EP0083370A1 - Matrice polymere contenant 5-((3,4-dimethoxy-phenethyl)methylamino)-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile - Google Patents

Matrice polymere contenant 5-((3,4-dimethoxy-phenethyl)methylamino)-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile

Info

Publication number
EP0083370A1
EP0083370A1 EP19820902504 EP82902504A EP0083370A1 EP 0083370 A1 EP0083370 A1 EP 0083370A1 EP 19820902504 EP19820902504 EP 19820902504 EP 82902504 A EP82902504 A EP 82902504A EP 0083370 A1 EP0083370 A1 EP 0083370A1
Authority
EP
European Patent Office
Prior art keywords
weight
diffusion matrix
dimethoxyphenyl
methylamino
matrix
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19820902504
Other languages
German (de)
English (en)
Inventor
Alec Dell Keith
Wallace Snipes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Key Pharmaceuticals Inc
Original Assignee
Key Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Key Pharmaceuticals Inc filed Critical Key Pharmaceuticals Inc
Publication of EP0083370A1 publication Critical patent/EP0083370A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles

Definitions

  • 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.
  • 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
  • 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.
  • the polar plasticizer is glycerol present in an amount of from about 2 to about 60% by weight.
  • 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.
  • 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.
  • 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.
  • 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 such as polyethylene glycol and polypropylene glycol may replace all or part of the glycerol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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 I 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
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une matrice polymère autoportante de diffusion permet la libération soutenue de 5- AD(3,4-diméthoxyphénétyl)méthylamino BD-2-(3,4-diméthoxyphényl)-2-isopropylvaléronitrile de manière à administrer 5- AD(3,4-diméthoxyphénéthyl)méthylamino BD-2-(3,4-diméthoxyphényl)-2-isopropylvaléronitrile à un patient et procurer au patient un effet anti-angineux et le soulager d'autres troubles cardiaques. La matrice comprend de 1 à 60 % environ d'un plastifiant polaire, de 6 à 30 % environ en poids de polyvinylalcool, de 2 à 30 % environ en poids de polyvinylpyrrolidone, et de 2 à 5 % environ de 5- AD(3,4-diméthoxyphénétyl)méthylamino BD-2-(3,4-diméthoxyphényl)-2-isopropylvaléronitrile pour produire une libération soutenue de ce 5- AD(3,4-diméthoxyphénétyl)méthylamino BD-2-(3,4-diméthoxyphényl)-2-isopropylvaléronitril pendant une période prolongée.
EP19820902504 1981-07-08 1982-07-08 Matrice polymere contenant 5-((3,4-dimethoxy-phenethyl)methylamino)-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile Withdrawn EP0083370A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28139081A 1981-07-08 1981-07-08
US281390 1994-07-27

Publications (1)

Publication Number Publication Date
EP0083370A1 true EP0083370A1 (fr) 1983-07-13

Family

ID=23077097

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19820902504 Withdrawn EP0083370A1 (fr) 1981-07-08 1982-07-08 Matrice polymere contenant 5-((3,4-dimethoxy-phenethyl)methylamino)-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile

Country Status (2)

Country Link
EP (1) EP0083370A1 (fr)
WO (1) WO1983000091A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690683A (en) * 1985-07-02 1987-09-01 Rutgers, The State University Of New Jersey Transdermal varapamil delivery device
US5422118A (en) * 1986-11-07 1995-06-06 Pure Pac, Inc. Transdermal administration of amines with minimal irritation and high transdermal flux rate
ES2109377T3 (es) 1991-12-18 1998-01-16 Warner Lambert Co Proceso para la preparacion de una dispersion solida.
US7758883B2 (en) 2002-10-18 2010-07-20 Aqueous Pharma Limited Three layer artificial tear formulation
US7051156B2 (en) 2002-11-06 2006-05-23 Synology Inc. Raid-5 disk having cache memory

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2155658A (en) * 1936-01-08 1939-04-25 Chemische Forschungs Gmbh Surgical and medical preparations
US2160503A (en) * 1936-02-14 1939-05-30 Chemische Forschungs Gmbh Blood stancher
US2127896A (en) * 1936-08-13 1938-08-23 Vohrer Herbert Method of producing elastic objects from polyvinyl alcohols
US2693438A (en) * 1951-02-21 1954-11-02 Norwich Pharma Co Preformed, nonadherent films for application to open lesions
BE638231A (fr) * 1962-03-16
US3742951A (en) * 1971-08-09 1973-07-03 Alza Corp Bandage for controlled release of vasodilators
US4210633A (en) * 1978-10-20 1980-07-01 Eli Lilly And Company Flurandrenolide film formulation
US4291015A (en) * 1979-08-14 1981-09-22 Key Pharmaceuticals, Inc. Polymeric diffusion matrix containing a vasodilator

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8300091A1 *

Also Published As

Publication number Publication date
WO1983000091A1 (fr) 1983-01-20

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Effective date: 19830908

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Inventor name: SNIPES, WALLACE

Inventor name: KEITH, ALEC DELL