NOVEL GASTRO-RETENTIVE DOSAGE FORMS

• US 20120015031A1
• Filed: 07/13/2011
• Published: 01/19/2012
• Est. Priority Date: 07/14/2010
• Status: Abandoned Application

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: SESHA, Ramesh
• Application Number:
  US13/181,605
• Publication Number:
  US 20120015031A1
• Time in Patent Office: Days
• US Class Current: 424/472
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• 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 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• 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 9/284 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• 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 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

A gastro-retentive pharmaceutical dosage form comprising a therapeutically effective amount of at least one opioid, at least one form of acetaminophen, optionally an opioid antagonist and at least one pharmaceutically acceptable excipient, which dosage form is retained in the stomach for at least four hours and is suitable for once daily or twice daily administration. Also provided is a method of treating pain by administering the dosage form to a patient in need thereof. The acetaminophen is either in slow release form or in immediate release form or as combination of both.

Claims

1. A pharmaceutical dosage form comprising a therapeutically effective amount of at least one opioid, acetaminophen and at least one pharmaceutically acceptable excipient wherein the said dosage form is retained in the stomach for at least four hours.

2. A pharmaceutical dosage form according to claim 1, comprising a therapeutically effective amount of at least one opioid, acetaminophen, and at least one pharmaceutically acceptable excipient wherein the said dosage form is retained in the stomach for at least four hours, wherein between on an average 10% and 30% per hour of opioid initially present at 0 hours, is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

3. A pharmaceutical dosage form according to claim 1, comprising:

a) a core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen, and a second release layer comprising acetaminophen without an opioid; and

b) a coat comprising the said core, wherein the dosage form is retained in the stomach for at least four hours and is suitable for once daily or twice daily administration.

4. A pharmaceutical a dosage form according to claim 1, comprising a) a compressed core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen dispersed in a slow-release matrix;

and a second release layer comprising acetaminophen with or without an opioid dispersed in a second release matrix;

b) at least one permeable membrane pouch comprising the said core;

c) an encapsulating coat and the said dosage form is retained in the stomach for at least four hours and is suitable for once daily or twice daily administration.

5. A pharmaceutical dosage form according to claim 1, wherein the acetaminophen is in immediate release form.

6. A pharmaceutical dosage form according to claim 1, wherein the acetaminophen is in slow release form.

7. A pharmaceutical dosage form according to claim 1, comprising:

a) a core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen, and a second release layer comprising acetaminophen without an opioid; and

b) a coat comprising the said core, wherein between on an average 10% and 25% per hour of opioid initially present at 0 hours, is released between 0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm.

8. A pharmaceutical dosage form according to claim 1, comprising:

a) a core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen, and a second release layer comprising acetaminophen without an opioid; and

b) a coat comprising the said core, wherein when tested in vitro using a USP Type I apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm,

Between 10% and 25% of opioid released between 0 and about 2 hours of measurement,

Between about 30% and 60% of opioid released between 2 and about 7 hours of the measurement,

Between about 50% and 75% of opioid released between 7 and about 12 hours of measurement, and

Between about 75% and 100% of opioid released after about 20 hours of measurement.

9. A pharmaceutical dosage form according to claim 1, wherein at least one layer comprises a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

10. A pharmaceutical dosage form according to claim 1, wherein at least one layer comprises a physical mixture of polyvinyl acetate, polyvinylpyrrolidone, a binder, opioid;

and wherein;

the ratio of the first release layer/second release layer (w/w) is between from about 1.0 and to about 0.1.

11. A pharmaceutical dosage form according to claim 1, adapted to be used for a period of every four hours, or every six hours, every eight hours, every twelve hours or every twenty-four hours.

12. A pharmaceutical dosage form according to claim 1, wherein either the first release layer or the second release layer or both prepared by compression.

13. A pharmaceutical dosage form according to claim 1, wherein the number of release layers is at least two and wherein the order of layers is immaterial.

14. A pharmaceutical dosage form according to claim 1, wherein the dosage form comprises from about 1 to about 800 mg of opioid, and from about 1 mg to about 1000 mg of acetaminophen.

15. A pharmaceutical dosage form according to claim 1, which, when administered to a patient in need thereof, provides a mean time to maximum plasma concentration (T_max) of opioid ranging from about four to about sixteen hours and the said dosage form is suitable once daily or twice daily administration.

16. A pharmaceutical dosage form according to claim 1, wherein the said opioid is selected from the group consisting of alfentanil, axomadol, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, faxeladol, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tapentadol, and tramadol and the dosage form is retained in stomach for at least four hours and is suitable for once daily or twice daily administration.

17. A pharmaceutical dosage form according to claim 1, comprising an Opioid, acetaminophen and an opioid antagonist and at least one pharmaceutically acceptable excipient and adapted for treating pain and pain related disorders.

18. A process of preparing a pharmaceutical dosage form according to claim 1, comprising a) a core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen, and a second release layer comprising acetaminophen without an opioid;

and b) a coat comprising the said core, said process comprising compressing the second release layer over a separately prepared said first release layer.

19. A method of treating a disorder in a patient in need thereof, said method comprising administering an effective amount therefor of a pharmaceutical dosage form according to claim 1.

20. A method of treating a disorder according to claim 19, wherein the dosage form comprises:

a) a core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen, and a second release layer comprising acetaminophen without an opioid; and

b) a coat comprising the said core, wherein the dosage form is retained in the stomach for at least four hours and is suitable for once daily or twice daily administration.

21. A method of treating a disorder according to claim 19, wherein the dosage form comprises:

a) a compressed core comprising at least two release layers wherein a first release layer comprising at least one opioid with or without acetaminophen dispersed in a slow-release matrix; and

a second release layer comprising acetaminophen with or without an opioid dispersed in a second release matrix;

b) at least one permeable membrane pouch comprising the said core;

c) an encapsulating coat and the said dosage form is retained in the stomach for at least four hours and is suitable for once daily or twice daily administration.