WO1983000091A1

WO1983000091A1 - Polymeric diffusion matrix containing 5-ad(3,4-dimethoxyphenethyl)methylaminobd-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile

Info

Publication number: WO1983000091A1
Application number: PCT/US1982/000925
Authority: WO
Inventors: Incorporated Key Pharmaceuticals
Original assignee: Keith, Alec, Dell; Snipes, Wallace
Priority date: 1981-07-08
Filing date: 1982-07-08
Publication date: 1983-01-20
Also published as: EP0083370A1

Abstract

A self-supporting polymeric diffusion matrix for the sustained release of 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isop ropylvaleronitrile in order to deliver the 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isop ropylvaleronitrile to a patient and to provide the patient with an anti-anginal effect and with relief from other heart disorders. The matrix comprises from about 1 to about 60 % of a polar plasticizer, from about 6 to about 30 % by weight polyvinylalcohol, from about 2 to about 30 % by weight polyvinylpyrrolidone, and about 2 to 5 % of the 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isop ropylvaleronitrile to provide a sustained release of said 5[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopr opylvaleronitrile over a prolonged period.

Description

POLYMERIC DIFFUSION MATRIX CONTAINING 5-[ (3,4-DIMETHOXYPHENETHY )METHYLAMINO]-2-(3,4-

DIMETHOXYPHENYL)-2-ISOPROPYLVALERONITRILE The present invention relates to a polymeric diffu¬ sion matrix containing 5-[ (3,4-dimethoxyphenethyl)meth- ylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleroni- trile, also known as Verapa il. More particularly, the invention relates to a polymeric diffusion matrix con¬ taining 5-[ (3,4-dimethoxyphenethy1)methylamino]-2-(3,4- dimethoxyphenyl)-2-isopropylvaleronitrile characterized by a sustained release of the 5-[ (3,4-dimethoxypheneth- yDmethylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylva- leronitrile. 5-[ (3,4-Dimethoxy?henethyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropylvaleronitrile is a well known drug which acts as a calcium permeability blocking agent and is employed against angina pectoris and other heart disorders which respond to calcium permeability blocking.

A self-supporting polymeric diffusion matrix is provided for the sustained release of 5-[ (3,4-dimethoxy- phenethyl)methylamino] -2-(3,4-dimethoxyphenyl)-2-isopro- pylvaleronitrile in order to deliver said 5-[(3,4-di- methoxyphenethyl)methylamino] -2-(3,4-dimethoxyphenyl)-2- isopropylvaleronitrile to a patient and provide said patient with an anti-angina effect, said matrix compris¬ ing from about 1 to about 60% by weight of a polar plasticizer; from about 6 to about 30% by weight poly- vinylalcohol; form about 2 to about 30% by weight poly- vinylpyrrolidone; and a pharmaceutically effective amount of 5-[ (3,4-dimethoxyphenethyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropylvaleronitrile about 2

O PI to 5% by weight, to provide a sustained release of said 5-[ (3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimeth- oxyphenyl)-2-isopropylvaleronitrile over a prolonged period.

Polar plasticizers suitable for use in this inven¬ tion include principally poly-lower alkylene oxides, but other polar plasticizers such as diethylphthalic dieth- ylphthalate may be used.

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 1 to about 15% by weight. A still further embodiment con¬ templates 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 exam¬ ple, both the polyvinylalcohol and the polyvinylpyrroli¬ done may be partially or 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 inven¬ tion, 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 inventors with success. The polyvinylalcohol should be hydro- lyzed, generally at least to the extent of 90% with a preferred embodiment being at least 95% hydrolyzed. The 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 particularly pre¬ ferred.

The amount by weight of the ingredients other than the polar plasticizer generally should be in the follow¬ ing ranges: Polyvinylalcohol is generally present in an amount of from about 6 to about 30% by weight, with 20% being a preferred embodiment; polyvinylpyrrolidone is present generally in an amount of from about 2 to about 30% by weight, with about 10% being preferred.

In particular embodiments of this invention the total amount of polyvinylalcohol and polyvinylpyrroli¬ done used is from about 25 to about 50% by weight.

The water-soluble polymer can be replaced with (in addition to agar) gum arabic, gum tragacanth, poly- acrylic acid, polymethacrylic acid, polyvinyloxazoli- done, polyvinylmorpholinone, and polyvinylpiperidone.

Polyalkylene glycols (poly-lower alkylene oxides) such as polyethylene glycol and polypropylene glycol may replace all or part of the glycerol.

In forming the matrix, excess water is not re¬ quired. In accordance with a preferred aspect of the invention, about 5% by weight 5-[ (3,4-dimethoxyphen- ethyl) ethylamino]-2-(3,4-dimethoxyphenyl)-2-isopropyl- valeronitrile is included in the diffusion matrix. The resultant homogeneous mixture is poured into forms preferably made of glass or stainless steel. For trans- dermal application, a diffusion matrix with a thickness of about 1 to about 3 mm is in accordance with, a pre¬ ferred aspect of this invention. This diffusion matrix can be cut to obtain the desired surface area once it is suitably cured.

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

OMPI In one method, the matrix is formed at atmospheric pressure. Water and polar plasticizer are first mixed together. A polar plasticizer such as glycerol or poly¬ ethylene glycerol is a necessary component in the ma¬ trix. A matrix formed without a polar plasticizer is not flexible and has poor diffusional contact with the skin, causing unreliable diffusion release. The poly¬ vinylalcohol 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 90 to about 95°C at atmospheric pressure to extend the polymers. If desired, the mix¬ ture 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 pa¬ tient. 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 homoge¬ neous mixture of the polymer solution and drug is ob¬ tained, the mixture is read to be cast to form in a drug-containing diffusion matrix. After casting, the mixture is cooled to a temperature such that gelation occurs.

In another method, the polymeric material is heated under pressure to accomplish dissolution in the mixture, the 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-di- methoxyphenyl)-2-isopropylvaleronitrile is mixed in and the material is extruded under pressure into a mold of suitable size and geometry. The use of pressure allows for the incorporation of higher amounts of polymeric material into the matrix, up to 60% total polyvinylpyr¬ rolidone and polyvinylalcohol content, thus improving film strength content, and dimensional stability and allowing for thinner matrices. This pressure method further reduces or eliminates altogether curing and/or drying time.

It has been further found that curing is facili¬ tated by subjecting the matrix to a temperature down to about -20°C immediately after casting, especially when polyethylene glycol is used as the plasticizer. The setting time 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. Soy phosphatides may be added as drug solubilizing agents in a concentration of 0.1-10% by weight. Up to 10% of one or more absorption facilita¬ tors to insure skin penetration such as dimethylsulf- oxide, decylmethylsulfoxime, or other penetration enhan¬ cers may also be added. Suitable preservatives, such as sodium benzoate, may be also added where indicated.

The present drug delivery device comprises the drug-containing diffusion matrix which can be applied as a transdermal patch with 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 poly¬ ethylene or Mylar tape is contemplated as one form of occlusive layer in accordance with the 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 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 invention is illustrated by the following non-limiting examples:

EXAMPLE I

Together there are mixed 20 gm glycerol and 55 ml water. This mixture is heated to 90°C; after reaching at least 70°C, there are slowly added 15 gm polyvinyl¬ alcohol (polyvinylalcohol 100% hydrolyzed, molecular weight 115,000) and 8 gm polyvinylpyrrolidone ( .w. 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 5-[ (3,4-dimethoxyphen- ethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropyl- valeronitrile, 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 0.2 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 of about 6.5

The diffusion matrix is applied to the skin of a patient in need of an anti-anginal- effect, the 5-[(3,4- dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)- 2-isopropylvaleronitrile 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-of cover much like a "band-aid".

EXAMPLE II

In place of the glycerol of Example I, 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 the of Example I.

EXAMPLE III In place of the polyvinylalcohol and polyvinylpyr¬ rolidone of Example I, there are substituted 2 gm agar¬ ose and 21 ml water, yielding a diffusion matrix for the delivery of 5-[ (3,4-dimethoxyphenethyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropylvaleronitrile.

EXAMPLE IV The following mixture, listed in parts by weight, is heated under pressure, about 3 atmospheres being suitable, to 110-130°C:

Polyvinylalcohol 20 parts (115,000 m.w.) Polyvinylpyrrolidone 15 parts (40,000 m.w.) Polyethylene glycol 5 parts (4,000 m.w.) Glycerol 3 parts

Verapamil 5 parts

Water to 100 parts

This mixture is first prepared by heating polyvinylal¬ cohol and water to effect dissolution. The polyethylene glycol molecular weight 4000, polyvinylpyrrolidone and glycerol are dissolved in cold water, and the two aque¬ ous mixtures are brought together under heat and pres¬ sure as described above. Finely divided 5-[(3,4-dimeth- oxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-iso- propylvaleronitrile is rapidly mixed into the viscous liquid and the mixture is extruded into an appropriate mold.

EXAMPLE V In place of polyethylene glycol molecular weight 4000, of Example IV, polyethylene glycol molecular weight 1000 is used in the mixture.

Claims

WHAT IS CLAIMED IS

1. A self-supporting polymeric diffusion matrix for the- sustained release of 5-[ (3,4-dimethoxyphen- ethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropyl- valeronitrile in order to deliver said 5-[ (3,4-dimeth- oxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-iso- propylvaleronitrile to a patient and provide said pa¬ tient with an anti-anginal effect and relief from other heart disorders, said matrix comprising from about 1 to about 60% of a polar plasticizer, from about 6 to about 30% by weight polyvinylalcohol, from about 2 to about 30% by weight polyvinylpyrrolidone, and about 2 to 5% of the 5-[ (3,4-dimethoxyphenethyl)methylamino]-2-(3,4-di- methoxyphenyl)-2-isopropylvaleronitrile to provide a sustained release of said 5-[ (3,4-dimethoxyphen- ethyl) ethylamino]-2-(3,4-dimethoxyphenyl)-2-isopropyl- valeronitrile over a prolonged period.

2. The polymeric diffusion matrix of claim 1, wherein the total content of polyvinylalcohol and poly¬ vinylpyrrolidone is from about 25% to about 60% by weight, based on the weight of the matrix.

3. The polymeric diff sion matrix of claim 1 or 2, wherein said polar plasticizer is glycerol.

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

5. The polymeric diffusion matrix of claim 3, wherein said polyvinylalcohol has a molecular weight of 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 15,000 to about 85,000.

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

O PI

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

9. The polymeric diffusion matrix of claim 1 or 2, 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 5 parts per weight glycerol.

10. The polymeric diffusion matrix of claim 1, wherein comprising about 20% by weight polyvinylalcohol of molecular weight about 115,000, about 15% by weight of polyvinylpyrrolidone of molecular weight about 40,000, about 5% by weight polyethylene glycol of mole¬ cular weight about 4000 and about 3% by weight glycerol.

OMPI