Dosage forms for administering combinations of drugs

• US 20080175897A1
• Filed: 12/06/2007
• Published: 07/24/2008
• Est. Priority Date: 03/06/2006
• Status: Active Grant

• Current Assignee: Pozen Incorporated (Aralez Pharmaceuticals Inc.)
• Original Assignee: Pozen Incorporated (Aralez Pharmaceuticals Inc.)
• Inventors: Plachetka, John, Gilbert, Donna
• Granted Patent: US 9,265,732 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/542 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• 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 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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

Abstract

The present invention is directed to dosage forms that can be used in therapeutic methods involving the oral co-administration of a combination of at least two drugs, one of which impairs gastrointestinal absorption and one of which does not. The dosage forms are designed so that the drug impairing absorption is not released into the gastrointestinal tract of a patient until after the drugs that do not impair absorption have been released and substantially absorbed. The invention may be used in treatment of migraine using a combination of triptans and NSAIDs or in the treatment of pain using a combination of NSAIDs and opioid analgesics.

Claims

1. A pharmaceutical composition in unit dosage form for oral administration, comprising:

a) a therapeutically effective amount of a first drug, wherein said first drug impairs the absorption of medication from the gastrointestinal tract of patients and essentially all of said first drug is either surrounded by a membrane that delays its release after ingestion or is formulated with components that delay its release after ingestion; and

b) a therapeutically effective amount of a second drug, wherein said second drug does not impair the absorption of medication from the gastrointestinal tract of patients;

and wherein, upon ingestion of said unit dosage form by a patient,

i) said second drug is released from said unit dosage form into the gastrointestinal tract of said patient before said first drug; and

ii) said first drug is not released from said unit dosage form for a period of time equal to at least one-fourth Tmax2, wherein Tmax2 is the time needed for said second drug to reach peak plasma concentration when said second drug is administered to a patient as the sole active agent.

2. The pharmaceutical composition of claim 1, wherein said unit dosage form is a multilayer tablet.

3. The pharmaceutical composition of claim 2, wherein the release of said first drug is delayed for a minimum of 15 minutes after ingestion and said second drug is released from said dosage from within 5 minutes after ingestion.

4. The pharmaceutical composition of claim 3, wherein:

a) essentially all of said first drug is in a single core layer; and

b) essentially all of said second drug is located in one or more layers outside of said core layer that include a disintegrant or a compound that causes effervescence.

5. The pharmaceutical composition of claim 1, wherein said dosage form is a capsule.

6. The pharmaceutical composition of claim 5, wherein the release of said first drug is delayed for a minimum of 15 minutes after ingestion and said second drug is released from said dosage from within 5 minutes after ingestion.

7. The pharmaceutical composition of claim 6, wherein;

a) said capsule comprises multiple particles of said first drug; and

b) essentially all of said second drug is located outside of said particles together with a disintegrant or a compound that causes effervescence.

8. The pharmaceutical composition of claim 1, wherein said first drug is a triptan.

9. The pharmaceutical composition of claim 8, wherein said triptan is selected from the group consisting of:

sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan and naratriptan.

10. The pharmaceutical composition of claim 9, wherein said triptan is sumatriptan present in said unit dosage form in an amount of between 25 and 100 mg and said second drug is either acetaminophen or an NSAID selected from the group consisting of:

ibuprofen;

flurbiprofen;

ketoprofen;

oxaprozin;

etodolac;

ketorolac;

nabumetone;

mefenamic acid;

indomethacin;

piroxicam;

celecoxib; and

rofecoxib.

11. The pharmaceutical composition of claim 10, wherein said second drug is naproxen, present in said unit dosage form in an amount of between 200 and 600 mg.

12. The pharmaceutical composition of claim 1, wherein said first drug is a opioid analgesic.

13. The pharmaceutical composition of claim 12, wherein said opioid analgesic is selected from the group consisting of:

alfentanil;

buprenorphine;

butorphanol;

codeine;

dezocine;

dihydrocodeine;

fentanyl;

hydrocodone;

hydromorphone;

levorphanol;

meperidine;

methadone;

morphine;

nalbuphine;

oxycodone;

oxymorphone;

pentazocine;

propiram;

propoxyphene;

sufentanil; and

tramadol.

14. The pharmaceutical composition of claim 13, wherein said second drug is either acetaminophen or an NSAID selected from the group consisting of:

naproxen;

ibuprofen;

flurbiprofen;

ketoprofen;

oxaprozin;

etodolac;

ketorolac;

nabumetone;

mefenamic acid;

indomethacin;

piroxicam;

celecoxib; and

rofecoxib.

23. A method of treating a patient for pain comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 1.

15. A pharmaceutical composition in unit dosage form for oral administration, comprising:

a) a first drug, wherein said first drug is a therapeutically effective amount of a triptan or an opioid analgesic; and

b) a therapeutically effective amount of a non-narcotic analgesic selected from the group consisting of;

acetaminophen and an NSAID;

and wherein,

i) said non-narcotic analgesic is released from said unit dosage form into the gastrointestinal tract of said patient within 5 minutes after said dosage form is ingested; and

ii) said triptan or opioid analgesic is either surrounded by a membrane that does not release it from said unit dosage form for at least 20 minutes after said dosage form is ingested or said triptan is formulated with components that delay its release for at least 20 minutes after said dosage form is ingested.

16. The pharmaceutical composition of claim 15, wherein said first drug is a triptan selected from the group consisting of:

sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, zolmitriptan and naratriptan.

17. The pharmaceutical composition of claim 16, wherein said non-narcotic analgesic is an NSAID selected from the group consisting of:

naproxen;

ibuprofen;

flurbiprofen;

ketoprofen;

oxaprozin;

etodolac;

ketorolac;

nabumetone;

mefenamic acid;

indomethacin;

piroxicam;

celecoxib; and

rofecoxib.

18. The pharmaceutical composition of claim 17, wherein said triptan is sumatriptan present in said unit dosage form in an amount of between 25 and 100 mg and said non-narcotic analgesic is naproxen, present in said unit dosage form in an amount of between 200 and 600 mg.

19. The pharmaceutical composition of claim 15, wherein said first drug is an opioid analgesic is selected from the group consisting of:

alfentanil;

buprenorphine;

butorphanol;

codeine;

dezocine;

dihydrocodeine;

fentanyl;

hydrocodone;

hydromorphone;

levorphanol;

meperidine;

methadone;

morphine;

nalbuphine;

oxycodone;

oxymorphone;

pentazocine;

propiram;

propoxyphene;

sufentanil; and

tramadol.

20. The pharmaceutical composition of claim 19, wherein said non-narcotic analgesic is an NSAID selected from the group consisting of:

naproxen;

ibuprofen;

flurbiprofen;

ketoprofen;

oxaprozin;

etodolac;

ketorolac;

nabumetone;

mefenamic acid;

indomethacin;

piroxicam;

celecoxib; and

rofecoxib.

21. The pharmaceutical composition of claim 20, wherein said NSAID is naproxen, present in said unit dosage form in an amount of between 200 and 600 mg.

22. The pharmaceutical composition of claim 21, wherein said unit dosage form is a tablet in which:

a) said naproxen and said opioid analgesic are separated from one another by a membrane

b) said naproxen is not in a layer that completely surrounds a layer or core containing said opioid analgesic; and

c) said naproxen is mixed with a disintegrant or a compound that causes effervescence.