Matrix tablet permitting the sustained release of indapamide after oral administration

• US 5,334,392 A
• Filed: 06/09/1992
• Issued: 08/02/1994
• Est. Priority Date: 06/18/1991
• Status: Expired due to Term

• Current Assignee: Les Laboratoires Servier (Servier Sas)
• Original Assignee: Adir SA
• Inventors: de Barochez, Bruno H., Cuine, Alain, Guez, David
• Primary Examiner(s): WEBMAN, EDWARD J
• Application Number:
  US07/895,787
• Time in Patent Office: 784 Days
• Field of Search: 424/484, 424/486, 424/488, 424/464, 424/465, 424/468, 424/470, 424/501, 514/929, 514/414
• US Class Current: 424/468
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The invention relates to a matrix tablet for the sustained release of indapamide which ensures a continuous and uniform release of the active principle after oral administration.

Claims

1. A sustained release indapamide matrix tablet consisting essentially of between 1 and 2.5 mg of indapamide, polyvidone, methylhydroxyalkylcellulose, and excipient, which exhibits linear sustained release for at least eight hours, wherein 50 percent of the total quantity of indapamide is released over a period of between 5 and 14 hours, which produces blood levels in humans of between 20 and 80 ng/ml for up to 24 hours after oral administration, produced by a process consisting essentially of the steps of:

(a) mixing indapamide with solid polyvidone having a molecular weight between 10,000 and 700,000 and an excipient;

(b) wetting the mixture of step (a) with an aqueous alcoholic solution to form a granulate;

(c) mixing the granulate with methylhydroxyalkylcellulose having a viscosity between 1,000 and 20,000 centipoises;

(d) lubricating the mixture of step (c) with a lubricating agent; and

(e) compressing the lubricated mixture of step (d) in a rotary tableting machine to produce a tablet having a hardness, measured by diametrical crushing, of 60 to 75N,

wherein the percentages of indapamide, methylhydroxyalkylcellulose, and polyvidone are respectively approximately 1%, between 30 and 50 percent, and between 2 and 10 percent of the total mass of the tablet, the excipient consisting essentially of a compound selected from the group consisting of sugar, colloidal silica, and lubricant.

2. The method of treating essential arterial hypertension for which indapamide is known to be effective which comprises the step of administering orally to a patient, an effective antihypertensive amount of a matrix tablet for the sustained release of indapamide of claim 1.

3. The matrix tablet of indapamide as claimed in claim 1, wherein the methylhydroxyalkylcellulose is methylhydroxypropylcellulose.

4. The method of delivering indapamide to a patient in need thereof comprising the step of orally administering to said patient a matrix tablet for the sustained release of indapamide according to claim 3.

5. A matrix tablet of claim 1, wherein the pharmaceutically-acceptable excipients are selected from the group consisting of lactose, colloidal silica, and lubricant.

6. The method of delivering indapamide to a patient in need thereof comprising the step of orally administering to said patient a matrix tablet for the sustained release of indapamide according to claim 5.

7. A process for producing a sustained release matrix tablet of indapamide consisting essentially of between 1 and 2.5 mg of indapamide, polyvidone, methylhydroxyalkylcellulose, and excipient, and exhibiting linear sustained release for at least eight hours, wherein 50 percent of the total quantity of indapamide is released over a period of between 5 and 14 hours to produce blood levels in humans of between 20 and 80 ng/ml for up to 24 hours after oral administration, consisting essentially of the steps of:

(a) mixing indapamide with solid polyvidone having a molecular weight between 10,000 and 700,000 and an excipient;

(b) wetting the mixture of step (a) with an aqueous alcoholic solution to form a granulate;

(c) mixing the granulate with methylhydroxyalkylcellulose having a viscosity between 1,000 and 20,000 centipoises;

(d) lubricating the mixture of step (c) with a lubricating agent; and

(e) compressing the lubricated mixture of step (d) in a rotary tableting machine to produce a tablet having a hardness, measured by diametrical crushing, of 60 to 75N;

wherein the percentages of indapamide, methylhydroxylalkylcellulose, and polyvidone are respectively approximately 1%, between 30 and 50 percent, and between 2 and 20 percent of the total mass of the tablet, the excipient consisting essentially of a compound selected from the group consisting of sugar, colloidal silica, and lubricant.

8. The method of claim 7, wherein the high-viscosity methylhydroxyalkylcellulose is methylhydroxypropylcellulose.

9. The method of claim 7, wherein the pharmaceutically-acceptable excipients are selected from the group consisting of lactose, colloidal silica, and lubricant.