Effect of pH, vehicles and chemical enhancers on the skin permeation of loratadine

The objective of this work was to investigate feasibility of transdermal delivery of loratadine. Effect of pH, vehicles and chemical enhancers on the skin permeation of loratadine was studied in vitro, using rat abdominal skin as a barrier. In the permeation studies, horizontal 2-chamber diffusion cells were used. The amount of loratadine transferred through the skin into the receptor solution, 30 % ethanolsaline solution (v/v), was determined at a predetermined time intervals for 8 h using a high performance chromatography (HPLC). The results showed that transdermal transport of loratadine was not significantly affected by pH. 30 % ethanol-saline solution in donor chamber was more effective than 40 % PGsaline solution in deliverying loratadine in vitro. Among the permeation enhancers (azone, oleic acid, menthol, and borneol) examined, l-menthol and borneol showed the greatest enhancing effect using ethanol as a solvent. Overall, these findings allow a rational approach for designing an effective loratadine transdermal delivery system, it is worth carrying out further investigations.Colegio de Farmacéuticos de la Provincia de Buenos Aire

“PFH/AGM-CBA/HSV-TK/LIPOSOME-Affibody”: Novel Targeted Nano Ultrasound Contrast Agents for Ultrasound Imaging and Inhibited the Growth of ErbB2-Overexpressing Gastric Cancer Cells

open access articleObjective: Gastric cancer is one of the most lethal malignancies in the world. However, the current research on the diagnosis and treatment of nano-ultrasound contrast agents in the field of tumor is mostly focused on breast cancer, ovarian cancer, prostate cancer, liver cancer, etc. Due to the interference of gas in the stomach, there is no report on the treatment of gastric cancer. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) therapy system is the most mature tumor suicide gene in cancer treatment. At the same time, in order to improve its safety and efficiency, we designed a gastric tumor targeted ultrasound-triggered phase-transition nano ultrasound contrast agent PFH/AGM-CBA/HSV-TK/Liposome (PAHL)-Affibody complex. Methods: In our study, guanidinylated SS-PAAs polymer poly(agmatine/N, N′-cystamine-bis-acrylamide) (AGM-CBA) was used as a nuclear localization vector of suicide gene to form a polyplex, perfluorohexane (PFH) was used as ultrasound contrast agent, liposomes were used to encapsulate perfluorohexane droplets and the polyplexes of AGM-CBA/HSV-TK, and affibody molecules were conjugated to the prepared PAHL in order to obtain a specific targeting affinity to human epidermal growth factor receptor type 2 (ErbB2) at gastric cancer cells. With the aid of ultrasound targeted microbubble destruction technology and the nuclear localization effect of AGM-CBA vector, the transfection efficiency of the suicide gene in gastric cancer cells was significantly increased, leading to significant apoptosis of gastric cancer cells. Results: It was shown that PAHL-Affibody complex was nearly spherical with an average diameter of 560 ± 28.9 nm, having higher and specific affinity to ErbB2 (+) gastric cells. In vitro experiments further confirmed that PAHL could target gastric cancer cells expressing ErbB2. In a contrast-enhanced ultrasound scanning study, the prepared ultrasound-triggered phase-change nano-ultrasound contrast agent, PAHL, showed improved ultrasound enhancement effects. With the application of the low-frequency ultrasound, the gene transfection efficiency of PAHL was significantly improved, thereby inducing significant apoptosis in gastric cancer cells. Conclusion: This study constructs PFH/AGM-CBA/HSV-TK/Liposome-Affibody nano ultrasound contrast agent, which provides new ideas for the treatment strategy of ErbB2-positive gastric cancer and provides some preliminary experimental basis for its inhibitory effect

A simple method to improve the dissolution of repaglinide and exploration of its mechanism

In the present study, a simple and rapid method was developed to improve the in vitro dissolution of repaglinide, an oral antidiabetic drug, which was based on addition of meglumine in 50% (v/v) ethanol to dissolve repaglinide, and the drug dissolved in meglumine/50% ethanol was used directly with a binder to prepare tablets. The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum (IR), ultraviolet (UV) measurement through dual wavelength, differential scanning calorimetry (DSC) and X-ray powder diffraction methods. Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography (HPLC) method. The solubility data showed that with the meglumine concentration increasing, the solubility of repaglinide was increased. Meanwhile, tablets with the molar ratio of repaglinide and meglumine 1:2 (n/n) resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine, and nearly equal to the commercial preparations of NovoNorm®, which concluded that meglumine had a great role in promoting the dissolution of repaglinide. The results of IR and UV dual wavelength methods suggested the formation of repaglinide–meglumine (REP–MEG) molecular complex. DSC results showed that the melting peak of repaglinide disappeared in the REP–MEG coprecipitate, which indicated that repaglinide was stable when existing at amorphous or molecular state. The experiment of X-ray powder diffraction showed that with the solubilization of meglumine, the crystal diffraction peak of repaglinide disappeared, which further inferred that repaglinide was formed complexes with meglumine. It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry. This study also provides a feasible way to enhance the dissolution of drugs with low solubility, which will be leading to improved bioavailability of these drugs

Liquisolid technique and its applications in pharmaceutics

Most of the newly developed drug candidates are lipophilic and poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder, is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened

A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy

Venous malformation (VM), which causes severe damage to patients’ appearance and organ function, is one of the most common vascular malformations. At present, many drugs in clinical treatment cause various adverse reactions. Herein, we synthesized cationic amphiphilic gelators (TA6, TA8, and TA9) by introducing saturated carbon chains of different lengths to tranexamic acid (TA), which could self-assemble into low-molecular-weight gels (LMWGs) as drug delivery carriers by hydrogen bonds, van der Waals forces, and hydrophobic interactions. The rheological properties, gelation driving force and drug release profiles of TA6, TA8, and TA9 hydrogels were characterized, and the results indicated that the hydrogels prepared in this study possessed the typical characteristics of a gel and could release drugs slowly. More importantly, the TA9 gelator showed significant pharmacological activity, in that it served as both an active drug compound and a drug carrier. The in vitro experiments demonstrated that TA9 induced HUVECs death and hemolysis by destroying cell membranes in a dose-dependent manner, and caused cell death and hemolysis at a concentration of 0.09 µM/mL. Meanwhile, we found TA9 could interact not only with fibrinogen, but also with other endogenous molecules in the blood. After the administration of TA9 hydrogel for 15 days, macroscopic imaging and histological evaluation in mice and rabbits displayed obvious thrombi, inflammatory reactions, and venous embolization, indicating that the mechanism of the TA9 hydrogel in treating VM was involved in two processes. Firstly, the TA9 hydrogel relied on its mechanical strength to physically block veins and continuously release TA9, in situ, for targeted therapy. Then, TA9 destroyed endothelial cells and damaged venous walls critically, causing thrombi. Most excitingly, TA9 was hydrolyzed to TA by enzymes that inhibited the degradation of thrombi by plasmin to prolong the embolization time and to promote venous fibrosis. Compared with other clinically available sclerosants, the degradation of TA9 also empowered a better biocompatibility and biodegradability for the TA9 hydrogel. In conclusion, we synthesized a potentially safe and effective derivative of TA and developed a low-molecular-weight gel as a self-delivery system for TA in treating VM

Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration

The purpose of this study was to compare the pharmacokinetic profiles of tetramethylpyrazine phosphate (TMPP) in plasma and extracellular fluid of the cerebral cortex of rats via three delivery routes: intranasal (i.n.), intragastric (i.g.) and intravenous (i.v.) administration. After i.n., i.g. and i.v. administration of a single-dose at 10 mg/kg, cerebral cortex dialysates and plasma samples drawn from the carotid artery were collected at timed intervals. The concentration of TMPP in the samples was analyzed by HPLC. The area under the concentration–time curve (AUC) and the ratio of the AUCbrain to the AUCplasma (drug targeting efficiency, DTE) was calculated to evaluate the brain targeting efficiency of the drug via these different routes of administration. After i.n. administration, TMPP was rapidly absorbed to reach its peak plasma concentration within 5 min and showed a delayed uptake into cerebral cortex (tmax=15 min). The ratio of the AUCbrain dialysates value between i.n. route and i.v. injection was 0.68, which was greater than that obtained after i.g. administration (0.43). The systemic bioavailability obtained with i.n. administration was greater than that obtained by the i.g. route (86.33% vs. 50.39%), whereas the DTE of the nasal route was 78.89%, close to that of oral administration (85.69%). These results indicate that TMPP is rapidly absorbed from the nasal mucosa into the systemic circulation, and then crosses the blood–brain barrier (BBB) to reach the cerebral cortex. Intranasal administration of TMPP could be a promising alternative to intravenous and oral approaches

RETRACTED: Chen et al. A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy. <i>Pharmaceutics</i> 2022, <i>14</i>, 343

The Pharmaceutics Editorial Office retracts the article, “A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy” [...

Exosome-based small RNA delivery: Progress and prospects

RNA interfering (RNAi), mediated by small interfering RNAs and microRNAs, is currently one of the most promising tools of gene therapy. Small RNAs are capable of inducing specific post-transcriptional gene silencing, providing a potentially effective platform for the treatment of a wide array of diseases. However, similar to other nucleic acid-based drugs, the major hurdle of RNAi therapy is lack of efficient and non-immunogenic delivery vehicles. Currently, viruses, synthetic polymers, and lipid-based carriers are among the most widely studied vehicles for small RNA delivery. However, many drawbacks are reported to be associated with these delivery vehicles. There is a pressing need to replace them with more efficient and better-tolerated approaches. Exosomes secreted from the endocytic compartment of live cells, are a subtype of endogenous extracellular vesicles that transfer genetic and biochemical information among different cells, thus playing an important role in cell-cell communication. Recently, accumulating attention has been focused on harnessing exosomes as nanaocarriers for small RNAs delivery. Due to their natural role in shuttling endogenous nucleic acid in our body, exosomes may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing foreign RNA carriers. Importantly, exosomes own intrinsic homing capacity that can guide small RNAs across natural membranous barriers. Moreover, such a capacity can be further improved by adding appropriate targeting moieties. In this manuscript, we briefly review the progress and challenges of RNAi therapy, and discuss the potential of exosomes' applications in small RNA delivery with focus on the most recent advances in exosome-based small RNA delivery for disease therapy