Conversion of liquid filled gelatin capsules into controlled release systems by multiple coatings

• US 6,419,952 B2
• Filed: 05/25/2001
• Issued: 07/16/2002
• Est. Priority Date: 12/17/1998
• Status: Expired due to Fees

• Current Assignee: Encinal Pharmaceutical Investments, LLC
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Wan, Jiansheng, Dong, Liang C., Wong, Patrick S. -L.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): DI NOLA BARON, LILIANA
• Application Number:
  US09/866,036
• Publication Number:
  US 20010036472A1
• Time in Patent Office: 417 Days
• Field of Search: 424/456, 424/451, 424/452, 424/453, 424/457, 424/468, 424/469, 424/473, 424/463
• US Class Current: 424/463
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

A dosage form comprising a gelatin capsule formed with a composite wall and containing a liquid, active agent formulation where the wall comprises a barrier layer formed over the external surface of the gelatin capsule, an expandable layer formed over the barrier layer and a semipermeable layer formed over the expandable layer is described. The dosage forms and methods provide for the conversion of standard gelatin, liquid formulation capsules into controlled, release dosage forms that permit the controlled release of the active agent into the environment of use over time.

Claims

1. A dosage form comprising (a) a gelatin capsule containing a liquid, active agent formulation;

(b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule;

(i) a deformable barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and

(c) an orifice formed or formable through the wall.

2. The dosage form of claim 1, wherein the expandable layer is hydro-activated.

3. The dosage form of claim 1, wherein the expandable layer is an osmotic layer.

4. The dosage form of claim 2, wherein the deformable barrier layer is impermeable to water.

5. The dosage form of claim 1, wherein the deformable barrier layer is formed as a coating on the gelatin capsule.

6. The dosage form of claim 5, wherein the expandable layer is formed as an osmotic layer coated on the barrier layer.

7. The dosage form of claim 6, wherein the semipermeable layer is formed as a coating on the osmotic layer.

12. The dosage form of claim 1, wherein the deformable barrier layer forms a seal between the expandable layer and the environment at the exit orifice.

16. The dosage form of claim 1, wherein the active agent is selected from the group consisting of acetaminophen, cyclosporin, ethchlorvynol, nifedipine, etoposide, digoxin, ranitidine hydrochloride, calcifediol, ethosuximide, calcitriol, paclitaxel, valproic acid, tretinoin, isotretinoin, indinavir, lamivudine, stavudine, nelfinavir mesylate, saquinavir mesylate, ritonavir, zidovudine, didanosine, nevirapine, ganciclovir, zalcitabine, fluoexetine, sertraline, paroxetine, bupropion, nefazodone, mirtazpine, mianserin, zanamivir, olanzapine, risperidone, quetiapine fumurate, buspirone, alprazolam, lorazepam, clorazepate dipotassium, clozapine, sulpiride, amisulpride, methylphenidate, and pemoline and pharmaceutically-acceptable salts and esters thereof.

17. The dosage form of claim 1, wherein the active agent comprises cyclosporin.

18. The dosage form of claim 1, wherein the active agent comprises acetaminophen.

19. The dosage form of claim 1, wherein the active agent comprises isotretinoin.

20. The dosage form of claim 1, wherein the active agent comprises valproic acid.

8. A method of converting a gelatin capsule containing a liquid active agent formulation into a controlled release dosage form which comprises forming a composite wall over the gelatin capsule by sequentially forming a deformable barrier layer on the external surface of the gelatin capsule, an expandable layer over the deformable barrier layer and a semipermeable layer over the expandable layer.

9. The method of claim 8, wherein at least one of the forming steps comprises a coating step.

10. The method of claim 8, which comprises forming an exit orifice in the wall by sequentially forming an opening in the wall having a diametric dimension greater than the final diameter of the exit orifice and filling the opening with a material in which the exit orifice may be formed.

11. A method of manufacturing a controlled release dosage form comprising a gelatin capsule containing a liquid active agent formulation, which method comprises the steps of (1) forming a deformable barrier layer surrounding the gelatin capsule;

(2) forming an expandable layer surrounding the deformable barrier layer-gelatin capsule;

(3) removing a portion of the expandable layer in an area in which an exit orifice is to be located without compromising the integrity of the deformable barrier layer in the area;

(4) forming a semipermeable layer surrounding the intermediate dosage form prepared through step (4); and

forming an exit orifice in the area exposing at least a portion of the gelatin capsule.

13. A dosage form comprising a gelatin capsule containing a liquid, active agent formulation, the gelatin capsule being surrounded by a deformable barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting at least a portion of the deformable barrier layer, a semipermeable layer surrounding at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use.

14. The dosage form of claim 13, wherein the expandable layer is in one or more discrete sections.

15. The dosage form of claim 13, wherein the expandable layer is in two discrete sections which are applied individually to the respective ends of the capsule.