Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.

Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.

Dibutylstannanediyl (2Z,2'Z)-bis(4-(benzylamino)-4-oxobut-2-enoate inhibits prostate cancer progression by activating p38 MAPK/PPARα/SMAD4 signaling.

Organotin (IV) compounds are a focus of research for potential use in cancer chemotherapy. Here, we established anticancer profile of dibutyltin (IV) carboxylate derivatives in prostate cancer (PCa) model. We determined cytotoxicity of a library of dibutyltin (IV) carboxylate derivatives and observed that dibutylstannanediyl (2Z,2'Z)-bis(4-(benzylamino)-4-oxobut-2-enoate (Ch-620; 10 µM) was minimally toxic to normal fibroblasts. Ch-620 (1-1.25 µM) inhibited proliferation of PCa and melanoma cells on short- and long-term exposures with induction of cell cycle arrest. Ch-620 treatment increased population of apoptotic cells, as assessed by flow cytometry, and activated caspase 3. Proteomics showed activation of PPARα, with repression of SMAD4 and integrin ß5 (ITGB5) in Ch-620-treated PCa cells. Further analysis demonstrated that Ch-620 resulted in phosphorylation of p38 MAPK, upregulation of PPARα and decreased expression of SMAD4 and ITGB5 with reduced migration of PCa cells. In vivo studies in PC3M grafted athymic nude mice showed that Ch-620 (5 µg/week; 7 weeks) treatment reduced tumor growth as opposed to untreated controls. Immunoblot analysis of tumors demonstrated upregulated p-p38 MAPK and PPARα, followed by a decline in SMAD4 and ITGB5. Immunohistochemistry reinforced these results with increased caspase 3 and p-p38 MAPK and diminished Ki67 staining in Ch-620 treated animals. Taken together, our data indicate that Ch-620 inhibited proliferation of PCa through modulation of MAPK/PPARα/SMAD4 signaling. Organotin (IV) carboxylate compounds; specifically Ch-620 can be a potential anticancer agent for the treatment of PCa subject to detailed pre-clinical and clinical investigations. This unlocks prospects for the development of new tin-based drugs in cancer therapeutics.

Surfactant free synthesis of cationic nano-vesicles: A safe triple drug loaded vehicle for the topical treatment of cutaneous leishmaniasis.

The basic aim of the study was to develop and evaluate the triple drug loaded cationic nano-vesicles (cNVs), where miltefosine was used as a replacement of surfactant (apart from its anti-leishmanial role), in addition to meglumine antimoniate (MAM) and imiquimod (Imq), as a combination therapy for the topical treatment of cutaneous leishmaniasis (CL). The optimized formulation was nano-sized (86.2 ±â€¯2.7 nm) with high entrapment efficiency (63.8 ±â€¯2.1% (MAM) and 81.4 ±â€¯2.3% (Imq)). In-vivo skin irritation assay showed reduced irritation potential and a decrease in the cytotoxicity of cNVs as compared to conventional NVs (having sodium deoxycholate as a surfactant). A synergistic interaction between drugs was observed against intracellular amastigotes, whereas the in-vivo antileishmanial study presented a significant reduction in the parasitic burden. The results suggested the potential of surfactant free, triple drug loaded cNVs as an efficient vehicle for the safe topical treatment of CL.

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents.

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.

Antileishmanial Agents Co-loaded in Transfersomes with Enhanced Macrophage Uptake and Reduced Toxicity.

The prime objective of this study was to develop amphotericin B (AMB) and rifampicin (RIF) co-loaded transfersomal gel (AMB-RIF co-loaded TFG) for effective treatment of cutaneous leishmaniasis (CL). AMB-RIF co-loaded TF was prepared by the thin-film hydration method and was optimized based on particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (%EE), and deformability index. Similarly, AMB-RIF co-loaded TFG was characterized in terms of rheology, spread ability, and pH. In vitro, ex vivo, and in vivo assays were performed to evaluate AMB-RIF co-loaded TF as a potential treatment option for CL. The optimized formulation had vesicles in nanosize range (167 nm) with suitable PDI (0.106), zeta potential (- 19.05 mV), and excellent %EE of RIF (66%) and AMB (85%). Moreover, it had appropriate deformability index (0.952). Additionally, AMB-RIF co-loaded TFG demonstrated suitable rheological behavior for topical application. AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG showed sustained release of the incorporated drugs as compared to AMB-RIF suspension. Furthermore, RIF permeation from AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG was enhanced fivefold and threefold, whereas AMB permeation was enhanced by eightfold and 6.6-fold, respectively. The significantly different IC50, higher CC50, and FIC50 (p < 0.5) showed synergistic antileishmanial potential of AMB-RIF co-loaded TF. Likewise, reduced lesion size and parasitic burden in AMB-RIF co-loaded TF-treated mouse group further established the antileishmanial effect of the optimized formulation. Besides, AMB-RIF co-loaded TFG showed a better safety profile. This study concluded that TFG may be a suitable carrier for co-delivery of AMB-RIF when administered topically for the treatment of CL.

Knowledge, attitude and perceptions about Crimean Congo Haemorrhagic Fever (CCHF) among occupationally high-risk healthcare professionals of Pakistan.

BACKGROUND: Crimean Congo Haemorrhagic Fever (CCHF), a tropically neglected infectious disease caused by Nairovirus, is endemic in low middle-income countries like Pakistan. Emergency health care professionals (HCPs) are at risk of contracting nosocomial transmission of CCHF. We, therefore, aim to analyze the knowledge, attitudes, and perceptions (KAP) of at-risk physicians, nurses, and pharmacists in Pakistan and the factors associated with good KAP. METHOD: A validated questionnaire (Cronbach's alpha 0.71) was used to collect data from HCPs in two CCHF endemic metropolitan cities of Pakistan by employing a cross-sectional study design. For data analysis percentages, chi-square test and Spearman correlation were applied by using SPSS version 22. RESULTS: Of the 478 participants, 56% (n = 268) were physicians, 37.4% (n = 179) were nurses, and 6.5% (n = 31) were pharmacists. The proportion of HCPs with good knowledge, attitude, and perception scores was 54.3%, 81, and 69%, respectively. Being a physician, having more work experience, having a higher age, working in tertiary care settings, were key factors for higher knowledge (p < 0.001). The correlation coefficient showed significant positive correlation between attitude- perception (r = 0.560, p < 0.001). CONCLUSION: We have observed average knowledge of HCPs. Therefore, we recommend time to time education campaigns and workshops in highly endemic CCHF regions to be launched by health ministries and HCPs, in particular nurses, encouraged to follow authentic academic sources of information to prevent nosocomial transmission.

Nanotechnology based solutions for anti-leishmanial impediments: a detailed insight.

As a neglected tropical disease, Leishmaniasis is significantly instigating morbidity and mortality across the globe. Its clinical spectrum varies from ulcerative cutaneous lesions to systemic immersion causing hyperthermic hepato-splenomegaly. Curbing leishmanial parasite is toughly attributable to the myriad obstacles in existing chemotherapy and immunization. Since the 1990s, extensive research has been conducted for ameliorating disease prognosis, by resolving certain obstacles of conventional therapeutics viz. poor efficacy, systemic toxicity, inadequate drug accumulation inside the macrophage, scarce antigenic presentation to body's immune cells, protracted length and cost of the treatment. Mentioned hurdles can be restricted by designing nano-drug delivery system (nano-DDS) of extant anti-leishmanials, phyto-nano-DDS, surface modified-mannosylated and thiolated nano-DDS. Likewise, antigen delivery with co-transportation of suitable adjuvants would be achievable through nano-vaccines. In the past decade, researchers have engineered nano-DDS to improve the safety profile of existing drugs by restricting their release parameters. Polymerically-derived nano-DDS were found as a suitable option for oral delivery as well as SLNs due to pharmacokinetic re-modeling of drugs. Mannosylated nano-DDS have upgraded macrophage internalizing of nanosystem and the entrapped drug, provided with minimal toxicity. Cutaneous Leishmaniasis (CL) was tackling by the utilization of nano-DDS designed for topical delivery including niosomes, liposomes, and transfersomes. Transfersomes, however, appears to be superior for this purpose. The nanotechnology-based solution to prevent parasitic resistance is the use of Thiolated drug-loaded and multiple drugs loaded nano-DDS. These surfaces amended nano-DDS possess augmented IC50 values in comparison to conventional drugs and un-modified nano-DDS. Phyto-nano-DDS, another obscure horizon, have also been evaluated for their anti-leishmanial response, however, more intense assessment is a prerequisite. Impoverished Cytotoxic T-cells response followed by Leishmanial antigen proteins delivery have also been vanquished using nano-adjuvants. The eminence of nano-DDS for curtailment of anti-leishmanial chemotherapy and immunization associated challenges are extensively summed up in this review. This expedited approach is ameliorating the Leishmaniasis management successfully. Alongside, total to partial eradication of this disease can be sought along with associated co-morbidities.

Development of novel biopolymer-based nanoparticles loaded cream for potential treatment of topical fungal infections.

OBJECTIVE: Biodegradable polymers are extensively used due to their efficient safety profiles. The aim of the current study was to fabricate, evaluate, and characterize biodegradable, biocompatible fluconazole (FLZ) loaded chitosan (CHS) chondroitin sulfate (CS) nanoparticles (NPs) for topical delivery. Polymers utilized in the formulation not only served as a carrier system but also aided in fighting with complex etiology of the disease due to their innate antifungal activities. METHODS: NPs were prepared by the complex coacervation method, then were optimized for various parameters and subsequently loaded into a cream. RESULTS: Scanning electron microscopic (SEM) analysis showed spherical morphology of the NPs. Prepared NPs showed an average particle size in the range of 350-450 nm and an encapsulation efficiency (EE) of 86%. The polydispersity index (PDI) was found to be 0.148 that showed a uniform distribution of NPs. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of any electrostatic interaction between ingredients. In vitro drug release analyses exhibited a sustained release of the drug and higher antifungal activity than free FLZ. Ex vivo permeability and drug distribution in different skin layers ensured a site-specific delivery of the FLZ-NPs. As compared with free FLZ and other control groups, the prepared NPs also exhibited significantly higher antifungal activity against Candida albicans (p < .01). CONCLUSION: It was concluded from the results that the FLZ-NPs laden cream could be a potential candidate for topical and site-specific delivery of the drug cargo for the potential treatment of fungal infections.

Macrophage targeting with the novel carbopol-based miltefosine-loaded transfersomal gel for the treatment of cutaneous leishmaniasis: in vitro and in vivo analyses.

OBJECTIVE: The purpose of this study was to develop novel carbopol-based miltefosine-loaded transfersomal gel (HePCTG) for the treatment of cutaneous leishmaniasis (CL) via efficient targeting of leishmania infected macrophages. METHODS: Miltefosine-loaded transfersomes (HePCT) were prepared by ethanol injection method followed by their incorporation into carbopol gel to form HePCTG. The prepared HePCT were assessed for physicochemical properties including mean particle size, polydispersity index, zeta potential, entrapment efficiency, morphology, and deformability. Similarly, HePCTG was evaluated for physiochemical and rheological attributes. The in vitro release, skin permeation, skin irritation, anti-leishmanial activity, and in vivo efficacy in BALB/c mice against infected macrophages were also performed for HePCT. RESULTS: The optimized HePCT displayed a particle size of 168 nm with entrapment efficiency of 92%. HePCTG showed suitable viscosity, pH, and sustained release of the incorporated drug. Furthermore, HePCT and HePCTG demonstrated higher skin permeation than drug solution. The results of macrophage uptake study indicated improved drug intake by passive diffusion. The lower half maximal inhibitory concentration value, selectivity index and higher 50% cytotoxic concentration  value of HePCT compared to that of HePC solution demonstrated the improved anti-leishmanial efficacy and non-toxicity of the formulation. This was further confirmed by the notable reduction in parasite load and lesion size observed in in vivo anti-leishmanial study. CONCLUSION: It can be stated that the formulated HePCTG can effectively be used for the treatment of CL.

An efficient approach for development and optimisation of curcumin-loaded solid lipid nanoparticles' patch for transdermal delivery.

This study aimed to develop and optimise a Curcumin-loaded SLNs (C-SLNs) patch through a new approach for transdermal delivery. C-SLNs were optimised through the response surface central composite design using the modified injection method. Optimised C-SLNs were loaded into a polyvinyl alcohol-based patch through the backing membrane method. Compatibility studies (FTIR, XRPD), in vitro release, ex vivo skin permeation, accelerated stability, and evaluation studies of the patch were also performed. Prepared C-SLNs exhibited average particle diameter of 170 ± 2 nm with an encapsulation efficiency of 90 ± 3.5% (w/w) while SEM illustrated spherical shape of particles. In vitro release data ensured a sustained release for up to 72 hours. The enhancement ratio of C-SLNs based patch with permeation enhancer (PE) was high up to 6.5 folds as compared to patch without PE. It is concluded that the modified injection method is simple, economical, and less time consuming for the development of C-SLNs patch for the transdermal route.

The triphenyltin carboxylate derivative triphenylstannyl 2-(benzylcarbamoyl)benzoate impedes prostate cancer progression via modulation of Akt/FOXO3a signaling.

Prostate cancer (PCa) incidence is surging in United States and other parts of the world. Synthetic and natural compounds have been explored as potential modulators of PI3K/Akt signaling that is known to drive PCa growth. Here, we evaluated the efficacy of a series of triphenyltin (IV) carboxylate derivatives against PCa. From this library, triphenylstannyl 2-(benzylcarbamoyl)benzoate (Ch-319) resulted in reduced viability and induction of cell cycle arrest in PTEN-/- PC3M and PTEN+/- DU145 cells. In parallel, downregulation of PI3K p85/p110 subunits, dephosphorylation of Akt-1 and increase in FOXO3a expression were observed. In silico studies indicated binding interactions of Ch-319 within the ATP binding site of Akt-1 at Met281, Phe442 and Glu234 residues. Elevated po-pulation of apoptotic cells, activation of Bax and reduced Bcl2 expression indicated apoptosis by Ch-319. Pre-sensitization of PCa cells with Ch-319 augmented the effect of cabazitaxel, a commonly used taxane in patients with castration-resistant PCa. Next, in a prostate-specific PTENp-/- mice, Ch-319 showed reduced weights of genitourinary apparatus as compared to DMSO treated controls. Histological studies indicated absence of neoplastic foci in Ch-319 treated prostates. Consistently, dephosphorylation of Akt-1, reduced expression of PRAS40 and androgen receptor and increase in FOXO3a were observed in treated group. Notably, no overt organ toxicity was noted in Ch-319 treated animals. Our studies identify Akt/FOXO3a signaling as a target of triphenyltin (IV) carboxylate Ch-319 and provide a molecular basis of its growth inhibitory effect in PCa cells. We propose that Ch-319 has the potential to be developed as an anticancer agent against PCa.

Pharmacist-led counselling intervention to improve antiretroviral drug adherence in Pakistan: a randomized controlled trial.

BACKGROUND: Pakistan is facing a growing population of people living with human immunodeficiency (HIV). In this randomized controlled trial, we investigate if a pharmacist-led intervention can increase adherence to antiretroviral therapy (ART) for people living with HIV (PLWH). METHODS: Adults with HIV, who have been taking ART for more than 3 months were randomly assigned to receive either a pharmacist-led intervention or their usual care. Measures of adherence were collected at 1) baseline 2) just prior to delivery of intervention and 3) 8 weeks later. The primary outcomes were CD4 cell count and self-reported adherence measured with the AIDS Clinical Trial Group (ACTG) questionnaire. RESULTS: Post-intervention, the intervention group showed a statistically significant increase in CD4 cell counts as compared to the usual care group (p = 0.0054). In addition, adherence improved in the intervention group, with participants being 5.96 times more likely to report having not missed their medication for longer periods of time (p = 0.0086) while participants in the intervention group were 7.74 times more likely to report missing their ART less frequently (p < 0.0001). CONCLUSIONS: The findings support the improvement in ART adherence and HIV management. TRIAL REGISTRATION: The trial is registered with Australian New Zealand Clinical Trials Registry ( ACTRN12618001882213 ). Registered 20 November 2018.

Development of levosulpiride-loaded solid lipid nanoparticles and their in vitro and in vivo comparison with commercial product.

The aim of this study was to develop levosulpiride-loaded solid lipid nanoparticles (SLNs) with enhanced solubilisation and bioavailability. The levosulpiride loaded-SLNs were composed of levosulpiride, stearic acid, and tween 80 in their respective weight ratios of (1, 5, and 1.5 mg) dissolved in 1 ml distilled water. Physicochemical properties of the SLNs such as particle size, shape, crystallinity, and chemical interaction were evaluated. Further, the in vitro drug dissolution, pharmacokinetic and stability studies of the SLNs were performed. The SLNs were rounded shaped stable nanoparticles with average diameter of 200 nm. They demonstrate 1.5- and 3-fold better drug dissolution when compared with the commercial product and levosulpiride powder, respectively. The SLNs enhanced the bioavailability of levosulpiride 3 times and 7 times, respectively, when compared with the commercial product and levosulpiride powder. It can be concluded that SLNs are capable to improve the dissolution and bioavailability of levosulpiride, even more than the commercial product.

Correction to: Preparation and Characterization of Nanostructured Lipid Carriers for Improved Topical Drug Delivery: Evaluation in Cutaneous Leishmaniasis and Vaginal Candidiasis Animal Models.

In the published manuscript, co-author Sarah Hendrickx name was misspelled and co-author Guy Caljon's last and first names were inadvertently switched.

Diagnostic and Treatment Strategies for COVID-19.

The world is facing lockdown for the first time in decades due to the novel coronavirus COVID-19 (SARS-CoV-2) pandemic. This has led to massive global economic disruption, placed additional strain on local and global public health resources and, above all, threatened human health. We conducted a review of peer-reviewed and unpublished data, written in English, reporting on the current COVID-19 pandemic. This data includes previously used strategies against infectious disease, recent clinical trials and FDA-approved diagnostic and treatment strategies. The literature was obtained through a systematic search using PubMed, Web of Sciences, and FDA, NIH and WHO websites. Of the 98 references included in the review, the majority focused on pathogen and host targeting, symptomatic treatment and convalescent plasma utilization. Other sources investigated vaccinations in the pipeline for the possible prevention of COVID-19 infection. The results demonstrate various conventional as well as potentially advanced in vitro diagnostic approaches (IVD) for the diagnosis of COVID-19. Mixed results have been observed so far when utilising these approaches for the treatment of COVID-19 infection. Some treatments have been found highly effective in specific regions of the world while others have not altered the disease process. The responsiveness of currently available options is not conclusive. The novelty of this disease, the rapidity of its global outbreak and the unavailability of vaccines have contributed to the global public's fear. It is concluded that the exploration of a range of diagnostic and treatment strategies for the management of COVID-19 is the need of the hour.

Preparation and Characterization of Nanostructured Lipid Carriers for Improved Topical Drug Delivery: Evaluation in Cutaneous Leishmaniasis and Vaginal Candidiasis Animal Models.

The present study aimed to develop, characterize and evaluate the amphotericin B-loaded nanostructured lipid carriers (AmB-NLCs) for topical treatment of cutaneous leishmaniasis (CL) and vulvovaginal candidiasis (VVC). AmB-NLCs were characterized for particle size, zeta potential, encapsulation efficiency and surface morphology. Prepared NLCs were also characterized for in vitro drug release, ex vivo skin permeation and deposition before evaluating their in vitro and in vivo efficacy. Cytotoxicity of NLCs was assessed on MRC-5 cells, whereas skin irritation potential was evaluated in vivo using rats. Significant accumulation of drug in to the skin supported the topical application potential of drug-loaded NLCs. Encapsulation of AmB in NLCs resulted in enhanced in vitro potency against promastigotes and intracellular amastigotes of L. major JISH 118 (IC50 ± SEM = 0.02 ± 0.1 µM for both) compared with free drug (IC50 ± SEM = 0.15 ± 0.2 & 0.14 ± 0.0, respectively). Similar improved potency of AmB-NLCs was also observed for other Leishmania and fungal strains compared with drug solution. Topical application of AmB-NLCs on L. major-infected BALB/c mice caused a significant reduction in parasite burden per mg of lesion (65 × 108 ± 13) compared with the control group (> 167.8 × 108 ± 11). Topical AmB-NLCs gel demonstrated superior efficacy in the vaginal C. albicans rat model for VVC as compared with plain AmB gel. Moreover, results of in vitro cytotoxicity assay and in vivo skin irritation test confirmed AmB-NLCs to be non-toxic and safe for topical use. In conclusion, NLCs may have promising potential as carrier for topical treatment of various conditions of skin and mucosa.

Design, Preparation and evaluation of various parameters of controlled release matrices of losartan potassium using polymers combination.

Controlled release formulations are administered once a day and reduce frequency of dose and ensuring patient's compliance. In the current research controlled release matrices of losartan potassium formulated with polymeric combinations of ethocel grade 7 with carbopol 934P NF using different concentrations of polymers. In some polymeric tablets, Co-excipients like CMC, Starch, HPMC was added by replacing of 10% of filler in formulations at 10:5. Tablets were prepared by direct compression method and evaluated for physicochemical characteristics. USP Method-1 (rotating basket method) was used to carry out dissolution study in phosphate buffer pH 6.8. Drug release kinetics determined and comparison of dissolution patterns was done with reference tablets. The polymeric combinations well retarded drug release and drug was released by anamolous non-fickian diffusion mechanism. Dissolution profiles of tested tablets and reference tablets were found not similar. Drug release rate was increased by co-excipients. It was concluded from this research work that this polymeric combination can be used efficiently in designing of controlled release martices.

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo.

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7 °C remained liquid at 25 °C, but converted to gel at 30-36.5 °C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.

Development and Evaluation of Optimized Thiolated Chitosan Proniosomal Gel Containing Duloxetine for Intranasal Delivery.

Proniosomes offer excellent potential for improved drug delivery, through versatile routes, by overcoming the permeation barriers faced by several drugs. The study was aimed to develop a thiomer gel containing duloxetine proniosomes for the intranasal delivery, improving its bioavailability and brain delivery through olfactory system. Duloxetine-loaded proniosomes were optimized through Design-Expert Software, prepared by coacervation phase separation method and then characterized in vitro for different vesicle features, and permeation enhancement potential using various techniques. The formulation F2, out of all the trials, fulfilled the maximum requisite of highest entrapment efficiency (76.21 ± 1.24%) and minimum vesicle size (223.91 ± 11.07 nm). The F2 was embedded in thiolated chitosan gel rendering it mucoadhesive and further characterized. The in vitro release showed a sustained drug release from the mucoadhesive proniosomal gel with only 54% drug release as compared to that of 71% from proniosome over 8 h, following Higuchi drug release model. Ex vivo permeation studies showed the enhancement ratio for the mucoadhesive proniosomal gel to be 1.86-fold greater than proniosomes, indicating a significant improvement in transmucosal permeation. The results suggest that incorporation of proniosomes into thiolated gel can significantly improve its mucoadhesion and retention time in the nasal cavity for providing a sustained drug release. Thus, gel formulation could be considered as a promising approach for efficient intranasal drug delivery of duloxetine. Graphical Abstract.

Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Improved Oral Bioavailability of Chlorpromazine: In Vitro and In Vivo Evaluation.

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility-with extensive first-pass metabolism-can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT14) were found to be 178 ± 16, -21.4, and 85.5%, respectively. Long chain triglyceride (LCT14) showed a 1.5-fold increased elimination half-life (p < 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p < 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT14) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine.