Methods of Reducing Alcohol-Induced Dose Dumping for Opioid Sustained Release Oral Dosage Forms

• US 20090221621A1
• Filed: 10/31/2006
• Published: 09/03/2009
• Est. Priority Date: 10/31/2005
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Sathyan, Gayatri, Davar, Nipun
• Application Number:
  US12/084,396
• Publication Number:
  US 20090221621A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Disclosed are methods of sustained release administration of opioids, including but not limited to hydromorphone and oxycodone, that exhibit improved properties with respect to co-ingestion with aqueous alcohol.

Claims

1. A method of use of a hydromorphone sustained release dosage form comprising providing the dosage form to a patient population which includes individuals that can be expected to at least occasionally co-ingest the dosage form with an alcoholic beverage, wherein the dosage form when tested in vivo on a population of test subjects has:

(a) a mean arithmetic ratio of;

(i) a single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 1.9;

1; and

/or

(b) a ratio of;

(i) an individual test subject'"'"'s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) the same test subject'"'"'s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 5;

1; and

/or

(c) a ratio of;

(i) a median single dose, time to maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a median single dose, time to maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is in the range of from about 0.5 to about 1.0.

3. The method of claim 1 or 2 wherein the dosage form satisfies all of in vivo tests (a), (b), and (c).

4. The method of claim 1 or 2 wherein the dosage form satisfies at least one of in vivo tests (a), (b), and (c) when the alcohol concentration in the aqueous solution of (a)(i), (b)(i), and/or (c)(i) is about 40% volume/volume.

5. The method of claim 4 wherein the dosage form satisfies all of in vivo tests (a), (b), and (c).

9. The method of claim 1, 2, 6, or 7 wherein the dosage form comprises an immediate release component for immediate release of hydromorphone.

19. The method of claim 1, 2, 6, 7, 10, 11, 15, or 16 wherein the dosage form comprises an opioid antagonist.

20. The method of claim 1, 2, 6, 7, 10, 11, 15, or 16 wherein the dosage form is a once-per-day dosage form.

21. The method of claim 1, 2, 6, 7, 10, 11, 15, or 16 wherein the dosage form is a twice-per-day dosage form.

22. The method of claim 1, 2, 6, 7, 10, 11, 15, or 16 wherein the dosage form is an osmotic sustained release dosage form.

23. The method of claim 1, 2, 6, 7, 10, 11, 15, or 16 wherein the dosage form is provided to patients without special label warnings to physicians and/or patients regarding potential lethal effects from taking the dosage form with alcohol.

24. The method of claim 1, 2, 10, or 11 wherein the ratios of (a), (b), and (c) are determined under fasted conditions.

2. A method for reducing adverse effects associated with alcohol-induced dose dumping in patients who are orally receiving sustained release hydromorphone comprising:

providing a sustained release dosage form which comprises hydromorphone; and

administering the dosage form to a patient;

wherein the dosage form when tested in vivo on a population of test subjects has;

(a) a mean arithmetic ratio of;

(i) a single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 1.9;

1; and

/or

(b) a ratio of;

(i) an individual test subject'"'"'s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) the same test subject'"'"'s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 5;

1; and

/or

(c) a ratio of;

(i) a median single dose, time to maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a median single dose, time to maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is in the range of from about 0.5 to about 1.0.

6. A method of use of a hydromorphone sustained release dosage form which comprises a dose of hydromorphone and a sustained release dosing structure, said method comprising providing the dosage form to a patient population which includes individuals that can be expected to at least occasionally co-ingest the dosage form with an alcoholic beverage, wherein when tested using an in vitro test method that employs a test medium that comprises aqueous alcohol at a concentration of about 20% volume/volume, the dosage form releases less than or equal to about 50 weight percent of the dose of hydromorphone in a period of about 2 hours following initiation of the in vitro test method.

8. The method of claim 6 or 7 wherein the dosage form satisfies the in vitro test when the alcohol concentration in the test medium is about 40% volume/volume.

7. A method for reducing adverse effects associated with alcohol-induced dose dumping in patients who are orally receiving sustained release hydromorphone comprising:

providing a sustained release dosage form which comprises a dose of hydromorphone; and

administering the dosage form to a patient;

wherein when tested using an in vitro test method that employs a test medium that comprises aqueous alcohol at a concentration of about 20% volume/volume, the dosage form releases less than or equal to about 50 weight percent of the dose of hydromorphone in a period of about 2 hours following initiation of the in vitro test method.

10. A method of use of an opioid sustained release dosage form comprising providing the dosage form to a patient population which includes individuals that can be expected to at least occasionally co-ingest the dosage form with an alcoholic beverage, wherein the dosage form when tested in vivo on a population of test subjects has:

(a) a mean arithmetic ratio of;

(i) a single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 1.9;

1; and

/or

(b) a ratio of;

(i) an individual test subject'"'"'s single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) the same test subject'"'"'s single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 5;

1; and

/or

(c) a ratio of;

(i) a median single dose, time to maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a median single dose, time to maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is in the range of from about 0.5 to about 1.0.

12. The method of claim 10 or 11 wherein the dosage form satisfies all of in vivo tests (a), (b), and (c).

13. The method of claim 10 or 11 wherein the dosage form satisfies at least one of in vivo tests (a), (b), and (c) when the alcohol concentration in the aqueous solution of (a)(i), (b)(i), and/or (c)(i) is about 40% volume/volume.

14. The method of claim 13 wherein the dosage form satisfies all of in vivo tests (a), (b), and (c).

18. The method of claim 10, 11, 15, or 16 wherein the dosage form comprises an immediate release component for immediate release of the opioid.

11. A method for reducing adverse effects associated with alcohol-induced dose dumping in patients who are orally receiving a sustained release opioid comprising:

providing a sustained release dosage form which comprises an opioid; and

administering the dosage form to a patient;

wherein the dosage form when tested in vivo on a population of test subjects has;

(a) a mean arithmetic ratio of;

(i) a single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 1.9;

1; and

/or

(b) a ratio of;

(i) an individual test subject'"'"'s single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) the same test subject'"'"'s single dose maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is equal to or less than about 5;

1; and

/or

(c) a ratio of;

(i) a median single dose, time to maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume

to

(ii) a median single dose, time to maximum plasma opioid concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol

that is in the range of from about 0.5 to about 1.0.

15. A method of use of an opioid sustained release dosage form which comprises a dose of an opioid and a sustained release dosing structure, said method comprising providing the dosage form to a patient population which includes individuals that can be expected to at least occasionally co-ingest the dosage form with an alcoholic beverage, wherein when tested using an in vitro test method that employs a test medium that comprises aqueous alcohol at a concentration of about 20% volume/volume, the dosage form releases less than or equal to about 50 weight percent of the dose of the opioid in a period of about 2 hours following initiation of the in vitro test method.

17. The method of claim 15 or 16 wherein the dosage form satisfies the in vitro test when the alcohol concentration in the test medium is about 40% volume/volume.

16. A method for reducing adverse effects associated with alcohol-induced dose dumping in patients who are orally receiving a sustained release opioid comprising:

providing a sustained release dosage form which comprises a dose of an opioid; and

administering the dosage form to a patient;

wherein when tested using an in vitro test method that employs a test medium that comprises aqueous alcohol at a concentration of about 20% volume/volume, the dosage form releases less than or equal to about 50 weight percent of the dose of the opioid in a period of about 2 hours following initiation of the in vitro test method.