CA1163195A - Polymeric diffusion matrix containing a vasodilator - Google Patents

Abstract

ABSTRACT
A polymeric diffusion matrix containing a vasodilator is provided comprising from about 2 to about 60% of a polar plasticizer, e.g., glycerol, from about 2 to about 15% of a matrix component, e.g., polyvinylalcohol, from about 2 to about 10% of a water-soluble polymer with hydration sites, e.g., polyvinylpyrrolidone, which in combination with the remaining ingredients yields a matrix capable of sustained release of a vasodilator drug dispersed therein, and the balance water, the percentages being by weight.

Description

~ :~ 6 3 1 ~5 POLYMERIC DIFFUSION MATRIX C~NTAINING A VASODILATOR
SUMMARY OF THE INVENTION
The present invention relates to a polymeric diffusion matrix containing a vasodilator. More particularly, the invention relates to a polymeric diffusion matrix containing a vasodilator charaeterized by a sustained release of the vasodilator. Furthermore, the polymerie diffusion matrix is self-supporting.
In one embodiment, a polymeric diffusion matrix is pro-vided eomprising frorn about 2 to about 60% glycerol, from about 2 to about 15% polyvinylalcohol, from about 2 to about10% of a water-soluble polymer with hydration sites ~hich in combi.nation wlth the remaining ingredients (ineluding a vaso-dilator) yields a matrix capable of sustained release of a vasodilator dispersed therein, and the balance water, the pereenta~es being by weigh-t. Preferably, the water-soluble polymer is polyvinylpyrrolidone. The polyvinylaleohol prefer-ably has a moleeular weight of from about 50,000 to about 150,000, partieularly from about 100,000 to about 150,000 and the polyvinylpyrrolidone preferably has a molecular weight of from about 15,000 to about 80,000, partieularly from about 20,000 to about 60,000. The ~lycerol is preferably presen-t in an amount of about 35% to about 55%.
The glycerol (a polar plastieizer~ in the diffusion matrix ean be replaced in whole or in part with propylene glycol or polyalkylene glycols such as polyethylene glycol and polypropylene glycol. Polyethylene gl.ycols particularly those having molecular weights ranging from about 200 to about 1,000 can be used as the polar plasticizer. If poly-ethylene glycol is used in admi~ture with glycerol, theglycol can have a molecular weight of up to abou-t 4,000.

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It has been Eound that a polar plasticizerr e.g., glycerol, i5 a necessary component in the matrix. A diffusion matrix formed with no polar plastici~er is not flexible and has poor diffusional contact with the skin causing unreliable diffusion release.
It is possible to replace the polyvinylalcohol matrix componen-t with polymers of hydroxye-thylacrylate, polymers of hydroxyethylmethacrylate, polymers of hydroxypropylacrylate, and polymers of hydroxypropylmethacrylate. It is possible to use homopolymers or copolymers of the hydroxyalkyl(meth)-acrylates.
The water-soluble polymer can be (in addition to poly-vinylpyrrolidone) any of agar, agarose, gum arabic, gum tragacanth, polyacrylic acid, polymethacrylic acid, poly-vinyloxazolidone, polyvinylmorpholinone, and polyvinylpi-peridone.
In a preferred embodiment, a polymeric diffusion matrix suitable for the transdermal delivery of a vasodilator is provided comprising from about 2 to about 60~ glycerol, from about 2 to about 15% polyvinyl alcohol, from about 2 to about 10% oE a water-soluble polymer with hydration sites which in combination with the remaining ingredients yields a matrix capable of sustained release of a vasodilator dis-persed therein, and the balance water, the percentages being by weight. Preferably, the water-soluble polymer is polyvi-nylpyrrolidone. The polyvinylalcohol preferably has a mole-cular weight of from about 50,000 to about 150,000, particu-larly from about lO0,000 to about 150,000 and the polyvinyl-pyrrolidone preferably has a molecular weight of from about 15,000 to about 80,000, particularly from about 20,000 to about 60,000.
BRIEF DESCRIPTION OF THE DRI~WIN(~S
Figure l shows a plan view of a bandage having incor-porated therein the vasodilator-containing self-supporting polymeric diffusion matrix of the present inven-tion; and ~ 1~3~95 Figure 2 illustrates a cross-sectional view along line 2-2` in Figure 1.
DETAILED DESCRIPTION OF TH~ IN~ENT:[ON
~ ccordin~ to the presen-t inven-tion, a polymeric diffu-sion matrix is pxovided comp~ising, ~n ~ weight basis, fromabout 2 to about 60% glycerol, from about 2 to about 15 polyvinylalcohol, from about 2 to about 10% of a water~
soluble polymer wi-th hydration sites which is compatible with the remainder of the ingreaients o~ the diffusion ma-trix to permit the sustained release of a vasodilator, the balance being water. This water-so]uble polymer comple-ments the polyvinylalcohol by providing reten-tion of shape of the desired diffusion matrix. A representative example of a water-soluble polymer with hydration sites suitable for the present invention is polyvinylpyrrolidone. The matrix contains a therapeutically effective amount of a vasodilator for topical or transdermal application to a patient, thus forming a vasodilator drug delivery device.
In a first embodiment, the present invention provides a diffusion matrix for the application of a vasodilator to a patient (vasodilator drug delivery matrix). In another aspect of the present inven-tion, the transdermal or topical application of vasodilator drugs is contemplated via the diffusion matrix. Thé diffusion matrix of the present invention provides a steady release of the drug to the patient over an extended period of time, typically 24 hours.
In the uncured matrix, the glycerol is present in an amount of from about 2 to 60%. When trinitroglycerol is the vasodilator to be applied, the amount of glycerol preferably should be within the range of from about 35 to 55%. Prefer-ably, the glycerol has a minimum specific gravity oE
1.23 g/ml.
The polyviny~alcohol is present in the uncured matrix in an amount of from about 2 to about 15%, preferably from about 4 to about 9% by weigh-t. Preferably, the ~ ~3:~9~ :

polyvinylalcohol has a molecular weight of at least about 70,000. Most preferably, the molecular weight is from about 100,000 to about 15~,000.
The water-soluble polymer with hydration sites is pre-sent in the uncured matri~ in an amount aE from about 2 toabout lOP~, preferably from about 2 to about 5%, by weight.
In a preferred embodiment, polyvinylpyrrolidone is used as the water soluble polymer. The molecular weight for the polyvinylpyrrolidone should be selected to maintain water solubility. In general, this molecular weight should be within the range of fxom about 15,000 to about 80,000, pre-ferably from about 20,000 to about 60,000, and most prefer-ably from abou-t 35,000 to about 50,000. The polyvinylpyr-rolidone may be replaced by other ingredients which permit sustained release. The balance of the matrix comprises essentially water.
In its cured state, the polymeric diffusion matrix com-prises from about 2 to about 55~, preferably from about 4 to about 35% glycerol, from about 4 to about 30%, preferably from about 8 to about 20% polyvinylalcohol; from about 2 to about 20%, preferably from about 4 to about 10~, o~ a water~
soluble polymer having hydration sites, pre~erably polyvinyl-pyrrolidone, and -the balance water, all percen-tages being by weight. The molecular weight ranges for the polyvinylalcohol and polyvinylpyrrolidone are the same for cured and uncured diffusion matrices. The cured matrix has a density of about 1.2 g/ml. It is noted that the weigh-t ratio of glycerol to water in the cured matrix is about 0.6-1.8:1, preferably about 1:1. The cured matrix shows little swelling when immersed in water and will not dissolve in water at room temperature. However, if the water is heated to boiling, the diffusion matrix will dissolve.
~ t least one vasodilator is dispersed throughout the diffusion matrix when the diffusion matrix is used as a vaso-dilator drug delivery device. The type of vasodilator which ,,.,~ ~

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may be dispersed in the di~fusion matrix of -the present invention includes any vasodilator which is capable of being - transdermally or topically administered to a patient. With the sustained release of the drug at a relatively steady rate over a prolonged period, -typically 24 hours, the pa-tient is provided with the benefit of a steady application of the vasodilator over the prolonged period.
The vasodilators employed in the present invention gen-erally include those agents suitable for systemic absorption through the external body skin in accordance with their known dosages and uses. Representative vasodilators are compounds having nitrate ion. Representative vasodilators include amyl nitrate, nitroglycerin (trinitroglycerol), sodium nitrate, erythrityl tetranitrate, pentaerythritol tetranitrate, isosorbide dinitrate, mannitol hexanitrate, trolnitrate phosphate (triethanolamine biphospha-te), and the like.
When trinitroglycerol is used, it is ordinarily present in the form of lactose triturate. It is necessary to have an active adsorbent surface for the trinitroglycerol. The active adsorbent surface can be supplied by lactose, insolu-bilized starch, micronized cellulose, silica gel, di- and oligosaccharides having a degree of solubility from lower than to up to twice that of lactose, and cyclitols.
When lactose is employed as the insoluble active adsor-bent surface material, it is necessary to make certain there is enough polar plasticizer, e.g~, glycerol, and not too ~uch water, as this would cause the lactose to become solu-bilized. Solubilization will prolong the setting time and may decrease adhesion to the backing.
The amount of the vasodilator dispersed in the diffu-sion matrix can be varied in accordance with the desired dosage and the length of time the matrix is to remain on the skin. ~owever, the amount of the vasodilator i~cluded in the matrix should ~enerally be in excess o~ the amount which ~3~9~

is to be delivered to the patient. If the diffusion matrix is to be used for 24 hours, a suitable excess of the vasodi-lator should be included to assure appropriate release kine-tics. For example, if it is desired to apply about 10 mg. of trinitroglycero] to a patient over 24 hours, a roughly six-fold excess of the trinitroglycerol should be included in the diffusion matrix. Accordingly, from 50 to 70 mg. is considered a preferred amount to provide a 10 mg. release of trinitroglycerol over a 24-hour period. Quite obviously, the optimum amount that should be included in the diffusion matrix will vary according to factors such as the period of release of the drug.
In a preferred embodiment, there is used trinitrogly-cerol (also known as 1,2,3,-propanetriol trinitrate or nitroglycerin), which is useful in coronary medicine as a vasodilator. It is preferred to add the trinitroglycerol in the form of lactose triturate. In addition, the ratio of lactose triturate to the water and glycerol should avoid proportions where the trinitroglycerol may separate and raise an explosion hazard. A preferred lactose triturate is a composition comprising 10% nitrogiycerin and 90~ beta-lactose.
In forming the trinitroglycerol-containing matrix, ex-cess water is not required. Hence, this matrix comprises from about 35 to about 60~, preferably from about 45 to about 55% glycerol; from about 2 to about 15%, preferably from about 4 to about 9% polyvinylalcohol; from about 2 to about 10%, preferably from about 2 to about 5% polyvinylpyrroli-done, and the balance being essentially water, all percen-tages being by weight. The amount of water evaporated from the uncured matrix is negligible, hence the higher percentage for the glycerol. For this matrix, the weight ratio of gly-cerol to total polvmers is usually greater than 1, preferably from about 1.4 to 15:1.
The amount of trinitroglycerol which should be used is ~ 1~3 ~ ~

based upon a desired delivery of about 5 or 10 mg. per patient over a 24-hour period. The diffusion matrix drug delivery system of the present invention to deliver the 5 or 10 mg. in the 24-hour period should contain about ~0 to 60 mg. of the trinitroglycerol. To reach this objective, the concentration of the trinitroglycerol in the diffusion matrix and -the area of the diffu~ion matrix are factors to consider. In accordance with a preferred aspect of the pre-sent inventionr ~rom about 0~1 to about 4.0~ by weight trinitroglycerol is included in the diffusion matrix. In apreferred aspect of the present inven-tion, 80 ml. o~ the solution is mixed with 20 gm. of lactose tri-turate; this mix-ture is mechanically stirred until it is homogeneous. The resultant homogeneous mixture is poured into forms preferably made of glass or stainless steel, these forms or templates producing a diffusion matrix having a thickness of abou-t 3 to about 4 mm., in accordance with a preferred aspect of the presen~c invention. This diffusion matrix is either cast or cut into pieces of the desired size. In a pre~erred aspect, ~quares of about one inch on each side r or about 6.5 cm2, have been preparea for ease of application to the pa-tient.
The following methods may be used for preparing the dif-fusion matrix of the present invention:
In a first method, the matrix is formed at atmos-pheric pressure. Water and glycerol are first mixed together.
Since alkaline solutions of nitroglycerin or other organic nitrates have relatively poor stability, the pH of the gly-cerol/water mix-ture is adjusted so tha-t it is ei-ther neutral or slightly acidic, i.e., the pH ranging from about 6.5 to about 7Ø In a preferred embodiment, the pH is adjusted to within the above-mentioned range by adding sodium citrate and citric acid to the mixture.
The polyvinylalcohol and polyvinylpyrrolidone are then added to the glycerol-water mixture at room temperature, with agitation. The mixture is heated to a tempecature within

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g the range of from about 90 to about 95C at atmospheric pres-sure to extend the polymers. The mixture is held at this temperature for about one hour. I~ desired, the mixture may be maintained at this tempexature for a period of about 48 hours prior to the addition of the drug. Thus, the mixture is stable for a period of about ~ hours and may be kept for such a period before being mixed with the drug to be delivered to the patient. Thereafter, the mixture is cooled to 80C and stirred for an additional hour to remove bubbles from the mix-ture. The drug to be applied to the patient is then added tothe mixture, with thorough agitation. Once a homogeneous mix-ture of the polymer solution and drug is obtained, the mix-ture is ready to be cast into sheets of the drug-containiny diffu-sion matrix. In a preferred embodiment, the drug may be dis-solved or dispersed by agitation in a suitable solvent such asglycerin and water. The thus-obtained solution can be main-tained at room temperature for prolonged periods without deterioration.
In a second method, water and glycerol are mixed, with the pH of the mixture adjusted to a desired value by adding suitable amounts of sodium citrate and citric acid.
Thereafter, the polyvinylalcohol and polyvinylpyrrolidone are added. The resulting mixture is then heated to a temperature of about 120C at a pressure of about 2 atmospheres absolute.
The temp~rature is maintained for about 1 hour without any mechanical agitation. In a preferred embodiment, the heating may be performed in an autoclave. Since bubbles are not formed when the heating is conducted in an autoclave, such a procedure is preferred. Thereafter, the temperature is lowered to about 20 to about 80C whereupon the drug to be applied to the patient is added. After the drug has been hbmogeneously dispersed in the fluid mixture, the mixture is poured into molds to form sheets of the drug-con-taining dif-fusion matrix.
In the above methods and for the case of trinitroglycerol 1 9 ~

g and other drugs hav;ny similar limitations, the drug must be added and mixed thoroughly when the polymer mixture ~s in the liquid state. In the case o~ using lacto~e triturate, the mixture should be cast within about 30 minutes after the drug has been introduced into the polymer solution. ~'his is impor-tant in order to avoid the setting of the polymer solution prior to casting.
It has been found that curing is facilita-ted by sub-jecting the matrix to a temperature down to about -20C imme-diately after casting. The setting period is quickenedconsiderably.
The temperature at which the drug is to be added to the matrix solutlon depends on the stability and volatility of the drug. For example, trinitroglycerol begins to decompose at a temperature of above abou-t 50C. Accordingly, in pre-paring a trinitroglycerol-containing diffusion matrix, the matrix solution mixture is cooled to about 50C, whereupon the trinitroglycerol is added. The drug-containing diffusion solution is then cast into molds to form sheets of the final product~ In addition, for trinitroglycerol, the pH of the solution mixture should be kept slightly acidic, i.e., be-tween 6.5 and 7.0 since trinitroglycerol is stabilized within this pH range.
Sodium dodecyl sulfate or sorbitan (Tween-20) or other detergents may be added in an amount of 0.1 to 10% by weight, based on the matrix, as a dispersing agent, if desired.
For vasodilators that are alcohol-soluble, it may be desirable to add in the initial mixture of glycerol and water, ethanol or isopropanol in an amount of from 2 to 40% by weight, based on the matrix, to facilitate the preparation of a diffusion matrix for such alcohol-soluble drugs.
An absorp-tion facilitator to insure skin penetration such as dimethylsulfoxide, decylmethylsulfoxide, or other penetra-tion enhancers may be added.

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I~ it is desired to increase the effective lifetime of the diEfusion matrix, a drug reservoir may also be attached to the di~fusion matrix. The diffusion matrix may also be used to help with local vasodilation to assist in the solution of physiological problems resulting from local circulatory deficiencies, for example, to promote circulation in the ex-tremities o~ a patient.
The present drug delivery device comprises the drug-containing diffusion matrix and means for fastening the matrix to the skin of a patient. Such means can take various form~, such as an occlusive backing layer forming a kind of "bandage"
with the diffusion matrix being held against the skin of a pa-tient being treated. A polyethylene or Myla-c tape is contem-plated as one form of occlusive layer in accordance with the present invention. It can also take the form of an elastic band, such as a cloth band, a rubbery band or other material.
Here, the diffusion matrix is placed directly on the s~in and held in place by such elastic band which typically will be placed over the arm or wrist of the patient. An intermediate adhesive layer between the diffusion matrix and the skin capa-ble of permitting the transdermal application oE the drug can also be used.
As a preferred embodiment in the packaging of the present matrix, the drug-con-taining diffusion matrix is placed in a cavity provided in an inert backing material. Useful backing materials include metal foils such as aluminum foil, polyole-fins such as polyethylene and polypropylene, polyesters such as Mylar ~polye-thylene terephthalate), polyamides such as nylon, and the like. The drug-containing diffusion matrix can be poured in its molten state into the cavity and permittea to cool. An adhesive layer is provided on the backing material surrounding the cavity. To prevent evapora-tive loss in the surface of the matrix, the adhesive layer and the matrix are sealed with a release layer. To use the device, the patient peels off the release layer and places the device in intimate 1 163~9~
~ L~ -contact with his s~in. The exposed adhesive layer secures the device to the pa~ient. A concentration gradient.existing normal to the surface of the matri~ and the patient's skin facilitates diffusion of the drug through -the matrix into the patient's body. Thus, -there is provided a device whereby a drug is delivered transdermally to a patient at a steady rate over a prolonged period of time.
The construction of a preferred embodiment for the pack-aging of the present inven-tion is shown in further detail in Figures 1 and 2. As illustrated in the Figures, the package comprises a bandage having cover layer 12 and backing mem~er 10. The diffusion matrix 14 having a vasodilator ~e.g., trinitroglycerol) dispered therein is placed in cavity 16 in backing member lO. The diffusion matrix may be poured in its molten state into cavity 16 in backing member lO and permitted to cure. Alternatively, the molten polymeric mixture ~with or without a drug) is cast to form a thin sheet which is cut, after curiny, into smaller sheets to fit the particular appli-cation of the matrix. Individual smaller sheets may then be placed in cavity 16 in backing member lO. The area 18 sur-rounding the matrix in the backing member lO is heat-sealed to prevent the matrix from being removed from the backing mem-ber. The backing member lO is formed of a laminate comprisiny an outer layer 20 made of a polyester, such as polyethylene terephthalate, an intermediate layer 22 made of a metallic foil, e.g., aluminum foil, and an inner layer 24 made of an ionomer, such as Surlyn. A layer of pressure-sensitive adhe-sive 26 is provided on the surface of the inner layer sur-rounding the heat-sealed portion. It is noted that the adhe-sive does not cover the matrix.
The matrix is prevented from coming into contact withthe atmosphere by placiny cover layer 12 thereon, which seals the matrix. The cover layer is also formed of a laminate having the same construction as the backing layer, i.e., an outer layer 28 made of a polyester, e.g., polyethylene 7 163~ ~S

terephthalate; an intermediate layer 30 made of a metallic foil, e.g., aluminum foil; and an inner layer 32 of an iono-mer, e.g., Surlyn. The surface 34 of the inner layer coming into contact with the pressure-sensitive adhesive 26 on the backing member 10 is coated with a release layer to permit easy removal of the cover layer.
To apply the drug to the patient, the cover layer is peeled off. The exposed matrix is then taped onto a suitable portion of the patient's body, e.g., arm or wrist, to allow the drug to diffuse thereinto.
In the preferred embodiment wherein trinitroglycerol is dispersed in the polymeric diffusion matrix, the molten matrix is cast into cavities provided in the backing member.
The matrix is permitted to cure for a short period (e.g.
about 10 minutes to abou-t one hour) and is sealed by placing the cover layer over the backing member.
The method of administration o~ this invention is suit-able also for adaptation to buccal and especially to sublin-gual administration. Because of the much higher rate oE
absorption through the mucosa by that route, much shorter periods of administration are required.
The invention is illustrated by the following non-limiting Examples:
EXA~PLE I
Glycerol (45 ml.), water (~5 ml.~ and 1~ by weight sodium citrate are mixed together and the pH adjusted to 7 through addition of sodium citrate and citric acid. This mixture is heated to 90C; after reaching at least 70C, there are slowly added 7 gm. polyvinyl alcohol (PVA 100~
hydrolyzed, molecular weight 115,000) and 5 gm. polyvinyl-pyrrolidone (mw. 40,000). The mixture is stirred at 90C
until solu-tion is effected, which may take abou-t 10 minutes, it being appreciated that with larger quanti-ties, a consider-ably longer period of time may be needed. ~0 ml. of this 35 solution are then mixed with 20 gm. lactose triturate (10~ -1 1~31g~
-~3-nitroglycerin and 90% lactose), this mixture ~hen being rnechanically stirred until homogeneous. This homogeneous mix-ture is then poured into forms made of glass or stainless steol which serve as templates to produce a diffusion matrix 5 having a thickness of about 3 to 4 mm. This diffusion matrix is then cut into square pieces of about l inch on each side, i.e., to provide a total surface area of about 6.5 cm2.
To establish that a polar plasticizer such as glycerol is a necessary matrix component, a drug-free diffusion matrix 10 of Fxample I and a drug-free matrix of Example I without a glycerol component were prepared. Both matrices were doped with crystal viole~. When applied to human skin, the matrix contains glycerol displayed a uniform color transfer from the surface of the diffusion matrix to the surface of the 15 skin. The glycerol-free matrix, when applied to human skin, gave a spotty diffusion pattern. This is believed to estab-lish that a polar plasticizer is a necessary element of the diffusion matrix of the instant invention in order to achieve uniorm diffusion characteristics.
Rather than pouring the homogeneous mixture in Example I
into forms, injection molding can be used. In injection mol-ding, the foil backing is placed in a series of molds and the polymeric mix~ure is injectioned molded therein to form the final product.
A preferred foil is a "polyfoil" having consecutive layers of polyethylene, aluminum, polyethylene, polyester (polyethylene terephthalate). The first polyethylene layer has the diffusion matrix adhered thereto and the polyester layer represents the backing layer. A particularly preferred 30 "polyfoil" is Ludlow CX-220 available from the Ludlow Co., Ludlow, Massachusetts.
Although the polyvinylalcohol of Example I was lOOeo hydrolyzed, it is possible to use partially hydrolyzed poly-vinylalcohols. Tests have bcen conducted using 75, 88~ 96, 97, 98, and 99~ hydrolyzed polyvinylalcohols. With hydrolysis 1 ~3~

levels below 90%, some struct-~ral weakness, shrinkage, and even some phase separation are observed. It is preferred to use polyvinylalcohols tha~ are at least 90%, preferably 95%, hydrol~zed.
EXAMPLE II
Example I is repeated with the exception that 3 gm. of agar is used instead of polyvinylpyrrolidone. Calcium chlo-ride is included in the mixture also and is present in an amount of 1% by weight.
EXAMPLE III
The diffusion matrix of Example I is applied to a patient ~y placing it against the wrist, shoulder or other sites of the patient.
EXAMPLE IV
The diffusion matrix of Example I is applied to a patient by first attaching the diffusion matrix to a Mylar or poly-ethylene backing layer. This occlusive backing l~yer is pro-vided with an adhesive whereby the di~fusion matrix is held in contact with the skin as part of this "bandage".
EXAMPLE V
948 g. of 96% glycerol and 644 g. of water are mixed together. 27 g. of sodium citrate, 159 g. of polyvinyl alco hol (molecular weight 115,000), 93 g. of polyvinylpyrrolidone (molecular weight 40,000) are dissolved in the glycerol/water mixture by continuous stirring and maintaining at a tempera-ture of about 90C.
In a separate container, 600 g. of lactose triturate (10%
nitroglycerin and 90% lactose) is dispersed in 315 g. glycerol and 214 g. water with agitation at room temperature.
When the polymers have gone into solution, the lactose triturate dispersion is poured therein. The mixture is mixed thoroughly at a temperature range of between 50 and 55C to form a homogeneous mixture. The container is kept covered.
The homogeneous mixture is poured into orms made of glass or stainless steel which serve as templates to produce ~ ~3~
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a drug-containing diffusion matrix having a thickness of about 3 to 4 mm. This diE -~sion matrix is then cut into square pieces of about 1 inch on each side, i.e., to provide a total surEace area of about 6.5 cm .
EXAMPLE VI ~
Example V is repeated except that sodium polyacrylate having a molecular weight of 100,000 (a preferred molecular weight range of the polyacrylic acid ori salt pol~mer) is used instead of polyvinvlpyrrolidone.
EXAMPLE VII
Male dogs are anesthetized with sodium pentothal.
Through surgical incisions, catheters are positioned in the femoral veins of each hind leg and in the abdominal arota.
Flow gauges are placed on the internal iliacs of both hind limbs. On a well-shaved area of the medial surface of the leEt thigh, a nitroglycerin-containing polymer ma~rix o~tained in Example I is taped in place and remains undisturbed for 4 hours. The right hind limb receives no matrix or treatment of any kind. After application of the matrix, blood samples (5 ml.) are taken from the catheters in each of the femoral veins and from that in the abdominal aor~a at 15, 30, 60, 120, 1~0, and 240 minutes. Once drawn, the blood samples are put in ice, centrifuged (for 10 minutes) at 0C, and 2 ml. plasma is transferred to a silanized ~with an alkylated silicone oil) glass tube. To each tube, 5 ml. n-pentane is also added and the nitroglycerin is extracted for 1 hour with gentle shaking a~ 0C. The pentane phase is then transferred to a ~ ml.
capacity Reacti-Vial and evaporated to near dryness. The residue is then dissolved in 30 microliter benzene containing ~ nanograms para-nitro-anisole used as the external standard.
1-.0 to 50.0 microliters of this solution is -then injected for nitroglycerin quantitation using GLC-Electron Cap-ture Dectection. (A Ilewlett-Packard 4610A Gas chromatograph equipped with a 63Ni-electron capture detector.) Separation is achieved on a 4 ~oot ~ 3 mm. I.D. glass column packed with ~ ~63~5 l0~ SE-30 on 1001120 mesh GAS-C~IROM QTM. Thc column is main-tained at 140C while the injection-port tcmperaturc is 170C
and the detector temperature is 220C. A nitroglycerin cali-bration curve is constructed from the analyses of nitroglyc-5 erin-spiked blank plasma.
The results from the above tcst runs, summarized in Table I, show dramatically that nitroglycerin is absorbed transepi-dermally from the matrix over the entire 4 hour period. Also, the levels attained in the venous blood draining the limb con-10 taining the matrix are approximately proportional to the ma-trix surface area in contact with the skin.
From the results of the studies here discussed, it is evident that transepidermal nitroglycerin absorption has occurred from the matrix to blood.
The nitroglycerin absorption rate appears to be fairly constant from 30-240 minutes as depicted by the essentially non-varying arterial nitroglycerin plasma levels.

~ ~3~g~ i ABLE I
MATRIX SIZE 2" x 3"2" x 1" 1" x 1"
STUDY NO. 1 2 3 SAMPLE nanOgralnS ni~rog1ycerin per ml. p1asma ARTERIAI,- 15 minØ 7 0.1 n . 3 "- 30 min. 0.6 0.2 0.5 - 60 min. 0. 7 0.2 "-120 min. 0.9 0.5 4 "-180 min. 1.3 0.7 0.5 10 "-240 min. 1.3 0.2 0.3 EXPERIMENTAL
VENOUS- 15 min. 1.0 5.7 0.4 "- 30 min. 0.5 8.3 0.3 "- 60 min. 15.311.4 0.5 15 ~-120 min. 26.9 7.6 0.8 "-180 min. 32.913.7 0.6 "-240 min. 32.0 5.6 0.2 CONTROL
VENOUS- 15 min. 0.4 9.2 0.1 20 ll- 30 min. 0.621.6 0.2 "--60 min. 7.4 4.5 0,3 "-120 min. 2.313.0 0.4 "-180 min. 9.914.5 0.4 "240 min. 13.9 4.1 0.2 .

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EXAMPLE VIII
Five male mongrel dogs, free of disease, are anesthetized with sodium pentobarbltal. Under a septic surgical procedure, a catheter is inserted into the right artrium via -the jugular vein Eor the removal of blood samples from the right heart.
An arterial catheter is placed in the right carotid artery for the continuous recording of arterial blood pressure. Both cathe-ters are exteriori~ed at the back of the neck.
The animals are allowed to recover from the anesthetic and are studied 24 hours later in the fasted, conscious state while resting comfortably in a supporting harness.
Each animal is allowed to become famil1ar with the labo-ratory surroundings and when completely acclimated, a 20 ml.
reference blood sample is obtained from the right heart cath-eter. A 1.0" x 1.0" square of the nitroglycerin-containing polymer matrix obtained in Example I is then applied to a well-shaved area of the right lateral ches-t wall. The matrix is held securely in place with surgical -tape. After applica-tion of the polymer matrix, 5.0 ml. blood samples are obtained 20 at: 15 min., 30 min., 45 min., 1 hr., 2 hr., 3 hr., 4 hr., 5 hr., 6 hr., 7 hr., 8 hr., 9 hr., 10 hr., 11 hr., 12 hr., 14 hr., 16 hr., 18 hr., 20 hr., 22 hr., and 24 hr. The ani-mals are conscious and unrestrained during the entire 24 hour period of sampling. At no time do the animals display any unfavorable effects due to the transcutaneous administration of nitroglycerin.
Immediately after drawing, blood samples are put in ice and transferred to a walk-in refrigerator and centrifuged for 10 minutes at O~C. A 2 ml. ali~uot of plasma is taken from each specimen and transferred to individual silanized (with an alkylated silicone oil) glass tubes. A 5 ml. volume of n-pentane is added to each tube and the nitroglycerin is extrac-ted for 60 minutes with gentle shaking at 0C. The pentane phase is transferred to a 5 ml. capacity Reacti-Vial and evap-orated to near dryness. The residue is dissolved in 30 ~ ~3:~9~ ~

~.
microliters of benzene eontaining 2 nanograms of para-nitro-anisole used as the external standard. A 1 r 0 to 5.0 micro-liter aliquot of this solution is injeeted for nitroglycerin qunat.itation using GLC-Eleetron Capture De-tection (Hewlett~
Packard 4610A Gas Chromatograph equipped with a 63Ni-electron capture detector.) Separa-tion is achieved on a 4 foot x 3 mm.
I.D. glass eolumn paeked with 10% SE-30 on 100/120 mesh GAS-Chrom QTM. The column is maintained at 140C while the injec-tion-port temperature is 170C and detec-tor temperature:
220C. A nitroglyeerin calibration curve is construeted from the analyses of nitroglyeerin-spieked blank plasma.
Table 2 summarizes the plasma nitroglycerin data from the dogs. At each time point the mean + the standard devia-tion is lis-ted in the Table.

~ ~3~ ~

TA~LL 2 HOURS ng nitroglycerin / ml. plasma POST DOG #1 DOG #2 DOG #3 DOG #4 DOG ~5 5 DOGS -~/-S.D
APPLICATION
5 0.25 0.1 0.4 --~ 0.4 -~- 0.3 0.1 0.50 0.1 0.3 0.0 0.2 0.2 0.1 0.1 0.75 0.1 0.3 0.0 0.1 0.2 0.1 0.1 1.00 0.2 0.2 0.2 0.1 0.4 0.2 0.1 2.00 0.2 0.6 0.0 0.2 0.3 0.3 0.2 103,00 2.1 0.4 0.0 0.9 0.2 0.7 0.8

4.00 0.5 0.8 0.1 0.3 0.3 0.4 0.3

5.00 0.2 1.0 0.3 0.2 0.1 0.4 0.4

6~.00 0.2 0.6 0.2 0.6 0.9 0.5 0.3

7.00 0.9 0 7 0.5 0.3 1.2 0.7 0.4 158.00 0.2 2.4 0.7 0.4 0.5 0.8 o,g 9.00 0.2 0.6 0.3 0~3 0.1 0.3 0.2 10~00 Ool 0.8 0.6 0.3 0.7 0.5 0.3 11~00 0~1 0~8 0~1 0~4 0~5 0~4 0~3 12.00 0.4 0.6 0.4 0.3 0.1 0.3 0.2 2014.00 ~ 0 4 0.2 0.2 0.2 0.2 0.1 16.00 0.1 0.4 0.3 0.6 0.3 0.4 0.2 18.00 0.3 1.2 0.3 0.3 0.4 0.5 0.4 20.00 ~.3 0.4 0.5 0.3 0.2 0.3 0.1 22.00 0.2 1.1 0.7 --- --- 0.7 0.5 2524.00 0.3 0. 4 ~~~ ~~~ ~~~ O ~ 4 0 ~ 1 ~ ~3~

It should be noted tha-t if the data of the animal tests reported supra are plotted graphically, the data show that there is still a suhstantial release of the drug to the sub~
ject even after 24 hours. It is believed that the fluctua-tions in the individual readings wi-th the fi~e dogs tested is at least in part due to deficiencies in testing procedures and measurement techniques. Subsequent to the animal testing referred to above, there have been clinical trials using the polymeric diffusion matrix of Example V on several patients and these clinical trials also establish that the drug is released over a 24-hour period via the transdermal route.

Claims (25)

CLAIMS:

1. A self-supporting polymeric diffusion matrix suit-able for the transdermal delivery of a vasodilator comprising from about 2 to about 60% of a polar plasticizer selected from the group consisting of glycerol, propylene glycol, and a polyalkylene glycol, from about 2 to about 15% of a matrix component selected from the group consisting of polyvinylal-cohol, a polymer of hydroxyethylacrylate, a polymer of hydrox-yethylmethacrylate, a polymer of hydroxypropylacrylate, and a polymer of hydroxypropylmethacrylate, from about 2 to about 10% of a water-soluble polymer with hydration sites which in combination with the remaining ingredients yields a matrix capable of sustained release of a vasodilator dispersed there-in, at least one vasodilator suitable for transdermal delivery to a patient, and the balance water, the percentages being by weight.

2. The polymeric diffusion matrix of claim 1 wherein said water-soluble polymer is selected from the group consis-ting of polyvinylpyrrolidone, agar, agarose, gum arabic, gum tragacanth, polyacrylic acid, polymethacrylic acid, polyvinyl-oxazolidone, polyvinylmorpholinone, and polyvinylpiperidone.

3. The polymeric diffusion matrix of claim 2 wherein said water-soluble polymer is polyvinylpyrrolidone.

4. The polymeric diffusion matrix of claim 3 wherein said matrix component is polyvinylalcohol having a molecular weight of from about 50,000 to about 150,000.

5. The polymeric diffusion matrix of claim 4 wherein said polyvinylalcohol has a molecular weight of from about 100,000 to about 150,000.

6. The polymeric diffusion matrix of claim 3 wherein said polyvinylpyrrolidone has a molecular weight of from about 20,000 to about 60,000.

7. The polymeric diffusion matrix of claim 3 wherein said matrix component is polyvinylalcohol having a molecular weight of from about 100,000 to about 150,000 and said poly-vinylpyrrolidone has a molecular weight of from about 20,000 to about 60,000. .

8. The polymeric diffusion matrix of claim 1 wherein said vasodilator is trinitroglycerol.

9. The polymeric diffusion matrix of claim 1 wherein said vasodilator is lactose triturate.

10. The polymeric diffusion matrix of claim 1 wherein said vasodilator is nitroglycerin and said nitroglycerin is attached to an active adsorbent surface.

11. The polymeric diffusion matrix of claim 10 wherein said adsorbent surface is provided by a member selected from the group consisting of lactose, insolubilized starch, micro-nized cellulose, silica gel, di- and oligosaccharides having a degree of solubility from lower than up to twice that of lactose, and cyclitols.

12. A self-supporting polymeric diffusion matrix suit-able for the delivery of a drug having a vasodilator effect comprising from about 35 to about 60% glycerol, from about 4 to about 9% polyvinylalcohol, from about 2 to about 5% of a water-soluble polymer with hydration sites which in combina-tion with the remaining ingredients yields a matrix capable of sustained release of a vasodilator drug dispersed therein, a therapeutically effective amount of trinitroglycerol and the balance water, the percentages being by weight.

13. The polymeric diffusion matrix of claim 12 wherein said water-soluble polymer is polyvinylpyrrolidone having a molecular weight of from about 20,000 to about 60,000.

14. The polymeric diffusion matrix of claim 12 wherein said glycerol is present in an amount of from about 45 to about 55%.

15. The polymeric diffusion matrix of claim 8 wherein said polyvinylalcohol has a molecular weight of from about 100,000 to about 150,000.

16. A method of delivering a vasodilator drug to a patient over a prolonged period at a steady rate which com-prises applying to said patient a self-supporting polymeric diffusion matrix suitable for the transdermal delivery of a vasodilator drug, said mixture comprising from about 2 to about 60% of a polar plasticizer compound selected from the-group consisting of glycerol, propylene glycol, and a polyal-kylene glycol, from about 2 to about 15% of a matrix component selected from the group consisting of polyvinyl alcohol, a polymer of hydroxyethylacrylate, a polymer of hydroxyethyl-methacrylate, a polymer of hydroxypropylacrylate, and a poly-mer of hydroxypropylmethacrylate, from about 2 to about 10%
of a water-soluble polymer with hydration sites which in com-bination with the remaining ingredients yields a matrix capable of sustained release of a vasodilator drug dispersed therein, at least one vasodilator drug suitable for transder-mal delivery to said patient, and the balance water, the per-centages being by weight.

17. The method of claim 16 wherein said vasodilator drug is trinitroglycerol.

18. The method of claim 17 wherein said water soluble polymer in said matrix is polyvinylpyrrolidone, said polyvi-nylpyrrolidone having a molecular weigh-t of from about 20,000 to about 60,000.

19. The method of claim 17 wherein said matrix component is polyvinylalcohol having a molecular weight of from about 100,000 -to 150,000.

20. A self-supporting polymeric diffusion matrix for the sustained release of trinitroglycerol to a patient by trans-dermal application, said matrix comprising:
a. from about 2 to about 60% by weight glycerol;
b. from about 2 to about 15% by weight polyvinylalcohol;
c. from about 2 to about 10% by weight polyvinyl-pyrrolidone; and d. a pharmaceutically effective amount of trinitroglycerol.

21. A self-supporting polymeric diffusion matrix for the sustained release of trinitroglycerol to a patient for transdermal application, said matrix comprising a. from about 35 to about 55% by weight glycerol;
b. from about 4 to about 15% by weight polyvinylal-cohol having a molecular weight of from about 100,000 to about 150,000;
c. from about 2 to about 10% by weight polyvinyl-pyrrolidone having a molecular weight of from about 20,000 to about 60,000; and d. a pharmaceutically effective amount of trinitroglycerol.

22. The polymeric diffusion matrix of claim 21 formed from an aqueous mixture.

23. A self-supporting polymeric diffusion matrix for the sustained release of trinitroglycerol to a patient by trans-dermal application, said matrix containing about equal parts water and glycerol, about 7% by weight polyvinylalcohol having a molecular weight of about 115,000, about 5% by weight poly-vinylpyrrolidone having molecular weight of about 40,000, and a pharmaceutically effective amount of trinitroglycerol.

24. The polymeric diffusion matrix of claim 23 wherein said trinitroglycerol is present in the form of lactose triturate.

25. A self-supporting polymeric diffusion matrix suit-able for the transdermal delivery of a drug, said matrix comprising a. from about 2 to about 60% of a polar plasticizer selected from the group consisting of glycerol, propylene glycol and a polyalkylene glycol;
b. from about 2 to 15% of a matrix component selected from the group consisting of polyvinylalcohol, a polymer of hydroxyethyacrylate, a polymer of hydroxyethylmeth-acrylate, a polymer of hydroxypropylacrylate, and a polymer of hydroxypropylmethacrylate;
c. from about 2 to about 10% of a water-soluble polymer with hydration sites, which in combination with the remaining ingredients yields a matrix capable of sustained release of a drug dispersed therein; and d. the balance water, the percentages being by weight.