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The objective of the present study was to evaluate the potential of solid dispersion adsorbate to improve the solubility and bioavailability of rivaroxaban (RXN). Solid dispersion adsorbate (SDA) of RXN was developed by fusion method using PEG 4000 as carrier and Neusilin as adsorbent. A 32 full factorial design was utilized to formulate various SDAs. The selected independent variables were amount of carrier (X1) and amount of adsorbate (X2). The responses measured were time required for 85% drug release (Y1) and saturated solubility (Y2). MTT assay was employed for cytotoxicity studies on Caco-2 cells. In vivo pharmacokinetics and pharmacodynamic evaluations were carried out to assess the prepared SDA. Pre-compression evaluation of SDA suggests the prepared batches (B1-B9) possess adequate flow properties and could be used for compression of tablets. Differential scanning calorimetry and X-ray diffraction data signified the conversion of crystalline form of drug to amorphous form, a key parameter accountable for improvement in drug dissolution. Optimization data suggests that the amount of carrier and amount of adsorbate significantly (P < 0.05) influence both dependent variables (time required for 85% drug release and saturated solubility). Post-compression data signifies that the compressibility behavior of prepared tablets were within the official standard limits. Significant increase (P < 0.0001) in the in vitro dissolution characteristics of RXN was noticed in optimized SDA (>85% in 10 min) as compared to pure drug, marketed product and directly compressible tablet. Cytotoxicity studies confirm nontoxicity of prepared RXN SDA tablets. Higher Cmax and AUC achieved with RXN SDA tablets indicated enhancement in oral bioavailability (~3 folds higher than the RXN suspension). Higher bleeding time and percentage of platelet aggregation noticed with RXN SDA tablets further substantiate the efficacy of the prepared formulation. In summary, the results showed the potential of RXN SDA tablets to enhance the bioavailability of RXN and hence can be an alternate approach of solid dosage form for its development for commercial application.

Rapid growth of construction industry brings innovation and complexity in construction project. As we all know, there are numerous numbers of stakeholders are associated in single project including designers, engineers, contractor and daily workers. Single construction project creates tremendous number of documents throughout its life. Management of these documents has become essential as it has a great potential to overcome against time and cost overruns. Proper documentation helps project manager at the time of disputes between stakeholders. This paper depicts the current situation of documentation in Surat with current method used by construction person. As paper proceed, it shows various category of documents managed by construction persons on current project. Also, WhatsApp and e-mail are mainly used for document transfer to various stakeholders, engineers and contractor. Disputes between stakeholders is derived the top most issue due to improper documentation from Relative Importance Index calculation. Based on output of spearman correlation, disputes between stakeholders and miscommunication between team members are highly correlated with each other. Further spearman rank correlation shows that there is highly agreement between responses on project manager and PMC owner.

This study aims to evaluate the risk of postoperative mortality in octogenarians undergoing emergency laparotomy. 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. 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). 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.

Low aqueous solubility is one of the major reasons for the poor clinical efficacy of carvedilol in oral therapy. The aim of the present investigation was to evaluate the potential of liquisolid compact technique to enhance the dissolution rates of carvedilol and thereby the bioavailability. Liquisolid compacts were prepared using polyethylene glycol 400, Neusilin US2 and Aerosil 200. Experimental design and optimization was carried out by applying a 32 factorial design (batches D1-D9) to examine the effects of independent variables (amount of load factor and the excipient ratio) on dependent variables (angle of repose and % drug release). Differential scanning calorimetry and X-ray diffraction studies suggested transformation of carvedilol to amorphous in D6, a key factor responsible for dissolution rate improvement. This effect was evidenced in the dissolution data of D6 (>95% drug dissolved in 30 min) where the drug release kinetics followed Weibull model. It was observed that the amount of load factor influenced angle of repose and excipient ratio affected drug dissolution of liquisolid compacts. Pharmacokinetic profile of D6 was prominent, demonstrating greater carvedilol absorption than the control in rats. The observed increase in systemic bioavailability of carvedilol AUC0-∞ (p

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.

Due to the complex and diverse nature of epilepsy and antiepileptic drugs (AEDs), the implementation of therapeutic drug monitoring (TDM) can contribute significantly to the overall improvement of clinical outcome in epilepsy. Establishing and interpreting an individual serum drug concentration range by TDM is beneficial to prevent recurrence of epilepsy, as well as to avoid adverse drug effects. It enables optimization of dosage regimen, especially in case of drugs that follow non-linear pharmacokinetics, and in special populations such as pregnancy, pediatrics, geriatrics, critically ill, and liver and renal impairment. This review summarizes the ongoing clinical practice utilizing TDM of first-generation or conventional AEDs, such as valproic acid, phenytoin, carbamazepine, phenobarbital, primidone, ethosuximide, clonazepam, clobazam, piracetam, and sulthiame. Prospective and retrospective data describing the serum drug concentration–efficacy–toxicity relationship, pharmacokinetic parameters, activity of metabolites, overdose and treatment, and drugs that alter pharmacokinetics, have been described. The therapeutic decision should not be finalized based on serum drug concentration alone; other important factors to be considered are clinical laboratory data, patient history, signs and symptoms, pharmacogenetics, and electroencephalogram.

OBJECTIVE: Clinical utility of lornoxicam in oral therapy is primarily restricted by the low solubility and gastric adverse effects. This study evaluated the prospective of optimized proniosomal gel to improve the clinical efficacy of lornoxicam and compare with oral therapy. METHODS: Proniosomes were formulated by coacervation phase separation technique using span 60, lecithin and cholesterol. A four-factor three-level Box-Behnken design was used to evaluate the effect of amount of four independent variables; span 60 (X(1)), cholesterol (X(2)), lecithin (X(3)) and lornoxicam (X(4)) on response variables; vesicle size (Y(1)), entrapment efficiency (Y(2)) and transdermal flux (Y(3)). The selected proniosomal gel (F19) was characterized, and evaluated for the transdermal efficacy by ex vivo and in vivo experiments. RESULTS: Optimization study signifies that amount of formulation components (span 60, cholesterol, lecithin and lornoxicam) influence the vesicle size, entrapment efficiency and/or transdermal flux. Optimized formulation F19 exhibited nano size with high entrapment efficiency, adequate zeta potential, greater transdermal flux and better stability (at refrigerated conditions). The entrapment of lornoxicam in the bilayers of proniosome vesicles was confirmed by differential scanning calorimeter. Release profile of F19 was distinct (p

Rapid advancement in drug discovery process is leading to a number of potential new drug candidates having excellent drug efficacy but limited aqueous solubility. By virtue of the submicron particle size and distinct physicochemical properties, nanosuspension has the potential ability to tackle many formulation and drug delivery issues typically associated with poorly water and lipid soluble drugs. Conventional size reduction equipment such as media mill and high-pressure homogenizers and formulation approaches such as precipitation, emulsion-solvent evaporation, solvent diffusion and microemulsion techniques can be successfully implemented to prepare and scale-up nanosuspensions. Maintaining the stability in solution as well as in solid state, resuspendability without aggregation are the key factors to be considered for the successful production and scale-up of nanosuspensions. Due to the considerable enhancement of bioavailability, adaptability for surface modification and mucoadhesion for drug targeting have significantly expanded the scope of this novel formulation strategy. The application of nanosuspensions in different drug delivery systems such as oral, ocular, brain, topical, buccal, nasal and transdermal routes are currently undergoing extensive research. Oral drug delivery of nanosuspension with receptor mediated endocytosis has the promising ability to resolve most permeability limited absorption and hepatic first-pass metabolism related issues adversely affecting bioavailability. Advancement of enabling technologies such as nanosuspension can solve many formulation challenges currently faced among protein and peptide-based pharmaceuticals.

Therapeutic efficacy of zolmitriptan in oral therapy is primarily limited by the biopharmaceutical issues. The objective of this study is to design and optimize chitosan-based buccal bioadhesive system for the effective delivery of zolmitriptan in the treatment of migraine. Factorial design (32) is constructed and conducted in a fully randomized manner to study all nine possible experimental runs. The films were prepared by solvent casting method by varying the content of chitosan (X1) and polyvinyl alcohol (X2). The effect of these two independent variables on swelling index (Y1), percent drug release in 15 min (Y2) and 5 h (Y3), and mucoadhesive strength (Y4) of prepared films was evaluated. The physical and chemical characteristics displayed by the prepared films (F1–F9) were found to be optimal. It was observed that the factor X1 has positive and X2 has negative effect on response Y1. In contrast, factor X1 showed negative effects on drug release at both time intervals (15 min and 5 h) while X2 displayed positive responses for these variables (Y2 and Y3). However, the mucoadhesion increased with an increase in factor X1 and decreased when the factor X2 was increased. Indeed, the desirable characteristics exhibited by the film F7 are ideal for buccal application. Greater flux (63.93 ± 12.51 μg/cm2/h) demonstrated in ex vivo studies substantiated the potential of optimized film to effectively deliver zolmitriptan across the buccal membrane. This study concludes that the chitosan-based buccal film (F7) could be used in both prophylaxis and acute treatment of migraine, although need to be proved in vivo.

Promethazine hydrochloride (PMZ-HCl) is a classical anti-motion sickness drug which has oral bioavailability (25 %) due to extensive hepatic first pass metabolism. To overcome this drawback, novel, fast dissolving sublingual film (FDSF) of drug was developed. FDSF was formulated using pullulan and propylene glycol (PG) by solvent casting method. Complete taste masking was successfully obtained with HP β-CD, aspartame and grape fruit flavour. Complex of drug was proved using Fourier transfer infrared spectroscopy, differential scanning calorimetry and X-ray diffraction studies. Optimization of concentration of pullulan and PG was done using 32 full factorial design. Batches were evaluated for the parameters like elongation, tensile strength, folding endurance and in vitro disintegration studies. In vitro dissolution indicated 100 % drug release within 7.5 min. Environmental scanning electron microscopy studies also showed uniform drug distribution and integrity of film. In vivo sublingual absorption in human indicated that 70 % of drug absorbed in 10 min. The stability studies indicated that label should state “Store at cool, dry place” at temperature 25 °C. So by formulating the taste masked FDSF of PMZ-HCl will give faster onset of action and avoid unnecessary drug intake leading to traveller friendly formulation.

Solid dispersions of valdecoxib were prepared with the objective of dissolution enhancement by melt granulation technique using polyvinyl pyrollidone (PVP K 30) and polyethylene glycol (PEG 4000) alone (1:1) and in combination (1:0.5:0.5). Phase solubility studies showed a linear increase in valdecoxib solubility with increase in polymer concentration in both the cases. The FTIR spectroscopic studies showed the stability of valdecoxib and absence of well defined valdecoxib—PVP K 30–PEG 4000 interaction. Powder X-ray diffraction (XRD) and differential scanning calorimeter (DSC) were used to characterize the solid state of the dispersion, indicated a complete transformation of drug from crystalline to amorphous form. In vitro dissolution studies performed in 0.1 N HCl showed a significant enhance in dissolution rate when PEG 4000 and PVP K 30 were used in combination. Improved drug dissolution by both the carriers may be attributed to the improved wettability, reduction in drug crystallinity and solubilizing effects from solid dispersions of valdecoxib. Accelerated stability studies of solid dispersion with PVP K 30 and PEG 4000 does not show any significant change in the drug content and dissolution profile in 6 months study period. This study concluded that the dissolution rate of valdecoxib can be modulated by appropriate levels of hydrophilic carriers.

An inguinal hernia containing appendix is termed an Amyand's hernia. It is an uncommon and rare condition estimated to be found in approximately 1 % of adult inguinal hernia repairs. Depending on the extent of inflammation in the hernia sac and obstruction of hernia, clinical presentation can vary. We report a case of Amyand's hernia in a 22-year-old male who presented with history of right inguinal hernia for 6 months duration. Operation revealed hernia sac containing inflamed appendix hence appendectomy was performed.