Overdose and Alcohol Sensitive Immediate Release System (OASIS) for Deterring Accidental Overdose or Abuse of Drugs.

Death from an accidental or intentional overdose of sleeping tablets has increased exponentially in the USA. Furthermore, the simultaneous consumption of sleeping tablets with alcoholic beverages not only intensifies the effect of sleeping tablets but also leads to blackouts, sleepwalking, and death in many cases. In this article, we proposed a unique and innovative technology to prevent multi-tablet and alcohol-associated abuse of sleeping tablet. Agonist- and antagonist-loaded polymeric filaments of appropriate Eudragit® polymers were prepared using hot melt extrusion. Metoprolol tartrate and hydrochlorothiazide were used as model drugs in place of zolpidem tartrate (agonist-BCS class I) and flumazenil (antagonist-BCS class IV), respectively. Crushed filaments were converted into a tablet with a novel rapidly soluble co-processed alkalizing agent. Dissolution studies of single tablet and multiple tablets (5) in fasted state simulated gastric fluid (FaSSGF) confirmed that the release of the agonist was significantly (p < 0.0001) reduced in multi-tablet dissolution. Furthermore, the release of antagonist was significantly higher when tablet was exposed to FaSSGF+20% ethanol and various alcoholic beverages. Thus, appropriate use of Eudragit® polymer's chemistry could help design a tablet to prevent the release of agonist in case of overdose and simultaneous release of antagonist when consumed with alcohol.

Development of a solid supersaturated self-nanoemulsifying preconcentrate (S-superSNEP) of fenofibrate using dimethylacetamide and a novel co-processed excipient.

BACKGROUND: Recrystallization of drug and incomplete drug release from liquisolid formulation are two major hurdles in the development of a supersaturated self-nanoemulsifying drug delivery system. The aim of this research work was to develop a solid supersaturated self-nanoemulsifying drug delivery system of fenofibrate (FB) for enhanced dissolution. METHODS: FB loaded supersaturated self-nanoemulsifying preconcentrate (superSNEP) was prepared using dimethyl acetamide (DMA), medium chain triglycerides (MCT), and kolliphor EL. Co-processed excipients (CPE) prepared using inorganic microporous silica (Neusilin US2, Florite 100, or Aerosil 200) and hydrophilic polymers (Polyvinyl alcohol, HPMC, and Kollidon VA64) were evaluated for flow property, BET surface area, and adsorption capacity. Lipophilic fluorescent probe (coumarin-6) was used to investigate the extent of self-emulsification. The formulation was further characterized for solid state, in-vitro cytotoxicity in caco-2 cell line and in-vitro dissolution in a sink and non-sink conditions. RESULTS: Optimized superSNEP with 20% w/v FB loading spontaneously formed nanoglobules of 40 ± 2.7 nm. DMA based self-nanoemulsifying system was found to be nontoxic to Caco-2 cell even at a very high concentration. CPE prepared using PVA and Florite 100 (1:1 weight ratio) showed the highest adsorption capacity (1 mL/g) and complete release of oil as depicted by fluorescence study. DSC thermogram and PXRD of S-superSNEP confirmed that FB remained in a solubilized state. S-superSNEP showed significantly faster and higher dissolution of FB in sink and non-sink conditions compared to the plain API. CONCLUSION: DMA and PVA-F100 based novel co-processed excipient could be potentially useful for the development of solid supersaturated self-nanoemulsifying drug delivery system for enhancing dissolution of lipophilic drugs.

Abuse Deterrent Immediate Release Egg-Shaped Tablet (Egglets) Using 3D Printing Technology: Quality by Design to Optimize Drug Release and Extraction.

Opioid abuse is a growing problem and has become a national health crisis over the past decade in the USA. Oral ingestion, snorting, and injection are the most commonly employed routes of abuse for an immediate release product. To circumvent these issues, we have developed an egg-shaped tablet (egglet) using fused deposition modeling (FDM) 3D printing technology. Drug-loaded polymeric filaments (1.5 mm) were prepared using hot melt extrusion (HME) followed by printing into egglets of different sizes and infill densities. Based on printability and crush resistance, polyvinyl alcohol (PVA) was found to be the most suitable polymer for the preparation of abuse deterrent egglets. Further, egglets were evaluated and optimized for mechanical manipulation using household equipment, milling, particle size distribution, solvent extraction, and drug release as per the FDA guidance (November 2017). A multifactorial design was used to optimize egglets for solvent extraction and drug release. Extreme hardness (> 500 N) and very large particle size (> 1 mm) on mechanical manipulation confirmed the snorting deterring property while less than 15% drug extraction in 5 min (% Sext) demonstrated the deterrence for injection abuse. Quality target product profile D85 < 30 min and % Sext < 15 was achieved with egglets of 6 mm diameter, 45% infill density, and 15% w/w drug loading. Dose of drug can be easily customized by varying dimension and infill density without altering the composition. HME coupled with FDM 3D printing could be a promising tool in the preparation of patient-tailored, immediate release abuse deterrent formulation.

Erlotinib-Valproic Acid Liquisolid Formulation: Evaluating Oral Bioavailability and Cytotoxicity in Erlotinib-Resistant Non-small Cell Lung Cancer Cells.

Lung cancer patients develop acquired resistance to tyrosine kinase inhibitors including erlotinib (ERL) after few months of primary treatment. Evidently, new chemotherapy strategies to delay or overcome the resistance are urgently needed to improve the clinical outcome in non-small cell lung cancer (NSCLC) patients. In this paper, we have investigated the cytotoxic interaction of ERL and valproic acid (VA) in ERL-resistant NSCLC cells and developed a liquisolid formulation of ERL-VA for improving oral bioavailability of ERL. ERL is weakly basic, biopharmaceutical classification system (BCS) class II drug with extremely poor aqueous solubility while VA is a branched chain fatty acid. Ionic interaction between ERL and VA (1:2 M ratio) resulted in significant enhancement in saturation solubility of ERL at different pH range. Liquisolid formulation of ERL-VA (EVLF) developed using PEG 400 and mesoporous calcium silicate was characterized for solid state and in vitro dissolution in biorelevant dissolution medium (FaSSIF and FeSSIF). Cytotoxicity of ERL was enhanced by 2-5 folds on co-incubation with VA in HCC827/ERL cell line. Flow cytometry analysis using AnnexinV-FITC assay demonstrated that VA and ERL alone have poor apoptotic effect on HCC827/ERL cells while combination showed around 69% apoptotic cells. Western blot analysis confirmed the role of survivin in overcoming resistance. In vivo pharmacokinetic studies of EVLF in rats demonstrated a 199% relative bioavailability compared to ERL suspension. Thus, EVLF could be a promising alternative to current ERL formulations in the treatment of NSCLC.

Aerosolized nanoliposomal carrier of remdesivir: an effective alternative for COVID-19 treatment in vitro.

Aim: To formulate an aerosolized nanoliposomal carrier for remdesivir (AL-Rem) against coronavirus disease 2019. Methods: AL-Rem was prepared using modified hydration technique. Cytotoxicity in lung adenocarcinoma cells, stability and aerodynamic characteristics of developed liposomes were evaluated. Results: AL-Rem showed high encapsulation efficiency of 99.79%, with hydrodynamic diameter of 71.46 ± 1.35 nm and surface charge of -32 mV. AL-Rem demonstrated minimal cytotoxicity in A549 cells and retained monolayer integrity of Calu-3 cells. AL-Rem showed sustained release, with complete drug release obtained within 50 h in simulated lung fluid. Long-term stability indicated >90% drug recovery at 4°C. Desirable aerosol performance, with mass median aerodynamic diameter of 4.56 ± 0.55 and fine particle fraction of 74.40 ± 2.96%, confirmed successful nebulization of AL-Rem. Conclusion: AL-Rem represents an effective alternative for coronavirus disease 2019 treatment.

Lay abstract Remdesivir is one of the first drugs approved for the treatment of coronavirus disease 2019. Currently, it is administered via an injection into the bloodstream. This means that the drug circulates around the entire body and only a limited amount reaches the diseased site ­ the lungs. Frequent dosing is therefore required, which needs expert personnel and multiple hospital visits and can result in serious side effects. In this study, the authors developed specialized, nanosized particles containing the drug remdesivir that can be administered directly into the lungs. This could drastically minimize side effects, enhance efficacy and allow easy self-administration at home. The results of the study are promising but require additional investigation.

ß-cyclodextrin polymer/Soluplus® encapsulated Ebselen ternary complex (EßpolySol) as a potential therapy for vaginal candidiasis and pre-exposure prophylactic for HIV.

Epidemiological findings have discussed recurrent and persistent vulvovaginal candidiasis to be a major manifestation of HIV infected women. Conversely, women with vulvovaginal candidiasis have higher risk of acquiring HIV transmitted during intercourse. Common treatments for such conditions include combined antiretroviral and antifungal therapy. Drug-Drug interaction is a major problem encountered due to common CYP450 metabolic pathway of azoles and antiretroviral drugs. Ebselen (EB), lipophilic, organo-selenium compound has demonstrated promising anti-HIV and anti-fungal activity. The aim of current research was to develop and characterize a rapidly soluble and non-cytotoxic vaginal film of ebselen which could serve dual purpose of treating vulvovaginal candidiasis and pre-exposure prophylactic (PrEP) against HIV. Ebselen/cyclodextrin polymer/Soluplus® (1:10:10) ternary complex (EßpolySol) showed 200 fold enhancement in aqueous solubility and no degradation of EB in thermogravimetry analysis. EßpolySol film with tensile strength of 33.12 ± 1.98 N/cm2 disintegrated within 30 sec, presented instant drug release with no apparent precipitation in simulated vaginal fluid. EßpolySol film showed compatibility with HEC-1A monolayer and HeLa cells compared to VCF®. EßpolySol film showed MIC of 20 µM against Candida species and IC50 of 0.71 µM against HIV.