Enzyme Responsive Vaginal Microbicide Gels Containing Maraviroc and Tenofovir Microspheres Designed for Acid Phosphatase-Triggered Release for Pre-Exposure Prophylaxis of HIV-1: A Comparative Analysis of a Bigel and Thermosensitive Gel

The challenges encountered with conventional microbicide gels has necessitated the quest for alternative options. This study aimed to formulate and evaluate a bigel and thermosensitive gel, designed to combat the challenges of leakage and short-residence time in the vagina. Ionic-gelation technique was used to formulate maraviroc and tenofovir microspheres. The microspheres were incorporated into a thermosensitive gel and bigel, then evaluated. Enzyme degradation assay was used to assess the effect of the acid phosphatase enzyme on the release profile of maraviroc and tenofovir microspheres. HIV efficacy and cytotoxicity of the microspheres were assessed using HIV-1-BaL virus strain and HeLa cell lines, respectively. Maraviroc and tenofovir release kinetics followed zero-order and Higuchi model kinetics. However, under the influence of the enzyme, maraviroc release was governed by first-order model, while tenofovir followed a super case II transport-mechanism. The altered mode of release and drug transport mechanism suggests a triggered release. The assay of the microspheres suspension on the HeLa cells did not show signs of cytotoxicity. The thermosensitive gel and bigel elicited a progressive decline in HIV infectivity, until at concentrations of 1 μg/mL and 0.1 μg/mL, respectively. The candidate vaginal gels have the potential for a triggered release by the acid phosphatase enzyme present in the seminal fluid, thus, serving as a strategic point to prevent HIV transmission.

NEW DOSAGE FORM IN AYURVEDA - THERMO-SENSITIVE VAGINAL GEL OF PVK EXTRACT

Rasashastra & Bhaisajya Kalpana is the prime branch of Ayurveda because of the preparation of medicine described in this branch. In ancient times pharmacokinetics of the drug was described in the principle of Dosha and Dushya which is a comprehensive matter for Ayurvedic professionals. But for global acceptance, we need to describe this view (pharmacokinetics) in the form of pharmacological language and convert this ancient medicine in the form of new dosage forms like gel, granules, syrup etc. Panchavalkal Kashaya was described for the treatment of women disease wounds and ulcers in different Ayurvedic texts like Charaka Samhita, Sharangdhara Samhita, Kashyapa Samhita, Bharat Bhaisajya Ratnakar, Bhava-Prakash. In this article, an attempt has been made to describe how to prepare the thermo-sensitive vaginal gel form, of Panchavalkal Kashaya extract for the use of women diseases like leucorrhoea. The thermosensitive gel is in the liquid form at room temperature (20- 25°C) and undergoes gelation when in contact with body fluid (35-37°C). There are many thermo-sensitive polymers like cellulose derivatives, poloxamer, poly (ethylene oxide) /poly (D, L- lactic acid-glycolic acid). Keywords: Ayurveda, Panchvalkal Kashaya, Thermo-sensitive gel, Charaka Samhita.

Suppression of Intracellular Reactive Oxygen Species in Human Corneal Epithelial Cells via the Combination of Quercetin Nanoparticles and Epigallocatechin Gallate and In Situ Thermosensitive Gel Formulation for Ocular Drug Delivery

Oxidative stress can cause several severe ophthalmological diseases. In this study, we developed a thermosensitive gel as a delivery system for two antioxidant substances, namely, quercetin and epigallocatechin gallate. The quercetin was loaded in the PLGA nanoparticles using a solvent displacement method. The physical and chemical stability of the quercetin nanoparticles were evaluated, and the degradation kinetics of the quercetin in the nanoparticles was investigated. The in vitro antioxidant and intracellular reactive oxygen species inhibition of the quercetin nanoparticles, combined with the epigallocatechin gallate (EGCG), were determined using a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and a 2,7-dichlorodihydrofluorescein fluorescent probes, respectively. The thermosensitive gel loaded with the quercetin nanoparticles and EGCG was formulated. We confirmed that quercetin nanoparticles displayed the desired physical characteristics, release kinetics, and stability. The combination of quercetin nanoparticles and EGCG suggested the additive effect of antioxidant activity. We also demonstrated the superior intracellular ROS inhibition activity of the quercetin nanoparticles and EGCG with n-acetyl cysteine. The thermosensitive gel showed an appropriate gelation temperature and time for ocular drug delivery. Our results provide promising prospects for applying the thermosensitive gel loaded with quercetin nanoparticles and EGCG as an efficient drug delivery system for antioxidant activity in human corneal epithelial cells.

Control of Inflammation by a Thermosensitive Lovastatin-Loaded Hydrogel

Objectives: Statins have been proposed as interesting pharmacological treatment for periodontal diseases because of their pleiotropic effect. Statins modulate bone metabolism, immuno-inflammatory complex and bacterial clearance. However, their systemic administration is associated to side effects. Therefore, their local administration has been suggested. The aim of this study was to evaluate the potential pro-regenerative effects of a thermosensitive gel functionalized by lovastatin on Porphyromonas gingivalis elicited inflammation in vitro and bone regeneration in vivo. Methods: Physical and chemical properties of a thermosensitive lovastatin loaded chitosan gel were evaluated. The anti-inflammatory effect of lovastatin was assessed in vitro by RT-qPCR and Elisa. In vivo, a model of calvarial defect was used to confirm the pro-regenerative effect on periodontal wound healing. Results: In vitro, lovastatin was able to decrease TNF-α secretion in P.gingivalis stimulated cells (p<0.05). In vivo, local application of chitosan gel functionalized with lovastatin improved wound healing at calvarial site in comparison with untreated controls and mice treated with systemic statin administration. Conclusions: This study demonstrates the potential regenerative effects of local application of a thermosensitive gel functionalized by lovastatin.

Rapid High-Performance Liquid Chromatography Method for Levodopa Quantitation at Low UV Wavelength: Application of Pharmacokinetics Study in Rat Following Intranasal Delivery

Levodopa is widely administered orally in clinical treatment of Parkinson’s disease; however, due to levodopa various oral absorption and low bioavailability, intranasal delivery seems to be a suitable alternative route of administration. Pluronic F-127 is a thermosensitive polymer, which can form gel at nasal cavity temperature and increase drug residence time. In this study, a rapid High Performance Liquid Chromatography (HPLC) method was validated in presence of internal standard to determine pharmacokinetic parameters following levodopa administration to rats in three different intravenous solution, intranasal solution and intranasal thermosensitive gel groups. A precised (96.7%) and accurate (95.0%) HPLC method was validated at low UltraViolet (UV) wavelength of 208 nm that showed limit of detection and limit of quantitation of 59 and 177 ng/mL, respectively. Specificity results showed no interference for levodopa with endogenous serum materials, and serum extraction efficacy was 93%. Pharmacokinetic parameters including bioavailability of 75 and 85% with mean residence time of 78 and 94 min were estimated for intranasal solution and thermosensitive gel using the validated HPLC method, which indicated that levodopa nasal gel may be a good alternative with appropriate pharmacokinetic outcome. Therefore, the validated levodopa HPLC analysis method at low UV wavelength was efficiently applied in pharmacokinetic study.