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 solid oral extended release dosage form, comprising:
an extended release matrix comprising an active agent, magnesium stearate, butylated hydroxytoluene and polyethylene oxide (PEO) having an approximate molecular weight of 1 million Da to 15 million Da based on rheological measurements, wherein the PEO comprises at least about 30% (by weight) of the total weight of the dosage form,
a film coat overcoated on the extended release matrix,
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, and
wherein the dosage form is expanded upon curing, as measured by a decrease in density of at least about 1.0% as determined by Archimedes Principle using a liquid of known density (ρ 0 ).
2. The solid oral extended release dosage form of claim 1 , wherein the PEO has an approximate molecular weight of 2 million Da to 8 million Da based on rheological measurements.
3. The solid oral extended release dosage form of claim 2 , 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.
4. The solid oral extended release dosage form of claim 3 , that is cured at a curing temperature ranging from about 62° C. to about 90° C.
5. The solid oral extended release dosage form of claim 4 , that is cured at a curing temperature ranging from about 68° C. to about 85° C.
6. The solid oral extended release dosage form of claim 5 , wherein the curing time is from about 15 minutes to about 10 hours.
7. The solid oral extended release dosage form of claim 6 , wherein the curing time is from about 30 minutes to about 4 hours.
8. The solid oral extended release dosage form of claim 7 , when subjected to a maximum force of about 196 N or about 439 N in a tablet hardness test, does not break.
9. The solid oral extended release dosage form of claim 8 , wherein the tablet when subjected to an indentation test resists a work of at least about 0.06 J without cracking.
10. The solid oral extended release dosage form of claim 9 , wherein the active agent is an opioid analgesic.
11. The solid oral extended release dosage form of claim 10 , wherein the opioid analgesic is selected from 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, etorphine, dihydroetorphine, fentanyl and derivatives, 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, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol or pharmaceutically acceptable salts thereof.
12. The solid oral extended release dosage form of claim 11 , wherein the opioid analgesic is oxycodone hydrochloride.
13. The solid oral extended release dosage form of claim 12 , that provides a mean t max of oxycodone at about 2 to about 6 hours.
14. The solid oral extended release dosage form of claim 13 , comprising from about 10 mg to about 160 mg oxycodone hydrochloride and wherein the dosage form provides a mean maximum plasma concentration (C max ) of oxycodone from about 6 ng/mL to about 240 ng/mL.
15. The solid oral extended release dosage form of claim 14 , wherein the oxycodone hydrochloride has a 14-hydroxycodeinone level of less than about 25 ppm.
16. The solid oral extended release dosage form of claim 15 , further comprising a PEO having an approximate molecular weight of 100,000 Da to 900,000 Da based on rheological measurements.
17. The solid oral extended release dosage form of claim 16 , wherein the total amount of PEO comprises at least about 65% (by wt) of the total weight of the dosage form.
18. The solid oral extended release dosage form of claim 17 , wherein the total amount of PEO comprises at least about 80% (by wt) of the total weight of the dosage form.
19. A solid oral extended release dosage form comprising: (i) an extended release matrix comprising from about 10 mg to about 160 mg oxycodone hydrochloride, magnesium stearate, butylated hydroxytoluene and polyethylene oxide (PEO) having an approximate molecular weight of 1 million Da to 15 million Da based on rheological measurements, wherein the PEO comprises at least about 30% (by weight) of the total weight of the dosage form and (ii) a film coat overcoated on the extended release matrix; wherein 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 dosage form is expanded upon curing, as measured by a decrease in density of at least about 1.0% as determined by Archimedes Principle using a liquid of known density (ρ 0 ).
20. A solid oral extended release dosage form comprising: (i) an extended release matrix comprising oxycodone hydrochloride, magnesium stearate, butylated hydroxytoluene and polyethylene oxide (PEO) having an approximate molecular weight of 1 million Da to 15 million Da based on rheological measurements and (ii) a film coat overcoated on the extended release matrix; 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 oxycodone hydrochloride 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 and wherein the dosage form is expanded upon curing, as measured by a decrease in density of at least about 1.0% as determined by Archimedes Principle using a liquid of known density (ρ 0 ).