Multilayered controlled-release oral solid pharmaceutical forms

• US 5,681,583 A
• Filed: 04/25/1995
• Issued: 10/28/1997
• Est. Priority Date: 07/09/1993
• Status: Expired due to Term

• Current Assignee: APR Applied Pharma Research SA (RELIEF THERAPEUTICS Holding SA)
• Original Assignee: APR Applied Pharma Research SA (RELIEF THERAPEUTICS Holding SA)
• Inventors: Maggi, Lauretta, Conte, Ubaldo, Giunchedi, Paolo
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/397,187
• Time in Patent Office: 917 Days
• Field of Search: 424/472, 424/473, 424/466, 424/468
• US Class Current: 424/472
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer

Abstract

Multilayered controlled-release solid pharmaceutical composition in tablet form suitable for oral administration comprising at least two layers containing active material in association with excipients and additives. One layer of the tablet releases a portion of the drug quickly while the other layer and optionally further layers release portions of the drug more gradually.

Claims

1. A solid pharmaceutical composition for oral administration, comprising:

at least one first layer consisting essentially of a first active material and a disintegrating or superdisintegrating compound which is a cross-linked polyvinylpyrrolidone, sodium carboxy methylcellulose, carboxymethyl starch, potassium methacrylate--divinylbenzene copolymer, a polyvinylalcohol, a starch, a microcrystalline cellulose, a dextrin, beta cyclodextrin, and mixtures thereof; and

at least one second layer located on said first layer containing a portion of said first active material or a second active material and an excipient or adjuvant selected from the group consisting of hydroxypropylmethylcellulose of molecular weight 1,000 to 4,000,000, hydroxypropylcellulose of molecular weight from 2,000 to 2,000,000, a carboxyvinylpolymer, a polyvinylalcohol, a glucan, a scleroglucan, a mannan, a xanthan, alginic acid, methylcellulose and a polymethylcellulose;

said active material in said first layer being released upon administration to a host at a rate faster than the rate of release of said active material in said second layer.

2. A pharmaceutical composition according to claim 1, wherein said disintegrating or superdistintegrating compound is present in an amount of 10 to 90% by weight of said first layer.

3. A pharmaceutical composition according to claim 2, wherein said disintegrating or superdisintegrating compound is present in an mount of 20 to 70% by weight of said first layer.

4. A pharmaceutical composition according to claim 1, wherein said said first layer further comprises an adjuvant selected from the group consisting of starch, pregelled starch, calcium phosphate, mannitol, lactose, sucrose, glucose, sorbitol and microcrystalline cellalose, a binding agent, a lubricant and an antiadhering compound.

5. A pharmaceutical composition according to claim 4, wherein said binding agent is selected from the group consisting of gelatin, polyvinylpyrrolidone, methyl cellalose, starch water, ethylcellulose, gum arabic and tragacanth gum.

6. A pharmaceutical composition according to claim 4, wherein said lubricants and antiadhering compounds are selected from the group consisting of magnesium stearate, stearic acid, colloidal silica, glyceryl monostearate, a polyoxyethyleneglycol of 400 to 50000 number average molecular weight, hydrogenated castor oil, waxes and a glyceride.

7. A pharmaceutical composition according to claim 1, wherein said first layer includes an effervescent agent capable of causing rapid disintegration of said first layer when said composition comes into contact with an aqueous environment.

8. A pharmaceutical composition according to claim 7, wherein said aqueous environment is gastric juice.

9. A pharmaceutical composition according to claim 7 wherein said first layer includes a compound that can produce effervescence in an acid environment selected from the group consisting of alkali metal carbonates, alkaline-earth metal carbonates, sodium bicarbonate and glycine sodium carbonate.

10. A pharmaceutical composition according to claim 7, where said first layer includes a compound that can produce effervescence and disintegration of said first layer independently of pH selected from the group consisting of citric add, tartaric acid and fumaric add.

11. A pharmaceutical composition according to claim 7, wherein said effervescent agent capable of producing effervescence is present in an amount of 3 to 40% by weight of said first layer.

12. A pharmaceutical composition according to claims 1, and further comprising a second and a third layer including a same or different active material together with a disintegrating or superdisintegrating compound which is a cross-linked polyvinylpyrrolidone, sodium carboxy methylcellulose, carboxymethyl starch, potassium methacrylate--divinylbenzene copolymer, a polyvinylalcohol, a starch, a microcrystalline cellulose, a dextrin, beta cyclodextrin, and mixtures thereof, and excipients and adjuvants.

13. A pharmaceutical composition according to claim 12, wherein said disintegrating or superdisintegrating compound in said second and third layer is present in each layer in an amount of 5 to 90% by weight of the said layer.

14. A pharmaceutical composition according to claim 1, wherein said adjuvant contained in said at least one second layer is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, starch water, ethylcellulose, arabic gum and tragacanth gum.

15. A pharmaceutical composition according to claim 1, wherein said adjuvant of said at least one second layer is selected from the group consisting of glyceryl monostearate, semi-synthetic glycerides, glyceryl palmitostearate, glyceryl behenate, microcrystalline cellulose, sodium carboxymethylcellulose, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid and colloidal silica.

16. A pharmaceutical composition according to claim 1, wherein said adjuvant of said at least one second layer is selected from the group consisting of hydrogenated castor oil, fatty acids, waxes, glycerides and polyoxyethyleneglycol with a molecular weight of from 400 to 60,000.

17. A pharmaceutical composition according to claim 1, wherein said active material is selected from the group consisting of steroidol anti-inflammatories non-steroidal anti-inflammatories (NSAID1), sleeping substances, tranquilizers, active substances for preventing anginous and hypertensive attacks, antihistamines and antiasthmatic drugs, and combinations thereof.

18. A pharmaceutical composition according to claim 17, wherein said anti-inflammatory is selected from the group consisting of diclofenac sodium, indomethacin, ibuprofen, ibuprofen lysine salt, ketoprofen, diflunisal, piroxicam, naproxen and flurbiprofen.

19. A pharmaceutical composition according to claim 17, wherein said sleeping substance or tranquilizer is selected from the group consisting of diazepam, nitrazepam, fluorozepam, oxazepam and chlorodiazepoxide.

20. A pharmaceutical composition according to claim 17, wherein said antianginous and antihypertensive active material is selected from the group consisting of diltiazem, trapidil, verapamil, urapidil and benziodarone dipyridamole.

21. A pharmaceutical composition according to claim 17, wherein said antihistaminic or antiasthmatic material is selected from the group consisting of ephedrine, terfenadine, theophylline, chloropheniramine and termutiline.

22. A pharmaceutical composition according to claim 1, wherein said first layer has a thickness from 0.5 to 5 mm and contains from 1 to 90% by weight of active material.

23. A pharmaceutical composition according to claim 1, wherein said second layer has a thickness of from 0.1 to 6.0 mm and contains from 1 to 90% by weight of active material and from 10 to 90% by weight of said excipient or adjuvant.

24. A pharmaceutical composition according to claim 1, wherein said second layer contains a portion of the same active material as present in said first layer.

25. A pharmaceutical composition according to claim 1, wherein an active material different from that present in said first layer is present in said second layer.

26. A pharmaceutical composition according to claim 1, wherein a third layer is present and contains an active material and an adjuvant as defined in claim 1.