ABUSE DETERRENT COMPOSITIONS AND METHODS OF USE
Orally administrable pharmaceutical compositions, methods of administration, and methods of making the same are provided. The pharmaceutical compositions provide abuse deterrent properties.
1 . An orally administrable pharmaceutical composition comprising a drug, wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the area under the curve (AUC) of a major metabolite of the drug after a period of time is at least 15% of the AUC of the major metabolite achieved after oral administration of an intact form of the pharmaceutical composition after the same period of time.
2 . The orally administrable pharmaceutical composition of claim 1 , wherein the area under the curve (AUC) of a major metabolite of the drug after a period of time is at least 20% of the AUC of the major metabolite achieved after oral administration of an intact form of the pharmaceutical composition after the same period of time.
3 . The orally administrable pharmaceutical composition of claim 1 , wherein the area under the curve (AUC) of a major metabolite of the drug after a period of time is at least 25% of the AUC of the major metabolite achieved after oral administration of an intact form of the pharmaceutical composition after the same period of time.
4 . The orally administrable pharmaceutical composition of claim 1 , wherein the period of time is selected from the group consisting of: 0.5 hour, 1 hour, and 2 hours.
5 . The orally administrable pharmaceutical composition of claim 1 , wherein the AUC 0-t of a major metabolite of the drug after a period of time is at least 40% of the AUC 0-t of the major metabolite achieved after oral administration of an intact form of the pharmaceutical composition after the same period of time.
6 . The orally administrable pharmaceutical composition of claim 1 , wherein the composition comprises a drug, a pH-dependent agent, and a pH-independent agent, wherein about 60% or more of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
7 . The orally administrable pharmaceutical composition of claim 1 , wherein the composition comprises a drug, a pH-dependent agent, and a pH-independent agent, wherein no more than 50% of the total amount of drug in the pharmaceutical composition is released within 1 hour and about 50% or more of the total amount of drug in the pharmaceutical composition is released after 8 hours under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
8 . The orally administrable pharmaceutical composition of claim 1 , wherein the drug is selected from the group consisting of: central nervous stimulants, opioids, barbiturates, benzodiazepines, and sedatives.
9 . The orally administrable pharmaceutical composition of claim 1 , wherein the drug is selected from the group consisting of alfentanil, 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, 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, and tramadol.
10 . The orally administrable pharmaceutical composition of claim 1 , wherein the drug is morphine.
11 . An orally administrable pharmaceutical composition comprising 60 mg of morphine or a salt thereof, wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the area under the curve (AUC) of morphine-6-glucuronide (M6G) after a period of time is at least 100 ng·h/mL.
12 . The orally administrable pharmaceutical composition of claim 11 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC 0-t of morphine-6-glucuronide (M6G) is at least 100 ng·h/mL.
13 . The orally administrable pharmaceutical composition of claim 11 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC 0-t of morphine-6-glucuronide (M6G) is about 150 to about 750 ng·h/mL.
14 . The orally administrable pharmaceutical composition of claim 11 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC 0-t of morphine-6-glucuronide (M6G) is about 200 to about 500 ng·h/mL.
15 . The orally administrable pharmaceutical composition of claim 11 , wherein the composition comprises morphine or a salt thereof, a pH-dependent agent, and a pH-independent agent, wherein about 60% or more of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
16 . The orally administrable composition of claim 11 , wherein the composition comprises morphine or a salt thereof, a pH-dependent agent, and a pH-independent agent, wherein no more than 50% of the total amount of drug in the pharmaceutical composition is released within 1 hour and about 50% or more of the total amount of drug in the pharmaceutical composition is released after 8 hours under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
17 . An orally administrable pharmaceutical composition comprising 60 mg of morphine or a salt thereof, wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the area under the curve (AUC) of morphine-6-glucuronide (M6G) after a period of time is at least 0.1 ng·h/mL, wherein the period of time is selected from the group consisting of 0.5 hour, 1 hour, and 2 hours.
18 . The orally administrable pharmaceutical composition of claim 17 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC of morphine-6-glucuronide (M6G) at 0.5 hour is about 0.2 to about 750 ng·h/mL.
19 . The orally administrable pharmaceutical composition of claim 17 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC of morphine-6-glucuronide (M6G) at 1 hour is about 1 to about 15 ng·h/mL.
20 . The orally administrable pharmaceutical composition of claim 17 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC of morphine-6-glucuronide (M6G) at 2 hour is about 10 to about 75 ng·h/mL.
21 . The orally administrable pharmaceutical composition of claim 17 , wherein the composition comprises a drug, a pH-dependent agent, and a pH-independent agent, wherein about 60% or more of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
22 . The orally administrable composition of claim 17 , wherein the composition comprises a drug, a pH-dependent agent, and a pH-independent agent, wherein no more than 50% of the total amount of drug in the pharmaceutical composition is released within 1 hour and about 50% or more of the total amount of drug in the pharmaceutical composition is released after 8 hours under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of drug in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
23 . An orally administrable pharmaceutical composition comprising morphine or a salt thereof, wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the area under the curve (AUC) of morphine-6-glucuronide (M6G) after a period of time is at least about 0.5 ng·h/mL/mg (ng·h/mL per mg of morphine).
24 . The orally administrable pharmaceutical composition of claim 23 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC 0-t of morphine-6-glucuronide (M6G) is about 1 to about 20 ng·h/mL/mg (ng·h/mL per mg of morphine).
25 . The orally administrable pharmaceutical composition of claim 23 , wherein the composition is configured such that when the pharmaceutical composition is administered intranasally in physically compromised form to a subject, the AUC 0-t of morphine-6-glucuronide (M6G) is about 2.5 to about 15 ng·h/mL/mg (ng·h/mL per mg of morphine).
26 . The orally administrable composition of claim 23 , wherein the composition comprises morphine, a pH-dependent agent, and a pH-independent agent, wherein about 60% or more of the total amount of morphine in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of morphine in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.
27 . The orally administrable composition of claim 23 , wherein the composition comprises morphine, a pH-dependent agent, and a pH-independent agent, wherein no more than 50% of the total amount of morphine in the pharmaceutical composition is released within 1 hour and about 50% or more of the total amount of morphine in the pharmaceutical composition is released after 8 hours under the following dissolution conditions: 0.1 N HCl, 500 mL, USP Apparatus 2 (paddle), 50 rpm, 37° C.; and wherein about 25% or less of the total amount of morphine in the pharmaceutical composition is released after 60 minutes under the following dissolution conditions: DI water, 500 mL, USP Apparatus 2 (Paddle), 50 rpm, 37° C.