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Planta Med 2009; 75 - P-91
DOI: 10.1055/s-2009-1216529

Preformulation Evaluation of Δ9-Tetrahydrocannabinol Prodrugs – a Tool for Establishing Physicochemical Characteristics of Compounds at an Early Stage

SB Upadhye 1, S Majumdar 1, 2, W Gul 2, 3, MA ElSohly 2, 3, MA Repka 1, 2
  • 1Department of Pharmaceutics, School of Pharmacy, University of Mississippi, University, MS 38677
  • 2National Center for Natural Products Research (NCNPR), School of Pharmacy, University of Mississippi, University, MS 38677
  • 3ElSohly Laboratories, Incorporated, 5 Industrial Park Drive, Oxford, Mississippi 38655, USA

Δ9-Tetrahydrocannabinol (THC, Fig. 1) is the primary active ingredient of the plant Cannabis sativa (marijuana) and is responsible for the majority of the pharmacological effects. While THC in marijuana is mainly known for its abuse potential, it also exhibits the therapeutic effects in the treatment of nausea and vomiting during cancer chemotherapy. The only dosage form currently approved by FDA is an oral, soft gelatin capsule (Marinol®). This dosage form is expensive, resulting in inconsistent pharmacological effects and pharmacokinetic profiles. Hence, prodrugs of THC are synthesized for the delivery by transbuccal route. The objective is to enhance the thermal stability and permeation properties of the hemisuccinate ester prodrug of Δ9-tetrahydrocannabinol (THC-HS) by complexation with random methylated beta cyclodextrin (RAMEB). An inclusion complex of THC-HS/RAMEB was prepared by freeze-drying THC-HS and cyclodextrin (1:2 and 1:10 ratios). Stability was evaluated at 4°C, 25°C and 40°C in open and closed vials over a period of 1 month. Diffusion of THC-HS from THC-HS/RAMEB complex, across porcine buccal mucosa, was studied at 37°C, using side-by-side diffusion cells. The degradation rate was higher in open vials as compared to closed vials. The permeability of THC-HS/RAMEB (1:2) freeze-dried complex was increased four-fold and that of the 1:10 complex increased two-fold compared to the permeability of the THC-HS alone. The inclusion complex of THC-HS/RAMEB significantly enhances the thermal stability and permeation properties of THC-HS.

Effect of temperature on stability of THC-HS: RAMEB complex.

Effect of RAMEB on permeability of THC-HS.

Acknowledgements: Grant Number P20RR021929 – National Center For Research Resources (NIH/NCRR). References: [1] Munjal M, et al. (2006), AAPS Pharm SciTech, 7(3): E1–E12