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. 2008 Oct 1;362(1-2):126-32.
doi: 10.1016/j.ijpharm.2008.06.025. Epub 2008 Jul 5.

Chemical stability and bioadhesive properties of an ester prodrug of Delta 9-tetrahydrocannabinol in poly(ethylene oxide) matrices: effect of formulation additives

Sridhar Thumma  1 , Soumyajit Majumdar, Mahmoud A ElSohly, Waseem Gul, Michael A Repka
Affiliations

Chemical stability and bioadhesive properties of an ester prodrug of Delta 9-tetrahydrocannabinol in poly(ethylene oxide) matrices: effect of formulation additives

Sridhar Thumma et al. Int J Pharm. .

Abstract

The objective of the present research was to stabilize a novel hemiglutarate ester prodrug of Delta(9)-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 degrees C/60% RH. The prodrug was very stable in both of the final formulations at the end of the 3 months at 40 degrees C/75% RH.

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Figures

Figure 1
Figure 1
Chemical structure of THC-HG.
Figure 2
Figure 2
Influence of wetting time on the bioadhesion of THC-HG-PEO polymeric matrices. The matrices (n = 5) were fabricated at 110 ° C.
Figure 3
Figure 3
Influence of various bioadhesive polymer on the (a) peak adhesive force and (b) work of adhesion of THC-HG-PEO matrices (n = 5).
Figure 4
Figure 4
Influence of bioadhesive polymers concentration on the (a) peak adhesive force and (b) work of adhesion of THC-HG-PEO matrices (n = 5).
Figure 5
Figure 5
Influence of drug loading and contact time on the (a) peak adhesive force and (b) work of adhesion of THC-HG-PEO matrices (n = 5).
Figure 6
Figure 6
Stability of THC-HG in PEO matrices in presence of (a) acidic pH modifiers and (b) basic pH modifiers. The matrices (n = 3) were fabricated at 110 ° C and stored at 40° C/75% RH.
Figure 7
Figure 7
Stability of THC-HG in the final formulations. The matrices (n = 3) were fabricated at 110 ° C and stored at 40° C/ 75% RH.
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