Influence of plasticizers on the stability and release of a prodrug of Delta(9)-tetrahydrocannabinol incorporated in poly (ethylene oxide) matrices.
The objective of this research was to stabilize a heat-labile novel prodrug of Delta(9)-tetrahydrocannabinol (THC), THC-hemiglutarate (THC-HG), in polyethylene oxide (PEO) [PolyOx WSR N-80 (PEO N-80), MW 200,000 Daltons] polymeric matrix systems produced by hot-melt fabrication for systemic delivery of THC through the oral transmucosal route. For this purpose, the effects of processing conditions (processing temperature and heating duration), plasticizer type and concentration and storage conditions on the stability of the prodrug were investigated. The selected plasticizers studied included vitamin E succinate (VES), acetyltributyl citrate (ATBC), triethyl citrate (TEC), triacetin and polyethylene glycol 8000 (PEG 8000). Furthermore, the influence of plasticizer concentration on drug release was also studied. The stability of THC-HG in PEO matrices was influenced by all the aforementioned variables. Films processed at 110 degrees C for 7min were found to be favorable for hot-melt processing with a post-processing drug content of 95%, while significant degradation of THC-HG ( approximately 42%) was observed in those processed at 200 degrees C for 15min. The degradation of the prodrug during hot-melt fabrication and also upon storage was considerably reduced in the presence of the plasticizers investigated, VES being the most effective. Modulation of the microenvironmental pH to an acidic range via incorporation of citric acid in PEO-plasticizer matrices significantly improved the stability of the prodrug, with almost 90% of the theoretical drug remaining as opposed to only 15% remaining in PEO-only matrices when stored at 40 degrees C for up to 3 months. The release of drug from PEO matrices was influenced both by the plasticizer type and concentration. A faster release resulted from water-soluble plasticizers, PEG 8000 and triacetin, and with increasing concentration. However, a slower release was observed with an increase in concentration of water-insoluble plasticizers, VES and ATBC.
Thumma
Sridhar
S
Department of Pharmaceutics, The University of Mississippi, MS 38677, USA.
ElSohly
Mahmoud A
MA
Zhang
Shuang-Qing
SQ
Gul
Waseem
W
Repka
Michael A
MA
D019343:Citric Acid / Q000737:chemistry; D013759:Dronabinol / Q000008:administration & dosage / Q000737:chemistry*; D004355:Drug Stability; D010968:Plasticizers / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D014783:Viscosity
D010968:Plasticizers; D011355:Prodrugs; D019343:Citric Acid; D011092:Polyethylene Glycols; D013759:Dronabinol