Enteric coated pharmaceutical tablet and method of manufacturing

• US 6,331,316 B1
• Filed: 04/14/2000
• Issued: 12/18/2001
• Est. Priority Date: 07/17/1998
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wiley, Gary J., Ullah, Ismat
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Seidleck, Brian K.
• Application Number:
  US09/549,455
• Time in Patent Office: 613 Days
• Field of Search: 424/464, 424/468, 424/474, 424/475, 424/479, 424/482, 424/480, 424/458, 424/451, 424/478, 514/23
• US Class Current: 424/482
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV

Abstract

A high drug load enteric coated pharmaceutical composition is provided which includes a core in the form of a tablet and which is comprised of a medicament which is sensitive to a low pH environment of less than 3, such as ddl, and having an enteric coating formed of methacrylic acid copolymer and a plasticizer. The tablets may be of varying sizes and may be orally ingested individually or a plurality of tablets sufficient to attain a desired dosage may be encapsulated in a dissolvable capsule. The tablets have excellent resistance to disintegration at pH less than 3 but have excellent drug release properties at pH greater than 4.5. A novel method of making said pharmaceutical composition is also disclosed.

Claims

1. A pharmaceutical tablet comprising a core comprising 2′

,3′

-dideoxyinosine (ddl), a binder or filler, a disintegrant, and a lubricant, wherein said core is coated with an enteric coating comprising a methacrylic acid copolymer and a plasticizer, said enteric coating having a pH of 5.0±

0.1, wherein said enteric coating imparts protection to said core so that said core is afforded protection in a pH environment of 3 or less while capable of releasing the ddl at a pH of 4.5 or higher, wherein said tablet contains no protective subcoat between the core and the enteric coating.

2. The tablet of claim 1, wherein said binder is microcrystalline cellulose, sodium carboxymethylcellulose, microcrystalline cellulose and carboxymethylcellulose sodium, hydroxypropylmethyl cellulose, pregelatinized starch, potassium alginate, or sodium alginate.

3. The tablet of claim 2, wherein the binder is microcrystalline cellulose.

4. The tablet of claim 1, wherein the lubricant is magnesium stearate.

5. The tablet of claim 1, wherein the disintegrant is sodium starch glycolate, croscarmellose sodium, corn starch, or cross-linked polyvinylpyrrolidone.

6. The tablet of claim 5, wherein the disintegrant is sodium starch glycolate.

7. The tablet of claim 1, wherein the methacrylic acid copolymer is methacrylic acid copolymer, Type C.

8. The tablet of claim 1, wherein the plasticizer is diethyl phthalate, triethyl citrate, triacetin, tributyl sebecate, or polyethylene glycol.

9. The tablet of claim 8, wherein the plasticizer is diethyl phthalate.

10. The tablet of claim 1, having the following composition:

11. A pharmaceutical tablet of claim 1, wherein said core comprises ddl in an amount in the range of from about 1 to about 99.5% by weight of said core.

12. A dissolvable capsule containing a plurality of the tablets of claim 1.

13. A process for the preparation of a pharmaceutical tablet of claim 1 comprising the steps of:

(a) preparing a blend comprising ddl suitable for tableting;

(b) tableting said blend into a plurality of individual tablets; and

(c) coating said tablets.

14. The process of claim 3, wherein said preparing step comprises the steps of

(a) blending a mixture comprised of ddl, a binder, a disintegrant, and a first portion of a lubricant;

(b) passing said mixture through a #40 size mesh screen;

(c) reblending said mixture;

(d) slugging said blend and passing the formed slugs successively through #10 and 20 size mesh screens; and

(e) adding a second portion of lubricant and re-blending.

15. The process of claim 14, wherein said mixture formed in step (c) is slugged using a ¾

″

flat face punch.

16. The process of claim 13, wherein said tableting step (b) is performed using {fraction (3/16)}″

round, plain, deep concave punches to obtain tablets of the desired weight.

17. The process of claim 13, wherein said tablets have a hardness of 3-6 SCU.

18. The process of claim 13, wherein preparation of said coating comprises the steps of:

(a) mixing a methacrylic acid copolymer with approximately half the amount of water required to attain the desired formulation;

(b) adding a plasticizer to the mixture of step (a) and stirring until said plasticizer is in complete solution;

(c) adding sodium hydroxide solution to adjust the pH of the mixture of step (b) to 5.0; and

(d) while stirring the mixture of step (c) adding water in a sufficient amount to bring the mixture to its desired formula weight.

19. The process of claim 13, wherein said coating step (c) comprises the steps of:

(a) pre-warming said tablets in a fluid bed spraying apparatus to approximately 45-50°

C.;

(b) spraying said tablets with said coating; and

(c) drying said tablets.

20. The process of claim 14, wherein said binder is microcrystalline cellulose.

21. The process of claim 14, wherein said lubricant is magnesium steak rate.

22. The process of claim 14, wherein said disintegrant is sodium starch glycolate.

23. The process of claim 13, wherein said enteric coating comprises methacrylic acid copolymer and diethyl phthalate.

24. The process of claim 23, wherein said methacrylic acid polymer is Type C.

25. A process for the preparation of a pharmaceutical tablet of claim 1 comprising the steps of:

(a) preparing a wet mass blend by a wet granulation process for the formation of granules for tableting;

(b) tableting said granules into a plurality of individual tablets;

(c) coating said tablets with an enteric coating polymer and plasticizer in an aqueous media; and

(d) blending said coated tablets with an anti-adherent.

26. The process of claim 25, wherein said preparing step comprises the steps of:

(a) blending a mixture comprised of a ddl, a binder, a disintegrant, and a filler;

(b) adding a predetermined amount of water or granulation solvent to form a wet blend;

(c) sizing said blend into granules to aid drying;

(d) drying said granules to remove excess moisture;

(e) sizing said dried granules into granules suitable for tableting; and

(f) adding lubricant, disintegrant, one or more fillers, one or more binders, and other excipients for tableting said granules.

27. The process of claim 25, wherein preparation of said coating comprises the steps of:

(a) mixing a methacrylic acid copolymer with approximately 50 g of water;

(b) adding a plasticizer to the mixture formed in step (a) and stirring until said plasticizer is in complete solution;

(c) adding sodium hydroxide solution to adjust the pH of the mixture of step (b) to 5.0; and

(d) while stirring the mixture of step (c) adding water in a sufficient amount to bring the mixture to its desired formula weight.

28. The process of claim 25, wherein said coating step (c) comprises the steps of:

(a) pre-warming said tablets in a fluid bed spraying apparatus to approximately 45-50°

C.;

(b) spraying said tablets with said coating; and

(c) drying said tablets.

29. The process of claim 26, wherein said binder is microcrystalline cellulose.

30. The process of claim 26, wherein said lubricant is magnesium stearate.

31. The process of claim 26, wherein said disintegrant is sodium starch glycolate.

32. The process of claim 25, wherein said enteric coating comprises methacrylic acid copolymer and diethyl phthalate.

33. The process of claim 32, wherein said methacrylic acid polymer is Type C.

34. The process of claim 25, wherein said anti-adherent is talc.

35. The process of claim 25, further comprising the step of filling said coated tablets prepared in step (d) into a capsule.