Drug dispensing wound dressing

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: PA1 dicyclohexyl methane diisocyanate; PA1 a polytetramethylene ether polyol having a molecular weight in the range of 1000-3000 daltons; and PA1 1,4-butane diol. That solution is then admixed with the pharmacoactive agent, formed into a film and cured.

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.

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. 
FNT *tradename of Ciba Geigy for tetrakis [methylene 
(3,5-di-tert-butyl-4-hydroxy-hydrocinnamate)], an antioxidant. 
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.