 wt. %
diethoxyacetophenone, is co-dissolved with 12 grams of TECOFLEX
EG-60D.RTM. in 2000 grams of methylene chloride. To this solution,
10 grams of fumed silica (CAB-O-SIL M-S.RTM. are added). The result
is a thixotropic mixture, suitable for the production of continuous
liquid films. This mixture displays a viscosity of 370 cps at
23.degree. C. 20 RPM, spindle #2, which is ideal for admixture with
drugs to form the wound dressings of the present invention, and is
the preferred thixotropic UV curable mixture.
EXAMPLE 6
The constituents of example 5 are intimately mixed for 10 minutes,
and deaerated until all entrained gases are removed.
At this stage pharmacoactive substances such as 1% by weight
thrombin (a coagulant) and 4% by weight gentamycin sulfate, (a
wide-spectrum antibiotic) are incorporated into the above liquid by
gentle mixing for 30 minutes until a uniform (homogeneous) blend is
obtained.
A film of the resulting mixture is then formed by drawing, rolling,
or spraying as in example 1.
Curing is accomplished by exposure to U.V. radiation, typically
between 219 to 425 nanometers for 20 seconds at 0.5
watts/CM.sup.2.
EXAMPLE 7
The constituents of example 5 are intimately mixed for 10 minutes,
and deaerated until all entrained gases are removed.
At this stage, pharmacoactive substances such as 1% by weight
thrombin (a coagulant) and 6% by weight gentamycin sulfur (a wide
spectrum antibiotic), are incorporated into the above liquid by
gentle mixing for 30 minutes until a uniform blend is obtained.
This example produced the preferred medicated UV-curable
composition. A film of the resulting mixture may then be formed by
drawing, rolling, or spraying as in example 1.
Curing is accomplished by exposure to U.V. radiation, typically
between 219 to 425 nanometers for 20 seconds at 0.5
watts/CM.sup.2.
EXAMPLE 8
Preparation of Medicated Wound Dressings:
Supporting fabric is saturated with TECOFLEX.RTM.SG-93A (the 95
Shore A product mentioned at p.7 of U.S. Ser. No. 600,568)
hydrophobic polymer, by drawing the fabric vertically into a 12%
solids solution of the hydrophobic polymer in chloroform. Pull
speed is fully controlled so that a continuous film enveloping the
fabric is formed, having a desired thickness of 2-4 mils.
The resulting saturated fabric is coated on one side by rolling or
spraying with nitrogen the hydrophilic, thixotropic, UV-curable
oligomer of Example 5, and subsequently curing the liquid into an
elastomeric film by exposing the oligomer to UV radiation between
219 and 425 nm for 20 seconds at 0.5 watts/CM.sup.2.
Finally, a thin coat of pressure sensitive adhesive is applied onto
the cured, hydrophilic elastomeric film. The resulting
multi-layered structure is then assembled on release paper, cut and
packaged, and is ready to use.
The invention may be embodied in other specific forms without
departing from the spirit of essential characteristics thereof. The
present embodiments are therefore to be considered in all respects
as illustrative and not restrictive, the scope of the invention
being indicated by the appended claims rather than by the foregoing
description, and all changes which come within the meaning and
range of equivalency of the claims are therefore intended to be
embraced therein.
* * * * *