Nanoshells prepared by atomic layer deposition - Long acting depots of indomethacin

There is a trend in pharmaceutical research and development to develop depot formulations with dosing once weekly, once monthly, or even less frequently. A novel approach to achieve long acting injectable suspensions is to produce dense inorganic nanoshells with atomic layer deposition (ALD) on active pharmaceutical ingredients. Such particles can be suspended in an aqueous vehicle and administered subcutaneously. The purpose of this work was to study the release of a model drug, indomethacin, coated with aluminium oxide nanoshells. Indomethacin was ball-milled to a median particle size of 6 µm. The nanoshells were produced with a proprietary ALD process that is trademarked as PharmaShell® by Nanexa AB. The drug load was determined with HPLC-UV to 82 wt%. The test materials were administered subcutaneously in rats (1, 10, and 100 mg/kg) from which blood samples were collected during 12 weeks. Plasma was generated and analyzed with regards to indomethacin using UPLC-MS/MS. The release rate was dramatically slower for the nanoshell coated indomethacin compared with uncoated indomethacin. Drug was released in vivo during more than 12 weeks for the 10 and 100 mg/kg doses, and during 10 weeks for the 1 mg/kg dose, while uncoated indomethacin was eliminated with a half-life of 15 h, as calculated from the release data by fitting a one phase decay function. The exposure levels were similar as earlier reported for therapeutic indomethacin doses, but significantly sustained in the present study using coated drug particles in rats. In conclusion, this is the first long-term in vivo evaluation of nanoshell depot formulations. The stable plasma concentrations for more than 12 weeks demonstrate that nanoshells can enable long-term depot injections with high drug load.