Sequestered antagonist formulations

Abstract

Disclosed is an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact, such that the ratio of the mean Cmax of the antagonist after single dose oral administration of the dosage form after tampering to the mean Cmax of antagonist after single dose oral administration of an intact dosage form is at least 1.5:1.

Description

[0001] This application claims the benefit of U.S. Provisional Serial No. 60 / 310,533, filed Aug. 6, 2001, hereby incorporated by reference in its entirety.

[0002] Opioid formulations are sometimes the subject of abuse. A particular dose of oxycodone may be more potent when administered parenterally as compared to the same dose administered orally. Also, some formulations can be tampered with to provide the opioid agonist contained therein better available for illicit use. For example, a controlled release opioid agonist formulation can be crushed to provide the opioid contained therein available for immediate release upon oral or parenteral administration.

[0003] Opioid antagonists have been combined with certain opioid agonists to deter the parenteral abuse of opioid agonists. In the prior art, the combination of immediate release pentazocine and naloxone has been utilized in tablets available in the United States, commercially available as Talwin.RTM.Nx from Sanofi-Winthrop. Talwin ...

Examples

example 2

[0236] In Example 2, a substantially non-releasable form of an opioid antagonist (naltrexone HCL) was prepared by coating naltrexone particles with a coating that renders the antagonist substantially non-releasable.

[0237] Naltrexone HCl 2 mg Capsules (Formulation B)

[0238] Formula:

5 Amt / unit Amt / batch Ingredient (mg) (kg) Naltrexone HCl 2.0 0.04 Eudragit RSPO 96.0 1.92 Stearyl Alcohol 22.0 0.44 Dibasic Calcium 6.0 0.12 Phosphate Butylated Hydroxytoluene 1.0 0.02 (BHT) Size #2 Hard Gelatin N / A N / A Capsules Total 127.0 2.54

[0239] Process:

[0240] 1. Milling Pass stearyl alcohol flakes through a mill.

[0241] 2. Blending Mix Naltrexone HCl, Eudragit, milled Stearyl Alcohol, Dibasic Calcium Phosphate and BHT in a twin shell blender.

[0242] 3. Extrusion Continuously feed the blended material into a twin screw extruder and collect the resultant strands on a conveyor.

[0243] 4. Cooling Allow the strands to cool a Conveyor.

[0244] 5. Pelletizing Cut the cooled strands into pellets using a Pelletize...

example 3

Immediate Release Naltrexone HCl 0.5 mg Tablets

[0257] Formula:

8 Amt / unit Amt / batch Ingredient (mg) (kg) Wet Granulation Naltrexone HCl 0.5 0.1 Plasdone C-30 5.0 1.0 Avicel PH-102 58.0 11.6 Sterile Water for Injection 25.0* 5.0* Dry Mixing Avicel PH-102 58.0 11.6 Cab-O-Sil 0.3 0.06 Ac-Di-Sol 2.5 0.5 Magnesium Stearate 0.7 0.14 Total 125.0 25.0 * Remains as residual moisture only. Not included in total weight.

[0258] Process:

[0259] 1. Solution Preparation Dissolve Naltrexone HCl and Plasdone in Sterile Water for Injection.

[0260] 2. Wet Granulation Granulate Avicel PH-102 with solution as prepared in step 1.

[0261] 3. Drying Dry granulated material from step 2 in a fluid bed dryer.

[0262] 4. Milling Pass dried granulation through a Comil

[0263] 5. Mixing Mix milled granulation with remaining Avicel PH-102, Cab-O-Sil, Ac-Di-Sol, and Magnesium Stearate.

[0264] 6. Compression Compress granulation into tablets using a tablet press.

[0265] Dissolution Method

[0266] 9. Apparatus-USP Type II (Paddle...

example 4

[0271] This was an analytically blind, single dose, five treatments, 3-period crossover, pharmacokinetic study of two naltrexone pellet formulations (Formulation A and Formulation B) swallowed whole or after grinding compared with an immediate-release naltrexone reference swallowed whole in normal healthy subjects. This study assessed the pharmacokinetic (PK) profiles of the two different formulations (Formulation A and Formulation B) of a single dose of one (1) pellet (each containing 2 mg of naltrexone) when ground then swallowed whole and five (5) pellets (each containing 2 mg of naltrexone) when swallowed whole. This study also compared the pharmacokinetics of each formulation administration method to a single dose containing 1 mg of immediate release (IR) naltrexone when swallowed whole.

[0272] FIG. 1 shows the graphical representation of this study, which consisted of two groups (Group A and Group B) with 15 subjects in each group. The treatment order and treatments conditions ...

[0001] This application claims the benefit of U.S. Provisional Serial No. 60 / 310,533, filed Aug. 6, 2001, hereby incorporated by reference in its entirety.

[0002] Opioid formulations are sometimes the subject of abuse. A particular dose of oxycodone may be more potent when administered parenterally as compared to the same dose administered orally. Also, some formulations can be tampered with to provide the opioid agonist contained therein better available for illicit use. For example, a controlled release opioid agonist formulation can be crushed to provide the opioid contained therein available for immediate release upon oral or parenteral administration.

[0003] Opioid antagonists have been combined with certain opioid agonists to deter the parenteral abuse of opioid agonists. In the prior art, the combination of immediate release pentazocine and naloxone has been utilized in tablets available in the United States, commercially available as Talwin.RTM.Nx from Sanofi-Winthrop. Talwin ...

Examples

example 2

[0236] In Example 2, a substantially non-releasable form of an opioid antagonist (naltrexone HCL) was prepared by coating naltrexone particles with a coating that renders the antagonist substantially non-releasable.

[0237] Naltrexone HCl 2 mg Capsules (Formulation B)

[0238] Formula:

5 Amt / unit Amt / batch Ingredient (mg) (kg) Naltrexone HCl 2.0 0.04 Eudragit RSPO 96.0 1.92 Stearyl Alcohol 22.0 0.44 Dibasic Calcium 6.0 0.12 Phosphate Butylated Hydroxytoluene 1.0 0.02 (BHT) Size #2 Hard Gelatin N / A N / A Capsules Total 127.0 2.54

[0239] Process:

[0240] 1. Milling Pass stearyl alcohol flakes through a mill.

[0241] 2. Blending Mix Naltrexone HCl, Eudragit, milled Stearyl Alcohol, Dibasic Calcium Phosphate and BHT in a twin shell blender.

[0242] 3. Extrusion Continuously feed the blended material into a twin screw extruder and collect the resultant strands on a conveyor.

[0243] 4. Cooling Allow the strands to cool a Conveyor.

[0244] 5. Pelletizing Cut the cooled strands into pellets using a Pelletize...

example 3

Immediate Release Naltrexone HCl 0.5 mg Tablets

[0257] Formula:

8 Amt / unit Amt / batch Ingredient (mg) (kg) Wet Granulation Naltrexone HCl 0.5 0.1 Plasdone C-30 5.0 1.0 Avicel PH-102 58.0 11.6 Sterile Water for Injection 25.0* 5.0* Dry Mixing Avicel PH-102 58.0 11.6 Cab-O-Sil 0.3 0.06 Ac-Di-Sol 2.5 0.5 Magnesium Stearate 0.7 0.14 Total 125.0 25.0 * Remains as residual moisture only. Not included in total weight.

[0258] Process:

[0259] 1. Solution Preparation Dissolve Naltrexone HCl and Plasdone in Sterile Water for Injection.

[0260] 2. Wet Granulation Granulate Avicel PH-102 with solution as prepared in step 1.

[0261] 3. Drying Dry granulated material from step 2 in a fluid bed dryer.

[0262] 4. Milling Pass dried granulation through a Comil

[0263] 5. Mixing Mix milled granulation with remaining Avicel PH-102, Cab-O-Sil, Ac-Di-Sol, and Magnesium Stearate.

[0264] 6. Compression Compress granulation into tablets using a tablet press.

[0265] Dissolution Method

[0266] 9. Apparatus-USP Type II (Paddle...

example 4

[0271] This was an analytically blind, single dose, five treatments, 3-period crossover, pharmacokinetic study of two naltrexone pellet formulations (Formulation A and Formulation B) swallowed whole or after grinding compared with an immediate-release naltrexone reference swallowed whole in normal healthy subjects. This study assessed the pharmacokinetic (PK) profiles of the two different formulations (Formulation A and Formulation B) of a single dose of one (1) pellet (each containing 2 mg of naltrexone) when ground then swallowed whole and five (5) pellets (each containing 2 mg of naltrexone) when swallowed whole. This study also compared the pharmacokinetics of each formulation administration method to a single dose containing 1 mg of immediate release (IR) naltrexone when swallowed whole.

[0272] FIG. 1 shows the graphical representation of this study, which consisted of two groups (Group A and Group B) with 15 subjects in each group. The treatment order and treatments conditions ...

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