Sustained release of methantheline

Claim 2

A SUSTAINED RELEASE 864 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

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 70 to about 35% by weight of (D)(1) and from about 15 to about 49.8% by weight of (D)(2) based upon the total weight of (D)(1) and (D)(2) 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 8

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 70 to about 35% by weight of (D)(1) and from about 15 to about 49.8% by weight of (D)(2) based upon the total weight of (D)(1) and (D)(2) 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 9

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

Claim 10

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

Claim 11

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 12

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

Claim 13

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

Claim 14

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 70 to about 35% by weight of (A)(1); and from about 15 to about 49.8% by weight of (A)(2) based upon the total weight of (A)(1) and (A)(2) 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 15

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 70 to about 35% by weight of (A)(1); and from about 15 to about 49.8% by weight of (A)(2) based upon the total weight of (A)(1) and (A)(2) 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 16

A POLYMERIZABLE SULFUR-CONTAINING MATERIAL SELECTED FROM THE GROUP CONSISTING OF VINYL SULFONIC ACID, VINYLPROPANE SULFONIC ACID, AND P-VINYLBENZENE SULFONIC ACID, AND AMMONIUM SALTS THEREOF, ALKALI MTAL 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 P-VINYLBENZENE SULFONIC ACID, AND AMMONIUM SALTS THEREOF, ALKALI MTAL SALTS THEREOF, AND MIXTURES THEREOF, AND

Claim 18

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 70 TO ABOUT 35% BY WEIGHT OF (A)(1), AND FROM ABOUT 15 TO ABOUT 49.8% BY WEIGHT OF (A)(2) BASED UPON THE TOTAL WEIGHT OF (A)(1) AND (A)(2) IN THE MONOMER MIXTURE, B. A POLYMERIZED AND CURED INNER MATRIX WITHIN SAID OUTER MATRIX AND BEING A WATER-INSOLUBLE BU WATER SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:

Claim 19

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 70 TO ABOUT 35% BY WEIGHT OF (A)(1), AND FROM ABOUT 15 TO ABOUT 49.8% BY WEIGHT OF (A)(2) BASED UPON THE TOTAL WEIGHT OF (A)(1) AND (A)(2) IN THE MONOMER MIXTURE, B. A POLYMERIZED AND CURED INNER MATRIX WITHIN SAID OUTER MATRIX AND BEING A WATER-INSOLUBLE BU WATER SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:

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 44.4% 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 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 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 44.4% 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 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 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 a polyhydric alcohol; and wherein the monomer mixture contains from about 25 to about 44.4% 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 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 in said inner matrix.

Claim 23

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 44.4% 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 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 in said inner matrix.

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 44.4% 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 mixture into a powder; D. admixing said powder and a polymerizable monomer mixture containing:

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 44.4% 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 mixture into a powder; D. admixing said powder and a polymerizable monomer mixture containing:

Claim 26

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; wherein said polymerizable sulfur-containing material (B)(2) is selected from the group consisting of p-vinylbenzene sulfonic acid, ammonium salts thereof, alkali metal salts thereof, and mixtures thereof; and wherein each of said diesters (A)(2) 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 27

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:

Claim 28

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 29

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

Claim 30

The composition of claim 1 wherein each of said diesters (A)(2) and (B)(3) is selected from the group consisting of ethylene glycol diacrylate, ethylene gylcol 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 31

The composition of claim 1 wherein said diester (A)(2) is ethylene glycol dimethacrylate and said diester (B)(3) is tetraethylene glycol dimethacrylate.

Claim 32

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

Claim 33

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

Claim 34

The composition of claim 1 wherein the monomer mixture of the outer matrix contains from about 40 to about 70% by weight of (A)(1) and from about 20 to about 49.8% by weight of (A)(2) based upon the total weight of (A)(1) and (A)(2) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.4% 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 35

The composition of claim 3 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 36

The composition of claim 12 wherein the monomer mixture of the outer matrix contains from about 40 to about 70% by weight of (A)(1) and from about 20 to about 49.8% by weight of (A)(2) based upon the total weight of (A)(1) and (A)(2) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.4% 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 37

The composition of claim 1 wherein each of said monomers (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; and said diester (B)(3) is tetraethylene glycol dimethacrylate.

Claim 38

The composition of claim 14 wherein the monomer mixture of the outer matrix contains from about 40 to about 70% by weight of (A)(1) and from about 20 to about 49.8% by weight of (A)(2) based upon the total weight of (A)(1) and (A)(2) in said monomer mixture; and wherein the monomer mixture of the inner matrix contains from about 30 to about 44.4% 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 39

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 40

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 based upon the total weight of said outer matrix, said inner matrix, and said methantheline bromide in the composition.