Controlled release drug suspension delivery device

• US 5,582,838 A
• Filed: 12/22/1994
• Issued: 12/10/1996
• Est. Priority Date: 12/22/1994
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Pipkin, James D., Rork, Gerald S.
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/363,451
• Time in Patent Office: 719 Days
• Field of Search: 424/472, 424/473, 424/471, 424/470, 424/479, 424/480, 424/482
• US Class Current: 424/472
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28

Abstract

A device is disclosed for the controlled delivery of a beneficial agent, the device consisting of (i) a core comprising at least two layers, wherein at least one layer comprises a beneficial agent and a polymer which forms microscopic gel beads upon hydration and at least one layer which comprises a polymer which forms microscopic gel beads upon hydration; and (ii) an impermeable, insoluble coating which adheres to and surrounds the core and contains apertures which provide an area for the hydration and release of the microscopic gel beads.

Claims

1. A drug delivery device for the controlled in situ production and release of a suspension containing a beneficial agent, consisting of:

(a) a compressed core which comprises at least two layers, wherein at least one layer comprises an admixture of a therapeutically effective amount for those in need thereof, of a pharmaceutically active ingredient and a polymer which upon hydration forms microscopic polymer gel beads selected from the group consisting of sodium acrylate polymers and carboxypolymethylenes prepared from acrylic acid cross-linked with allyl ethers of sucrose or pentaerythritol; and

at least one other layer comprising a polymer which upon hydration forms microscopic polymer gel beads; and

(b) a water insoluble, water impermeable coating applied to the core, comprising a polymer and a plasticizer, which surrounds and adheres to the core, the polymer being selected from the group consisting of polyvinyl chloride, cellulose acetate, cellulose acetate butyrate or ethylcellulose, or combinations of these polymers, the plasticizer being selected from the group consisting of dibutylsebacate or triethylcitrate, the coating having apertures, exposing between about 5 and about 75% of the core surface.

2. The device of claim 1 wherein the polymer of the compressed core is selected from carboxypolymethylenes prepared from acrylic acid cross-linked with allyl ethers of sucrose or penterythritol and the pharmaceutically acceptable salts thereof.

3. The device of claim 1 wherein the amount of beneficial agent in the core comprises from about 1% to about 75% by weight of the core mixture.

4. The device of claim 1 wherein the beneficial agent is an HMG CoA reductase inhibitor.

5. The device of claim 4 wherein the beneficial agent is chosen from the group consisting of lovastatin, pravastatin and simvastatin.

6. The device of claim 1 wherein the beneficial agent is lovastatin.

7. The device of claim 1 wherein the beneficial agent is nifedipine.

8. The device of claim 1 wherein the amount of polymer, which upon hydration produces polymer gel beads in the core comprises from about 75% to about 10% by weight of the core mixture.

9. The device of claim 1, wherein the core mixture further comprises a polymer hydration modulating agent selected from the group consisting of acids, bases, salts sugars, surfactants and soluble polymers.

10. The device of claim 9, wherein the polymer hydration modulating agent is selected from the group consisting of sodium citrate, betamine hydrochloride, sodium bicarbonate, sodium carbonate and arginine.

11. The device of claim 1 wherein the insoluble, impermeable coating is selected from polyvinyl chloride, cellulose acetate, cellulose acetate butyrate or ethylcellulose.

12. The device of claim 1 wherein the apertures in the coating range in diameter from about 0.5 mm to about 2 mm.

13. The device of claim 12 wherein the apertures are arranged in an irregular pattern about the surface of the device.

14. A drug delivery device of claim 1, for the controlled in situ production and release of a suspension containing nifedipine, consisting essentially of:

(a) a compressed core comprising a first layer and a second layer, the first layer comprising a therapeutically effective amount for those in need thereof, of a pharmaceutically active ingredient and a polymer which forms polymer gel beads upon hydration, the polymer selected from the group consisting of sodium acrylate polymers and carboxypolymethylenes prepared from acrylic acid cross-linked with allyl ethers of sucrose or pentaerythritol; and

a second layer comprising a polymer which forms polymer gel beads upon hydration; and

(b) an insoluble, impermeable coating which surrounds and adheres to the core comprising a polymer and a plasticizer, the polymer being selected from the group consisting of polyvinyl chloride, cellulose acetate, cellulose acetate butyrate or ethylcellulose or combinations of these polymers, the plasticizer being selected from the group consisting of dibutylsebacate or triethylcitrate, the coating containing apertures which expose between about 10% and about 75% of the core surface.

15. The drag delivery device of claim 14, wherein the polymer is a carboxypolymethylenes prepared from acrylic acid cross-linked with allyl ethers of sucrose or penterythritol.

16. The drag delivery device of claim 14, wherein the insoluble, impermeable coating comprises cellulose acetate butyrate and triethylcitrate.

17. The drug delivery device of claim 14 which is in the form of a biconvex tablet, each convex side of the tablet being a face, each face having at least two apertures drilled through the coating to expose a portion of the core surface to the environment of use.

18. The drug delivery device of claim 17, wherein the apertures are drilled into only one face.

19. The drug delivery device of claim 18, wherein from about 10 to about 60 apertures are drilled into one face.

20. A process for the preparation of the device of claim 1 for the controlled release of an active agent wherein:

(a) the layers of the core are prepared separately by dry mixing or wet granulating the polymer which upon hydration produces polymer gel beads and granulating excipients, and dry mixing or wet granulating the pharmaceutically active ingredient with the polymer which upon hydration produces gelatinous microscopic beads and required excipients;

(b) compressing the mixtures into the appropriate layered-cores;

(c) applying the coating by either submersing the entire core into or spray coating the entire core with a suspension of the coating material; and

(d) drilling apertures through the coating to expose the desired core surface area.

21. The process of claim 20, wherein the pharmaceutically active ingredient is nifedipine.

22. The process of claim 20, wherein the pharmaceutically active ingredient is lovastatin.

23. The process of claim 20, wherein the pharmaceutically active ingredient is simvastatin.