Controlled release pharmaceutical compositions for prolonged effect

• US 8,821,928 B2
• Filed: 06/04/2008
• Issued: 09/02/2014
• Est. Priority Date: 06/04/2007
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Hemmingsen, Pernille Hoyrup, Pedersen, Anders Vagno, Bar-Shalom, Daniel
• Primary Examiner(s): Kwon, Brian-Yong
• Assistant Examiner(s): Stevens, Mark V
• Application Number:
  US12/602,953
• Publication Number:
  US 20100239667A1
• Time in Patent Office: 2,281 Days
• US Class Current: 424/466
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 35/00 Antineoplastic agents

Abstract

Layered pharmaceutical composition suitable for oral use in the treatment of diseases where absorption takes place over a large part of the gastrointestinal tract. The composition comprising A) a solid inner layer comprising i) an active substance, and ii) one or more disintegrants/exploding agents, one of more effervescent agents or a mixture thereof. the solid inner layer being sandwiched between two outer layers B1) and B2), each outer layer comprising iii) a substantially water soluble and/or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyglycol in the form of one of a) a homopolymer having a MW of at least about 100,000 daltons, and b) a copolymer having a MW of at least about 2,000 daltons, or a mixture thereof, and iv) an active substance, which is the same as in said solid inner layer A), and layer A being different from layer B, the layered composition being coated with a coating C) that has at least one opening exposing at least one surface of said outer layer, the coating being substantially insoluble in and impermeable to fluids and comprising a polymer, and the composition having a cylindrical form optionally with one or more tapered ends, wherein the ratio between the surface area of one end surface of the cylinder and the length of the cylinder is in a range of from 0.02 to 45 mm.

Claims

1. A layered pharmaceutical composition formulated and configured to provide controlled release of an active substance, the pharmaceutical composition comprising:

a solid inner layer (A) comprising the active substance and an effervescent agent selected to aid release of the active substance from the solid inner layer (A);

two outer layers (B1) and (B2) that are free of the effervescent agent, each of the two outer layers (B1) and (B2) comprising the active substance and a polymer selected from a substantially water soluble or crystalline polyglycol having a molecular weight (MW) of about 100,000 daltons or greater, or a substantially water soluble or crystalline polyglycol copolymer having a MW of about 2,000 daltons or greater, and;

a coating (C) that is impermeable to gastrointestinal fluids, the coating (C) comprising a polymer, wherein the coating (C) forms a shell around the solid inner layer (A) and the two outer layers (B1) and (B2), the solid inner layer (A) is positioned between the two outer layers (B1) and (B2) within the coating (C), and the shell formed by the coating comprises a length extending between two open ends with each of the two open ends exposing a surface area of each of the two outer layers (B1) and (B2);

wherein the solid inner layer (A), without the outer layers (B1) and (B2) and the coating (C), is formulated such that it disintegrates within 60 minutes when subjected to the disintegration test according to Ph. Eur.;

wherein the release of the active substance contained in the outer layers (B1) and (B2) follows a zero order release pattern for at least 80% w/w release of the total content of the active substance in the outer layers (B1) and (B2);

wherein the coating (C) appears as a substantially intact empty shell after the composition has been subjected to the dissolution test according to Ph. Eur.

2. The composition according to claim 1, wherein the active substance in the solid inner layer (A) is present in the form of a multiple unit formulation.

3. The composition according to claim 2, wherein the multiple unit formulation is a controlled release multiple unit formulation.

4. The composition according to claim 1, wherein the ratio between the surface area exposed at one of the open ends and the length of the shell is selected from about 0.02 to about 45 mm.

5. The composition according to claim 1, wherein the solid inner layer (A) further comprises a disintegrant.

6. The composition according to claim 1, wherein the effervescent agent is selected from a stable surface-modified sodium bicarbonate powder, citric acid, citric acid monohydrate, dextrates, fumaric acid, potassium bicarbonate, sodium bicarbonate, sodium citrate dehydrate, tartaric acid, or combinations thereof.

7. The composition according to claim 2, wherein the multiple unit formulation comprises a polymer, wherein the polymer in the multiple unit formulation is selected from a substantially water soluble or crystalline polyglycol homopolymer having a MW of about 100,000 daltons or greater, or a substantially water soluble or crystalline polyglycol copolymer having a MW of about 2,000 daltons or greater.

8. The composition according to claim 1, wherein the solid inner layer (A) further comprises a filler.

9. The composition according to claim 1, wherein the solid inner layer (A) further comprises a polymer, wherein the polymer in the solid inner layer (A) is selected from a substantially water soluble or crystalline polyglycol homopolymer having a MW of about 16,000 daltons or fewer, or a substantially water soluble or crystalline polyglycol copolymer having a MW of about 30,000 daltons or fewer.

10. The composition according to claim 9, wherein the polymer in the solid inner layer (A) is a substantially water soluble or crystalline polyglycol homopolymer having a MW of between about 1,000 daltons and about 16,000 daltons.

11. The composition according to claim 9, wherein the polymer in the solid inner layer (A) is a substantially water soluble or crystalline polyglycol copolymer having a MW of about 25,000 daltons or fewer.

12. The composition according to claim 1, wherein the active substance in the solid inner layer (A) is present in a form selected from pellets, beads, flakes, mini-tablets, granules, microspheres, nanoparticles, crystals, and combinations thereof.

13. The composition according to claim 5, wherein the concentration of the disintegrant in the solid inner layer (A) is about 5% w/w to about 80% w/w.

14. The composition according to claim 1, wherein the concentration of the effervescent agent in the solid inner layer (A) is about 5% w/w to about 80% w/w.

15. The composition according to claim 1, wherein the polymer in each of the two outer layers (B1) and (B2) is selected from a polyethylene glycol (PEG), mono- and dimethoxypolyethylene glycols (mPEGs), a copolymer of ethylene oxide and propylene oxide, or a copolymer of PEG and polypropylene glycol (PPG).

16. The composition according to claim 15, wherein the PEG or the PEO has a MW selected from a range of about 100,000 daltons to about 700,000 daltons.

17. The composition according to claim 15, wherein the copolymer of PEG and PPG has a MW selected from a range of about 4,000 daltons to about 15,000 daltons.

18. The composition according to claim 1, wherein the concentration of the polymer in each of the two outer layers (B1) and (B2) is selected from a range of about 5% w/w to about 100% w/w.

19. The composition according to claim 1, wherein at least one of the outer layers (B1) and (B2) further contains a second active substance different from the active substance of the solid inner layer (A).

20. The composition according to claim 19, wherein the release of the second active substance follows a zero order release pattern for at least 80% w/w release of the total content of the second active substance in the at least one of the outer layers (B1) and (B2).

21. The composition according to claim 1, wherein the polymer in the coating (C) is selected from ethylcellulose, cellulose acetate, cellulose propionate, cellulose nitrate, polyamide, polyethylene, polyethylene terephtalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, polytetrafluoroethylene, polylactic acid or polyglycolic acid and copolymers thereof, copolymers including ethylene vinyl acetate, styrene-butadienstyrene, styrene-isoprene-styrene, or combinations thereof.

22. The composition according to claim 1, wherein the coating (C) does not completely crumble or erode before at least one of the outer layers (B1) and (B2) has completely eroded and the solid inner layer (A) is released.

23. The composition according to claim 1, wherein at least one of the outer layers (B1) and (B2) erodes at a substantially constant rate, when exposed to an aqueous medium.

24. The composition according to claim 1, wherein the active substance in the solid inner layer (A) is subject to release after a lag time corresponding to the erosion time of at least one of the outer layers (B1) and (B2).

25. The composition according to claim 1, wherein the polymer in each of the two outer layers (B1) and (B2), and the polymer in the coating (C) are thermoplastic.

26. The composition according to claim 5, wherein the disintegrant is selected from sodium starch glycolate, povidone, sodium alginate, alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, chitosan, croscarmellose sodium, crospovidone, hydroxypropyl starch, hydroxypropyl cellulose low-substituted, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, pregelatinized starch, docusae sodium, guar gum, polacrilin potassium, or combinations thereof.

27. The composition according to claim 1, wherein the combined amount of the active substance and the effervescent agent in the solid inner layer (A) is about 70% w/w or greater.