Buprenorphine (also known as (2S)-2-[(−)-(5R,6R,7R,14S)-9a-cyclo-propyl-methyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-di-methylbutan-2-ol and marketed under the trade names SUBUTEX® (buprenorphine by Indivior PLC) and SUBOXONE® (buprenorphine/naloxone by Indivior PLC) for the treatment of opioid dependence. These products are in tablet and film formulations and are intended to deliver daily therapeutic levels of buprenorphine and are taken either buccally or sublingually. However, there are often issues with diversion in patients with an opioid dependence problem. There is a need therefore for a longer term, non-divertible method of administering buprenorphine which delivers a constant and effective dose of buprenorphine to the patient over a period of a month or longer, and which does not result in an accumulation of buprenorphine in the patient's metabolism.
Various sustained release methods are employed in the pharmaceutical industry, for example, a non-degradable buprenorphine implant, PROBUPHINE® (Titan Pharmaceuticals), has been shown to release buprenorphine for six months once implanted in patients. Although the implant may be efficacious to treat opioid dependence (Ling et al, JAMA, 304(14):1576-83 (2010)), it requires surgical procedure for placement in the patent and a second surgical procedure to remove the empty reservoir from the patient.
A biodegradable buprenorphine delivery system that can be easily injected and requires no surgical removal has also been investigated. Sigmon et al, Addiction, 101:420-432 (2006) reported a biodegradable polymer microcapsule depot system that was able to sustain plasma buprenorphine levels for at least 4 weeks after a single intramuscular injection. Such microcapsule systems, however, can only be produced by a complex manufacture process.
A flowable biodegradable liquid system is disclosed in WO 2011/154724. This system utilizes a biodegradable polymer, a biocompatible solvent, and buprenorphine, all solubilized as an injectable liquid that can slowly release buprenorphine for one month or longer. This system forms a solid implant in situ following injection.
US Publication No. 2013/0190341 discloses a lipid-based precursor formulation that utilizes phosphatidyl choline and glycerol dioleate to form a liquid crystal phase to control the release of buprenorphine. In order to make the formulation injectable, ethanol was added to dissolve all the components, including buprenorphine, to form a solution. Such a solution may provide buprenorphine plasma levels for up to 2 weeks after a single subcutaneous injection.
WO 2007/103185 discloses rapid-release buprenorphine suspensions in various solvent systems that form drug depots at the injection sites. The solvent systems include aqueous solutions and water immiscible sesame oil as well as water miscible organic solvents such as citric acid esters and polyethylene glycol. The slowest release formulation exemplified in the application released 53.97% buprenorphine in 6 days in mice, and achieved an analgesic effect for 4 to 5 days.
WO 2011/154725 describes buprenorphine aqueous suspensions containing surfactants with high buprenorphine drug loadings of 10% or more. Those suspensions appear to continuously release buprenorphine for about a month in rats and 14 to 20 days in dogs after a single subcutaneous or intramuscular injection.
Although all the systems described above allegedly provide sustained release of buprenorphine, there is still a need to develop better sustained release formulations of buprenorphine that are easy to prepare and easy to inject, with better release kinetics, and that can last at least a month or longer.