Controlled release pharmaceutical compositions for prolonged effect

• US 9,642,809 B2
• Filed: 07/29/2014
• Issued: 05/09/2017
• 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): Stevens, Mark V
• Application Number:
  US14/446,234
• Publication Number:
  US 20150024048A1
• Time in Patent Office: 1,015 Days
• 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 for controlled release of an active substance, comprising:

a solid inner layer (A) comprising the active substance and a disintegrant, the solid inner layer (A) being positioned between two outer layers (B1) and (B2),

each outer layer (B1) and (B2) comprising one or more substantially water soluble or crystalline polyethylene oxides (PEOs) having a molecular weight (MW) of about 100,000 daltons or greater, wherein the average molecular weight of the PEO present in each outer layer is about 100,000 daltons or greater, wherein each outer layer is free of the disintegrant, and wherein at least one of the outer layers (B1) and (B2) comprises the active substance, and

a coating (C) forming a shell covering the solid inner layer (A) and partially covering outer layers (B1) and (B2) with two openings exposing a surface of each outer layer (B1) and (B2), wherein the coating (C) comprises a polymer and is substantially insoluble in and impermeable to gastrointestinal fluids;

wherein the solid inner layer (A), without the outer layers (B1) and (B2) and the coating (C), disintegrates within 60 minutes when subjected to a disintegrating test according to the Eur. Ph; and

wherein the release of the active substance contained in at least one of 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).

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

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

4. The pharmaceutical composition of claim 2, wherein the active substance of the solid inner layer (A) is present in a form selected from pellets, beads, flakes, mini-tablets, granules, microspheres, nanoparticles, crystals, and combinations thereof.

5. The pharmaceutical composition of claim 2, wherein the multiple unit formulation of solid inner layer (A) comprises a polymer selected from the group consisting of (i) substantially water soluble or crystalline polyglycol homopolymers having a MW of about 100,000 daltons or greater and (ii) substantially water soluble or crystalline polyglycol copolymers having a MW of about 2,000 daltons or greater.

6. The pharmaceutical composition of claim 1, wherein solid inner layer (A) further comprises a filler.

7. The pharmaceutical composition of claim 1, wherein solid inner layer (A) further comprises a polymer selected from the group consisting of (i) substantially water soluble or crystalline polyglycol homopolymers having a MW of about 16,000 daltons or less and (ii) substantially water soluble or crystalline polyglycol copolymers having a MW of about 30,000 daltons or less.

8. The pharmaceutical composition of claim 7, wherein the polymer of 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.

9. The pharmaceutical composition of claim 7, wherein the polymer of the solid inner layer (A) is a substantially water soluble or crystalline polyglycol copolymer having a MW of about 25,000 daltons or less.

10. The pharmaceutical composition of claim 1, wherein the concentration of the disintegrant in the solid inner layer (A) is from about 5% w/w to about 80% w/w.

11. The pharmaceutical composition of claim 1, wherein each of the two outer layers (B1) and (B2) further comprises one or more block copolymers of ethylene oxide and propylene oxide.

12. The pharmaceutical composition of claim 1, wherein the average molecular weight of the PEO present in each outer layer is from about 100,000 daltons to about 700,000 daltons.

13. The pharmaceutical composition of claim 11, wherein the block copolymers of ethylene oxide and propylene oxide have a MW of from about 4,000 daltons to about 15,000 daltons.

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

15. The pharmaceutical composition of claim 1, wherein both of outer layers (B1) and (B2) comprise the active substance.

16. The pharmaceutical composition of claim 1, wherein at least one of outer layers (B1) and (B2) comprises a second active substance different from the active substance in the solid inner layer (A).

17. The pharmaceutical composition of claim 16, wherein both of outer layers (B1) and (B2) comprise the second active substance different from the active substance of solid inner layer (A).

18. The pharmaceutical composition of claim 16, wherein the composition exhibits zero order release of the second active substance present in outer layers layer(s) (B1) and/or (B2).

19. The pharmaceutical composition of claim 16, wherein the composition exhibits zero order release of at least 80% w/w of the second active substance present in outer layer(s) (B1) and/or (B2).

20. The pharmaceutical formulation of claim 1, wherein the polymer of the coating (C) is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate, cellulose nitrate, polyamide, polyethylene, polyethylene terephthalate, 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 and styrene-isoprene-styrene, and combinations thereof.

21. The pharmaceutical formulation of claim 20, wherein the polymer of the coating (C) is polylactic acid.

22. The pharmaceutical formulation of claim 1, wherein, when the formulation is exposed to an aqueous medium, 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 exposed.

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

24. The pharmaceutical formulation of claim 1, wherein, when the formulation is exposed to an aqueous medium, release of the active substance from the solid inner layer (A) is subject a lag time corresponding to the erosion time of at least one of the outer layers (B1) and (B2).

25. The pharmaceutical formulation of claim 1, wherein the coating (C) is a substantially intact empty shell after the composition has been subjected to dissolution testing according to USP 30, NF 25 (711), apparatus 2 (paddle method), in dissolution medium consisting of 0.1 M HCl or phosphate buffer (pH 6.8, pH 6.8 and 40% ethanol, or pH 7.2) in a dissolution medium volume of 900 ml or 1000 ml at a paddle speed of 50rpm.

26. The pharmaceutical formulation of claim 1, wherein the polymer of each of the two outer layers (B1) and (B2), and the polymer of the coating (C) are thermoplastic.

27. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from the group consisting of 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, and combinations thereof.