Sustained-release buprenorphine formulations
a buprenorphine and formulation technology, applied in the field of sustained-release buprenorphine formulations, can solve the problems of high rate of non-adherence, high cost to individuals, families, and society, and achieve the effect of reducing withdrawal symptoms
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example 1
[0053]Formulation D is a compound containing 200 mg / mL buprenorphine base in a form suitable for subcutaneous injection and allowing for the release of buprenorphine at therapeutic levels for at least 28 days. Following administration of Formulation D, day-to-day compliance over the ensuing month would not be a potential issue as it is with existing products that are administered on a daily basis. Also, since Formulation D contains buprenorphine base in a sustained release delivery formulation, the safety profile and clinical efficacy of Formulation D are expected to be similar to that of sublingually administered buprenorphine (e.g., SUBUTEX®) and buprenorphine / naloxone treatments (e.g., SUBUXONE®).
[0054]The primary goal of this study was to develop a model-based approach to rationally support and justify the dose and dosing regimen of Formulation D in Phase 2 and 3 trials. For this purpose, a modeling strategy was implemented to characterize the population pharmacokinetics of bupr...
example 2
[0078]This study implemented pharmacokinetic / pharmacodynamics (PK / PD) modeling to support the clinical development of Formulation D, a sustained-release formulation of buprenorphine for the treatment of opioid dependence. Such a formulation could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing the diversion of the product.
[0079]A population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of Formulation D. Another PK / PD model was developed using μ-opioid receptor occupancy data to predict efficacy of Formulation D after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated to opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects.
[0080]The resulting pharmacokinetic model accurately described buprenorphine and norbuprenorphine plasma concentrations. A saturable maximum effect (Emax) ...
example 3
[0083]As described in Examples 1 and 2, modeling showed that mu opioid receptor occupancy (RO)≥70% and buprenorphine plasma levels ≥2 ng / mL are needed to provide full blockade of opioid agonist effects (Nasser et al, Clin Pharmacokinet, 2014). This Example 3 was performed to assess Formulation D (containing 300 mg buprenorphine) blockade of hydromorphone-induced subjective and reinforcing effects, and to determine the accuracy of the modeling presented in Example 1 and 2 in a clinical setting.
[0084]39 subjects with opioid use disorder (not seeking treatment) first completed 3 hydromorphone challenges (0, 6, 18 mg intramuscular on 3 consecutive days in randomized order), then 3 hydromorphone challenges at the end of 14-day SUBOXONE® film stabilization. This was followed by two injections of Formulation D (containing 300 mg buprenorphine) separated by 28 days. For 12 weeks after the first Formulation D dose, on days 5-7 of each week, subjects received 3 hydromorphone challenges in ran...
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