Intranasal absorption of Delta(9)-tetrahydrocannabinol and WIN55,212-2 mesylate in rats.

The aim of this study was to examine the potential of the nasal route for systemic delivery of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and WIN55,212-2 mesylate. Anesthetized rats were surgically prepared to isolate the nasal cavity, into which Delta(9)-THC (10 mg/kg) or WIN55,212-2 (150 microg/kg) in propylene glycol alone or propylene glycol and ethanol (9:1) were administered. Rats were also administered Delta(9)-THC (1 mg/kg) and WIN55,212-2 (150 microg/kg) intravenously in order to determine absolute bioavailabilities of the nasal doses. Plasma Delta(9)-THC and WIN55,212-2 concentrations were determined by liquid chromatography/mass spectroscopy (LC/MS). The pharmacokinetics of the drugs after intranasal administration was best described by a one-compartment model with an absorption phase. WIN55,212-2 was absorbed more rapidly (T(max)=0.2-0.3h) than Delta(9)-THC (T(max)=1.5-1.6h) and to a higher extent than Delta(9)-THC. Addition of ethanol (10%) to the formulations had no significant effect on the C(max) after nasal administration (p>0.05). Furthermore, it had no significant effect on the absolute bioavailability (F(abs)): F(abs)=6.4+/-2.4% and 9.1+/-3.0% for Delta(9)-THC in propylene glycol, with and without ethanol, respectively. For WIN55,212-2, F(abs)=49.9+/-6.9% (propylene glycol alone) and 56.6+/-14.1% (propylene glycol with 10% ethanol). The results of the study showed that systemic delivery of Delta(9)-tetrahydrocannabinol and WIN55,212-2 could be achieved following nasal administration in rats.

LC-MS method for the estimation of delta8-THC and 11-nor-delta8-THC-9-COOH in plasma.

The aim of the present study was to develop a simple and sensitive LC-MS method for the estimation of delta8-tetrahydrocannabinol (delta8-THC) and its metabolite, 11-nor-delta8-tetrahydrocannabinol-9-carboxylic acid (11-nor-delta8-THC-9-COOH), in guinea pig plasma after topical drug application. The plasma samples were analyzed by LC-MS using negative-mode electrospray ionization detection and a simple liquid-liquid extraction technique. The mean recoveries for delta8-THC and its metabolite, 11-nor-delta8-THC-9-COOH, were 96.6 and 88.2%, respectively. The lower limits of quantification (LLOQ) for delta8-THC and 11-nor-delta8-THC-9-COOH were 3.97 and 7.26 nM, respectively. The topical treatment steady-state plasma concentrations of delta8-THC and 11-nor-delta8-THC-9-COOH were 8.24-27.63 and 19.66-23.17 nM, respectively, with a lag period of 0.3-2.2 h. This assay method is selective, sensitive, and reproducible for the determination of delta8-THC and 11-nor-delta8-THC-9-COOH at low concentrations in small volumes of plasma.

Intranasal delivery of recombinant human parathyroid hormone [hPTH (1-34)], teriparatide in rats.

The aim of this study was to explore the nasal route as an alternative to daily subcutaneous injections of hPTH (1-34). Anesthetized rats were surgically prepared and nasally dosed with aqueous solutions of hPTH (1-34). Plasma samples were assayed by radioimmunoassay and data generated fit to two-(intravenous) and one-(intranasal) compartment pharmacokinetic models using WinNonlin. The toxicity of hPTH (1-34) solution administered to the rats was assessed by screening its effect on transepithelial electrical resistance, potential difference, paracellular marker permeation, tissue viability, and protein leakage using the EpiAirway tissue model. The intranasal absorption of hPTH (1-34) was rapid; the absorption rate constants (alpha) were 33.2+/-24 h(-1) [without bovine serum albumin (BSA)] and 9.8+/-5.1 h(-1) (with 1% BSA). The maximum plasma concentrations (Cmax): 151+/-24 pg/mL (without BSA) and 176+/-37 (with 1% BSA) were attained within approximately 15 min. The intranasal bioavailabilities (Fabs) were 12.1+/-3.4% (without BSA) and 17.6+/-1.5% (with 1% BSA). The hPTH (1-34) formulation administered to the rats had no detrimental effect on the EpiAirway tissue epithelial electrical parameters and functional integrity. Based on the results of this study, the nasal route appears to be a prospective alternative to subcutaneous injections of hPTH (1-34).

Transdermal delivery of the synthetic cannabinoid WIN 55,212-2: in vitro/in vivo correlation.

PURPOSE: The aim of the current investigation was to evaluate the percutaneous absorption of the synthetic cannabinoid WIN 55,212-2 in vitro and in vivo. METHODS: The in vitro permeation studies of WIN 55,212-2 in human skin, hairless guinea pig skin, a polymer membrane with adhesive, and a skin/polymer membrane composite were conducted in flowthrough diffusion cells. The pharmacokinetic parameters for WIN 55,212-2 were determined after intravenous administration and topical application of Hill Top Chambers and transdermal therapeutic systems (TTS) in guinea pigs. RESULTS: The in vitro permeation studies indicated that the flux of WIN 55,212-2 through hairless guinea pig skin was 1.2 times more than that through human skin. The flux of WIN 55,212-2 through human and guinea pig skin was not significantly higher than that through the corresponding skin/polymer membrane composites. The mean guinea pig steady-state plasma concentrations after topical 6.3 cm2 chamber and 14.5 cm2 TTS patch applications were 5.0 ng/ml and 8.6 ng/ml, respectively. CONCLUSIONS: The topical drug treatments provided significant steady-state plasma drug levels for 48 h. The observed in vivo results from the Hill Top Chambers and TTS patches in the guinea pigs were in good agreement with the predicted plasma concentrations from the in vitro data.

In vitro/in vivo correlation studies for transdermal delta 8-THC development.

The present study was carried out in order to develop a transdermal therapeutic system (TTS) for Delta(8)-THC. The in vitro permeability studies of Delta(8)-THC in human skin and hairless guinea pig skin with and without a rate-controlling membrane were conducted in flow-through diffusion cells. Delta(8)-THC pharmacokinetic parameters were determined after topical application of transdermal patches and intravenous administration in guinea pigs. The in vitro results indicated that there was no significant difference in the mean flux or in the permeability coefficient of Delta(8)-THC in human skin versus hairless guinea pig skin. The flux of Delta(8)-THC through the human skin/membrane composite was not significantly lower than that through the hairless guinea pig skin/membrane composite; and the skin controlled the Delta(8)-THC delivery rate. Intravenous doses of Delta(8)-THC followed a two-compartment model with a significant distribution phase. On application of the TTS patch, the plasma concentration of Delta(8)-THC reached a mean steady-state level of 4.4 ng/mL within 1.4 h and was maintained for at least 48 h. Significant amounts of metabolites were observed in the plasma after topical application. The in vitro-study predicted plasma concentration following application of the transdermal patch was in agreement with the observed guinea pig plasma concentrations of Delta(8)-THC.