Chemical stability and bioadhesive properties of an ester prodrug of Δ9-tetrahydrocannabinol in poly(ethylene oxide) matrices: Effect of formulation additives

Abstract

The objective of the present research was to stabilize a novel hemiglutarate ester prodrug of Δ9-tetrahydrocannabinol (THC), in polyethylene oxide (PEO) polymeric matrices produced by hot-melt fabrication, for systemic delivery of THC through the oral transmucosal route. For this purpose, the influence of pH modifiers and antioxidants employed as stabilizing agents in these matrices was investigated. Based on the stability studies, two final formulations were made, and the stability of the active was assessed in these systems. In addition, the bioadhesive properties of PEO matrices were studied as a function of bioadhesive polymer type and concentration, contact time, drug loading and wetting time. Of all of the polymers investigated, bioadhesion was highest with Carbopol® 971p. Bioadhesion increased with bioadhesive polymer concentration and wetting time to a certain level beyond which there was no further contribution. Both the contact time and drug loading influenced the bioadhesion. Severe degradation of the prodrug was observed during storage, even at room temperature (75% at the end of 3 months). Incorporation of the stabilizing agents in the PEO matrices reduced the degradation of the prodrug considerably. Citric acid was the most effective of all of the pH modifiers studied. Among the various antioxidants utilized, degradation was observed least in presence of BHT and ascorbic acid. Only 7.6% and 8.2% of prodrug degraded in these matrices, respectively, as compared to the PEO only matrices (59.4%) at the end of 3 months at 25 °C/60% RH. The prodrug was very stable in both of the final formulations at the end of the 3 months at 40 °C/75% RH.

Enhanced Solubility, Stability, and Transcorneal Permeability of Delta-8-Tetrahydrocannabinol in the Presence of Cyclodextrins

“…A number of pharmacological and histological studies strongly suggest direct role of ocular CB1 receptors in the lowering of the IOP by the cannabinoids (1,2). Additionally, Δ 9 -THC has also been reported to reduce glutamate and N-methyl-Daspartate-induced retinal ganglionic cell death through its CB1 agonist activity (1)(2)(3)(6)(7)(8)(9). Moreover, the antioxidant property of Δ 9 -THC protects neurons against oxidative stress associated with glutamate-induced excitotoxicity (2,8,9).…”

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

“…1), was selected as a promising ODV prodrug, because of its highest relative bioavailability (192%) and peak concentration (C max ) of ODV both in the total brain (180.0 ng g −1 ) and in the hypothalamus (514.5 ng g −1 ) in rats. Stabilities of active ingredient is one of the important influencing factors for pharmaceutical investigation, especially for ester derivatives, which are sensitive to enzymes, acidic and alkaline conditions, etc (Thumma et al, 2008;Leriche et al, 2012). Hence, in present investigation, the stabilities evaluation in vitro, i.e., in aqueous, rat whole blood and liver mirosomes of O-19 were determined.…”

Influence of Processing Parameters and Formulation Factors on the Bioadhesive, Temperature Stability and Drug Release Properties of Hot-Melt Extruded Films Containing Miconazole

“…The probe lined with mucosa was set to approach the sample with a predetermined speed of 1 mm/s and applied a force of 3.5 N. The test speed was 0.1 mm/s. These parameters were chosen based on previous studies (10). The influence of the following variables on bioadhesion was studied: In vitro release studies (n=3) were tested using a Hanson SR8-Plus dissolution test system according to the US Pharmacopeia 31 apparatus 5, paddle-over-disk method.…”

“…Numerous mechanisms of bioadhesion have been studied and proposed, such as surface energy and contact angle considerations, polymer chain inter-penetration, and the swelling rate of a polymer interacting with skin or mucin (8). Numerous factors will affect the bioadhesive property, for example, drug content (9), wetting time, bioadhesive polymer type, bioadhesive polymers concentration, and contact times (10). Moreover, Repka and McGinity concluded that methods developed using a Chatillon testing apparatus may be employed as a novel technique to determine bioadhesion of hot-melt extruded films (11).…”