WO1982000099A1

WO1982000099A1 - Polymeric diffusion matrix for administration of drugs

Info

Publication number: WO1982000099A1
Application number: PCT/US1981/000893
Authority: WO
Inventors: Pharma Inc Key; A Keith; W Snipes
Original assignee: Key Pharma
Priority date: 1980-07-09
Filing date: 1981-06-26
Publication date: 1982-01-21
Also published as: GB2089210A; NO820722L; DE3152182A1; IT1237327B; SE8201337L; JPS57500980A; NO153638C; CH658597A5; CA1163559A; SE447448B; BE889549A; NO153638B; AU7415181A; GB2089210B; IT8219833A0; FR2486397A1; NL8120270A

Abstract

A polymeric diffusion matrix for administering a drug is provided comprising from about 2 to about 60% of a polar plasticizer, e.g., glycerol, from about6 to about 20% of polyvinylalcohol, from about 2 to about 10% of polyvinylpyrrolidone, and a pharmaceutically effective amount of drug, yielding a matrix capable of sustained release of a vasodilator drug dispersed therein, and the balance water, the percentages being by weight. The drugs include terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenylpropanolamine, and chlorpheniramine maleate.

Description

POLYMERIC DIFFUSION MATRIX FOR ADMINISTRATION OF DRUGS SUMMARY OF THE INVENTION The present invention relates to a polymeric diffusion matrix containing one or more drugs suitable for transdermal administration to a patient. More particularly, the invention relates to a polymeric diffusion matrix containing one or more of such drugs characterized by a sustained relase of such drugs. Among the drugs suitable for administration in the polymeric diffusion matrix of this invention are terbutaline, ephedrine, clonidine, phenylephrine, estradiol esters, phenyl propanolamine, and chlorpheniramine maleate.

A self-supporting polymeric diffusion matrix is provided for the sustained release of a drug or drugs in order to transdermally deliver said drug to a patient, and provide said patient with a therapeutic effect, said matrix comprising from about 2 to about 60% by weight of a polar plasticizer; from about 6 to about 20% by weight polyvinylalcohol; from about 2 to about 10% by weight polyvinylpyrrolidone; and a pharmaceutically effective amount of drug to- provide a sustained release of said drug over a prolonged period.

In one embodiment the polar plasticizer is glycerol present in an amount of from about 2 to about 60% by weight. In another embodiment the polar plasticizer is polyethylene glycol present in an amount of from about 2 to about 15% by weight. A still further embodiment contemplates a mixture of glycerol and polyethylene glycol wherein the latter is present in an amount by weight of from about 1 to about 5 parts per weight glycerol.

The self-supporting polymeric diffusion matrix generally contains a mixture of polyvinylalcohol and polyvinylpyrrolidone, although it will be understood that other polymeric mixtures may be used provided they yield the desired sustained release effect. For example, both the polyvinylalcohol and the polyvinylpyrrolidone may be completely replaced with from about 1 to about 9% agar or agarose, and preferably from about 1.5 to 3% agar or agarose, 2% agar or agarose being particularly preferred.

As the polyvinylalcohol used in the present invention there is generally contemplated one having a molecular weight from about 50,000 to about 150,000, and more preferably about 100,000 to about 150,000, 115,000 having been used in related systems of the present inventors with success. The polyvinylalcohol should be hydrolyzed, generally at least to the extent of 90%, with a preferred embodiment being at least 95% hydrolyzed. Polyvinylpyrrolidone should have a molecular weight of from about 15,000 to about 85,000, and more preferably from about 20,000 to about 60,000. Polyvinylpyrrolidone with a molecular weight of 40,000 is a particularly preferred embodiment.

The amount by weight of the ingredients other than the polar plasticizer generally should be in the following ranges: polyvinylalcohol is generally present in an amount of from about 6 to about 20% by weight, with 10% being a preferred embodiment; polyvinylpyrrolidone is present generally in an amount of from about 2 to about 10% by weight.

The water-soluble polymer can be replaced with (in addition to agar) gum arabic, gum tragacanth, polyacrylic acid, polymethacryliσ acid, polyvinyloxazolidone, polyvinylmorpholinone, and polyvinylpiperidone.

Polyalkylene glycols such as polyethylene glycol and polypropylene glycol may replace all or part of the glycerol.

It is possible to replace the polyvinylalcohol with polymers of hydroxyethylacrylate, polymers of hydroxyethylmethacrylate, polymers of hydroxypropy1aery1ate, and polymers of hydroxypropylmethacrylate.

In forming the matrix, excess water is not required. In accordance with a preferred aspect of the present invention, about 2% by weight of any of the drugs listed above are included in the diffusion matrix. 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 about 1 to about 3 mm. in accordance with a preferred aspect of the present invention. This diffusion is either cast or cut into pieces of the desired size.

The following methods may be used for preparing the diffusion matrix of the present invention.

In a first method, the matrix is formed at atmospheric pressure. Water and glycerol are first mixed together.

A polar plasticizer such a glycerol is a necessary component in the matrix. A matrix formed without a polar plasticizer is not flexible and has poor diffusional contact with the skin causing unreliable diffusion release.

The polyvinylalcohol and polyvinylpyrrolidone are then added to the polar plasticizer-water mixture at room temperature, with agitation. The mixture is heated to a temperature within the range of from about 90 to about 95°C at atmospheric pressure to extend the polymers. If desired, the mixture may be maintained at an elevated temperature for a period of time, based on polymer stability, prior to addition of the drug. Thus, the mixture is stable for a period of time and: may be kept for such a period before being mixed with the drug to be delivered to the patient. Thereafter, the mixture is temperature-adjusted and the drug to be applied to the patient is then added to the mixture, with thorough agitation. Once a homogeneous mixture of the polymer solution and drug is obtained, the mixture is ready to be cast to form in a drugcontaining diffusion matrix. After casting the mixture is cooled to a temperature such that gelation occurs. In a preferred embodiment, the drug may be dissolved by agitation in a suitable solvent such as glycerin and water. The thusobtained solution can be maintained at room temperature for prolonged period without deterioration.

It has been found that curing is facilitated by subjecting the matrix to a temperature down to about -20°C immediately after casting. The setting period is quickened considerably.

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.

An absorption facilitator to insure skin penetration such as dimethylsulfoxide, decylmethylsulfoxide, or other penetration enhancers may be added.

The present drug delivery device comprises the drugcontaining diffusion matrix and means for fastening the matrix to the skin of a patient. Such means can take various forms, such as an occlusive backing layer forming a kind of "bandage" with the diffusion matrix being held against the skin of a patient being treated. A polyethylene or Mylar tape is contemplated 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 skin 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 capable of permitting the transdermal application of the drug can also be used.

The amount of the drug to be delivered per day to the patient is in each case generally lower that the oral dosage. This is accounted for by the fact that in oral applications much of the drug can be expected to be lost by the first pass through the liver. To assure that the desired quantity of the drug is delivered, an excess of the drug should be incorporated in the matrix. Where terbutaline is used to provide a bronchodilator effect, the daily amount to be delivered is generally about 1 to about 20 mg., preferably about 1 mg. With ephedrine a decongestant effect is provided by delivering a daily amount of generally about 5 to about 30 mg., preferably about 20 mg. With clonidone an antihypertensive effect is provided by delivering a daily amount of generally about 0.2 to about 0.6 mg., preferably about 0.4 mg. With phenylephrine a decongestant effect is provided by delivering a daily amount of generally about 2 to about 50 mg. , perferably about 2.5 mg. With phenylpropanolamine bronchodilator and nasal decongestant effects are provided by delivering a daily amount of generally about 2 to about 50 mg. , preferably about 10 mg. With chlorpheniramine maleate an antihistaminic effect is provided by delivering a daily amount of generally about 1 to about 30 mg. , preferably about 3 mg. The estradiol esters used with this invention provide a uterine wall maintenance effect.

It will be appreciated that the above drugs may be added to the above mixture not only in the form of the pure chemical compound, but also in admixture with other drugs that may be transdermally applied or with other ingredients which are not incompatible with the desired objective of transdermally administering the drug to a patient. Thus, simple pharmacologically acceptable derivatives of the drugs such as ethers, esters, amides, acetals, salts, and the like may be used. With some drugs derivatives may actually be preferred.

The estradiol ester derivatives suitable for use according to this invention are pharmacologically acceptable esters particularly the 3-benzoate and 3-valerate esters of estradiol. Estradiol diacetate and other esters of a pharmocologically active type small enough to pass through the skin may also be used. The esters suitable for this invention provide a source of pharmacologically active estradiol in the bloodstream. It must also be understood that the estradiol esters contemplated herein may be administered in admixture with other drugs which are not incompatible with the desired therapeutic objective.

The invention is illustrated by the following non-limiting Examples:

EXAMPLE I

Together there are mixed 30 gm. glycerol and 45 ml. water. This mixture is heated to 90°C; after reaching at least 70°C there are slowly added 15 gm. polyvinylalcohol (PVA 100% hydrolyzed, molecular weight 115,000) and 8 gm. polyvinylpyrrolidone (mw. 40,000). The mixture is stirred at 90°C until solution is effected, which may take about 10 minutes; it will be appreciated that with larger quantities, a considerably longer period of time may be needed. 98 ml. of this solution is then mixed with 2 gm. terbutaline, this mixture then being mechanically stirred until homogeneous. The homogeneous mixture is then poured into forms made of glass or stainless steel which serve as templates to produce a diffusion matrix having a thickness of about 2 to about 3 mm. This diffusion matrix is then cut into pieces with a total surface area suitable for the administration of a pharmaceutically effective amount of terbutaline.

The diffusion matrix is applied to the skin of a patient in need of a bronchodilator effect, the terbutaline being transdermally delivered to the skin of the patient. The diffusion matrix is ideally applied to the skin of the patient by means of a single-piece bandage having th'e diffusion matrix in the center under the occlusive layer, the bandage being provided to the patient with a peel-of cover much like a "band-aid" .

EXAMPLE II

In place of the glycerol of Example I , there is substituted 5 gm. polyethylene glycol having a molecular weight of 1000 and 25 ml. water. The resultant diffusion matrix is more rigid than that of Example I.

EXAMPLE III In place of the glycerol of Example I, there is substituted 5 gm. polyethylene glycol (mw. 1,000), 4 gm. glycerol and 21 ml. water. The resultant diffusion matrix shares the improved rigidity of the diffusion matrix of Example II, while providing contact with the skin characteristic of the glycerol in this type of diffusion matrix.

EXAMPLE IV In place of the polyvinylalcohol and polyvinylpyrrilidone of Example I, there is substituted 2% by weight agarose, yielding a diffusion matrix for the transdermal delivery of terbutaline.

EXAMPLES V-XXIV Examples V-XXIV correspond to Examples I-IV, but for the substitution for terbutaline of the same amounts of the following drugs:

EXAMPLES DRUG

V-VIII ephedrine

IX-XII clonidine

XIII-XVI phenylephrine

XVII-XX phenylpropanolamine

XXI-XXIV chlorpheniramine maleate

Each of these drugs exhibits its characteristic therapeutic effect when administered via diffusion matrix.

EXAMPLE XXV Together there are mixed 20 gm. glycerol and 55 ml. water. This mixture is heated 90°C; after reaching at least 70 °C. There are slowly added 15 gm. polyvinylalcohol (PVA 100% hydrolyzed, molecular weight 115,000) and 8 gm. polyvinylpyrrolidone (mw. 40,000). The mixture is stirred at 90°C unitl solution is effected, which may take about 10 minutes; it will be appreciated that with larger guantities, a considerably longer period of time may be needed. 98 ml. of this solution is then mixed with 2 gm. estradiol diacetate, this mixture then being mechanically stirred until homogeneous. The homogeneous mixture is then poured into forms made of glass or stainless steel which serve as templates to produce a diffusion matrix having a thickness of about 1 to 2 mm. This diffusion matrix is then cut into square pieces of about 1 inch on each side, i.e., to provide a total surface area of about 6.5 cm².

The diffusion matrix is applied to the skin of a patient in need of uterine wall maintenance, the estradiol ester derivative being transdermally delivered. The diffusion matrix is ideally applied to the skin of the patient by means of a single-piece bandage having the diffusion matrix in the center under the occlusive layer, the bandage being provided to the patient with a peel-off cover much like a "band-aid".

EXAMPLE XXVI

Instead of casting the fluid homogeneous drug containing matrix with a 1 to 2 mm. thickness as disclosed in Example XXV, it is poured into oval forms 1 cm. thick. The cured diffusion matrix is applied in the form of a vaginal insert into a patient in need of uterine wall maintenance, the estradiol ester derivative being delivered in the vicinity of the cervix of the patient.

EXAMPLE XXVII

In place of the glycerol of Example XXV, there is substituted 10 gm. polyethylene glycol having a molecular weight of 1000 and 10 ml. water. The resultant diffusion matrix is more rigid than that of Example XXV, thus improving its ease of application in the form of a vaginal insert.

EXAMPLE XXVIII

In place of the glycerol of Example XXV, there is substituted 5 gm. polyethylene glycol (mw. 1000) , 4 gm. glycerol, and 11 ml. water. The resultant diffusion matrix shares the improved rigidity of the diffusion matrix of Example XXVII, while providing contact with the skin characteristic of the glycerol. This type of diffusion matrix is particularly suitable for transdermal application.

EXAMPLE XXIX In place of the polyvinylalcohol and polyvinylpyrrolidone of Example XXV, there is substituted 2 gm. agarose and 21 ml. water, yielding a diffusion matrix for the delivery of estradiol ester derivative.

Claims

CLAIMS :

1. A self-supporting polymeric diffusion matrix for the sustained release of a drug selected from the group consisting of estradiol esters suitable for transdermal delivery phenylpropanolamine, chlorpheniramine maleate, clonidine, phenylephrine, terbutaline, and ephedrine in order to transdermally deliver said drug to a patient and provide said patient with a therapeutic effect, said matrix comprising from about 2 to about 60% of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of said drug to provide a sustained release of said drug over a prolonged period.

2. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is glycerol.

3. The polymeric diffusion matrix of claim 1 wherein said polyvinylalcohol has a molecular weight of about 50,000 to about 150,000.

4. The polymeric diffusion matrix of claim 1 wherein said polyvinylalcohol has a molecular weight of about 100,000 to about 150,000.

5. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of from about 15,000 to about 85,000.

6. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of about 20,000 to about 60,000.

7. The polymeric diffusion matrix of claim 1 wherein said polyvinylpyrrolidone has a molecular weight of 40,000 and said polyvinylalcohol has a molecular weight of 115,000.

8. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is polyethylene glycol present in an amount of about 2 to about 15% by weight.

9. The polymeric diffusion matrix of claim 1 wherein said polar plasticizer is a mixture of glycerol and polyethylene glycol wherein said polyethylene glycol is present in an amount by weight of from about 1 to about 5 parts per weight glycerol.

10. A method for the transdermal delivery of terbutaline to a patient to provide said patient with a bronchodilator effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of terbutaline to provide a sustained release of said terbutaline over a prolonged period.

11. The method of claim 10 wherein said terbutaline is present in an amount to provide sustained release of about 1 to about 20 mg. per day.

12. A method for the transdermal delivery of ephedrine to a patient to provide said patient with a decongestant effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of ephedrine to provide a sustained release of said ephedrine over a prolonged period.

13. The method of claim 12 wherein said ephedrine is present in an amount to provide sustained release of about 5 to about 20 mg. per day.

14. A method for the transdermal delivery of clonidine to a patient to provide said patient with a antihypertensive effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of clonidine to provide a sustained release of said clonidine over a prolonged period.

15. The method of claim 14 wherein said clonidine is present in an amount to provide sustained release of about 0.2 to about 0.4 mg. per day.

16. A method for the transdermal delivery of phenylephrine to a patient to provide said patient with a decongestant effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of phenylephrine to provide a sustained release of said phenylephrine over a prolonged period.

17. The method of claim 16 wherein said phenylephrine is present in an amount to provide sustained release of about 2 to about 50 mg. per day.

18. A method for the transdermal delivery of phenylpropanolamine to a patient to provide said patient with a bronchodilator effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of phenylephrine to provide a sustained release of said phenylpropanolamine over a prolonged period.

19. The method of claim 18 wherein said phenylpropanolamine is present in an amount to provide sustained release of about 2 to about 50 mg. per day.

20. A method for the transdermal delivery of chlorpheniramine maleate to a patient to provide said patient with a antihistaminic effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a pharmaceutically effective amount of chlorpheniramine maleate to provide a sustained release of said chlorpheniramine maleate over a prolonged period.

21. The method of claim 20 wherein said chlorpheniramine maleate is present in an amount to provide sustained release of about 1 to about 30 mg. per day.

22. A method for the transdermal delivery of estradiol esters suitable for transdermal delivery to a patient to provide said patient with a uterine wall maintenance effect, comprising applying to said patient a self-supporting diffusion matrix comprising from about 2 to about 60% by weight of a polar plasticizer, from about 6 to about 20% by weight polyvinylalcohol, from about 2 to about 10% by weight polyvinylpyrrolidone, and a physiologically effective amount of ari estradiol ester suitable for transdermal delivery to provide a sustained release of said estradiol ester suitable for transdermal delivery over a prolonged period.