Honglei Xi

Formulation and in vitro/in vivo correlation of a drug-in-adhesive transdermal patch containing azasetron.

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two-chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO-TAK 87-9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy-induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches.

Transdermal patches for site-specific delivery of anastrozole: In vitro and local tissue disposition evaluation

Anastrozole is a potent aromatase inhibitor and there is a need for an alternative to the oral method of administration to target cancer tissues. The purpose of the current study was to prepare a drug-in-adhesive transdermal patch for anastrozole and evaluate this for the site-specific delivery of anastrozole. Different adhesive matrixes, permeation enhancers and amounts of anastrozole were investigated for promoting the passage of anastrozole through the skin of rats in vitro. The best in vitro skin permeation profile was obtained with the formulation containing DURO-TAK 87-4098, IPM 8% and anastrozole 8%. For local tissue disposition studies, the anastrozole patch was applied to mouse abdominal skin, and blood, skin, and muscle samples were taken at different times after removing the residual adhesive from the skin. High accumulation of the drug in the skin and muscle tissue beneath the patch application site was observed in mice compared with that after oral administration. These findings show that anastrozole transdermal patches are an appropriate delivery system for application to the breast tumor region for site-specific drug delivery to obtain a high local drug concentration.

Effect of unsaturated menthol analogues on the in vitro penetration of 5-fluorouracil through rat skin

To explore the structure-activity relationship for terpenes as transdermal penetration enhancers, unsaturated menthol analogues were synthesized in our study, including p-menth-1-en-3-ol (Compd 1), p-menth-4-en-3-ol (Compd 2), p-menth-4(8)-en-3-ol (Compd 3) and p-menth-8-en-3-ol (Compd 4). Their enhancing activity on the penetration of 5-fluorouracil through rat skin was evaluated by in vitro experiments. Attenuated total reflection-Fourier transform infrared spectroscopy, molecular modeling and transepidermal water loss (TEWL) were introduced to investigate the enhancer induced alteration in different skin lipid domains. The results indicated that Compd 3 achieved the highest enhancement ability with an enhancement ratio of 3.08. Other analogues were less effective than Compd 3, and no significant difference was found between them and menthol. Treatment of rat skin with these enhancers did not produce any shift in the stretching vibration of the methylene in hydrophobic lipid chains, but significantly improved the polar pathway across the rat skin as suggested by the increased TEWL. Molecular modeling results suggested that polar head groups of the skin lipids provided the main binding site for enhancer action. These findings indicated that the studied compounds enhanced drug transport by interacting with the polar domain of the skin lipid, instead of by affecting the arrangement of the hydrophobic chains.

Silicone adhesive, a better matrix for tolterodine patches—a research based on in vitro/in vivo studies

Objective: To design and optimize a drug-in-adhesive (DIA) type transdermal patch for tolterodine (TOL) based on acrylic and silicone matrixes. Methods: Initial in vitro studies were conducted to optimize the formulations. Two types of adhesive matrixes, drug loading, and enhancers were evaluated on the TOL transport across rabbit skin. For in vivo studies, patches were administered to rabbit abdominal skin. Pharmacokinetic assessments were performed based on plasma level of TOL up to 28 h for acrylic patch and 52 h for silicone patch after topical application. Results: The final formulation of acrylic adhesive type patch consisted of 10% TOL (w/w) and 5.8 × 10−4 mol isopropyl myristate (IPM) and 2.9 × 10−4 mol Span 80 in per unit gram (mol/g) of adhesive, while 2.5% TOL (w/w) and 2.9 × 10−4 mol/g IPM for silicone adhesive type patch. Comparison of the pharmacokinetic parameters between two types of patches showed that the steady-state concentration of silicone type patch was 2-fold higher than that of acrylic type patch being 0.97 mg/L versus 0.49 mg/L, and the absolute bioavailability was 27.5% for silicone type patch and 6.3% for acrylic type patch, respectively. In addition, the prediction of in vivo drug level from the in vitro permeation data of silicone adhesive formulation was in good agreement with actual observed concentration data in rabbits. Conclusion: These results indicate that the silicone type of TOL patch is an appropriate delivery system for the treatment of overactive bladder (OAB).

In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers.

Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy. Objective: As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro. Methods: The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated. Results: It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44 ± 12.03) μg·cm−2·h−1 to (1044.95 ± 71.99) μg·cm−2·h−1 (P < 0.01). Conclusion: These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro.

Formation of Ion Pairs and Complex Coacervates

Over the past several decades, there have been important advances in the field of transdermal drug delivery. However, for most drugs, the successful transdermal delivery is still limited due to the barrier function of the skin. The skin, especially its outermost layer, the stratum corneum (SC), poses a formidable barrier to the penetration of exogenous substances into the skin and only allows the penetration of drugs with low molecular weight, suitable solubility in oil and water, moderate partition coefficient, and low melting point. Generally, hydrophilic ionized drugs and other drugs with unfavorable physicochemical properties cannot pass adequately the skin barrier to exert their pharmacological effect. Ion pairs and complex coacervates are effective strategies to facilitate the transdermal penetration of this type of drugs.

l-Carvyl esters as penetration enhancers for the transdermal delivery of 5-fluorouracil.

To develop effective and safe penetration enhancers, a series of l-carvyl esters, namely, 5-isopropenyl-2-methylcyclohex-2-en-1-yl heptanoate (C-HEP), 5-isopropenyl-2- methylcyclohex-2-en-1-yl octanoate (C-OCT), 5-isopropenyl-2-methylcyclohex-2-en-1-yl decanoate (C-DEC), 5-isopropenyl-2-methylcyclohex-2-en-1-yl dodecanoate (C-DOD), 5-isopropenyl-2-methylcyclohex-2-en-1-yl tetradecanoate (C-TET), and 5-isopropenyl-2-methylcyclohex-2-en-1-yl palmitate (C-PAL), was synthesized from l-carveol and saturated fatty acids (C7–C16). The volatility of l-carveol and l-carvyl esters was evaluated by a live weight loss experiment. The enhancing effects of l-carvyl esters on 5-fluorouracil (FU) were investigated in the in vitro permeation experiment on rat skin. The stratum corneum (SC) uptakes of the enhancers were tested in vitro by gas chromatography. Only the l-carvyl esters with a moderate SC uptake, namely, C-OCT (C8), C-DEC (C10), and C-DOD (C12), showed a potential to enhance FU skin permeation. An evident parabolic relationship was found between the permeation enhancement of FU and the SC uptake of the l-carvyl esters. The l-carvyl esters with a chain length of C8–C12 seemed to be favorable for FU.