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Zero-order release of buprenorphine from an osmotically modulated once-a-day oral dosage form
Abstracts
The Journal of Pain
S77
(404) Effect of food on the pharmacokinetics of the hydrocodone extended-release tablet in healthy volunteers
(406) Zero-order release of buprenorphine from an osmotically modulated once-a-day oral dosage form
M Darwish, M Bond, C Shu, P Robertson, and W Tracewell; Cephalon, Inc., Frazer, PA
G Yeola, P Vavia, N Babul, and H Kao; TheraQuest Biosciences, Inc., Blue Bell, PA
Hydrocodone is available for the treatment of pain in the United States only as immediate-release formulations in combination with other medications. A new extended-release hydrocodone tablet has been developed that employs OraGuard technology, a novel platform that is intended to resist dose dumping when taken with alcohol or when pulverized. Two randomized, open-label, crossover studies were conducted to assess the effect of food on the pharmacokinetics of the hydrocodone bitartrate extended-release tablet (Study 1, 15 mg; Study 2, 90 mg). Each participant received hydrocodone extended-release (15 or 90 mg) in both fed and fasted states with 240 mL of water. Hydrocodone doses were separated by a minimum of 5 (Study 1) or 14 days (Study 2). Subjects had received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose. Pharmacokinetic parameters included peak plasma hydrocodone concentration (Cmax) and area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-N). Safety was also assessed. Thirty-one subjects completed Study 1; 35 completed Study 2. In Study 1, geometric mean Cmax in the fed and fasted state was 18.5 and 12.5 ng/mL and geometric mean AUC0-N was 210.8 and 193.5 nghr/mL, respectively. In Study 2, the corresponding Cmax was 86.1 and 60.6 ng/mL and AUC0-N was 1262 and 1135 nghr/mL, respectively. In both studies, confidence intervals for AUC met bioequivalence criteria (0.8, 1.25) for the fed and fasted states (Study 1: AUC0-N 1.035, 1.111; Study 2: AUC0-N 1.055, 1.161), while those for Cmax did not (Study 1: 1.354, 1.548; Study 2: 1.306, 1.509). Cmax was 40-45% higher under fed conditions in both studies. Adverse events were similar in fed and fasted states in Study 1 (36% vs 34%), but higher in the fasted state in Study 2 (16% vs 8%). Sponsored by Cephalon, Inc.
Although buprenorphine is an effective analgesic, its use has been limited to parenteral, sublingual and transdermal routes. Recently we demonstrated that buprenorphine can provide robust but short-lived analgesia by the oral route. This study involved the development of oral push pull bilayer tablets of extended release (ER) buprenorphine. The push pull osmotic bilayer tablet consisted of drug layer containing buprenorphine and polyethylene oxide (PEO) and push layer containing sodium chloride, iron red oxide, PEO and magnesium stearate. The core bilayer tablets were coated with semipermeable membrane (cellulose acetate) and a plasticizer(PEG 3350). A delivery orifice was mechanically drilled. The effects of the polymer, plasticizer, coating level and orifice diameter on drug release rate were evaluated. The optimized formulation was assessed in different release media (pH 1.2 then 6.8, pH 6.8, water) at 50-100 rpm. Drug release was directly proportional to the concentration of PEO in push layer and was inversely proportional to the coating weight gain. Increase in the coating thickness decreased the permeability of the semipermeable membrane thereby decreasing the rate of release. Change in orifice diameter (0.6 to 1.0 mm) did not significantly influence release. PEO improved hardness and friability of the core. Increase in plasticizer concentration increased the permeability of membrane and thus release rate. The rate and extent of drug release was independent of agitation and pH of release media. The optimized PPOP tablet of buprenorphine ER provided robust zero order release over 24 hours under a variety of dissolution conditions, consistent with once-daily dosage form. The manufacturing procedure was found to be reproducible and the formulations were stable after 6 month of accelerated stability studies. A QD dosage form of buprenorphine ER with a zero order release profile is therefore feasible, subject to clinical evaluation. Grant from TheraQuest.
(405) The in-vitro analgesic pharmacology of levorphanol: effect on NMDA, opioid and monoaminergic systems
(407) Novel, abuse deterrent extended release once-a-day dosage forms of the opioid analgesic, levorphanol
N Babul, A Rehni, H Kao, and Y Chang; TheraQuest Biosciences, Inc., Blue Bell, PA
N Babul, V Young, M Bakhshaee, A McNaughton, H Kao, and S Brown; TheraQuest Biosciences, Inc., Blue Bell, PA
An extended release, abuse deterrent once-a-day dosage form of levorphanol is presently under development. The in-vitro pharmacology is not well characterized. In-vivo, levorphanol shows reversal of analgesic tolerance to morphine and continued analgesia in the presence of the mu-1 specific opioid antagonist, naloxonazine. This study compared the in-vitro analgesic pharmacology of levorphanol versus morphine, hydromorphone, oxycodone, tramadol and tapentadol. 5-HT and NE reuptake inhibition was assayed with [3-H]5-HT and [3-H]NE in rat brain and hypothalamic synaptosomes, respectively (Perovic, Arzneim-Forsch, 1995). NMDA activity was assayed in the antagonist radio-ligand rat cerebral cortex assay using [3-H]TCP (Vignon, Brain Res, 1986). Mu, delta and kappa opioid-receptor binding was assayed with [3H]diprenorphine, [3H]DADLE and [3H]U69593, respectively (Zhang, JPET, 1998; Simonin, Mol Pharmacol 1994; Meng, PRONAS, 1993). Data were adjusted to anhydrous base content. In the 5-HT and NE assay, levorphanol provided activity comparable to tapentadol and tramadol. In the NMDA antagonist assay, levorphanol provided 93% inhibition of control specific binding at 5.8 x 10-6 M. In contrast, morphine, hydromorphone and oxycodone showed no significant activity in any of the foregoing assays. Compared to morphine, levorphanol was more potent at the mu, delta and kappa opioid-receptor. When adjusted for potency at the mu opioid-receptor (6:1), levorphanol was 5-times and 3-times more potent than morphine at the delta and kappa opioid receptors, respectively. Although there is widespread variability in the efficacy and safety response to opioids, clinicians are frustrated by the limited pharmacologic rationale for selection of a suitable opioid. Levorphanol appears to exert multimodal analgesia at ascending pain pathways and descending pain pathways through opioid agonism and norepinephrine reuptake inhibition, respectively, and as an NMDA antagonist. Further clinical evaluation of levorphanol in chronic pain is warranted. This study was supported by a grant from TheraQuest Biosciences, Inc.
Levorphanol is opioid analgesic for which no extended release (ER) dosage forms are described. Therefore, this study was designed to develop and evaluate abuse deterrent ER dosage forms of levorphanol. Approximately 20 formulations of levorphanol were tested to identify stable, ER dosage-forms with robust in-vitro dissolution, tamper-resistant profile and a release rate consistent with once-a-day dosing. Generally recognized as safe (GRAS) base excipients, comprising water insoluble thermosoftening waxes were chosen to impart an ER profile. The contribution of several release-rate modifiers, thixotropes and fractionated coconut oil were also evaluated. An HPLC method was developed for assay of levorphanol. Methodologies were developed to evaluate tamper resistance. Dosage forms were subjected to tampering, including crushing, grinding, dissolution, melting, needle aspiration, filtration and solvent extraction in order to determine their tamper-resistance relative to marketed products. The stability of the dosage forms manufactured under high temperature conditions was assessed. Four final abuse-deterrent levorphanol ER dosage forms with robust in vitro dissolution, tamper-resistance and release kinetics consistent with a Q24 hour dosing regimen were developed. The dosage-forms were liquid-filled into small hard-shell capsules to provide ease of swallowing to an elderly target population. Waxes with melting-point >50 C were selected. HPMC was chosen as the final release rate modifier and fumed silicon dioxide as the thixotrope. Fractionated coconut oil was found to reduce dosage form brittleness. Each excipient appeared to independently contribute to the tamper resistant properties. The dosage forms selected for Phase I evaluation provided a cumulative 24 hour release of about 65% to 95% in 600 mL of simulated intetinal fluid without enzyme at pH 6.8. Oral dosage-forms of levorphanol comprising a high melting-point wax, a release rate modifier, a thixotrope and fractionated coconut oil provided robust ER and tamperresistant profiles. Supported by a grant from TheraQuest Biosciences, Inc.
The Journal of Pain
S77
(404) Effect of food on the pharmacokinetics of the hydrocodone extended-release tablet in healthy volunteers
(406) Zero-order release of buprenorphine from an osmotically modulated once-a-day oral dosage form
M Darwish, M Bond, C Shu, P Robertson, and W Tracewell; Cephalon, Inc., Frazer, PA
G Yeola, P Vavia, N Babul, and H Kao; TheraQuest Biosciences, Inc., Blue Bell, PA
Hydrocodone is available for the treatment of pain in the United States only as immediate-release formulations in combination with other medications. A new extended-release hydrocodone tablet has been developed that employs OraGuard technology, a novel platform that is intended to resist dose dumping when taken with alcohol or when pulverized. Two randomized, open-label, crossover studies were conducted to assess the effect of food on the pharmacokinetics of the hydrocodone bitartrate extended-release tablet (Study 1, 15 mg; Study 2, 90 mg). Each participant received hydrocodone extended-release (15 or 90 mg) in both fed and fasted states with 240 mL of water. Hydrocodone doses were separated by a minimum of 5 (Study 1) or 14 days (Study 2). Subjects had received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose. Pharmacokinetic parameters included peak plasma hydrocodone concentration (Cmax) and area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-N). Safety was also assessed. Thirty-one subjects completed Study 1; 35 completed Study 2. In Study 1, geometric mean Cmax in the fed and fasted state was 18.5 and 12.5 ng/mL and geometric mean AUC0-N was 210.8 and 193.5 nghr/mL, respectively. In Study 2, the corresponding Cmax was 86.1 and 60.6 ng/mL and AUC0-N was 1262 and 1135 nghr/mL, respectively. In both studies, confidence intervals for AUC met bioequivalence criteria (0.8, 1.25) for the fed and fasted states (Study 1: AUC0-N 1.035, 1.111; Study 2: AUC0-N 1.055, 1.161), while those for Cmax did not (Study 1: 1.354, 1.548; Study 2: 1.306, 1.509). Cmax was 40-45% higher under fed conditions in both studies. Adverse events were similar in fed and fasted states in Study 1 (36% vs 34%), but higher in the fasted state in Study 2 (16% vs 8%). Sponsored by Cephalon, Inc.
Although buprenorphine is an effective analgesic, its use has been limited to parenteral, sublingual and transdermal routes. Recently we demonstrated that buprenorphine can provide robust but short-lived analgesia by the oral route. This study involved the development of oral push pull bilayer tablets of extended release (ER) buprenorphine. The push pull osmotic bilayer tablet consisted of drug layer containing buprenorphine and polyethylene oxide (PEO) and push layer containing sodium chloride, iron red oxide, PEO and magnesium stearate. The core bilayer tablets were coated with semipermeable membrane (cellulose acetate) and a plasticizer(PEG 3350). A delivery orifice was mechanically drilled. The effects of the polymer, plasticizer, coating level and orifice diameter on drug release rate were evaluated. The optimized formulation was assessed in different release media (pH 1.2 then 6.8, pH 6.8, water) at 50-100 rpm. Drug release was directly proportional to the concentration of PEO in push layer and was inversely proportional to the coating weight gain. Increase in the coating thickness decreased the permeability of the semipermeable membrane thereby decreasing the rate of release. Change in orifice diameter (0.6 to 1.0 mm) did not significantly influence release. PEO improved hardness and friability of the core. Increase in plasticizer concentration increased the permeability of membrane and thus release rate. The rate and extent of drug release was independent of agitation and pH of release media. The optimized PPOP tablet of buprenorphine ER provided robust zero order release over 24 hours under a variety of dissolution conditions, consistent with once-daily dosage form. The manufacturing procedure was found to be reproducible and the formulations were stable after 6 month of accelerated stability studies. A QD dosage form of buprenorphine ER with a zero order release profile is therefore feasible, subject to clinical evaluation. Grant from TheraQuest.
(405) The in-vitro analgesic pharmacology of levorphanol: effect on NMDA, opioid and monoaminergic systems
(407) Novel, abuse deterrent extended release once-a-day dosage forms of the opioid analgesic, levorphanol
N Babul, A Rehni, H Kao, and Y Chang; TheraQuest Biosciences, Inc., Blue Bell, PA
N Babul, V Young, M Bakhshaee, A McNaughton, H Kao, and S Brown; TheraQuest Biosciences, Inc., Blue Bell, PA
An extended release, abuse deterrent once-a-day dosage form of levorphanol is presently under development. The in-vitro pharmacology is not well characterized. In-vivo, levorphanol shows reversal of analgesic tolerance to morphine and continued analgesia in the presence of the mu-1 specific opioid antagonist, naloxonazine. This study compared the in-vitro analgesic pharmacology of levorphanol versus morphine, hydromorphone, oxycodone, tramadol and tapentadol. 5-HT and NE reuptake inhibition was assayed with [3-H]5-HT and [3-H]NE in rat brain and hypothalamic synaptosomes, respectively (Perovic, Arzneim-Forsch, 1995). NMDA activity was assayed in the antagonist radio-ligand rat cerebral cortex assay using [3-H]TCP (Vignon, Brain Res, 1986). Mu, delta and kappa opioid-receptor binding was assayed with [3H]diprenorphine, [3H]DADLE and [3H]U69593, respectively (Zhang, JPET, 1998; Simonin, Mol Pharmacol 1994; Meng, PRONAS, 1993). Data were adjusted to anhydrous base content. In the 5-HT and NE assay, levorphanol provided activity comparable to tapentadol and tramadol. In the NMDA antagonist assay, levorphanol provided 93% inhibition of control specific binding at 5.8 x 10-6 M. In contrast, morphine, hydromorphone and oxycodone showed no significant activity in any of the foregoing assays. Compared to morphine, levorphanol was more potent at the mu, delta and kappa opioid-receptor. When adjusted for potency at the mu opioid-receptor (6:1), levorphanol was 5-times and 3-times more potent than morphine at the delta and kappa opioid receptors, respectively. Although there is widespread variability in the efficacy and safety response to opioids, clinicians are frustrated by the limited pharmacologic rationale for selection of a suitable opioid. Levorphanol appears to exert multimodal analgesia at ascending pain pathways and descending pain pathways through opioid agonism and norepinephrine reuptake inhibition, respectively, and as an NMDA antagonist. Further clinical evaluation of levorphanol in chronic pain is warranted. This study was supported by a grant from TheraQuest Biosciences, Inc.
Levorphanol is opioid analgesic for which no extended release (ER) dosage forms are described. Therefore, this study was designed to develop and evaluate abuse deterrent ER dosage forms of levorphanol. Approximately 20 formulations of levorphanol were tested to identify stable, ER dosage-forms with robust in-vitro dissolution, tamper-resistant profile and a release rate consistent with once-a-day dosing. Generally recognized as safe (GRAS) base excipients, comprising water insoluble thermosoftening waxes were chosen to impart an ER profile. The contribution of several release-rate modifiers, thixotropes and fractionated coconut oil were also evaluated. An HPLC method was developed for assay of levorphanol. Methodologies were developed to evaluate tamper resistance. Dosage forms were subjected to tampering, including crushing, grinding, dissolution, melting, needle aspiration, filtration and solvent extraction in order to determine their tamper-resistance relative to marketed products. The stability of the dosage forms manufactured under high temperature conditions was assessed. Four final abuse-deterrent levorphanol ER dosage forms with robust in vitro dissolution, tamper-resistance and release kinetics consistent with a Q24 hour dosing regimen were developed. The dosage-forms were liquid-filled into small hard-shell capsules to provide ease of swallowing to an elderly target population. Waxes with melting-point >50 C were selected. HPMC was chosen as the final release rate modifier and fumed silicon dioxide as the thixotrope. Fractionated coconut oil was found to reduce dosage form brittleness. Each excipient appeared to independently contribute to the tamper resistant properties. The dosage forms selected for Phase I evaluation provided a cumulative 24 hour release of about 65% to 95% in 600 mL of simulated intetinal fluid without enzyme at pH 6.8. Oral dosage-forms of levorphanol comprising a high melting-point wax, a release rate modifier, a thixotrope and fractionated coconut oil provided robust ER and tamperresistant profiles. Supported by a grant from TheraQuest Biosciences, Inc.