Nitroglycerin preparations

A mixture of nitroglycerin and a water-insoluble vinylpyrrolidone polymer provides a polymeric matrix which gradually releases nitroglycerin upon application to the skin of a patient in the form of a film, gel or ointment. The water-insoluble vinylpyrrolidone polymer may be an uncrosslinked copolymer or a crosslinked homopolymer or copolymer. The polymer provides increased stability and reduced volatility of the nitroglycerin while permitting slow and sustained release of the drug upon topical application to the skin.

BACKGROUND OF THE INVENTION 
1. Field of Invention 
This invention relates to novel compositions of matter for topical 
application to humans and methods for providing therefrom a predetermined 
dosage of nitroglycerin. The novel compositions comprise stablized 
nitroglycerin in a form adapted for the slow and gradual release thereof 
so as to provide a sustained level of the drug in the blood of the 
patient. 
2. Description of the Prior Art 
Nitroglycerin (glyceryl trinitrate) has been in use for many years as a 
coronary vasodilator and is especially useful in the treatment of cardiac 
diseases such as angina pectoris. Nitroglycerin is generally used in the 
form of sublingual tablets or capsules, composite gradual release tablets, 
ointments and patches. 
Nitroglycerin is rapidly absorbed through mucous membranes and the effect 
of sublingual tablets starts some 3 minutes after taking the medication 
and lasts for about 30 minutes. The duration of the effect of tablets 
taken internally is of the same order of magnitude. 
Notwithstanding its efficacy, the high volatility and mobility of the 
nitroglycerin leads to a loss of the drug to the environment during 
storage and use. Thus, when tablets containing nitroglycerin and an 
excipient such as lactose are exposed to the atmosphere in a semienclosed 
or open container, the loss of nitroglycerin results in a change in the 
nitroglycerin content of the tablets. Further, the mobility of 
nitroglycerin is manifested by the migration of the drug from one tablet 
to another when such tablets are in contact with each other in a closed 
container over an extended period of time. 
The stabilization of nitroglycerin tablets against losses to the atmosphere 
by volatilization and tablet-to-tablet migration has been accomplished by 
the incorporation of water-soluble polyvinylpyrrolidone into the mixture 
of components used in the preparation of the tablets. Thus, Fung et al. in 
Journal of Pharmaceutical Sciences, 63, 1810 (1974), disclosed that the 
addition of polyvinylpyrrolidone to a tablet containing nitroglycerin and 
lactose, retarded the rate of evaporation of the nitroglycerin from the 
tablet. However, the solid phase stabilization did not affect the 
availability of the nitroglycerin in an aqueous environment because of the 
preferential solvation and the rapid solubilization of the 
vinylpyrrolidone homopolymer in water. 
German DOS 2,301,664 and British Pat. No. 1,427,881 disclose the 
prolongation of the storage stability of nitroglycerin by the addition of 
polyvinylpyrrolidone. U.S. Pat. No. 4,091,091 describes the stabilization 
of nitroglycerin against tablet-to-tablet migration by the incorporation 
of water-soluble polyvinylpyrrolidone in the mixture of a water-soluble 
excipient and nitroglycerin, while retaining the rapid solubility of the 
tablet in the mouth. 
The release of nitroglycerin as a result of the water-solubility of 
vinylpyrrolidone homopolymer or copolymers has also been utilized in an 
antianginal film or plate. Thus, British Patent Application 2 021610 A 
discloses that a thin film containing nitroglycerin, a water-soluble 
homopolymer or copolymer or acrylamide and/or vinylpyrrolidone and, 
optionally a dispersed solid fat, is applied to a site in the mouth and 
releases the medicament at a rate which is dependent upon the rate of 
solution of the polymer. 
Nitroglycerin is rapidly absorbed through unbroken skin as well as through 
mucous membranes in the mouth. U.S. Pat. No. 3,742,951 discloses a medical 
bandage or patch comprising a backing member, a reservoir containing 
nitroglycerin and a pressure sensitive adhesive coating. The reservoir is 
in the form of microcapsules or matrix layers which are polymeric, 
preferably silicone rubbers, and permeable to nitroglycerin. The rate of 
release of nitroglycerin is controlled by the permeability of the polymer 
in the microcapsule wall or matrix layer. U.S. Pat. No. 4,336,243 
discloses a transdermal delivery system for administration of 
nitroglycerin wherein the latter is present in microsealed compartments in 
a polymer which is insoluble in body fluids and through which the 
nitroglycerin can pass at a controlled rate. The polymer, preferably a 
silicone rubber, contains a hydrophilic solvent such as polyethylene 
glycol and a hydrophobic solvent such as mineral oil which partition and 
enhance the diffusion of nitroglycerin throughout the matrix. U.S. Pat. 
No. 4,291,015 discloses a water-containing polymeric matrix for the 
transdermal delivery of nitroglycerin. The matrix contains water and a 
polar plasticizer such as glycerin, with small amounts of a 
hydroxyl-containing polymer such as polyvinyl alcohol and a water-soluble 
polymer such as polyvinylpyrrolidone. The polymers provide retention of 
the shape of the water-containing matrix. 
The absorption of nitroglycerin through unbroken skin makes possible 
topical application in the form of ointments. Nitroglycerin ointments 
based on lanolin, vasoline or similar hydrophobic and practically 
water-insoluble bases are effective for about 3 to 4 hours. However, when 
these ointments are applied to the skin, part of the nitroglycerin is lost 
by volatilization and the base is rapidly absorbed into the skin. 
The present invention is directed towards improvements in stabilized 
nitroglycerin compositions which upon topical application will have 
reduced volatilization of the nitroglycerin, slow release of the drug upon 
contact with moisture and provide a slow and sustained release of the 
nitroglycerin so as to maintain the desired sustained level of the drug in 
the blood of the patient. This is accomplished by the incorporation of 
water-insoluble vinylpyrrolidone homopolymer or copolymers. 
The use of water-soluble polyvinylpyrrolidone in conjunction with 
medicaments other than nitroglycerin has been disclosed in a number of 
patents. Thus, U.S. Pat. No. 3,972,995 discloses a buccal dosage form in 
which the water-soluble homopolymer functions as a binder in an adhesive 
layer. U.S. Pat. No. 3,214,338 discloses a topical ointment in which the 
water-soluble homopolymer is added to an emulsifiable polyvinyl acetate 
powder. U.S. Pat. No. 3,803,300 discloses a film-forming ointment 
containing water-soluble vinylpyrrolidone homopolymer and copolymers. U.S. 
Pat. No. 3,287,222 discloses the use of the homopolymer as a water-soluble 
plasticizer in an impregnating solution for a synthetic fiber medical 
dressing. U.S. Pat. No. 4,210,633 discloses a water-soluble medicated film 
containing the water-soluble homopolymer. U.S. Pat. No. 3,608,070 
discloses a surgical dressing which is an ointment containing a 
vinylpyrrolidone copolymer, a thixotropic agent, a water-soluble 
plasticizer and a solvent such as aqueous ethanol. The film formed on 
drying the ointment is readily soluble in water. U.S. Pat. No. 2,776,924 
discloses the use of water-soluble polyvinylpyrrolidone to inhibit adverse 
reactions from therapeutic agents in topical application. 
In these prior art disclosures with medicaments other than nitroglycerin, 
vinylpyrrolidone polymers are used because of their film-forming ability 
and/or water solubility. The rapid solubilization of the polymer results 
in rapid release of the medicament. 
The prior art discloses that the use of water-insoluble, crosslinked 
polyvinylpyrrolidone also promotes the rapid release of medicament. Thus, 
British Pat. No. 1,380,171 discloses the use of crosslinked, 
water-insoluble polyvinylpyrrolidone in medicinal tablets containing a 
drug, to promote rapid disintegration of the tablet in aqueous fluids and 
increase the availability of the drug. Examples are provided which 
illustrate that the presence of water-insoluble polyvinylpyrrolidone 
results in more rapid disintegration and release of the drug as compared 
with the water-soluble polymer. German Patent Application 2,634,004 
discloses the use of crosslinked, insoluble polyvinylpyrrolidone as a 
carrier material for poorly soluble medicaments in order to accelerate the 
release thereof when administered orally. German Patent Application 
1,467,792 discloses the use of crosslinked polyvinylpyrrolidone as a 
disintegrating agent to increase the rate of disintegration of a tablet 
and to promote the extremely rapid release of the drug therein in the 
digestive tract. 
In a non-pharmaceutical application, British Pat. No. 1,090,184 discloses 
the use of polyvinylpyrrolidone as well as numerous other polymers soluble 
in nitroglycerin, including polymethyl methacrylate, polyvinyl acetate and 
non-hardened phenolformaldehyde resin, as gelatinizing additives in the 
production of explosive compositions. 
SUMMARY OF THE INVENTION 
The prior art teaches that water-soluble vinylpyrrolidone homopolymer 
complexes with nitroglycerin in a solid tablet or film and reduces the 
volatility and migration of the medicament without reducing the 
availability of the drug in an aqueous environment. The prior art also 
teaches that the presence of water-insoluble vinylpyrrolidone homopolymer 
promotes even more rapid release of a medicament. 
Surprisingly, it has now been discovered that the incorporation of 
water-insoluble vinylpyrrolidone homopolymers or copolymers in an 
ointment, gel or film containing nitroglycerin provides increased 
stability and reduced volatility of the nitroglycerin, while permitting 
slow release of the drug when applied topically to the skin. 
It has further been discovered that ointments with sustained release 
characteristics and reduced volatility of the nitroglycerin can be 
prepared by the admixture of a dispersion or solution of a water-insoluble 
vinylpyrrolidone polymer or copolymer with a nitroglycerin solution or 
triturate and a conventional hydrophobic base such as vasoline, lanolin 
and the like. 
It has further been discovered that films with sustained release 
characteristics and increased stability of the nitroglycerin can be 
prepared from a solution containing a water-insoluble vinylpyrrolidone 
polymer or copolymer and nitroglycerin, wherein the solution is applied 
per se or after thickening. 
DETAILED DESCRIPTION OF THE INVENTION 
According to the present invention, it has now been found that important 
advantages and improvements over prior art compositions containing 
nitroglycerin and methods of topical application thereof can be obtained 
by the admixture of a water-insoluble vinylpyrrolidone homopolymer or a 
water-insoluble vinylpyrrolidone copolymer. 
Water-soluble polyvinylpyrrolidone is a commercially available homopolymer 
and is prepared by the free radical polymerization of the monomer in water 
or an appropriate solvent. Water-insoluble polyvinylpyrrolidone, suitable 
for use in the practice of the present invention, may be prepared by 
heating the water-soluble vinylpyrrolidone homopolymer in air to 
150.degree. C. or in the presence of strong alkali at 100.degree. C. or in 
the presence of a free radical precursor such as ammonium peroxydisulfate 
at an elevated temperature such as 90.degree. C. or higher. Other methods 
for insolubilizing the water-soluble homopolymer will be obvious to those 
skilled in the art. 
A water-insoluble copolymer containing at least 95% vinylpyrrolidone may be 
prepared directly by the polymerization of vinylpyrrolidone in the 
presence of a polyunsaturated crosslinking monomer such as a 
dimethacrylate, e.g. ethylene glycol dimethacrylate, triethylene glycol 
dimethacrylate, trimethylolpropane trimethacrylate and the like, a 
polyallyl compound such as diethylene glycol bisallyl carbonate, triallyl 
glycerine, triallyl cyanurate, etc., a polymaleimide such as ethylene 
bismaleimide, or a polyvinyl compound such as divinylbenzene and the like. 
Water-insoluble copolymers of vinylpyrrolidone, which may be used in the 
practice of this invention, may be prepared by the copolymerization of 
vinylpyrrolidone with one or more appropriate comonomers in the 
proportions which yield water-insoluble, uncrosslinked copolymers. 
Suitable comonomers include acrylic esters, methacrylic esters, vinyl 
esters, crotonic esters, vinyl ethers, maleic half esters and diesters, 
vinylene carbonate, styrene, allyl esters, allyl ethers, etc. Other 
comonomers which are capable of copolymerizing with vinylpyrrolidone and 
are well known to those skilled in the art may also be used. Toxicological 
considerations restrict the choice of monomers to those which yield 
copolymers having a demonstrated lack of toxicological side-effects, on 
topical application to the skin. 
The acrylic, methacrylic, crotonic and maleic esters which may be used in 
the preparation of the water-insoluble vinylpyrrolidone copolymers which 
are effective in the practice of the present invention, include the esters 
of C.sub.1 -C.sub.40 linear, branched or cyclic alkanols, aralkanols, 
phenols and substituted phenols. The copolymers of vinylpyrrolidone and 
the acrylic, methacrylic, crotonic and maleic esters may be made by 
copolymerization of vinylpyrrolidone with the appropriate ester or by 
esterification of copolymers of vinylpyrrolidone and acrylic, methacrylic, 
crotonic and maleic acids or anhydrides, with the appropriate 
hydroxyl-containing compound. 
The vinyl esters and allyl esters which may be used in the preparation of 
the water-insoluble vinylpyrrolidone copolymers which are useful in the 
practice of this invention, include the esters of C.sub.1 -C.sub.40 
linear, branched or cyclic aliphatic, araliphatic or aromatic carboxylic 
acids. The copolymers of vinylpyrrolidone and the vinyl esters may be 
prepared by copolymerization of vinylpyrrolidone with the appropriate 
vinyl ester or by transesterification of copolymers of vinylpyrrolidone 
and vinyl acetate or other vinyl esters or by esterification of hydrolyzed 
copolymers of vinylpyrrolidone and vinyl acetate or other vinyl esters. 
The copolymers of vinylpyrrolidone and allyl esters may also be prepared 
either by direct copolymerization or by transesterification or 
esterification, analogous to the preparation of vinyl ester copolymers 
with vinylpyrrolidone. 
Graft copolymers made by grafting vinyl monomers onto polyvinylpyrrolidone 
may also be used, e.g. graft copolymers of polyvinylpyrrolidone with 
acrylic esters, methacrylic esters, styrene, vinyl acetate and the like. 
A crosslinking monomer such as previously described may be utilized in the 
preparation of the copolymers and graft copolymers of vinylpyrrolidone 
which are useful in the practice of the present invention. Additional 
comonomers such as unsaturated carboxylic acids including acrylic, 
methacrylic, crotonic and maleic acids or anhydrides may be incorporated 
in the copolymers. The uncrosslinked copolymers and graft copolymers of 
vinylpyrrolidone may be crosslinked in the presence of peroxides or under 
radiation, by methods well known to those skilled in the art. 
The water-insoluble copolymers of vinylpyrrolidone which may be used in the 
practice of the present invention may be prepared by any of the 
conventional methods known in the art, including bulk, solution, emulsion, 
suspension or dispersion polymerization, with appropriate free radical 
catalysts such as peroxygen compounds, azo compounds, redox systems, 
radiation and other catalytic techniques for initiating free radical 
polymerization. Since the method of polymerization is not an integral part 
of the practice of the present invention, any suitable method known to 
those skilled in the art may be used. 
The amount of one or more comonomers in the water-insoluble 
vinylpyrrolidone copolymers which are useful in the practice of the 
present invention, may be varied from 0.1 to 90% by weight. The actual 
amount is determined by the nature of the comonomer and the concentration 
necessary to produce a water-insoluble copolymer, either before or after 
copolymerization. 
The stabilized nitroglycerin compositions which are useful in the practice 
of the present invention and provide sustained release of the medicament, 
may be prepared by dissolving or dispersing the water-insoluble 
vinylpyrrolidone homopolymer or copolymer in a solvent such as 
isopropanol, ethanol or an alcohol-water mixture, and admixing the polymer 
solution or dispersion with a nitroglycerin solution in ethanol or a 
nitroglycerin trituration comprised of nitroglycerin and one or more 
excipients selected from the group consisting of lactose, beta-lactose, 
milk sugar, fructose, maltose, sucrose, mannitol, sorbitol and the like. 
The solution of uncrosslinked water-insoluble vinylpyrrolidone copolymer 
and nitroglycerin, in the absence or presence of an excipient, may be cast 
on a suitable surface and the solvent evaporated under ambient pressure or 
in vacuo, at ambient or slightly elevated temperature. The resultant film 
on the substrate surface or after removal from the substrate, contains 
stabilized nitroglycerin and may be cut into strips or tapes which can be 
taped to the skin of a patient for sustained release of the medicament. 
The solution of uncrosslinked, water-insoluble vinylpyrrolidone copolymer 
and nitroglycerin may be applied directly to the skin of the patient and 
permitted to evaporate to form a film thereon, containing stabilized 
nitroglycerin. The latter is slowly released from the film and absorbed 
into the skin of the patient. 
The solution of vinylpyrrolidone polymer and nitroglycerin may be 
conveniently applied to the skin using an aerosol formulation containing 
one or more low boiling propellants. Although fluorocarbon propellants 
such as trichloromonofluoromethane (Propellant 11). 
dichlorodifluoromethane (Propellant 12) and dichlorotetrafluoroethane 
(Propellant 114) are particularly effective, other propellants well known 
to those skilled in the art may be used. The solution of nitroglycerin and 
water-insoluble vinylpyrrolidone copolymer in ethanol may be pressurized 
in an aerosol can with a propellant. In order to control the amount of 
polymer and nitroglycerin applied to the skin, it is advantageous to use a 
metering valve which delivers precise quantities of solution. When applied 
in this manner, the propellant and solvent quickly evaporate leaving a dry 
film of controlled nitroglycerin content covering the desired area of 
skin. 
A gel or thickened solution of nitroglycerin and water-insoluble 
vinylpyrrolidone copolymer may be applied with greater control to a 
restricted area of skin than a low viscosity solution. The solution may be 
thickened by the addition of a small amount of a soluble high molecular 
weight inert polymer or a thicknener of the type well known to those 
skilled in the art. High surface area inorganic materials such as finely 
divided fumed silica are particularly effective thickeners. The addition 
of a small amount of such a material results in a marked increase in the 
viscosity of the solution. The resultant gel or thickened solution 
exhibits thixotropy and flows readily during application but does not 
spread after application to the skin. The large surface area of the 
thickener increases the rate of evaporation of the solvent and contributes 
to rapid drying and film formation. The complexed nitroglycerin is slowly 
released and absorbed into the skin of the patient. At the end of the 
desired treatment period, or sooner if undesirable reaction to the 
nitroglycerin is noted, the film may be removed by rubbing with soap and 
water or alcohol. 
A solution or dispersion of uncrosslinked, water-insoluble vinylpyrrolidone 
copolymer and nitroglycerin, or a dispersion of crosslinked 
vinylpyrrolidone homopolymer or copolymer and nitroglycerin, in the 
absence or presence of an excipient, may be applied to a porous or 
open-structured substrate such as gauze, bandage tissue or paper, and upon 
evaporation of the solvent, provides an impregnated structure containing 
stabilized nitroglycerin, which is released over an extended period of 
time when applied topically to the skin of a patient. 
The solution or dispersion of water-insoluble vinylpyrrolidone homopolymer 
or copolymer and nitroglycerin may be mixed, with stirring, with one or 
more ointment bases, such as petrolatum, vasoline, lanolin, stearin, 
spermaceti wax or other waxy or fatty material. The ointment may be 
applied directly to the skin of a patient or may be coated on a carrier 
such as a bandage or polymeric tape for topical application to the skin of 
a patient. The stabilized nitroglycerin is slowly released and absorbed 
into the skin of the patient for as long as 24 hours. 
The nitroglycerin in the vinylpyrrolidone homopolymer or 
copolymer-nitroglycerin composition used in the practice of the present 
invention, is slowly released and absorbed directly into the skin of the 
patient. However, although the vinylpyrrolidone homopolymer or copolymer 
is water-insoluble, the hydrophilicity of the vinylpyrrolidone contained 
therein results in moisture absorption, e.g. from perspiration on the skin 
of the patient, and extraction of the nitroglycerin from the composition, 
followed by absorption of the drug into the skin. The rate of extraction 
may be varied over a wide range and is dependent upon the concentration of 
vinylpyrrolidone in the copolymer and/or the extent of crosslinking, if 
any, in the homopolymer or copolymer. 
The concentrations of water-insoluble vinylpyrrolidone homopolymer or 
copolymer and nitroglycerin in the stabilized compositions of the present 
invention, may be varied over a wide range, depending upon the desired 
release rate. The nitroglycerin concentration may range from about 1 to 
about 6% of the total weight of the composition, while the concentration 
of water-insoluble vinylpyrrolidone homopolymer or copolymer may range 
from about 5 to about 500% of the weight of the nitroglycerin.

The following examples are non-limiting illustrative embodiments of the 
compositions and methods of the present invention. Variations thereof will 
be obvious to those skilled in the art. 
EXAMPLE I 
An uncrosslinked vinylpyrrolidone (VP) homopolymer, a crosslinked 98/2 
weight ratio vinylpyrrolidone/ethylene glycol dimethacrylate 
(VP/EGDM)copolymer, an uncrosslinked 70/30 weight ratio 
vinylpyrrolidone/lauryl methacrylate (VP/LM) copolymer and an 
uncrosslinked 79/21 weight ratio vinylpyrrolidone/vinyl acetate (VP/VA) 
copolymer were prepared by solution polymerization in cyclohexane using 
lauroyl peroxide as catalyst. The viscous reaction mixture was cast on a 
polytetrafluoroethylene sheet and the solvent was permitted to evaporate. 
The resultant thin film was dried at 60.degree. C. in a forced air oven, 
washed free of residual monomer, if any, with petroleum ether and redried 
in vacuo at 60.degree. C. 
Ointments were prepared by dissolving or suspending the various polymers in 
ethanol. An ethanol solution containing 10 w/v % nitroglycerin (NG) or a 
nitroglycerin-lactose powder containing 10 weight-% nitroglycerin was 
added slowly to the polymer solution or suspension with stirring. Vasoline 
was slowly added to the homogeneous polymer-nitroglycerin mixture with 
stirring. The final ointment composition contained 20% polymer and 4% 
nitroglycerin. A polymer-free ointment containing 4% nitroglycerin was 
prepared for comparison. 
In order to determine the stability of the nitroglycerin to evaporation 
under drastic conditions, samples of the ointments were placed on 
10.times.10 cm squares of filter paper. The coated paper was hung for 
several days until the ethanol evaporated. Samples containing 4% 
nitroglycerin were placed in a forced air oven at 45.degree. C. and 
removed after 4.5 to 17 days and analyzed for nitroglycerin content. 
In order to determine the rate of release of the nitroglycerin to an 
aqueous medium, sample of the coated filter paper containing dried 
ointments with 4% nitroglycerin were folded to make an envelope and placed 
in 250 ml Erlenmeyer flasks containing 100 ml deionized water. The flasks 
were placed in a 36.degree. C. thermostatted shaker bath and samples of 
the liquid phase were removed for nitroglycerin analysis after shaking for 
15, 30 and/or 60 minutes. 
The nitroglycerin analyses were carried out by a modification of the 
spectrophotometric method described by Fung et al. (J. Pharm Sci., 63, 
1810 (1974). 
The stability of the nitroglycerin to evaporation, as indicated by the 
results of the thermal aging at 45.degree. C., and the rate of release of 
the nitroglycerin in water at 36.degree. C., are summarized in Table I. 
The results in Table I indicate that the polymer-free control ointment lost 
all of the nitroglycerin after 4.5 days in the oven at 45.degree. C. while 
releasing 48 and 57% of the nitroglycerin in water at 36.degree. C. after 
15 and 30 minutes, respectively. The ointment containing the water-soluble 
uncrosslinked polyvinylpyrrolidone still retained 93% of the nitroglycerin 
after 17 days in the oven while releasing all of the nitroglycerin after 
30 minutes in water. The ointment containing water-insoluble crosslinked 
98/2 VP/EGDM copolymer retained 76% of the nitroglycerin after 17 days in 
the oven and released 45 and 65% of the nitroglycerin after 15 and 60 
minutes, respectively, in water. 
TABLE I 
__________________________________________________________________________ 
VP/EGDM 
VP/LM 
VP/LM 
VP/VA 
Polymer none 
VP 98/2 70/30 
70/30 
79/21 
__________________________________________________________________________ 
Ointment 
Polymer, % 0 20 
20 20 20 20 
NG, % 4 4 4 4 4* 4 
Thermal aging at 45.degree. C. 
Residual NG, % of original 
after 0 
days 100 100 
100 100 100 100 
4.5 days 0 100 100 
7 days 77 42 49 
8 days 83 
17 days 93 
76 13 20 77 
Extraction by water at 36.degree. C. 
Extracted NG, % of original 
after 
15 minutes 48 82 
45 0 0 58 
30 minutes 57 100 28 7 
60 minutes 65 31 29 71 
__________________________________________________________________________ 
*NG added as 10% NG in lactose 
The ointment containing the 70/30 VP/LM water-insoluble uncrosslinked 
copolymer was less stable to thermal aging than the crosslinked VP/EGDM 
ointment but released about 30% of the nitroglycerin after 60 minutes in 
water. The ointment containing the uncrosslinked water-insoluble 79/21 
VP/VA copolymer behaved in a manner similar to the ointment containing the 
crosslinked polyvinylpyrrolidone, retaining 77% of the nitroglycerin after 
17 days in the oven and releasing 58 and 71% of the nitroglycerin after 15 
and 60 minutes, respectively, in water. 
EXAMPLE II 
A 64/36 vinylpyrrolidone/2-ethylhexyl acrylate weight ratio copolymer was 
prepared in isopropanol solution using lauroyl peroxide as catalyst. After 
4.5 g of the 60% solution of the VP/EHA copolymer is isopropanol was mixed 
with 12 ml of a 10% w/v solution of glyceryl trinitrate in ethanol, 42 g 
of white petrolatum was mixed in to give an ointment containing 2% 
nitroglycerin. 
Nine patients suffering from coronary artery disease and angina pectoris 
were used in a clinical trial. A 5-10 cm long extrudate was dispensed from 
a metal tube containing the ointment onto the forearm of each patient, 
covered with an impermeable pad and taped in place. The effectiveness of 
the ointment was tested by radioisotopic techniques, using multigated 
equilibrium blood volumes. 
The first 5 patients were tested 5 hours after the application of the 
ointment. There was a significant improvement in left ventricular ejection 
fraction, diastolic volume decreased significantly at rest and systolic 
volumes decreased significantly at rest and during exercise. All 9 
patients were tested 24 hours after the application of the ointment. 
Ejection fractions improved both at rest and during exercise and diastolic 
and systolic volumes decreased at rest and during exercise. Thus, the 
application of the ointment containing 2% nitroglycerin and the VP/EHA 
copolymer had beneficial effects on the cardiovascular system as early as 
5 hours after application and the effects persisted for at least 24 hours. 
EXAMPLE III 
A 62.5/32.5/5 weight ratio vinylpyrrolidone/lauryl methacrylate/acrylic 
acid copolymer was prepared by polymerization in cyclohexane using lauroyl 
peroxide as catalyst. The polymer was isolated in the same manner as 
described in Example I. The polymer was dissolved in ethanol and blended 
with a 10% w/v solution of nitroglycerin in ethanol, to yield a solution 
containing 15% VP/LM/AA copolymer and 3% nitroglycerin. The solution was 
cast on a cotten tape and dried in air. The tape was applied to the 
forearm of a patient with angina pectoris and relieved the symptoms for 
more than 24 hours. EXAMPLE IV 
A 42.5/52.5/5 weight ratio vinylpyrrolidone/lauryl methacrylate/acrylic 
acid copolymer was prepared in the same manner as described in Example 
III. An ethanolic solution containing 10% VP/LM/AA copolymer and 3% 
nitroglycerin was mixed with lanolin to produce an ointment which was used 
to impregnate gauze and dried. The impregnated gauze was covered with a 
silicone-coated release paper and packed in a multilayer, heat-sealed 
pouch containing an aluminum foil layer. When needed, the impregnated 
gauze was removed from the storage pouch and taped to the arm of a patient 
with the symptoms of angina pectoris. The symptoms were relieved in about 
2 hours and the relief persisted for 24 hours. 
EXAMPLE V 
A 90/10 weight ratio vinylpyrrolidone/lauryl methacrylate copolymer as well 
as a 10/90 weight ratio copolymer was prepared by solution polymerization 
in cyclohexane using lauroyl peroxide as catalyst. 
The isolated 90/10 VP/LM copolymer was a brittle solid which was mixed with 
nitroglycerin-lactose powder in ethanol solution and the resultant 
solution containing 3% nitroglycerin was used to impregnate a gauze 
bandage. The dried impregnated bandage relieved the symptoms of angina 
pectoris within 1 hour after application to the arm of a patient. 
The isolated 10/90 VP/LM copolymer was a viscous semisolid which was 
converted into an ointment containing 10% VP/LM copolymer and 4% 
nitroglycerin. When applied to the arm of a patient and covered with an 
impermeable polymer film such as polyethylene, the ointment relieved the 
symptoms of angina pectoris for 24 hours. 
EXAMPLE VI 
A 70/30 weight ratio vinylpyrrolidone/lauryl methacrylate copolymer was 
prepared by solution polymerization in isopropanol using lauroyl peroxide 
as catalyst. The polymer was isolated as described in Example I. The 
polymer was dissolved in ethanol and blended with a 10% w/v solution of 
nitroglycerin in ethanol to yield a solution containing 16% VP/LM 
copolymer and 4% nitroglycerin. The solution was placed in an aerosol can 
fitted with a metering valve and pressurized with Propellants 11 and 12. A 
film was prepared by spraying the solution on a 10.times.10 cm square of 
filter paper. The film was formed very rapidly due to the evaporation of 
the volatile propellants and solvent. The sample was placed in an oven at 
45.degree. C. for 72 hours. Analysis indicated that the sample retained 
68% of the original amount of nitroglycerin. 
EXAMPLE VII 
The 70/30 weight ratio VP/LM copolymer prepared in Example VI was dissolved 
in ethanol and mixed with a 10% w/v solution of nitroglycerin in ethanol, 
as described in Example VI. A small amount of Aerosil 200 fumed silica was 
added in portions until a gel having a viscosity of about 10,000 cps was 
obtained. The gel was applied to a strip of filter paper and formed a 
flexible, nontacky film in 2 minutes. After 72 hours in an oven at 
45.degree. C., the film retained 71% of the original amount of 
nitroglycerin. 
Although the description and examples given hereinbefore have been limited 
to nitroglycerin, it should be understood that the present invention is 
applicable to the other organic nitrate esters known to those skilled in 
the art as coronary vasodilators, e.g. isosorbide dinitrate, erythrityl 
tetranitrate, etc.