Multiparticulate controlled porosity osmotic

• US 4,851,228 A
• Filed: 07/15/1987
• Issued: 07/25/1989
• Est. Priority Date: 06/20/1984
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Zentner, Gaylen M., Rork, Gerald S., Himmelstein, Kenneth J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Horne, Leon R.
• Application Number:
  US07/073,596
• Time in Patent Office: 741 Days
• Field of Search: 424/438, 424/467, 424/454, 424/473, 424/497, 424/405, 424/424, 424/426, 424/427, 424/433, 424/435
• US Class Current: 424/456
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

The instant invention is directed to a multiparticulate osmotic pump, for the controlled release of a pharmaceutically active agent to an environment of use, said pump comprising:

(I) a carrier medium which does not maintain its integrity in the environment of use;

(II) a multiple of tiny osmotic pump elements each consisting essentially of:

(A) a core comprises at least one pharmacologically active agent soluble in an external fluid, or a mixture of an agent having a limited solubility in the external fluid with an osmotically effective solute that is soluble in the fluid, which exhibit an osmotic pressure gradient across the wall against the external fluid surrounded by

(B) a rate controlling water insoluble wall, having a fluid permeability of 6.96×10^-18 to 6.96×10¹⁴ cm³ sec/g and a reflection coefficient of less than 0.5, prepared from:

(i) a polymer permeable to water but impermeable to solute and

(ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.

Claims

1. A multiparticulate osmotic pump, for the controlled release of a pharmaceutically active agent to an environment of use, said pump comprising:

(I) a carrier medium which does not maintain its integrity in the environment of use;

(II) a multiple of tiny osmotic pump elements each consisting essentially of;

(A) a core comprises at least one pharmacologically active agent soluble in an external fluid, or a mixture of an agent having a limited solubility in the external fluid with an osmotically effective solute that is soluble in the fluid, which exhibit an osmotic pressure gradient across the wall against the external fluid surrounded by

(B) a rate controlling water insoluble wall, having a fluid permeability of 6.96×

10^-18 to 6.96×

10^-14 cm³ sec/g and a reflection coefficient of less than 0.5, prepared from;

(i) a polymer permeable to water but impermeable to solute and

(ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.

2. The osmotic pump of claim 1, wherein said pore forming additive comprises:

(a) 0.1 to 50%, by weight, solid additive, based on the total weight of (i) and (ii), and/or

(b) 0.1 to 40%, by weight, liquid additive, based on the total weight of (i) and (ii), not to exceed a total weight % of pore forming additive of 60%.

3. The osmotic pump of claim 1, wherein said reflection coefficient is less than 0.1.

4. The osmotic pump of claim 1, further comprising:

(C) 0 to 50 parts per 100 parts of (i) and (ii) of plasticizer and flux regulating additives and

(D) 0 to 40 parts per 100 parts of (i) and (ii), of surfactant additive.

5. The osmotic pump of claim 1, wherein said water insolube wall is 1 to 1,000 microns thick and wherein 5 to 95% of the resulting wall pores are between 10 angstroms and 100 microns in diameter.

6. The osmotic pump of claim 5 wherein said wall is 20 to 500 microns thick and said wall pores are between 10 angstroms and 25 microns in diameter.

7. The osmotic pump of claim 1, wherein at least 0.05 ng of active agent are used.

8. The osmotic pump of claim 7, wherein at lest 1 microgram of active agent is used.

9. The osmotic pump of claim 1, wherein said polymer is selected from the group consisting of cellulose esters, acryalted polysaccharides, polyurethane, polymers of acrylic and methacrylic acid and esters thereof, poly (ortho ester)s, polyacetals and mixtures thereof.

10. The osmotic pump of claim 9, wherein said polymer is selected from the group consisting of cellulose esters and acylated polysaccharides.

11. The osmotic pump of claim 9 wherein said polymer is selected from the group consisting of polyurethanes and polymers of acrylic and methacrylic acid and esters thereof.

12. The osmotic pump of claim 9, wherein said polymer is selected from the group consisting of poly(ortho ester)s and polyacetals.

13. The osmotic pump of claim 1, wherein said pore forming additive is selected from the group consisting of water, alkali metal salts, alkaline earth metal salts, saccharides, aliphatic polyols, aromatic polyols and mixtures thereof.

14. The osmotic pump of claim 1, wherein 0.1 to 50%, by weight, of said pore forming additive is used.

15. The osmotic pump of claim 1, wherein said pH insensitive pore forming additive is selected from the group consisting of polyethylene glycol, sorbitol, glucose and mixtures thereof.

16. The osmotic pump of claim 1, wherein said active agent is selected from the group consisting of potassium chloride, sodium indomethacin trihydrate and cyclobenzaprine HCl.

17. The osmotic pump of claim 1, wherein said active agent is selected from the group consisting of quinoline carboxylic acids, naphthyridine carboxylic acids, pyrimidine carboxylic acids, and cinnoline carboxylic acids.

18. The osmotic pump of claim 1 wherein the carrier medium is solid.

19. The osmotic pump of claim 18 wherein the solid carrier medium is a soluble gelatin capsule or tablet matrix.

20. The osmotic pump of claim 19 wherein the solid carrier medium is a soluble gelatin capsule.