Pharmaceutical formulation

• US 8,361,498 B2
• Filed: 11/23/2010
• Issued: 01/29/2013
• Est. Priority Date: 01/30/2001
• 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, Clarke, Allan J.
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US12/952,677
• Publication Number:
  US 20110123608A1
• Time in Patent Office: 798 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: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention is directed to 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. A multicomponent pharmaceutical dosage form comprising

a) at least one first sub-unit being a drug substance-containing capsule compartment, which is soluble or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the capsule compartment, wherein the capsule compartment comprises an extruded and injection molded polymeric composition comprising:

1) an Aminoalkyl Methacrylate Copolymer E present in an amount ranging from about 50% to about 90% w/w;

2) at least one dissolution modifying excipient which is polyethylene oxide present in an amount ranging from about 5% to about 30% w/w; and

3) a lubricant present in an amount up to about 30% w/w; and

b) at least one second sub-unit being a solid matrix comprising a polymer and a drug substance, the polymer being soluble, dispersible or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the solid matrix; and

further wherein, at least prior to administration to a patient, the sub-units are assembled together into a dosage form.

2. The dosage form according to claim 1, wherein the polyethylene oxide is present in an amount ranging from about 10% to about 20% w/w.

3. The dosage form according to claim 1, further comprising a second dissolution modifying excipient selected from the group consisting of:

i) a swellable solid selected from the group consisting of polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, and other hydroxyalkycellulose derivatives present in an amount ranging from about 5% to about 60% w/w;

ii) a disintegrant selected from the group consisting of sodium starch glycollate, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, and copovidone, present in an amount ranging from about 5% to about 50% w/w;

iii) a non-reducing sugar selected from the group consisting of xylitol and mannitol, present in an amount ranging from about 2.5% to about 15% w/w;

iv) a water soluble filler comprising lactose, present in an amount ranging from about 5% to about 20% w/w;

v) a wicking agent selected from the group consisting of mannitol, lactose, and starch, present in an amount ranging from about 2.5% to about 70% w/w;

vi) an inorganic salt, present in an amount ranging from about 5% to about 10% w/w;

comprising sodium chloride, and combinations or mixtures thereof.

4. The dosage form according to claim 1, further comprising a second dissolution modifying excipient selected from the group consisting of ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose (HPMC), lactose, Starch 1500, croscarmellose sodium, copovidone, crospovidone, and combinations or mixtures thereof.

5. The 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 combinations or mixtures thereof.

6. The dosage form according to claim 5, wherein the lubricant is stearyl alcohol.

7. The dosage form according to claim 5, wherein the lubricant is present in an amount ranging from about 10% to about 12% w/w.

8. The dosage form according to claim 5 wherein the second dissolution modifying excipient is selected from the group consisting of lactose, HPMC, hydroxypropylcellulose (HPC), copovidone, and combinations or mixtures thereof.

9. The dosage form according to claim 8, wherein the polyethylene oxide is present in an amount ranging from about 10% to about 20% w/w, and the second dissolution modifying excipient is copovidone present in an amount ranging from about 5% to about 35% w/w.

10. The dosage form according to claim 9, further comprising a plasticizer, present in an amount ranging from about 0 to about 5% w/w, and/or a processing agent, present in an amount ranging from about 0% to about 10% w/w, and/or a surfactant, present in an amount ranging from about 0.25% to about 5% w/w.

11. The dosage form according to claim 10, wherein the plasticizer is selected from the 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 combinations or mixtures thereof.

12. The dosage form according to claim 10, wherein the processing agent is talc, present in an amount ranging from about 5% to about 10% w/w.

13. The dosage form according to claim 10, wherein the surfactant is selected from the group consisting of a block copolymer of ethylene oxide and propylene oxide, lecithin, sodium dioctyl sulfosuccinate, sodium lauryl sulfate, hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, the sorbitan fatty acid esters, polyethylene glycol, glyceryl monostearate, d-alpha-tocopheryl polyethylene glycol 1000 succinate, sucrose fatty acid esters, and combinations or mixtures thereof.

14. The dosage form according to claim 13, wherein the surfactant is a block copolymer of ethylene oxide and propylene oxide.

15. The dosage form according to claim 1, wherein the composition further comprises a second copolymer selected from the group consisting of Ammonio Methacrylate Copolymer Type A and Ammonia Methacrylate Copolymer Type B.

16. The dosage form according to claim 5, wherein the lubricant is stearyl alcohol, present in an amount ranging from about 5% to about 15% w/w.

17. The dosage form according to claim 15, wherein the composition further comprises a plasticizer, present in an amount up to about 10% w/w.

18. The dosage form according to 15, wherein the composition further comprises a processing agent present in an amount up to about 10% w/w.

19. The dosage form according to claim 1, wherein the drug substance-containing capsule compartment has a wall thickness ranging from about 0.3 mm to about 0.8 mm.

20. The dosage form according to claim 1, wherein the polymeric composition is selected from the group consisting of:

Aminoalkyl Methacrylate Copolymer E 75%, Stearyl alcohol 5%, Polyethylene oxide 20%;

Aminoalkyl Methacrylate Copolymer E 60%, Hydroxypropyl cellulose 10%, Polyethylene oxide 20%, and Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 60%, Hydroxypropylmethyl cellulose 20%, Polyethylene oxide 10%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 60%, Pregelatinized starch 20%, Polyethylene oxide 10%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 55%, Hydroxypropylmethyl cellulose 20%, Polyethylene oxide 10%, Lactose (regular) 5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 55%, Hydroxypropylmethyl cellulose 15%, Polyethylene oxide 10%, Lactose (regular) 5%, Starch 1500 5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 57.5%, Hydroxypropylmethyl cellulose 15%, Polyethylene oxide 10%, Lactose (regular) 5%, Progelatinized starch 2.5%, Stearyl alcohol 10%; and

Aminoalkyl Methacrylate Copolymer E 70%, Sucrose ester 10%, Polyethylene oxide 10%, Stearyl alcohol 10%.

21. The dosage form according to claim 1, wherein the polymeric composition is selected from the group consisting of:

Aminoalkyl Methacrylate Copolymer E 75%, Polyethylene oxide 10%, Talc 5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 70%, Polyethylene oxide 20%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 62.5%, Copovidone 17.5%, Polyethylene oxide 10%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 60%, Polyethylene oxide 20%, Talc 10%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 52.5%, Copovidone 17.5%, Polyethylene oxide 20%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 63.75%, Copovidone 8.75%, Polyethylene oxide 10%, Talc 7.5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 60%, Copovidone 20%, Polyethylene oxide 5%, Talc 5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 55%, Copovidone 5%, Polyethylene oxide 20%, Talc 10%, Stearyl alcohol 10%; and

Aminoalkyl Methacrylate Copolymer E 50%, Copovidone 16.5%, Polyethylene oxide 20%, Talc 3.5%, Stearyl alcohol 10%.

22. A multicomponent pharmaceutical dosage form comprising

a) at least one first sub-unit being a drug substance-containing capsule compartment, which is soluble or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the capsule compartment, wherein the capsule compartment comprises an extruded and injection molded polymeric composition comprising:

1) an Aminoalkyl Methacrylate Copolymer E present in an amount ranging from about 30% to about 90% w/w;

2) at least one dissolution modifying excipient which is polyethylene oxide present in an amount ranging from about 5% to about 30% w/w; and

3) a lubricant present in an amount up to about 30% w/w; and

b) at least one second sub-unit being a solid matrix comprising a polymer and a drug substance, the polymer being soluble, dispersible or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the solid matrix; and

further wherein, at least prior to administration to a patient, the sub-units are assembled together into a dosage form.

23. The dosage form according to claim 22, wherein the polymeric composition is selected from the group consisting of:

Aminoalkyl Methacrylate Copolymer E 30%, Copovidone 35%, Polyethylene oxide 20%, Talc 5%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 42.5%, Copovidone 17.5%, Polyethylene oxide 20%, Talc 10%, Stearyl alcohol 10%;

Aminoalkyl Methacrylate Copolymer E 48.75%, Copovidone 26.25%, Polyethylene oxide 10%, Talc 5%, Stearyl alcohol 10%; and

Aminoalkyl Methacrylate Copolymer E 40%, Copovidone 35%, Polyethylene oxide 10%, Talc 5%, Stearyl alcohol 10%.