Sustained release of methantheline

Claim 2

A SUSTAINED RELEASE 846 HOUR AFTER ADMINISTRATION METHANTHELINE ELUTING MULTIBARRIER PHARMACEUTICAL COMPOSITION COMPRISING: A. A POLYMERIZED AND CURED OUTER MATRIX OF A WATER-INSOLUBLE BUT WATER-SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:

Claim 3

POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL.

Claim 4

POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL.

Claim 5

POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL,

Claim 6

POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL,

Claim 7

A POLYMERIZABLE SULFUR-CONTAINING MATERIAL SELECTED FROM THE GROUP CONSISTING OF VINYL SULFONIC ACID, VINYLPROPANE SULFONIC ACID, AND STYRENE SULFONIC ACIDS, AMMONIUM SALTS THEREOF, ALKALI METAL SALTS THEREOF, AND MIXTURES THEREOF, AND

Claim 8

A POLYMERIZABLE SULFUR-CONTAINING MATERIAL SELECTED FROM THE GROUP CONSISTING OF VINYL SULFONIC ACID, VINYLPROPANE SULFONIC ACID, AND STYRENE SULFONIC ACIDS, AMMONIUM SALTS THEREOF, ALKALI METAL SALTS THEREOF, AND MIXTURES THEREOF, AND

Claim 9

monethylenically unsaturated ester selected from the group consisting of alkyl acrylates, alkyl methacrylates, vinyl esters of saturated monocarboxylic acids of up to 22 carbon atoms, and mixtures thereof, wherein the alkyl group of said methacrylates or acrylates contains from 1 to 22 carbon atoms; and

Claim 10

monethylenically unsaturated ester selected from the group consisting of alkyl acrylates, alkyl methacrylates, vinyl esters of saturated monocarboxylic acids of up to 22 carbon atoms, and mixtures thereof, wherein the alkyl group of said methacrylates or acrylates contains from 1 to 22 carbon atoms; and

Claim 11

MONOETHYLENICALLY UNSATURATED ESTER SELECTED FROM THE GROUP CONSISTING OF ALKYL ACRYLATES, ALKYL METHACRYLATES, VINYL ESTERS OF SATURATED MONOCARBOXYLIC ACIDS OF UP TO 22 CARBON ATOMS, AND MIXTURES THEREOF, WHEREIN THE ALKYL GROUP OF SAID METHYACRYLATE OR ACRYLATE CONTAINS FROM 1 TO 22 CARBON ATOMS, AND

Claim 12

MONOETHYLENICALLY UNSATURATED ESTER SELECTED FROM THE GROUP CONSISTING OF ALKYL ACRYLATES, ALKYL METHACRYLATES, VINYL ESTERS OF SATURATED MONOCARBOXYLIC ACIDS OF UP TO 22 CARBON ATOMS, AND MIXTURES THEREOF, WHEREIN THE ALKYL GROUP OF SAID METHYACRYLATE OR ACRYLATE CONTAINS FROM 1 TO 22 CARBON ATOMS, AND

Claim 13

a polymerizable sulfur-containing material selected from the group consisting of vinyl sulfonic acid, vinylpropane sulfonic acid, and styrene, sulfonic acids, ammonium salts thereof, alkali metal salts thereof; and mixtures thereof; and

Claim 14

a polymerizable sulfur-containing material selected from the group consisting of vinyl sulfonic acid, vinylpropane sulfonic acid, and styrene, sulfonic acids, ammonium salts thereof, alkali metal salts thereof; and mixtures thereof; and

Claim 15

The composition of claim 1 wherein each of said polymerizable monoesters (A) (1) and (B) (1) is selected from the group consisting of 2-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate, 2-hydroxy propyl methacrylate, diethylene glycol monomethacrylate, diethylene glycol monoacrylate, 2-hydroxy propyl acrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate, dipropylene glycol monomethacrylate, glyceryl methacrylate, and pentaerythritol methacrylate.

Claim 16

a polymerizable sulfur-containing material selected from the group consisting of vinyl sulfonic acid, vinylpropane sulfonic acid, and styrene sulfonic acids, ammonium salts thereof; alkali metal salts thereof; and mixtures thereof; and

Claim 17

a polymerizable sulfur-containing material selected from the group consisting of vinyl sulfonic acid, vinylpropane sulfonic acid, and styrene sulfonic acids, ammonium salts thereof; alkali metal salts thereof; and mixtures thereof; and

Claim 18

monoethylenically unsaturated ester selected from the group consisting of alkyl acrylates, alkyl methacrylates, vinyl esters of saturated monocarboxylic acids of up to 22 carbon atoms, and mixtures thereof, wherein the alkyl group of said methacrylate or acrylate contains from 1 to 22 carbon atoms; and

Claim 19

monoethylenically unsaturated ester selected from the group consisting of alkyl acrylates, alkyl methacrylates, vinyl esters of saturated monocarboxylic acids of up to 22 carbon atoms, and mixtures thereof, wherein the alkyl group of said methacrylate or acrylate contains from 1 to 22 carbon atoms; and

Claim 20

POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURE CONTAINS FROM ABOUT 25 TO ABOUT 44.3% BY WEIGHT OF (B) (1), FROM ABOUT 5 TO ABOUT 30% BY WEIGHT OF (B) (2), AND FROM ABOUT 5 TO ABOUT 25.2% BY WEIGHT OF (B) (3) BASED UPON THE TOTAL WEIGHT OF (B) (1), (B) (2), AND (B) (3) IN THE MONOMER MIXTURE, AND C. SAID POLYMERIZED AND CURED INNER MATRIX HAVING BEEN SOAKED FOR ABOUT 12 HOURS IN ISOTONIC SALINE SOLUTION CONTAINING PER 5 ML OF ISOTONIC SALINE SOLUTION AT LEAST ABOUT 100 MG OF METHANTHELINE BROMINE IN AN AMOUNT AT LEAST SUFFICIENT FOR THE TOTAL DOSAGE REQUIREMENT ADAPTED TO GRADUALLY ELUTE, UPON ADMINISTRATION DURING 864 HOURS OF A TREATMENT PERIOD, AND THEREBY ENTRAPPING THE METHANTHELINE BROMIDE IN SAID INNER MATRIX.

Claim 21

POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURE CONTAINS FROM ABOUT 25 TO ABOUT 44.3% BY WEIGHT OF (B) (1), FROM ABOUT 5 TO ABOUT 30% BY WEIGHT OF (B) (2), AND FROM ABOUT 5 TO ABOUT 25.2% BY WEIGHT OF (B) (3) BASED UPON THE TOTAL WEIGHT OF (B) (1), (B) (2), AND (B) (3) IN THE MONOMER MIXTURE, AND C. SAID POLYMERIZED AND CURED INNER MATRIX HAVING BEEN SOAKED FOR ABOUT 12 HOURS IN ISOTONIC SALINE SOLUTION CONTAINING PER 5 ML OF ISOTONIC SALINE SOLUTION AT LEAST ABOUT 100 MG OF METHANTHELINE BROMINE IN AN AMOUNT AT LEAST SUFFICIENT FOR THE TOTAL DOSAGE REQUIREMENT ADAPTED TO GRADUALLY ELUTE, UPON ADMINISTRATION DURING 864 HOURS OF A TREATMENT PERIOD, AND THEREBY ENTRAPPING THE METHANTHELINE BROMIDE IN SAID INNER MATRIX.

Claim 22

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and polyhydric alcohol; and wherein the monomer mixture contains from about 24 to about 49.3% by weight (A) (1); from about 34 to about 64.6% by weight of (A) (2); and from about 0.1 to about 1% by weight of (A) (3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in the monomer mixture; B. a polymerized and cured inner matrix within said outer matrix and being a water-insoluble but water-swellable hydrophilic polymer of a monomer mixture containing:

Claim 23

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and polyhydric alcohol; and wherein the monomer mixture contains from about 24 to about 49.3% by weight (A) (1); from about 34 to about 64.6% by weight of (A) (2); and from about 0.1 to about 1% by weight of (A) (3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in the monomer mixture; B. a polymerized and cured inner matrix within said outer matrix and being a water-insoluble but water-swellable hydrophilic polymer of a monomer mixture containing:

Claim 24

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 25 to about 44.3% by weight of (B) (1); from about 5 to about 30% by weight of (B) (2); and from about 5 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture; and C. said polymerized and cured inner matrix having been soaked for about 12 hours in isotonic saline solution containing per 5 ml of isotonic saline solution at least about 100 mg of methantheline bromide in an amount at least sufficient for the total dosage requirement adapted to gradually elute, upon administration during 864 hours of a treatment period; and thereby entrapping the methantheline bromide in said inner matrix.

Claim 25

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 25 to about 44.3% by weight of (B) (1); from about 5 to about 30% by weight of (B) (2); and from about 5 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture; and C. said polymerized and cured inner matrix having been soaked for about 12 hours in isotonic saline solution containing per 5 ml of isotonic saline solution at least about 100 mg of methantheline bromide in an amount at least sufficient for the total dosage requirement adapted to gradually elute, upon administration during 864 hours of a treatment period; and thereby entrapping the methantheline bromide in said inner matrix.

Claim 26

The composition of claim 1, wherein each of said monoesters (A) (1) and (B) (1 ) is 2-hydroxy ethyl methacrylate.

Claim 27

POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURE CONTAINS FROM ABOUT 24 TO ABOUT 49.3% BY WEIGHT (A) (1), FROM ABOUT 34 TO ABOUT 64.6% BY WEIGHT OF (A) (2), AND FROM ABOUT 0.1 TO ABOUT 1% BY WEIGHT OF (A) (3) BASED UPON THE TOTAL WEIGHT OF (A) (1), (A) (2), AND (A) (3) IN THE MONOMER MIXTURE, B. A POLYMERIZED AND CURED INNER MATRIX WITHIN SAID OUTER MATRIX AND BEING A WATER-INSOLUBLE BUT WATER-SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:

Claim 28

POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURE CONTAINS FROM ABOUT 24 TO ABOUT 49.3% BY WEIGHT (A) (1), FROM ABOUT 34 TO ABOUT 64.6% BY WEIGHT OF (A) (2), AND FROM ABOUT 0.1 TO ABOUT 1% BY WEIGHT OF (A) (3) BASED UPON THE TOTAL WEIGHT OF (A) (1), (A) (2), AND (A) (3) IN THE MONOMER MIXTURE, B. A POLYMERIZED AND CURED INNER MATRIX WITHIN SAID OUTER MATRIX AND BEING A WATER-INSOLUBLE BUT WATER-SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:

Claim 29

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 24 to about 49.3% by weight of (D) (1); from about 34 to about 64.6% by weight of (D) (2); and from about 0.1 to about % by weight of (D) (3) based upon the total weight of (D) (1), (D) (2), and (D) (3) in said monomer mixture; and E. then polymerizing to provide an outer matrix of the water-insoluble but water-swellable hydrophilic polymer of the monomer mixture containing the polymerizable monoester and diester.

Claim 30

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 24 to about 49.3% by weight of (D) (1); from about 34 to about 64.6% by weight of (D) (2); and from about 0.1 to about % by weight of (D) (3) based upon the total weight of (D) (1), (D) (2), and (D) (3) in said monomer mixture; and E. then polymerizing to provide an outer matrix of the water-insoluble but water-swellable hydrophilic polymer of the monomer mixture containing the polymerizable monoester and diester.

Claim 31

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 25 to about 44.3% by weight of (B) (1); from about 5 to about 30% by weight of (B) (2); and from about 5 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture; C. grinding the resulting composition of the methantheline bromide and inner matrix into a powder; D. admixing said powder and a polymerizable monomer mixture containing:

Claim 32

polymerizable diester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol; and wherein the monomer mixture contains from about 25 to about 44.3% by weight of (B) (1); from about 5 to about 30% by weight of (B) (2); and from about 5 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture; C. grinding the resulting composition of the methantheline bromide and inner matrix into a powder; D. admixing said powder and a polymerizable monomer mixture containing:

Claim 33

The composition of claim 1 wherein said monoethylenically unsaturated ester (A) (2) is selected from the group consisting of methyl methacrylate, ethyl methacrylate, isopropyl methacrylate, butyl methacrylate, capryl methacrylate, palmityl methacrylate, stearyl methacrylate, lauryl methacrylate, ethyl acrylate, methyl acrylate, isopropyl acrylate, butyl acrylate, lauryl acrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl stearate, and the vinyl ester of a saturated tertiary monocarboxylic acid having C9, C10, and C11 chain length.

Claim 34

The composition of claim 1 wherein said monoethylenically unsaturated ester (A) (2) is methylmethacrylate.

Claim 35

The composition of claim 1 wherein each of said diesters (A) (3) and (B) (3) is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate, 1,3-butylene dimethacrylate, 1,4-butylene dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, tetraethylene glycol dimethacrylate, and tetraethylene glycol diacrylate.

Claim 36

The composition of claim 1 wherein said diester (A) (3) is ethylene glycol dimethacrylate and said diester (B) (3) is tetraethylene glycol dimethacrylate.

Claim 37

The composition of claim 1 wherein said polymerizable sulfur-containing material is selected from the group consisting of styrene sulfonic acids, ammonium salts thereof, alkali metal salts thereof, and mixtures thereof.

Claim 38

The composition of claim 1 wherein said polymerizable sulfur-containing material is sodium p-vinylbenzene sulfonic acid.

Claim 39

The composition of claim 1 wherein the monomer mixture of the outer matrix contains from about 29 to about 49.3% by weight of (A) (1); from about 40 to about 64.6% by weight of (A) (2); and from about 0.5 to about 1% by weight of (A) (3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.3% by weight of (B) (1); from about 22 to about 30% by weight of (B) (2); and from about 22 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture of the inner matrix.

Claim 40

The composition of claim 1 wherein each of said polymerizable monoesters (A) (1) and (B) (1) is a monoester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof, and a polyhydric alcohol selected from the group consisting of ethylene glycol, 1,3-propanediol, diethylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, 1,6-hexamethylene glycol, 1,4-butanediol, glycerol, trimethylol propane, trimethylolethane, pentaerythritol, mannitol, and sorbitol.

Claim 41

The composition fo claim 1 wherein each of said polymerizable monoesters (A) (1) and (B) (1) is a monoester of a member selected from the group consisting of acrylic acid, methacrylic acid, and mixtures thereof; and a polyhydric alcohol selected from the group consisting of ethylene glycol, 1,3-propanediol, diethylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, 1,6-hexamethylene glycol, 1,4-butanediol, glycerol, trimethylol propane, trimethylolethane, pentaerythritol, mannitol, and sorbitol; wherein said polymerizable sulfur-containing material (B) (2) is selected from the group consisting of styrene sulfonic acids, ammonium salts thereof, alkali metal salts thereof, and mixtures thereof; and wherein each of said diesters (A) (3) and (B) (3) is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate, 1,3-butylene dimethacrylate, 1,4-butylene dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, tetraethylene glycol dimethacrylate, and tetraethylene glycol diacrylate, and where said monoethylenically unsaturated ester (A) (2) is selected from the group consisting of methyl methacrylate, ethyl methacrylate, isopropyl methacrylate, butyl methacrylate, capryl methacrylate, palmityl methacrylate, stearyl methacrylate, lauryl methacrylate, ethyl acrylate, methyl acrylate, isopropyl acrylate, butyl acrylate, lauryl acrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl stearate, and the vinyl ester of a saturated synthetic tertiary monocarboxylic acid having C9, C10, and C11 chain length.

Claim 42

The composition of claim 12 wherein each of said polymerizable monoesters (A) (1) and (B) (1) is selected from the group consisting of 2-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate, 2-hydroxy propyl methacrylate, diethylene glycol monomethacrylate, diethylene glycol monoacrylate, 2-hydroxy propyl acrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate, dipropylene glycol monomethacrylate, glyceryl methacrylate, and pentaerythritol methacrylate.

Claim 43

The composition of claim 13 wherein the monomer mixture of the outer matrix contains from about 29 to about 35% by weight of (A) (1); from about 40 to about 64.6% by weight of (A) (2); and from about 0.5 to about 1% by weight of (A) (3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.3% by weight of (B) (1); from about 22 to about 30% by weight of (B) (2); and from about 22 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture of the inner matrix.

Claim 44

The composition of claim 1 wherein each of said monoesters (A) (1) and (B) (1) is 2-hydroxy ethyl methacrylate, said sulfur-containing monomer (B) (2) is sodium p-toluene sulfonic acid; said diester (A) (2) is Ethylene glycol dimethacrylate; said diester (B) (3) is tetraethylene glycol dimethacrylate, and said monoethylenically unsaturated ester (A) (2) is methyl methacrylate.

Claim 45

The composition of claim 15 wherein the monomer mixture of the outer matrix contains from about 29 to about 49.3% by weight of (A) (1); from about 40 to about 64.6% by weight of (A) (2); and from about 0.5 to about 1% by weight of (A) (3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.3% by weight of (B) (1); from about 22 to about 30% by weight of (B) (2); and from about 22 to about 25.2% by weight of (B) (3) based upon the total weight of (B) (1), (B) (2), and (B) (3) in the monomer mixture of the inner matrix.

Claim 46

The composition of claim 1 wherein the outer matrix is present in an amount from about 50 to about 80% by weight and said inner matrix is present in an amount from about 5 to about 35% by weight based upon the total weight of said outer matrix, said inner matrix, and said methantheline bromide in the composition.

Claim 47

The composition of claim 1 wherein the outer matrix is present in an amount from about 65 to about 75% by weight and said inner matrix is present in an amount from about 10 to about 25% by weight of said outer matrix, said inner matrix, and said methantheline bromide in the composition.

Claim 48

The method for preparing the sustained release pharmaceutical composition of claim 1 which comprises: A. entrapping the methantheline bromide in an inner matrix in an amount at least sufficient for the total dosage requirement during a treatment period; B. the inner matrix being a water-insoluble but water-swellable hydrophilic polymer of a monomer mixture containing: