Satyanarayana Valiveti

Comparison of artificial sebum with human and hamster sebum samples.

To understand drug delivery to the sebum filled hair and sebaceous follicles, it is essential to use an artificial sebum as a surrogate of the human sebum for the investigation of drug transport properties. Artificial sebum L was developed in-house based on the chemical similarity to human sebum. The partition and diffusion of model compounds (ethyl 4-hydroxybenzoate, butyl 4-hydroxybenzoate, and hexyl 4-hydroxybenzoate) were measured in human sebum, hamster ear and body sebum (a commonly used animal model), and four representative artificial sebum samples (N, S, F, and L) in which artificial sebums, N, S and F were selected based on the available literature. DSC and NMR studies were also conducted on all sebums to compare their melting properties and chemical compositions. In vitro studies show that the partition coefficients of the three model compounds in artificial sebum L were similar to that of human sebum, whereas the hamster ear and body sebum, and other three artificial sebum samples were different from that of human sebum. Additionally, the in vitro sebum flux (microg/(cm(2)min) of three model compounds through artificial sebum L was closer to that of human sebum when compared with the other three artificial sebum (N, S and F), hamster body and hamster ear sebum. The results of this study indicate that the artificial sebum L could be used as an alternative to human sebum, as the physicochemical properties of this artificial sebum is relatively similar to human sebum.

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

AbstractPurpose. 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 flow-through 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.

Human skin permeation of Δ8‐tetrahydrocannabinol, cannabidiol and cannabinol

The purpose of this study was to quantify the in‐vitro human skin transdermal flux of Δ8‐tetrahydrocannabinol (Δ8‐THC), cannabidiol (CBD) and cannabinol (CBN). These cannabinoids are of interest because they are likely candidates for transdermal combination therapy. Differential thermal analysis and in‐vitro diffusion studies with human tissue were completed for the compounds. Heats of fusion, melting points and relative thermodynamic activities were determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue concentration and lag times were measured in the diffusion experiments. CBN had a lower heat of fusion and corresponding higher calculated relative thermodynamic activity than CBD. Ethanol concentrations of 30 to 33% significantly increased the transdermal flux of Δ8‐THC and CBD. Tissue concentrations of Δ8‐THC were significantly higher than for CBN. Lag times for CBD were significantly smaller than for CBN. The permeabilities of CBD and CBN were 10‐fold higher than for Δ8‐THC. Combinations of these cannabinoids with ethanol will be further studied in transdermal patch formulations in vitro and in vivo, as significant flux levels of all the drugs were obtained. CBD, the most polar of the three drugs, and other more polar cannabinoids will also be the focus of future drug design studies for improved transdermal delivery rates.

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.

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 (α) 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).

Permeation of WIN 55,212-2, a potent cannabinoid receptor agonist, across human tracheo-bronchial tissue in vitro and rat nasal epithelium in vivo

The aim of this study was to investigate the intranasal absorption of R‐(+)‐WIN 55,212‐2 mesylate in vivo and in vitro. Permeation experiments of R‐(+)‐WIN 55,212‐2 formulations with 2% dimethyl‐β‐cyclodextrin (DMβCD), 2% trimethyl‐β‐cyclodextrin (TMβCD) or 2% randomly methylated‐β‐cyclodextrin (RAMβCD) in 1:1 propylene glycol/saline and 1.5% propylene glycol + 3% Tween 80 in saline were conducted using EpiAirway™ tissue and an anesthetized rat nasal absorption model, respectively. Samples were analysed by liquid chromatography‐mass spectrometry. Mucosal tolerance was screened using paracellular marker permeation and tissue viability as indices. Nasal absorption of WIN 55,212‐2 was rapid, with a tmax (time of peak concentration) of 0.17 to 0.35 h in vivo. Relative to 1.5% propylene glycol + 3% Tween 80 (control), 1:1 propylene glycol/saline, RAMβCD, DMβCD and TMβCD resulted in 24‐, 20‐, 17‐ and 10‐fold WIN 55,212‐2 permeation increases in vitro, respectively. The in vivo absolute bioavailabilities were also increased with 1:1 propylene glycol/saline, RAMβCD, DMβCD and TMβCD compared to 1.5% propylene glycol + 3% Tween 80 (0.15 vs. 0.66‐0.77). The viability of the EpiAirway™ tissues was significantly reduced by DMβCD and TMβCD formulations. This study showed that WIN 55,212‐2 mesylate can be delivered via the nasal route. Absorption of R‐(+)‐WIN 55,212‐2 was rapid and bioavailability was significantly improved using methylated cyclodextrins and propylene glycol‐based cosolvent.