The effect of intraoperative wound protector use on the risk of surgical site infections in patients undergoing pancreatoduodenectomy: a systematic review and meta-analysis.

AIMS: To evaluate the effect of intraoperative wound protectors on the risk of surgical site infection (SSI) in patients undergoing pancreatoduodenectomy. METHODS: In compliance with PRISMA statement standards, electronic databases were searched to identify all studies comparing wound protector use with no wound protector use in patients undergoing pancreatoduodenectomy. SSI (superficial or deep) was considered primary outcome measure. The secondary outcome measures included superficial SSI, deep SSI, and organ-space SSI. Random effects modelling was applied to calculate pooled outcome data. The certainty of evidence was assessed using GRADE system. RESULTS: A total of 12159 patients from four studies were included. The included populations in both groups were comparable in terms of baseline characteristics. The use of wound protector was associated with lower risk of superficial or deep SSI (OR: 0.55, 95% CI 0.43-0.70, P<0.00001), superficial SSI (OR: 0.59, 95% CI 0.46-0.76, P<0.0001), and organ-space SSI (OR: 0.80, 95% CI 0.72-0.90, P=0.0002). There was no difference between the two groups in terms of the risk of deep SSI (OR: 0.68, 95% CI 0.43-1.06, P=0.09) although this may be subject to type 2 error. CONCLUSIONS: The results of current study suggests that the use of intraoperative wound protector during pancreatoduodenectomy may reduce the risk of postoperative SSI. The quality of the available evidence is moderate with high certainty. While evidence from future randomised controlled trials could increase the robustness of our conclusions, we do not hesitate to recommend the use of wound protectors during pancreatoduodenectomy based on the current evidence.

The current and future aspects of glioblastoma: Immunotherapy a new hope?

Glioblastoma (GBM) is the most perilous and highly malignant in all the types of brain tumor. Regardless of the treatment, the diagnosis of the patients in GBM is very poor. The average survival rate is only 21 months after multimodal combinational therapies, which include chemotherapy, radiation, and surgery. Due to the intrusive and infiltrative nature of GBM, it requires elective therapy for specific targeting of tumor cells. Tumor vaccine in a form of immunotherapy has potential to address this need. Nanomedicine-based immunotherapies have clutch the trigger of systemic and specific immune response against tumor cells, which might be the approach to eliminating the unrelieved cancer. In this mechanism, combination of immunomodulators with specific target and appropriate strategic vaccines can stifle tumor anti-immune defense system and/or increase the capabilities of the body to move up immunity against the tumor. Here, we explore the different types of immunotherapies and vaccines for brain tumor treatment and their clinical trials, which bring the feasibility of the future of personalized vaccine of nanomedicine-based immunotherapies for the brain tumor. We believe that immunotherapy could result in a significantly more stable reaction in GBM patients.

Intraperitoneal contamination index (Hajibandeh index) predicts nature of peritoneal contamination and risk of postoperative mortality in patients with acute abdominal pathology: a prospective multicentre cohort study.

OBJECTIVES: To assess whether intraperitoneal contamination index (ICI) (Hajibandeh index) derived from combined levels of CRP, lactate, neutrophils, lymphocytes, and albumin can predict the nature of intraperitoneal contamination in patients with acute abdominal pathology and to assess whether ICI can predict postoperative mortality in patients undergoing emergency laparotomy. METHODS: In order to prospectively validate the ICI, developed and validated retrospectively in our previous study, a multicentre prospective cohort study was conducted between January 2019 and June 2020 including all adult patients who presented with acute abdominal pathology requiring emergency laparotomy. ROC curve analysis was performed to determine discrimination and cut-off values of preoperative ICI that could predict the nature of intraperitoneal contamination and postoperative mortality. RESULTS: Overall, 269 patients were included in the prospective validation cohort which were compared with 234 patients in the primary cohort and 234 patients in the retrospective validation cohort. The analyses identified ICI of 24.76 as cut-off value for purulent contamination (AUC: 0.78, P < 0.0001; sensitivity: 82.4%, specificity: 60.9%); ICI of 33.84 as cut-off value for feculent contamination (AUC: 0.78, P < 0.0001; sensitivity: 82%, specificity: 67.8%), and ICI of 33.47 as cut-off value for postoperative mortality (AUC: 0.70, P < 0.0001; sensitivity: 72.7%, specificity: 58.47%). The results of the prospective validation cohort were comparable with the results of the primary and retrospective validation cohorts. CONCLUSIONS: Hajibandeh index predicts the presence of purulent and feculent intraperitoneal contamination in patients with acute abdominal pathology and postoperative mortality in patients undergoing emergency laparotomy. Future studies should investigate the effect of ICI use on the accuracy of preoperative prognostic scoring tools and on patient selection for operative or non-operative management of underlying abdominal pathology.

The risk and predictors of mortality in octogenarians undergoing emergency laparotomy: a multicentre retrospective cohort study.

OBJECTIVES: This study aims to evaluate the risk of postoperative mortality in octogenarians undergoing emergency laparotomy. METHODS: In compliance with STROCSS guideline for observational studies, we conducted a multicentre retrospective cohort study. All consecutive patients aged over 80 with acute abdominal pathology requiring emergency laparotomy between April 2014 and August 2019 were considered eligible for inclusion. The primary outcome measure was 30-day postoperative mortality, and the secondary outcome measures were in-hospital mortality and 1-year mortality. Statistical analyses included simple descriptive statistics, binary logistic regression analyses, and Kaplan-Meier survival statistics. RESULTS: A total of 523 octogenarians were eligible for inclusion. Emergency laparotomy in octogenarians was associated with 21.8% (95% CI 18.3-25.6%) 30-day postoperative mortality, 22.6% (95% CI 19.0-26.4%) in-hospital mortality, and 40.2% (95% CI 35.9-44.5%) 1-year mortality. Binary logistic regression analysis identified ASA status (OR, 2.49; 95% CI 1.82-3.38, P < 0.0001) and peritoneal contamination (OR, 2.00; 95% CI 1.30-3.08, P = 0.002) as predictors of 30-day postoperative mortality. The ASA status (OR, 1.92; 95% CI 1.50-2.46, P < 0.0001), peritoneal contamination (OR, 1.57; 95% CI 1.07-2.48, P = 0.020), and presence of malignancy (OR, 2.06; 95% CI 1.36-3.10, P = 0.001) were predictors of 1-year mortality. Log-rank test showed significant difference in postoperative survival rates among patients with different ASA status (P < 0.0001) and between patients with and without peritoneal contamination (P = 0.0011). CONCLUSIONS: Emergency laparotomies in patients older than 80 years with ASA status more than 3 in the presence of peritoneal contamination carry a high risk of immediate postoperative and 1-year mortality. This should be taken into account in communications with patients and their relatives, consent process, and multidisciplinary decision-making process for operative or non-operative management of such patients.

Enhanced Solubility and Bioavailability of Dolutegravir by Solid Dispersion Method: In Vitro and In Vivo Evaluation-a Potential Approach for HIV Therapy.

Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 µg/mL) when compared to the physical mixture (4.12 µg/mL) and pure drug (3.45 µg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 µg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 µg/h/mL) and pure drug (49.27±6.16 µg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.

Development and Optimization of Asenapine Sublingual Film Using QbD Approach.

Asenapine, an atypical antipsychotic agent, has been approved for the acute and maintenance treatment of schizophrenia and manic episodes of bipolar disorder. However, the extensive hepatic metabolism limits its oral bioavailability. Therefore, the objective of the current investigation was to develop sublingual film containing asenapine to enhance the therapeutic efficacy. Sublingual films containing asenapine were fabricated using polyethylene oxide and hydroxypropyl methylcellulose by solvent casting method. Design of experiment was used as a statistical tool to optimize the proportion of the film-forming polymers in order to establish the critical quality attributes of the drug formulation. The process was studied in detail by assessing risk of each step as well as parameters and material attributes to reduce the risk to a minimum. A control strategy was defined to ensure manufacture of films according to the target product profile by evaluation of intermediate quality attributes at the end of each process step. Results of optimized formulations showed rapid disintegration, adequate folding endurance, good percentage elongation, tensile strength, and viscosity. Besides, the results from the in vitro dissolution/ex vivo permeation studies showed rapid dissolution (100% in 6 min) and higher asenapine permeation (~ 80% in 90 min) through the sublingual epithelium. In vivo study indicates greater asenapine absorption (31.18 ± 5.01% of administered dose) within 5 min and was comparable with marketed formulation. In summary, the designing plan to develop asenapine formulation was successfully achieved with desired characteristics of the delivery tool for sublingual administration.

Development of HPLC Method for Quantification of Sinigrin from Raphanus sativus Roots and Evaluation of Its Anticancer Potential.

Sinigrin, a precursor of allyl isothiocyanate, present in the Raphanus sativus exhibits diverse biological activities, and has an immense role against cancer proliferation. Therefore, the objective of this study was to quantify the sinigrin in the R. sativus roots using developed and validated RP-HPLC method and further evaluated its' anticancer activity. To achieve the objective, the roots of R. sativus were lyophilized to obtain a stable powder, which were extracted and passed through an ion-exchange column to obtain sinigrin-rich fraction. The RP-HPLC method using C18 analytical column was used for chromatographic separation and quantification of sinigrin in the prepared fraction, which was attained using the mobile phase consisting of 20 mM tetrabutylammonium: acetonitrile (80:20%, v/v at pH 7.0) at a flow rate of 0.5 mL/min. The chromatographic peak for sinigrin was showed at 3.592 min for pure sinigrin, where a good linearity was achieved within the concentration range of 50 to 800 µg/mL (R2 > 0.99), with an excellent accuracy (-1.37% and -1.29%) and precision (1.43% and 0.94%), for intra and inter-day, respectively. Finally, the MTT assay was performed for the sinigrin-rich fraction using three different human cancer cell lines, viz. prostate cancer (DU-145), colon adenocarcinoma (HCT-15), and melanoma (A-375). The cell-based assays were extended to conduct apoptotic and caspase-3 activities, to determine the mechanism of action of sinigrin in the treatment of cancer. MTT assay showed IC50 values of 15.88, 21.42, and 24.58 µg/mL for DU-145, HCT-15, and A-375 cell lines, respectively. Increased cellular apoptosis and caspase-3 expression were observed with sinigrin-rich fraction, indicating significant increase in overexpression of caspase-3 in DU-145 cells. In conclusion, a simple, sensitive, fast, and accurate RP-HPLC method was developed for the estimation of sinigrin in the prepared fraction. The data observed here indicate that sinigrin can be beneficial in treating prostate cancer possibly by inducing apoptosis.

3D Printing Technologies: Recent Development and Emerging Applications in Various Drug Delivery Systems.

The 3D printing is considered as an emerging digitized technology that could act as a key driving factor for the future advancement and precise manufacturing of personalized dosage forms, regenerative medicine, prosthesis and implantable medical devices. Tailoring the size, shape and drug release profile from various drug delivery systems can be beneficial for special populations such as paediatrics, pregnant women and geriatrics with unique or changing medical needs. This review summarizes various types of 3D printing technologies with advantages and limitations particularly in the area of pharmaceutical research. The applications of 3D printing in tablets, films, liquids, gastroretentive, colon, transdermal and intrauterine drug delivery systems as well as medical devices have been briefed. Due to the novelty and distinct features, 3D printing has the inherent capacity to solve many formulation and drug delivery challenges, which are frequently associated with poorly aqueous soluble drugs. Recent approval of Spritam® and publication of USFDA technical guidance on additive manufacturing related to medical devices has led to an extensive research in various field of drug delivery systems and bioengineering. The 3D printing technology could be successfully implemented from pre-clinical phase to first-in-human trials as well as on-site production of customized formulation at the point of care having excellent dose flexibility. Advent of innovative 3D printing machineries with built-in flexibility and quality with the introduction of new regulatory guidelines would rapidly integrate and revolutionize conventional pharmaceutical manufacturing sector.

Mucoadhesive buccal film of almotriptan improved therapeutic delivery in rabbit model.

Administration of almotriptan as an oral therapy is largely limited because of poor aqueous solubility and rather low bioavailability. The aim of present investigation was to formulate oral mucoadhesive film of almotriptan to improve the drug delivery and desired therapeutic effects. Placebo films (F1-F8) were prepared by varying the concentrations of Proloc 15 (7.5-15% w/v) and Eudragit RL 100/RS 100 (15-30% w/v) polymers. Physicomechanical and pharmaceutical characteristics of drug loaded films (FA1-FA4) were examined. Selected FA4 film was evaluated in vivo by assessing the pharmacokinetic profile and compared with oral therapy in rabbits. FA1-FA4 films exhibited excellent physicomechanical properties and rapid hydration. A biphasic and considerably greater drug release (p < 0.05) was observed in FA3 and FA4 films contain higher amount of hydrophilic polymer. The rate of permeation of almotriptan was found to be significantly higher in FA4 than FA3 film (p < 0.005). Fourier transform infrared spectral scan indicates no incompatibility exists between the drug and polymers used. Differential scanning calorimetry thermogram represents the evidence of almotriptan amorphization and molecular dispersion of it in the film. Scanning electron microscopy images shows that FA4 possess good morphological features and hence suitable for use in the buccal application. In vivo data demonstrated rapid and efficient absorption (p < 0.005) of almotriptan with greater AUC0-12 (>2 folds, p < 0.0001) by FA4 film as compared to oral (control). In general, the data established the potential of FA4 film to improve the therapeutic delivery of almotriptan and offers a promising option in migraine therapy.

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-α in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

Development of Asialoglycoprotein Receptor-Targeted Nanoparticles for Selective Delivery of Gemcitabine to Hepatocellular Carcinoma.

Selective targeting of anticancer drugs to the tumor site is beneficial in the pharmacotherapy of hepatocellular carcinoma (HCC). This study evaluated the prospective of galactosylated chitosan nanoparticles as a liver-specific carrier to improve the therapeutic efficacy of gemcitabine in HCC by targeting asialoglycoprotein receptors expressed on hepatocytes. Nanoparticles were formulated (G1-G5) by an ionic gelation method and evaluated for various physicochemical characteristics. Targeting efficacy of formulation G4 was evaluated in rats. Physicochemical characteristics exhibited by nanoparticles were optimal for administering and targeting gemcitabine effectively to the liver. The biphasic release behavior observed with G4 can provide higher drug concentration and extend the pharmacotherapy in the liver target site. Rapid plasma clearance of gemcitabine (70% in 30 min) from G4 was noticed in rats with HCC as compared to pure drug (p < 0.05). Higher uptake of gemcitabine predominantly by HCC (64% of administered dose; p < 0.0001) demonstrated excellent liver targeting by G4, while mitigating systemic toxicity. Morphological, biochemical, and histopathological examination as well as blood levels of the tumor marker, alpha-fetoprotein, in rats confirmed the curative effect of G4. In conclusion, this study demonstrated site-specific delivery and enhanced in vivo anti-HCC efficacy of gemcitabine by G4, which could function as promising carrier in hepatoma.

Irrigation Versus Suction Alone in Laparoscopic Appendectomy: Is Dilution the Solution to Pollution? A Systematic Review and Meta-Analysis.

OBJECTIVES: To investigate outcomes of peritoneal irrigation versus suction without irrigation in patients undergoing emergency laparoscopic appendectomy. METHODS: We performed a systematic review and conducted a search of electronic information sources to identify all randomized controlled trials (RCTs) and observational studies investigating outcomes of irrigation versus suction alone in patients undergoing emergency laparoscopic appendectomy. We used the Cochrane risk of bias tool and the Newcastle-Ottawa scale to assess the risk of bias of RCTs and observational studies, respectively. Random-effects models were applied to calculate pooled outcome data. RESULTS: We identified 3 RCTs and 2 retrospective observational studies, enrolling 2511 patients. Our results suggested that there was no difference between peritoneal irrigation and suction alone in terms of intraabdominal abscess rate (odds ratio = 2.39, 95% confidence interval [CI] = 0.49-11.74, P = .28), wound infection (risk difference = 0.00, 95% CI = -0.04 to 0.05, P = .85), and length of stay (mean difference = -1.02, 95% CI = -3.10 to 1.07, P = .34); however, peritoneal irrigation was associated with longer operative time (mean difference = 7.12, 95% CI = 4.33 to 9.92, P < .00001). Our results remained consistent when randomized trials, adult patients, and pediatric patients were analyzed separately. CONCLUSIONS: The best available evidence suggests that the peritoneal irrigation with normal saline during laparoscopic appendectomy does not provide additional benefits compared with suction alone in terms of intraabdominal abscess, wound infection, and length of stay but it may prolong the operative time. The quality of the best available evidence is moderate; therefore, high-quality RCTs, which are adequately powered, are required to provide more robust basis for definite conclusions.

Engineered Cry1Ac-Cry9Aa hybrid Bacillus thuringiensis delta-endotoxin with improved insecticidal activity against Helicoverpa armigera.

Recombinant Bt construct was prepared by exchange of pore forming domain I with cry1Ac to cry9Aa gene by overlap extension PCR (OE-PCR) technique. Construction of cry1Ac-cry9Aa was accomplished by six base pair homology at 3' ends of PCR products of domain I of cry1Ac and domain II and III of cry9Aa. The recombinant toxin was also modified by deletion of N-terminal alpha helix-1 of recombinant toxin. Both Cry toxins were expressed in E. coli BL21(DE3) plysS and purified by His-tag purification. Upon insect bioassay analysis against devastating crop pest Helicoverpa armigera, toxicity of recombinant toxin was found around fivefold higher than native Cry1Ac while alpha helix-1 deleted N-terminal modified toxin did not resulted in significant increase in toxicity. The recombinant Cry toxins such as Cry1Ac-Cry9Aa and Cry1Ac-Cry9AaMod may be used for insect pest control.

Nasal Delivery to the Brain: Harnessing Nanoparticles for Effective Drug Transport.

The nose-to-brain drug-delivery system has emerged as a promising strategy to overcome the challenges associated with conventional drug administration for central nervous system disorders. This emerging field is driven by the anatomical advantages of the nasal route, enabling the direct transport of drugs from the nasal cavity to the brain, thereby circumventing the blood-brain barrier. This review highlights the significance of the anatomical features of the nasal cavity, emphasizing its high permeability and rich blood supply that facilitate rapid drug absorption and onset of action, rendering it a promising domain for neurological therapeutics. Exploring recent developments and innovations in different nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, micelles, nanoemulsions, nanosuspensions, carbon nanotubes, mesoporous silica nanoparticles, and nanogels unveils their diverse functions in improving drug-delivery efficiency and targeting specificity within this system. To minimize the potential risk of nanoparticle-induced toxicity in the nasal mucosa, this article also delves into the latest advancements in the formulation strategies commonly involving surface modifications, incorporating cutting-edge materials, the adjustment of particle properties, and the development of novel formulations to improve drug stability, release kinetics, and targeting specificity. These approaches aim to enhance drug absorption while minimizing adverse effects. These strategies hold the potential to catalyze the advancement of safer and more efficient nose-to-brain drug-delivery systems, consequently revolutionizing treatments for neurological disorders. This review provides a valuable resource for researchers, clinicians, and pharmaceutical-industry professionals seeking to advance the development of effective and safe therapies for central nervous system disorders.

Advances in Nanocarrier Systems for Overcoming Formulation Challenges of Curcumin: Current Insights.

Curcumin, an organic phenolic molecule that is extracted from the rhizomes of Curcuma longa Linn, has undergone extensive evaluation for its diverse biological activities in both animals and humans. Despite its favorable characteristics, curcumin encounters various formulation challenges and stability issues that can be effectively addressed through the application of nanotechnology. Nano-based techniques specifically focused on enhancing solubility, bioavailability, and therapeutic efficacy while mitigating toxicity, have been explored for curcumin. This review systematically presents information on the improvement of curcumin's beneficial properties when incorporated, either individually or in conjunction with other drugs, into diverse nanosystems such as liposomes, nanoemulsions, polymeric micelles, dendrimers, polymeric nanoparticles, solid-lipid nanoparticles, and nanostructured lipid carriers. Additionally, the review examines ongoing clinical trials and recently granted patents, offering a thorough overview of the dynamic landscape in curcumin delivery. Researchers are currently exploring nanocarriers with crucial features such as surface modification, substantial loading capacity, biodegradability, compatibility, and autonomous targeting specificity and selectivity. Nevertheless, the utilization of nanocarriers for curcumin delivery is still in its initial phases, with regulatory approval pending and persistent safety concerns surrounding their use.

Neoadjuvant chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: Meta-analysis and trial sequential analysis of randomized controlled trials.

We aimed to compare resection and survival outcomes of neoadjuvant chemoradiotherapy (CRT) and immediate surgery in patients with resectable pancreatic cancer (RPC) or borderline resectable pancreatic cancer (BRPC). In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards, a systematic review of randomized controlled trials (RCTs) was conducted. Random effects modeling was applied to calculate pooled outcome data. Likelihood of type 1 or 2 errors in the meta-analysis model was assessed by trial sequential analysis. A total of 400 patients from four RCTs were included. When RPC and BRPC were analyzed together, neoadjuvant CRT resulted in a higher R0 resection rate (risk ratio [RR]: 1.55, p = 0.004), longer overall survival (mean difference [MD]: 3.75 years, p = 0.009) but lower overall resection rate (RR: 0.83, p = 0.008) compared with immediate surgery. When RPC and BRPC were analyzed separately, neoadjuvant CRT improved R0 resection rate (RR: 3.72, p = 0.004) and overall survival (MD: 6.64, p = 0.004) of patients with BRPC. However, it did not improve R0 resection rate (RR: 1.18, p = 0.13) or overall survival (MD: 0.94, p = 0.57) of patients with RPC. Neoadjuvant CRT might be beneficial for patients with BRPC, but not for patients with RPC. Nevertheless, the best available evidence does not include contemporary chemotherapy regimens. Patients with RPC and those with BRPC should not be combined in the same cohort in future studies.

Design, Development, and Evaluation of Constant Voltage Iontophoresis for the Transungual Delivery of Efinaconazole.

The efficacy of topical antifungal therapy in onychomycosis has been hindered by the failure of the antimycotic to permeate the nail plate. This research aims to design and develop a transungual system for the effective delivery of efinaconazole utilizing constant voltage iontophoresis. Seven prototype drug-loaded hydrogel formulations (E1-E7) were prepared to assess the influence of solvent (ethanol) and cosolvent (Labrasol®) on transungual delivery. Optimization was performed to evaluate the effect of three independent variables; voltage, solvent-to-cosolvent ratio, and penetration enhancer (PEG 400) concentration on critical quality attributes (CQAs), such as drug permeation and loading into the nail. The selected hydrogel product was characterized for pharmaceutical properties, efinaconazole release from the nail, and antifungal activity. Preliminary data indicates ethanol, Labrasol®, and voltage influence the transungual delivery of efinaconazole. Optimization design indicates a significant impact by applied voltage (p-0.0001) and enhancer concentration (p-0.0004) on the CQAs. Excellent correlation between selected independent variables and CQAs was confirmed by the high desirability value (0.9427). A significant (p < 0.0001) enhancement in the permeation (~78.59 µg/cm2) and drug loading (3.24 µg/mg) was noticed in the optimized transungual delivery with 10.5 V. FTIR spectral data indicates no interaction between the drug and excipients, while the DSC thermograms confirmed the amorphous state of the drug in the formulation. Iontophoresis produces a drug depot in the nail that releases above the minimum inhibitory concentration level for an extended period, potentially reducing the need for frequent topical treatment. Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte. Overall, the promising results obtained here demonstrate the prospective of this non-invasive method for the effective transungual delivery of efinaconazole, which could improve the treatment of onychomycosis.

Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers.

The therapeutic effectiveness of paliperidone in the treatment of schizophrenia has been limited by its poor oral bioavailability; hence, an alternative route could be appropriate. This study investigates the feasibility of developing a buccal film impregnated with paliperidone-loaded nanostructured lipid carriers (NLCs) and assesses the potential to enhance its bioavailability. Box-Behnken-based design optimization of NLCs was performed by examining the particles' physical characteristics. The polymeric film was used to load optimized NLCs, which were then assessed for their pharmaceutical properties, permeability, and pharmacokinetics. The optimization outcomes indicated that selected formulation variables had a considerable (p < 0.05) impact on responses such as particle size, entrapment efficiency, and % drug release. Desired characteristics such as a negative charge, higher entrapment efficiency, and nanoparticles with ideal size distribution were shown by optimized NLC dispersions. The developed film demonstrated excellent physico-mechanical properties, appropriate texture, good drug excipient compatibility (chemically stable formulation), and amorphous drug nature. A sustained Weibull model drug release (p < 0.0005) and superior flux (~5-fold higher, p < 0.005) were seen in NLC-loaded film compared to plain-drug-loaded film. The pharmacokinetics profile in rabbits supports the goal of buccal therapy as evidenced by significantly higher AUC0-12 (p < 0.0001) and greater relative bioavailability (236%) than the control. These results support the conclusion that paliperidone-loaded NLC buccal film has the potential to be an alternate therapy for its effective administration in the treatment of schizophrenia.

Design, Development, and Evaluation of Treprostinil Embedded Adhesive Transdermal Patch.

Clinical application of treprostinil in pulmonary arterial hypertension is hampered by adverse effects caused by its high dosing frequency. The objective of this investigation was to Formulate an adhesive-type transdermal patch of treprostinil and evaluate it both in vitro and in vivo. A 32-factorial design was utilized to optimize the selected independent variables (X1: drug amount, X2: enhancer concentration) on the response variables (Y1: drug release, Y2: transdermal flux). The optimized patch was evaluated for various pharmaceutical properties, skin irritation, and pharmacokinetics in rats. Optimization results signify considerable influence (p < 0.0001) of X1 on both Y1 and Y2, as compared to X2. The optimized patch possesses higher drug content (>95%), suitable surface morphology, and an absence of drug crystallization. FTIR analysis revealed compatibility of the drug with excipients, whereas DSC thermograms indicate that the drug exists as amorphous in the patch. The adhesive properties of the prepared patch confirm adequate adhesion and painless removal, while the skin irritation study confirms its safety. A steady drug release via Fickian diffusion and greater transdermal delivery (~23.26 µg/cm2/h) substantiate the potential of the optimized patch. Transdermal therapy resulted in higher treprostinil absorption (p < 0.0001) and relative bioavailability (237%) when compared to oral administration. Overall, the results indicate that the developed drug in the adhesive patch can effectively deliver treprostinil through the skin and could be a promising treatment option for pulmonary arterial hypertension.

Intranasal Administration of Dolutegravir-Loaded Nanoemulsion-Based In Situ Gel for Enhanced Bioavailability and Direct Brain Targeting.

Dolutegravir's therapeutic effectiveness in the management of neuroAIDS is mainly limited by its failure to cross the blood-brain barrier. However, lipid-based nanovesicles such as nanoemulsions have demonstrated their potential for the brain targeting of various drugs by intranasal delivery. Thus, the purpose of this study was to develop a Dolutegravir-loaded nanoemulsion-based in situ gel and evaluate its prospective for brain targeting by intranasal delivery. Dolutegravir-loaded nanoemulsions were prepared using dill oil, Tween® 80, and Transcutol® P. Optimization of the nanoemulsion particle size and drug release was carried out using a simplex lattice design. Formulations (F1-F7 and B1-B6) were assessed for various pharmaceutical characteristics. Ex vivo permeation and ciliotoxicity studies of selected in situ gels (B1) were conducted using sheep nasal mucosa. Drug targeting to the brain was assessed in vivo in rats following the nasal delivery of B1. The composition of oil, surfactant, and cosurfactant significantly (p < 0.05) influenced the dependent variables (particle size and % of drug release in 8 h). Formulation B1 exhibits pharmaceutical characteristics that are ideal for intranasal delivery. The mucosal steady-state flux noticed with BI was significantly greater (p < 0.005) than for the control gel. A histopathology of nasal mucosa treated with BI showed no signs of toxicity or cellular damage. Intranasal administration of B1 resulted in greater Cmax (~six-fold, p < 0.0001) and AUC0-α (~five-fold, p < 0.0001), and decreased Tmax (1 h) values in the brain, compared to intravenous administration. Meantime, the drug level in the plasma was relatively low, suggesting less systemic exposure to Dolutegravir through intranasal delivery. In summary, the promising data observed here signifies the prospective of B1 to enhance the brain targeting of Dolutegravir by intranasal delivery and it could be used as a feasible and practicable strategy for the management of neuroAIDS.