Pharmaceutical compositions

• US 9,226,901 B2
• Filed: 09/25/2013
• Issued: 01/05/2016
• Est. Priority Date: 01/09/2008
• Status: Active Grant

• Current Assignee: LOCL Pharma, Inc. (Charleston Laboratories, Inc.)
• Original Assignee: LOCL Pharma, Inc. (Charleston Laboratories, Inc.)
• Inventors: Ameling, John, Schachtel, Bernard, Takigiku, Ray, Bosse, Paul
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US14/036,946
• Publication Number:
  US 20140030322A1
• Time in Patent Office: 832 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/515 Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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 9/4808 : 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 9/5084 : 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 1/08 : for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• 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 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Methods and compositions are provided which comprise effective amounts of analgesic to treat a subject, including reducing or eliminating an adverse effect associated with the analgesic.

Claims

1. A tablet comprising two layers and containing a single analgesic for the treatment of acute pain in a subject in need thereof, comprising:

a) a first layer formulated for controlled-release comprising, an opioid analgesic effective to treat acute pain, wherein the opioid analgesic is oxycodone or a pharmaceutically acceptable salt thereof and is present in an amount of about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg; and

b) a second layer formulated for immediate-release comprising, an antiemetic effective to reduce nausea or vomiting associated with the opioid analgesic, wherein the antiemetic is promethazine or a pharmaceutically acceptable salt thereof and is present in an amount of from about 12.5 mg to about 50 mg,

wherein the tablet comprises one or more excipients, wherein the one or more excipients comprise;

carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl methylcellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, glyceryl monostearate 40-50, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, triethyl citrate, or yellow ferric oxide, and

wherein;

i) about 70% to about 80% of the promethazine or the pharmaceutically acceptable salt thereof is released in about 5 minutes to about 10 minutes following contact of the tablet with a dissolution fluid as measured by USP Apparatus 2 (Paddle),

ii) about 30% to about 40% of the opioid analgesic or the pharmaceutically acceptable salt thereof is released within about 5 minutes to about 10 minutes following contact of the tablet with a dissolution fluid as measured by USP Apparatus 2 (Paddle), and

iii) the tablet provides an effective amount of the promethazine or the pharmaceutically acceptable salt thereof to reduce nausea or vomiting associated with the opioid analgesic for about 4 to about 6 hours following administration to the subject, and an effective amount of the oxycodone or the pharmaceutically acceptable salt thereof to treat acute pain for about 4 to about 6 hours following administration to the subject.

2. The tablet of claim 1, wherein the tablet further comprises a stimulant.

3. The tablet of claim 2, wherein the stimulant is aminophylline, caffeine, oxtriphylline, theophylline, amphetamine, benzphetamine, dextroamphetamine, diethylpropion, mazindol, methamphetamine, methylphenidate, dexmethylphenidate, pemoline, sibutramine, modafinil, atomoxetine, phendimetrizine, phentermine, adrafinil, phenylpropanolamine, pseudoephedrine, synephrine, amphetaminil, furfenorex, or a pharmaceutically acceptable salt of each of the forgoing.

4. The tablet of claim 1, wherein the tablet further comprises an opioid antagonist or an abuse deterrent agent.

5. The tablet of claim 4, wherein the opioid antagonist agent or abuse deterrent agent comprises nalmefene, naloxone, naltrexone, cyclazacine, levallorphan, niacin, or a pharmaceutically acceptable salt of each of the forgoing.

6. The tablet of claim 4, wherein the tablet comprises an abuse deterrent agent that is a gel-forming agent.

7. The tablet of claim 6, wherein the gel-forming agent comprises a pharmaceutically acceptable polymer.

8. The tablet of claim 7, wherein the pharmaceutically acceptable polymer is selected from the group consisting of polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, carbomers, and combinations thereof.

9. The tablet of claim 7, wherein the pharmaceutically acceptable polymer is capable of forming a viscous gel upon contact with a solvent, wherein the viscous gel resists crushing and snorting.

10. The tablet of claim 1, wherein the tablet is an enteric-coated tablet.

11. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 5 mg.

12. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 7.5 mg.

13. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 10 mg.

14. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 15 mg.

15. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 20 mg.

16. The tablet of claim 1, wherein the opioid analgesic is oxycodone or the pharmaceutically acceptable salt thereof and is present in an amount of about 30 mg.

17. The tablet of claim 1, wherein about 100% of the promethazine or the pharmaceutically acceptable salt thereof is released in about 40 minutes following contact of the tablet with the dissolution fluid as measured by USP Apparatus 2 (Paddle).

18. The tablet of claim 1, wherein about 90% of the opioid analgesic or the pharmaceutically acceptable salt thereof is released in about 60 minutes following contact of the tablet with the dissolution fluid as measured by USP Apparatus 2 (Paddle).

19. The tablet of claim 1, wherein the tablet has a hardness of about 5 to about 15 kiloponds.

20. The tablet of claim 1, wherein the tablet has a hardness of about 15 kiloponds.

21. The tablet of claim 1, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in the amount of about 50 mg.

22. The tablet of claim 1, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in the amount of about 12.5 mg.

23. The tablet of claim 1, wherein the promethazine or the pharmaceutically acceptable salt thereof is present in the amount of about 25 mg.

24. A method of treating pain in a subject comprising administering to the subject the solid two layer composition tablet of claim 1.

25. A method of alleviating an adverse effect associated with administration of an opioid analgesic to a subject, the method comprising administering to the subject the tablet of claim 1.

26. The method of claim 25, wherein the adverse effect is nausea or vomiting.

27. A method of reducing or preventing nausea associated with administration of an opioid analgesic to a subject, the method comprising administering to the subject the tablet of claim 1.

28. A method of reducing or preventing vomiting associated with administration of an opioid analgesic to a subject, the method comprising administering to the subject the tablet of claim 1.

29. The tablet of claim 1, wherein the tablet comprises the pharmaceutically acceptable salt of the promethazine, wherein the pharmaceutically acceptable salt of the promethazine is promethazine hydrochloride.

30. The tablet of claim 1, wherein the promethazine hydrochloride is present in an amount of about 12.5 mg.