Tamper resistant dosage forms
The present invention relates to pharmaceutical dosage forms, for example to a tamper resistant dosage form including an opioid analgesic, and processes of manufacture, uses, and methods of treatment thereof.
1. A process of preparing a solid oral extended release pharmaceutical dosage form, comprising:
combining:
(1) polyethylene oxide, and
(2) oxycodone hydrochloride, to form a composition;
shaping the composition to form an extended release matrix formulation; and
curing said extended release matrix formulation at a temperature ranging from about 68° C. to about 85° C. for about 30 minutes to about 4 hours, to form the dosage form,
wherein the extended release matrix comprises:
from about 10 mg to about 160 mg oxycodone hydrochloride;
a polyethylene oxide (PEO) having an approximate molecular weight of 2 million Da to 8 million Da based on rheological measurements; and
a PEO having an approximate molecular weight of 100,000 Da to 900,000 Da based on rheological measurements,
wherein the PEO comprises at least about 30% (by weight) of the total weight of the dosage form,
wherein the dosage form provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., is between 12.5 and 55% (by wt) active agent released after 1 hour, between 25 and 65% (by wt) active agent released after 2 hours, between 45 and 85% (by wt) active agent released after 4 hours and between 55 and 95% (by wt) active agent released after 6 hours,
wherein the dosage form provides an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C., characterized by the percent amount of active released at 0.5 hours, that deviates no more than about 20% points 0.5 hours from the corresponding in-vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C. without ethanol,
wherein the dosage form is a tablet,
wherein the dosage form when subjected to a maximum force of about 196 N or about 439 N in a tablet hardness test, does not break,
wherein the tablet when subjected to an indentation test resists a work of at least about 0.06 J without cracking,
wherein the dosage form provides a mean t max of oxycodone at about 2 to about 6 hours,
wherein the administration of the dosage form provides a mean maximum plasma concentration (C max ) of oxycodone from about 6 ng/mL to about 240 ng/mL, and
wherein the oxycodone hydrochloride has a 14-hydroxycodeinone level of less than about 25 ppm.
2. The process of claim 1 , wherein the total amount of PEO in the dosage form comprises at least about 65% (by wt) of the total weight of the dosage form.
3. The process of claim 1 , wherein the total amount of PEO in the dosage form comprises at least about 80% (by wt) of the total weight of the dosage form.