Effect of Terpenes on the enhancement of skin permeation of lipophilic drugs: A systematic review

Objectives@#The stratum corneum (SC) remains an obstacle to the passage of drugs applied topically. Several investigations have focused on enhancing the penetration of drugs through the SC by integrating permeation enhancers (PE) into the drug formulation. Terpenes are among the PE utilized in formulations and are categorized by the regulatory bodies as generally recognized as safe (GRAS). This study aimed to comparatively analyze the skin permeation enhancing effect of terpenes on lipophilic drugs. @*Methods@#The present study reviewed the effects of terpenes on the permeation of lipophilic small-molecule drugs through the skin using original research published between 2000 - 2022 retrieved from PubMed®. The search phrase used was (lipophilic drug) AND (terpene) AND (permeation enhancer). @*Results@#Terpenes increase the percutaneous permeation of lipophilic small molecule drugs by 1.06 – 256.80-fold. Linear correlation analysis of terpenes’ cLog P with enhancement ratio (ER) revealed moderate and strong positive correlations in pig skin (r = 0.21) and mouse skin (r = 0.27), and rat skin (r = 0.41) and human skin (r = 0.67), respectively. Drug cLog P is a poor (r = -0.06) predictor of permeation enhancement. Terpenes with cLog P higher than 2.40 had ER greater than 10. Higher ERs (>30) were recorded for nerolidol, carvacrol, borneol, terpineol, limonene, menthone, pulegone, and menthol among the terpene-chemical penetration enhancers. @*Conclusion@#cLog P of terpene-based chemical permeation enhancers (CPE) is strongly correlated with ER of lipophilic drugs across human skin. Non-polar groups in terpenes and hydrogen bond interactions by terpenes with SC lipid enhance cutaneous drug penetration of lipophilic drugs.

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

ABSTRACT Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.

Research Progress of Lipid Emulsion in the Treatment of Cardiovascular Drugs Poisoning / 中华急诊医学杂志

Cardiovascular drugs are commonly used in clinical medicine,which can cause refractory shock and cardiac arrest when poisoning.Lipid emulsion was mainly used for detoxification of lipophilic anesthetics poisoning in the past.Recently more and more studies and clinical cases suggest that lipid emulsion can be adopted as one of therapies for cardiovascular drugs poisoning.Now we review and focus on the research status of the lipid emulsion in the treatment of cardiovascular drugs poisoning,the related mechanisms of detoxification,therapeutic regimen and adverse effect.

Improving Oral Bioavailability of Agaricoglycerides by Solid Lipid-Based Self-Emulsifying Drug Delivery System.

Agaricoglyceride A (AGA), showed strong activities against neurolysin. The objectives of this study was to prepare solid self-emulsifying drug delivery system (sSEDDS) by spray drying the SEDDS (liquid system) using Aerosil 200 as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of AGA from sSEDDS. The AGA formulated in the sSEDDS was quickly and completely dissolved within 20min, both in 0.1N HCl and phosphate buffer pH 6.8 dissolution media, whereas AGA powder was significantly less dissoluble. Meanwhile, the sSEDDS formulation was stable for at least 90days at room temperature. the plasma levels of AGA in the solid SEDDS group at the dose level (15mg/kg) remained detectable for up to 1.5 h after the oral dose. After oral administration to rats, a significant increase (P<0.0001) in the Cpmax and AUC0→24 h were observed in the sSEDDS group when compared with the AGA powder group. Furthermore, AGA-loaded sSEDDS exerted significant antinociceptive properties and alleviated pain insults in mice. The results suggest that the sSEDDS could be considered and further evaluated for the oral delivery of lipophilic poorly soluble drugs for which an oral route of administration is desirable.