Method and composition for the preparation of controlled long-acting pharmaceuticals for oral administration

• US 4,680,323 A
• Filed: 12/01/1983
• Issued: 07/14/1987
• Est. Priority Date: 12/01/1983
• Status: Expired due to Term

• Current Assignee: Hans Lowey
• Original Assignee: Hans Lowey
• Inventors: Lowey, Hans
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US06/556,844
• Time in Patent Office: 1,321 Days
• Field of Search: 424/19, 424/35, 424/20, 424/22, 514/781, 514/965, 524/43
• US Class Current: 524/43
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• 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

Abstract

A novel pharmaceutical composition is disclosed. It comprises a sustained release pharmaceutical carrier suitable for admixture with active ingredients comprising:

(a) 5.5-98.5% by weight of hydroxypropyl methylcellulose;

(b) 0.25-4.5% by wieght of hydroxypropyl cellulose;

(c) 1-90% by weight of a carboxyvinyl polymer.

Claims

1. A sustained release pharmaceutical carrier suitable for admixture with active ingredients comprising:

(a) 5.5-98.5% by weight of hydroxypropyl methylcellulose;

(b) 0.25-4.5% by weight of hydroxypropyl cellulose;

(c) 1-90% by weight of a carboxyvinyl polymer.

2. A sustained release pharmaceutical carrier as defined in claim 1 wherein the hydroxypropyl cellulose has a viscosity in the range of 1,000 to 1,500 centipoise for a 2% aqueous solution at 25°

C.

3. A sustained release pharmaceutical carrier as defined in claim 1 adapted for facilitating the absorption of large molecules through the buccal pouch of the mouth containing a sweetening agent at least 30 times as sweet as sugar.

4. A sustained release pharmaceutical carrier according to claim 1, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

5. A sustained release pharmaceutical carrier suitable for admixture with active ingredients comprising:

(a) 10-80% by weight of hydroxypropyl methylcellulose;

(b) 1.0-3.5% by weight of hydroxypropyl cellulose;

(c) 3-75% by weight of a carboxyvinyl polymer.

6. A sustained release pharmaceutical carrier according to claim 5, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

7. A sustained release pharmaceutical carrier suitable for admixture with active ingredients and particularly adapted for preparation of compositions suitable for administration of active ingredients through the buccal pouch of the mouth which comprises:

(a) 2-35% by weight of hydroxypropyl methylcellulose having a viscosity of about 50 centipoise for a 2% aqueous solution at 20°

C.;

(b) 3-85% by weight of hydroxypropyl methylcellulose having a viscosity of about 4,000 centipoise for a 2% aqueous solution at 20°

C.; and

(c) 2-40% by weight of hydroxypropyl methylcellulose having a viscosity of about 15,000 centipoise for a 2% aqueous solution at 20°

C.;

(d) 0.5-40% by weight of hydroxpropyl methylcellulose having a viscosity of about 100,000 centipoise for a 2% aqueous solution at 20°

C.;

(e) 0.25-4.5% by weight of hydroxypropyl cellulose; and

(f) 1-90% of a carboxyvinyl polymer having a viscosity of 30,000 to 40,000 centipoise for a 3.0% by weight neutralized solution.

8. A sustained release pharmaceutical carrier as defined in claim 7 wherein the hydroxypropyl cellulose has a viscosity in the range of 1,000 to 1,500 centipoise for a 2% aqueous solution at 25°

C.

9. A sustained release pharmaceutical carrier according to claim 7, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

10. A sustained release pharmaceutical composition which comprises a carrier and an active therapeutic agent incorporated within said carrier, said carrier comprising:

(a) 5.5-98.5% by weight of hydroxypropyl methylcellulose;

(b) 0.25-4.5% by weight of hydroxypropyl cellulose;

(c) 1-90% by weight of a carboxyvinyl polymer.

11. A sustained release pharmaceutical carrier as defined in claim 10 adapted for facilitating the absorption of large molecules through the buccal pouch of the mouth containing a sweetening agent at least 30 times as sweet as sugar.

12. A sustained release pharmaceutical composition as defined in claim 11 wherein said therapeutic agent is present in an amount of 0.25 to 700 mg.

13. A sustained release pharmaceutical composition as defined in claim 11 wherein the hydroxypropyl cellulose has a viscosity of 1,000 to 1,500 for a 2% aqueous solution at 25°

C.

14. A sustained release pharmaceutical carrier as defined in claim 10 which is zero order with respect to its release of active ingredient.

15. A sustained release pharmaceutical carrier as defined in claim 10 which is adapted for use in a one-a-day tablet.

16. A sustained release pharmaceutical composition as defined in claim 10 wherein the said therapeutic agent is present in from 0.25 to 700 mg.

17. A sustained release pharmaceutical composition as defined in claim 10 wherein the carrier contains hydroxypropyl cellulose having a viscosity of 1,000 to 1,500 centipoise for a 2% aqueous solution at 25°

C.

18. A sustained release pharmaceutical composition according to claim 10, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

19. A sustained release pharmaceutical composition which comprises a carrier and an active therapeutic agent incorporated within said carrier, said carrier comprising:

(a) 10-80% by weight of hydroxypropyl methylcellulose;

(b) 1.0-3.5% by weight of hydroxypropyl cellulose; and

(c) 3-75% by weight of a carboxyvinyl polymer.

20. A sustained release pharmaceutical composition according to claim 19, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

21. A sustained release pharmaceutical composition adapted for administration via the buccal pouch of the mouth which comprises a sustained release carrier and an active therapeutic agent, said carrier comprising:

(a) 2-35% by weight of hydroxypropyl methylcellulose having a viscosity of about 50 centipoise for a 2% aqueous solution at 20°

C.;

(b) 3-85% by weight of hydroxypropyl methylcellulose having a viscosity of about 4,000 centipoise for a 2% aqueous solution at 20°

C.; and

(c) 2-40% by weight of hydroxypropyl methylcellulose having a viscosity of about 15,000 centipoise for a 2% aqueous solution at 20°

C.;

(d) 0.5-40% by weight of hydroxypropyl methylcellulose having a viscosity of about 100,000 centipoise for a 2% aqueous solution at 20°

C.;

(e) 0.25-4.5% by weight of hydroxypropyl cellulose; and

(f) 1-90% of a carboxyvinyl polymer having a viscosity of 30,000 to 40,000 centipoise for a 3.0% by weight neutralized solution.

22. A sustained release pharmaceutical composition according to claim 21, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

23. A method for producing a sustained zero-order time release of an active pharmaceutical agent in the gastro-intestinal tract comprising:

forming an ingestible tablet containing a carrier of hydroxypropyl methylcellulose, hydroxypropyl cellulose and a carboxy vinyl polymer, together with an effective amount of a pharmaceutically active agent;

ingesting the tablet; and

allowing the tablet to transit the gastro-intestinal tract and to slowly dissolve by the action of gastro-intestinal fluids thereupon, whereby the weakly acidic carboxy vinyl polymer reacts to form salts under the alkaline conditions in the small intestine of the gatro-intestinal tract to thereby produce a coating of the active pharmaceutical agent on the small intestine of the gastro-intestinal tract, which coating remains in place and from which the pharmaceutically active agent is slowly absorbed through the mucosa of the small intestine into the blood stream over a sustained period of from twelve to twenty-four hours, which is in excess of the time taken by an undissolved remnant of the tablet to transit the gastro-intestinal tract.

24. A method for producing a sustained zero-order time release of an active pharmaceutical agent in the gastro-intestinal tract utilizing an ingestible tablet prepared according to claim 23, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.

25. A method for facilitating the sustained time-release and absorption of large molecules of a pharmaceutically active agent through the mucosa of the buccal pouch of the mouth comprising:

forming a buccal tablet containing a carrier of hydroxypropyl methylcellulose, hydroxypropyl cellulose and a carboxy vinyl polymer, together with an effective amount of a pharmaceutically active agent having a molecule size larger than the normal permeability of the mucosa in the buccal pouch of the mouth, and a sweetening agent at least thirty times as sweet as sugar;

placing the buccal tablet in the buccal pouch of the mouth; and

allowing saliva in the buccal pouch of the mouth to slowly dissolve the tablet such that the sweetener contacts the mucosa lining the buccal pouch of the mouth and causes an increase in the permeability of the mucosa to allow the molecules of the pharmaceutically active agent to penetrate and be absorbed into the bloodstream over a sustained period.

26. A method for facilitating the sustained time-release and absorption of large molecules of a pharmaceutically active agent through the mucosa of the buccal pouch of the mouth, utilizing a buccal tablet prepared according to claim 25, wherein the carboxyvinyl polymer is a polymer of acrylic acid or polyacrylic acid, cross-linked with a polyalkenyl polyether.