Pharmaceutical formulations

• US 8,673,350 B2
• Filed: 07/21/2004
• Issued: 03/18/2014
• Est. Priority Date: 07/21/2003
• Status: Expired due to Fees

• Current Assignee: Capsugel Belgium NV (Lonza Group AG)
• Original Assignee: Capsugel Belgium NV (Lonza Group AG)
• Inventors: McAllister, Stephen Mark, Raby, Ronald K. Jr., Brown, Adrian
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US10/565,462
• Publication Number:
  US 20060177496A1
• Time in Patent Office: 3,527 Days
• Field of Search: None
• US Class Current: 424/451
• 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: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

The present invention is directed to novel pharmaceutically acceptable polymeric compositions suitable for injection molding of single or multi-component pharmaceutical dosage forms comprising a plurality of drug substance containing sub-units, being capsule compartments and/or solid sub-units comprising a solid matrix of a polymer which contains a drug substance, the sub-units being connected together in the assembled dosage form by a weld between parts of the assembled dosage form.

Claims

1. An extruded and injection-molded multi-component pharmaceutical dosage form comprising a plurality of sub-units comprising:

a capsule shell providing pulsatile release of a drug substance contained within the shell, wherein the shell comprises a substantially pH-independent pharmaceutical composition comprising;

i) a copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, with a molecular weight of about 220,000 and a ratio of free carboxyl groups to ester groups of 1;

10 present in an amount of about 15 to about 50% w/w,

ii) at least two hydroxypropylcellulose polymers, present in an amount of about 20% to about 70% w/w, wherein one of the hydroxypropylcellulose polymers is a hydroxypropylcellulose polymer with an average molecular weight of 80,000 and the second hydroxypropylcellulose polymer is selected from a group consisting of a hydroxypropylcellulose polymer with an average molecular weight of 140,000 and a hydroxypropylcellulose polymer with an average molecular weight of 370,000;

iii) a lubricant present in an amount of about 10% to about 25% w/w;

iv) at least one dissolution modifying excipient selected from a disintegrant, a swellable solid, a non-reducing sugar, a water soluble filler, a wicking agent, or an inorganic salt, in combination or mixture thereof, present in an amount of about 2.5% to about 70% w/w;

v) a surfactant present in an amount of about 0 to about 10%, and

vi) a plasticizer present in an amount of about 0 to about 10% w/w and/or a processing agent present in an amount of 0 to about 10% w/w; and

a solid sub-unit comprising a pharmaceutical polymeric composition soluble, dispersible or disintegrable in a patient'"'"'s gastro-intestinal environment for release of a second drug substance contained in the solid sub-unit, and

wherein at least prior to administration to a patient, the capsule shell is filled with the drug substance, and the plurality of sub-units are assembled into the dosage form.

2. The multi-component pharmaceutical dosage form according to claim 1, wherein the capsule shell has a wall thickness ranging from about 0.3 to about 0.8 mm.

3. The multi-component pharmaceutical dosage form according to claim 1, wherein the capsule shell and the solid sub-unit have different dissolution or disintegration characteristics in the patient'"'"'s gastro-intestinal environment.

4. The multi-component pharmaceutical dosage form according to claim 1, wherein the capsule shell comprises a hydroxypropylcellulose polymer having a molecular weight of about 80,000, and a hydroxypropylcellulose polymer having a molecular weight of about 140,000 and wherein each polymer is present in an amount of about 30 to about 32% w/w.

5. The multi-component pharmaceutical dosage form according to claim 1, wherein capsule shell comprises a hydroxypropylcellulose having a molecular weight of about 80,000 and a hydroxypropylcellulose polymer having a molecular weight of about 370,000, and wherein each polymer is present in an amount of about 30 to about 32% w/w.

6. The multi-component pharmaceutical dosage form according to claim 1, wherein the lubricant is selected from the group consisting of stearyl alcohol, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, fumed silica, and mixtures thereof.

7. The multi-component pharmaceutical dosage form according to claim 6 wherein the lubricant is stearyl alcohol.

8. The multi-component pharmaceutical dosage form according to claim 7 wherein the stearyl alcohol is present in an amount of about 10 to about 15% w/w.

9. The multi-component pharmaceutical dosage form according to claim 1 wherein the at least one dissolution modifying excipient is selected from the group consisting of a disintegrant and a swellable solid, the non-reducing sugar is selected from the group consisting of xylitol and mannitol, the water soluble filler is selected from the group consisting of lactose and starch, the inorganic salt is sodium chloride, and mixtures thereof.

10. The multi-component pharmaceutical dosage form according to claim 9 wherein the disintegrant is selected from a group consisting of sodium starch glycollate, croscarmellose sodium, crospovidone, copovidone, and mixtures thereof.

11. The multi-component pharmaceutical dosage form according to claim 10 wherein the disintegrant is present in an amount of about 10 to about 40% w/w.

12. The multi-component pharmaceutical dosage form according to claim 10 wherein the disintegrant is present in an amount of about 20 to about 30% w/w.

13. The multi-component pharmaceutical dosage form according to claim 1 wherein the plasticizer is selected from a group consisting of triethyl citrate (TEC), tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, castor oil and mixtures thereof.

14. The multi-component pharmaceutical dosage form according to claim 1 wherein the processing agent is talc present in an amount of about 1 to about 5% w/w.

15. The multi-component pharmaceutical dosage form according to claim 1 wherein the solid sub-unit composition further comprises an absorption enhancer.

16. The multi-component pharmaceutical dosage form according to claim 15 wherein the absorption enhancer is selected from the group consisting of chitosan, lecithin, lectin, a sucrose fatty acid ester, Vitamin E-TPGS and mixtures thereof.

17. The multi-component pharmaceutical dosage form according to claim 1 wherein the copolymer is present in an amount of about 15 to about 30% w/w.

18. The multi-component pharmaceutical dosage form according to claim 1, wherein the surfactant is present in an amount of less than about 5% w/w.

19. The multi-component pharmaceutical dosage form according to claim 18 wherein the surfactant is selected from the group consisting of sodium dodecyl sulphate and a block copolymer of ethylene oxide and propylene oxide.

20. The multi-component pharmaceutical dosage form according to claim 19 wherein the sodium dodecyl sulphate is present in an amount of less than about 2% w/w.

21. The multi-component pharmaceutical dosage form according to claim 1 wherein the lubricant is stearyl alcohol, and the at least one dissolution modifying excipient is a disintegrant selected from the group consisting of sodium starch glycollate, croscarmellose sodium, and mixtures thereof.

22. The multi-component pharmaceutical dosage form according to claim 1 wherein the surfactant is sodium dodecyl sulphate, present in an amount of less than about 2% w/w, and the swellable solid is present in an amount of less than about 20% w/w.

23. The multi-component pharmaceutical dosage form according to claim 21 wherein the sodium starch glycollate and/or croscarmellose sodium are present in an amount of about 10% w/w.

24. The multi-component pharmaceutical dosage form according to claim 1, wherein the copolymer is present in an amount of about 15 to about 25% w/w.

25. The multi-component pharmaceutical dosage form according to claim 1 wherein the pharmaceutical composition is selected from the group consisting of:

Copolymer 24%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 80,000 30%, hydroxypropylcellulose polymer having a molecular weight of 140,000 30%, sodium starch glycollate 2%, sodium dodecyl sulfate 1%, and polyoxypropylene-polyoxyethylene block copolymers 1%;

Copolymer 24%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 80,000 30%, hydroxypropylcellulose polymer having a molecular weight of 370,000 30%, sodium starch glycollate 2%, sodium dodecyl sulfate 1%, and polyoxypropylene-polyoxyethylene block copolymers 1%;

Copolymer 24%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 140,000 30%, hydroxypropylcellulose polymer having a molecular weight of 370,000 30%, sodium starch glycollate 2%, sodium dodecyl sulfate 1%, and polyoxypropylene-polyoxyethylene block copolymers 1%;

Copolymer 24%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 80,000 32%, hydroxypropylcellulose polymer having a molecular weight of 140,000 32%;

Copolymer 29%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 80,000 25%, hydroxypropylcellulose polymer having a molecular weight of 140,000 30%, sodium starch glycollate 2%, sodium dodecyl sulfate 1%, and polyoxypropylene-polyoxyethylene block copolymers 1%; and

Copolymer 21%, Stearyl alcohol 12%, hydroxypropylcellulose polymer having a molecular weight of 80,000 32%, hydroxypropylcellulose polymer having a molecular weight of 140,000 32%, sodium starch glycollate 2%, and polyoxypropylene-polyoxyethylene block copolymers 1%.

26. The multi-component pharmaceutical dosage form according to claim 1, wherein the plurality of sub-units contain the same drug substance.