Chemical stabilization of a Δ9-tetrahydrocannabinol prodrug in polymeric matrix systems produced by a hot-melt method: Role of microenvironment pH

Abstract

This research was conducted in order to fabricate stable polyethylene oxide (PEO)-based transmucosal systems of a Delta(9)-tetrahydrocannabinol (THC) prodrug, a hemisuccinate ester, using a hot-melt method. Since Delta(9)-tetrahydrocannabinol-hemisuccinate (THC-HS) was heat labile, a series of processing aids were evaluated in order to facilitate hot-melt production at lower temperatures, thereby reducing THC-HS degradation. The stability of THC-HS was influenced both by the processing conditions such as heating time and temperature, and the postprocessing storage conditions. The type of formulation additive also affected the extent of degradation. In the presence of polyethylene glycol (PEG)-400, the percentage of relative degradation of THC-HS to THC was 13.5% and 49.4% at 80 degrees C and 120 degrees C, respectively. In contrast, incorporation of vitamin E succinate (VES) reduced processing degradation to 2.1% and 9.2%, respectively, under the same conditions. Severe degradation of THC-HS was observed during storage, even under freezing conditions (-18 degrees C). A VES-Noveon AA-1 combination was observed to best stabilize the prodrug systems both during processing and postprocessing. Stabilization of THC-HS was achieved in these polyethylene oxide matrices at 4 degrees C, with almost 90% of theoretical drug remaining for up to 8 months. Investigation of the pH effect revealed that the pH of the microenvironment in these polymeric systems could be modulated to significantly improve the stability of THC-HS, degradation being the least in a relatively acidic medium.

Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol

“…Hot-melt processing has been demonstrated to be a viable method for the preparation of drug-incorporated polymeric matrices (8)(9)(10)(11)(12). Hot-melt processing requires a pharmaceutical grade thermoplastic polymer that can be processed at relatively low temperatures (low melting or glass transition temperatures) due to thermal sensitivity of many drugs.…”

Chemistry and Biological Activity of Tetrahydrocannabinol and its Derivatives

“…Interestingly Perlin et al mentioned that rectal administration was not successful and no significant blood levels were detected [152]. More recently Munjal et al, developed a transmucosal system based on polyethylene oxide (PEO) polymers, which are commonly used for the production of suppositories [150]. In this study the heat-labile ∆9-THC hemisuccinate was used to produce suppositories varying in PEO composition by the hot-melt technique (120 • C).…”

“…Marinol and Sativex are given orally to the patient but, as indicated, the poor solubility of ∆9-THC is responsible for its slow onset and release from drug carriers like soft gelatine capsules [150]. Quite frequently a large variety in the bioavailability and a significant first pass effect can be observed in animal tests and patients.…”

Influence of plasticizers on the stability and release of a prodrug of Δ9-tetrahydrocannabinol incorporated in poly (ethylene oxide) matrices

“…A survey of the scientific literature indicates that there are only four references on prodrugs of THC (all of them on THC-hemisuccinate) that have focused on studying the stability and bioavailability of the drug in various dosage forms [12][13][14]. Elsohly et al have incorporated the hemisuccinate pro-drug in lipophilic suppository bases and observed a significantly improved bioavailability (~64%) when administered rectally in dogs [12].…”