Morphine controlled release system

• US 9,375,428 B2
• Filed: 09/25/2014
• Issued: 06/28/2016
• Est. Priority Date: 03/26/2003
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Fischer, Gina, Bar-Shalom, Daniel, Slot, Lillian, Andersen, Christine
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US14/496,561
• Publication Number:
  US 20150079150A1
• Time in Patent Office: 642 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Described are controlled release oral pharmaceutical composition comprising an erodible matrix composition comprising a polyethylene oxide, a therapeutically effective amount of an opioid or a pharmaceutically acceptable salt, complex, solvate or anhydrate thereof, or a mixture thereof and, optionally, one or more pharmaceutically acceptable excipients, and a coating on the matrix composition, wherein the coating has at least one opening exposing a surface of an end portion of the matrix composition, thereby allowing controlled release of the opioid by erosion of the matrix surface, wherein the composition exhibits zero order release of at least 80% of the opioid contained in the composition. The matrix may have a cylindrical shape having a long axis and a conus-shaped end portion having a largest diameter and a smallest diameter, such that the surface area exposed increases during erosion of the conus-shaped end portion.

Claims

1. A controlled release oral pharmaceutical composition, comprising

(i) an erodible matrix composition having a cylindrical shape having a long axis and a conus-shaped end portion having a largest diameter and a smallest diameter, wherein the conus-shaped end portion extends across from about 5% to about 50% of the long axis of the cylindrical shape and the ratio of the largest diameter to the smallest diameter of the conus-shaped end portion is from about 2.5 to 1 to about 1.2 to 1, wherein the matrix composition comprises:

(a) a first polyethylene oxide having a molecular weight selected from the group consisting of about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons and about 400,000 daltons,

(b) a therapeutically effective amount of an opioid or a pharmaceutically acceptable salt, complex, solvate or anhydrate thereof, or a mixture thereof and, optionally,

(c) one or more pharmaceutically acceptable excipients, and

(ii) a coating on the matrix composition, comprising

(a) a material selected from the group consisting of cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylenem polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS), and

(b) a plasticizer,

wherein the coating has at least one opening exposing a surface of the conus-shaped end portion of the matrix composition, thereby allowing controlled release of said opioid by erosion of said matrix surface, wherein the surface area exposed increases during erosion of the conus-shaped end portion,

wherein the coating and the matrix composition are formed by injection molding,

wherein the composition exhibits zero order release of at least 80% of the opioid contained in the composition, and

wherein about 75% w/w of the opioid is released from the composition within 4-10 hours when subject to a dissolution test in accordance with USP 24, NF 19, (711), Dissolution, employing Apparatus 2 equipped with a paddle using 1000 mL of 0.1 N hydrochloric acid dissolution medium and a paddle rotation of 120 rpm for the first 120 minutes, and a buffer solution having a pH of 6.8 and a paddle rotation of 50 rpm thereafter.

2. The pharmaceutical composition of claim 1, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, morphine 6-glucuronide, morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof, and mixtures thereof.

3. The pharmaceutical composition according to claim 1, wherein the opioid is selected from the group consisting of morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, dihydromorphine, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof, and mixtures thereof.

4. The pharmaceutical composition according to claim 1, wherein the opioid is selected from the group consisting of hydrocodone, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

5. The pharmaceutical composition according to claim 1, wherein the opioid is selected from the group consisting of oxycodone, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

6. The pharmaceutical composition of claim 1, wherein the opioid is selected from the group consisting of morphine, morphine 6-glucuronide, morphine 3-glucuronide, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

7. The pharmaceutical composition of claim 1, wherein the erodible matrix composition does not comprise polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.

8. The pharmaceutical composition of claim 1, wherein the matrix composition comprises from about 10 to about 60% w/w/of the opioid.

9. The pharmaceutical composition of claim 1, wherein the coating is substantially insoluble in and impermeable to aqueous media.

10. The pharmaceutical composition according to claim 1, wherein, in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.

11. The pharmaceutical composition of claim 1, wherein the coating comprises polylactic acid.

12. The pharmaceutical composition of claim 11, wherein the plasticizer of the coating comprises polyethylene oxide.

13. The pharmaceutical composition of claim 1, wherein the ratio of the largest diameter to the smallest diameter of the conus-shaped end portion is about 1.2 to 1.

14. The pharmaceutical composition of claim 1, wherein the cones-shaped end portion extends across about 5% of the long axis of the cylindrical shape of the matrix composition.

15. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprises a block copolymer of ethylene oxide and propylene oxide having a molecular weight of from about 4,000 to about 30,000 daltons.

16. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprises a poloxamer.

17. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprises a second polyethylene oxide having a different molecular weight than the first polyethylene oxide, wherein the average molecular weight of the polyethylene oxides in the matrix composition is selected from the group consisting of about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, and about 300,000 daltons.

18. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprises a second polyethylene oxide having a different molecular weight than the first polyethylene oxide, wherein the molecular weight of the second polyethylene oxide in the matrix composition is selected from the group consisting of about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons, and about 400,000 daltons.

19. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprising an antioxidant selected from the group consisting of TPG, TPGS, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid.

20. The pharmaceutical composition of claim 1, wherein the matrix composition further comprises a cellulose derivative selected from the group consisting of microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

21. The pharmaceutical composition according to claim 1, wherein the matrix composition further comprises a release modifier selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.

22. The pharmaceutical composition of claim 1, wherein the matrix composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of mannitol, xylitol, sorbitol and inositol.

23. The pharmaceutical composition according to claim 1, formulated for once-daily administration.

24. The pharmaceutical composition according to claim 1, formulated for twice-daily administration.