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Ummarah Kanwal,1 Shahid Mukhtar,1 Muzzamil Waheed,2 Arifa Mehreen,3 Nasir Abbas,1 Rahat Shamim,1 Khalid Hussain,1 Fatima Rasool,1 Amjad Hussain,1 Nadeem Irfan Bukhari1 1Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan; 2Government College University, Faisalabad, 38850, Pakistan; 3University of Lahore, Lahore, PakistanCorrespondence: Nadeem Irfan BukhariPunjab University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, 54000, PakistanTel +923004259738Email nadeem_irfan@hotmail.comPurpose: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance.Material and Method: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase.Results: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0– 50 ng/mL and 0.01– 2.0 μg/mL for SIM with percent recoveries of 92.85– 101.53% and 94.51– 117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective.Conclusion: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.Keywords: differential release, Eudragit S100, Eudragit RSPO, DCP-Eudragit blend, quality by design, polymers, amlodipine besylate, simvastatin

Asad Majeed Khan,1,2 Muhammad Hanif,1 Nadeem Irfan Bukhari,3 Rahat Shamim,3 Fatima Rasool,3 Sumaira Rasul,4 Sana Shafique5 1Faculty of Pharmacy, Bahauddin Zakriya University, Multan, Pakistan; 2Lahore Pharmacy College, Lahore Medical and Dental College, Lahore, Pakistan; 3University College of Pharmacy, University of the Punjab, Lahore, Pakistan; 4Institute of Molecular Biology and Biotechnology, Bahauddin Zakriya University, Multan, Pakistan; 5Faculty of Pharmacy, Rippha International University, Lahore, PakistanCorrespondence: Muhammad Hanif; Nadeem Irfan Bukhari Email Muhammad.hanif@bzu.edu.pk; nadeem_irfan@hotmail.comBackground: Severe bleeding and perforation of the colon and rectum are complications of ulcerative colitis which can be treated by a targeted drug delivery system.Purpose: Development of colon-targeted delivery usually involves a complex formulation process and coating steps of pH-sensitive methacrylic acid based Eudragit®. The current work was purposefully designed to develop dicalcium phosphate (DCP) facilitated with Eudragit-S100-based pH-dependent, uncoated mesalamine matrix tablets.Materials and Methods: Mesalamine formulations were compressed using wet granulation technique with varying compositions of dicalcium phosphate (DCP) and Eudragit-S100. The developed formulations were characterized for physicochemical and drug release profiles. Infrared studies were carried out to ensure that there was no interaction between active ingredients and excipients. Artificial neural network (ANN) was used for the optimization of final DCP-Eudragit-S100 complex and the experimental data were employed to train a multi-layer perception (MLP) using quick propagation (QP) training algorithm until a satisfactory root mean square error (RMSE) was reached. The ANN-aided optimized formulation was compared with commercially available Masacol®.Results: Compressed tablets met the desirability criteria in terms of thickness, hardness, weight variation, friability, and content uniformity, ie, 5.34 mm, 7.7 kg/cm2, 585± 5 mg (%), 0.44%, and 103%, respectively. In-vitro dissolution study of commercially available mesalamine and optimized formulation was carried out and the former showed 100% release at 6 h while the latter released only 12.09% after 2 h and 72.96% after 12 h which was fitted to Weibull release model with b value of 1.3, indicating a complex release mechanism.Conclusion: DCP-Eudragit-S100 blend was found explicative for mesalamine release without coating in gastric and colonic regions. This combination may provide a better control of ulcerative colitis.Keywords: ulcerative colitis, DCP-Eudragit-S100 complex, phosphatidylserine, Weibull release model

Ummarah Kanwal,1,2 Nadeem Irfan Bukhari,2 Nosheen Fatima Rana,3 Mehreen Rehman,1 Khalid Hussain,2 Nasir Abbas,2 Arshad Mehmood,4 Abida Raza1 1NILOP Nanomedicine Research Laboratories, National Institute of Lasers and Optronics, Pakistan Institute of Engineering and Applied Sciences Islamabad, Pakistan; 2University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan; 3Department of Biomedical Engineering and Sciences, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, Islamabad, Pakistan; 4Material Division, National Institute of Lasers and Optronics, Pakistan Institute of Engineering and Applied Sciences Islamabad, Islamabad, Pakistan Purpose: This study was aimed to develop doxorubicin-loaded quaternary ammonium palmitoyl glycol chitosan (DOX–GCPQ) nanoformulation that could enable DOX delivery and noninvasive monitoring of drug accumulation and biodistribution at tumor site utilizing self-florescent property of doxorubicin.Materials and methods: DOX–GCPQ amphiphilic polymeric nanoformulations were prepared and optimized using artificial neural network (ANN) and characterized for surface morphology by atomic force microscopy, particle size with polydispersity index (PDI), and zeta potential by dynamic light scattering. Fourier transformed infrared (FTIR) and X-ray diffractometer studies were performed to examine drug polymer interaction. The ANN-optimized nanoformulation was investigated for in vitro release, cellular, tumor, and tissue uptake.Results: The optimized DOX–GCPQ nanoformulation was anionic spherical micelles with the hydrodynamic particle size of 97.8±1.5 nm, the PDI of

Muhammad Farhan Sohail,1–3 Mubashar Rehman,4,5 Hafiz Shoaib Sarwar,2 Sara Naveed,1 Omer Salman,6 Nadeem Irfan Bukhari,7 Irshad Hussain,3 Thomas J Webster,5 Gul Shahnaz21Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, 2Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 3Department of Chemistry, SBA School of Science and Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore, 4Department of Pharmacy, University of Lahore-Gujrat Campus, Gujrat, 5Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 6Department of Pharmacy, University of Lahore, Lahore Campus, 7University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan Abstract: The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research. Keywords: anticancer, permeability enhancement, solubility enhancement, P-glycoproteins, efflux pump, first-pass metabolism

This study reviews privatization effect of Malaysian drug distribution system on prices of cardiovascular and blood products. After privatization prices show variable pattern, increased to (5%) after a year of privatization, decreased to 0.098% in 1997-2000 and again increased to 80% in year 2001-2003. The increase in prices after privatization could not be correlated with inflation rate and was not explained by any pricing mechanism. Comparison with International Reference Prices showed tremendously higher prices for most of the drugs. The findings invite enacting of price control mechanisms and adapting a reference and differential medicine pricing system to curb public expenditures. [ABSTRACT FROM AUTHOR]

The present study was aimed to ameliorate the issue of solubility and thereby, bioavailability of ketoprofen, a BCS Class II drug. The sustained release matrix tablets (MT) were prepared using surfactant-assisted wet granulation (SAWG) with 1-5% of different surfactants. The tablet characteristics were within the compendial limits. The selected sustained release-compliant matrix tablet formulation containing granules prepared using 3% Soluplus® (MT2) released the drug by swelling-erosion. In human volunteers, MT2 attained the maximum plasma concentration (C max ) of 5.72µg /ml ± 0.30 h, time to C max (T max ) of 5.56 ± 0.30 h and maintained the plasma concentration above its minimum effective concentration (MEC), 0.7 µg.ml -1 till 24h. A control formulation, prepared from granules without surfactant (MT16), promptly attained C max of 9.62 ± 0.76 µg/ml within 1h but rapidly declined to below MEC in 8h. Area under the curve from initial point to infinity (AUC 0-∞ ) of MT2 (78.65 ± 7.64 µg.h.ml -1 ) was 2.29 folds higher than 34.39 ± 3.06 µg.h.ml -1 of MT16. With decreased C max , increased AUC 0-∞ , delayed T max and retained ketoprofen concentration above MEC for longer time, MT2 corresponded with the in-vitro sustained drug release characteristic. There is a likelihood of administration of once-a-day single dose of MT2 without plasma fluctuations, expected from two doses of MT16. SAWG helped developing a swellable-erodible sustained release matrix tablet formulation of ketoprofen with the desired biopharmaceutical and pharmacokinetics properties, merely by addition of Soluplus® in granules and without incorporation of any special ingredients or the major manipulation of the formulative ingredients in the formulation., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: The pharmaceutical sector in Pakistan has grown over a period with export potential, however, there are certain barriers in the framework that regulate the growth and export of domestically manufactured pharmaceuticals. The purpose of this study was to highlight the current challenges that hinder the export of pharmaceuticals, especially to the countries with stringent regulatory authorities (SRA), as perceived by the domestic pharmaceutical industry experts, and to highlight the facilitators that may help to resolve the identified challenges., Methods: In a qualitative study, the data were collected from the consented experts from the pharmaceutical industries in Lahore, Karachi, Peshawar, and Quetta. Industrial experts with a minimum of 10 years of experience and who were serving at managerial levels or above were recruited through purposive sampling. The semi-structured interviews were conducted for the collection of data from industrial experts. Thematic content analysis was applied to conclude the data., Results: Data analysis generated 4 themes and 16 codes. The export of pharmaceuticals, despite having greater potential was regarded as poor, which was attributed to the following: (a) inadequate industrial research and development, particularly on new molecules (b) non-compliance with the cGMP standards, (c) absence of high-tech equipment, (d) unwillingness of the pharmaceutical companies for bioequivalence studies on their generics, (e) unavailability of locally manufactured active pharmaceutical ingredients, (f) disruption in the supply of imported raw material, (g) poor international market perception about local pharmaceutical products and (h) lack of support from regulatory in process expedition. The respondents also suggested the measures for overcoming the above challenges to boost the export of domestic pharmaceuticals and expand their international market share in countries with SRA., Conclusion: Export from Pakistan to the SRA countries can be enhanced with mandatory bioequivalence studies during generic registration. The pharmaceuticals export could effectively contribute to the national economy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mubarak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective and Significance: Reducing the dimensions, when other additives are present, shows potential as a method to improve the dissolution and solubility of biopharmaceutical classification system class II drugs that have poor solubility. In this investigation, the process involved grinding naproxen with nicotinamide with the aim of improving solubility and the rate of dissolution., Methods: Naproxen was subjected to co-milling with urea, dimethylurea, and nicotinamide using a planetary ball mill for a duration of 90 min, maintaining a 1:1 molar ratio for the excipients (screening studies). The co-milled combinations, naproxen in its pure milled form, and a physical mixture were subjected to analysis using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), and solubility assessment. The mixture displaying the highest solubility (naproxen-nicotinamide) was chosen for further investigation, involving testing for intrinsic dissolution rate (IDR) and Fourier-transform infrared spectroscopy (FTIR) after co-milling for both 90 and 480 min., Results and Conclusion: The co-milled combination, denoted as S-3b and consisting of the most substantial ratio of nicotinamide to naproxen at 1:3, subjected to 480 min of milling, exhibited a remarkable 45-fold increase in solubility and a 9-fold increase in IDR. XRPD analysis of the co-milled samples demonstrated no amorphization, while SEM images portrayed the aggregates of naproxen with nicotinamide. FTIR outcomes negate the presence of any chemical interactions between the components. The co-milled sample exhibiting the highest solubility and IDR was used to create a tablet, which was then subjected to comprehensive evaluation for standard attributes. The results revealed improved compressibility and dissolution properties.

Homemade medicinal remedies used to treat both acute and chronic ailments for centuries need to be transformed into modern evidence-based dosage forms. Therefore, the present study aimed to develop buccal dispersible film, syrup and effervescent granules of an extemporaneous antigout homemade remedy. The dosage forms were prepared using holistic remedy (HR) as an active entity and excipients masking disagreeable features. The dosage forms and HR were subjected to physicochemical evaluation, and standardised by a reversed-phase HPLC method using chlorogenic acid, caffeic acid, vanillin, and ferulic acid as analytical standards. The standardised dosage forms were investigated for antigout activity using an appropriate model. The dosage forms were found to be physically elegant and phytochemically aligned with HR. The developed dosage forms contained the selected markers and possessed antigout activity. Hence, these standardised and evidence-based dosage forms may have wider acceptance in the market compared to HR.

The intricate relationship between smoking and the effects of the antiplatelet drug clopidogrel has been termed the "smoker's paradox". This paradox details the enhanced efficacy of clopidogrel in smokers compared to non-smokers. This review begins with an exploration of the proposed mechanisms of the smoker's paradox, particularly drawing attention to the induction of cytochrome P450 (CYP) isoenzymes via tobacco smoke, specifically the enzymes CYP1A2 and CYP2C19. Moreover, an investigation of the effects of genetic variability on the smoker's paradox was undertaken from both clinical and molecular perspectives, delving into the effects of ethnicity and genetic polymorphisms. The intriguing role of CYP1A2 genotypes and the response to clopidogrel in smoking and non-smoking populations was examined conferring insight into the individuality rather than universality of the smoker's paradox. CYP1A2 induction is hypothesised to elucidate the potency of smoking in exerting a counteracting effect in those taking clopidogrel who possess CYP2C19 loss of function polymorphisms. Furthermore, we assess the comparative efficacies of clopidogrel and other antiplatelet agents, namely prasugrel and ticagrelor. Studies indicated that prasugrel and ticagrelor provided a more consistent effect and further reduced platelet reactivity compared to clopidogrel within both smoking and non-smoking populations. Personalised dosing was another focus of the review considering patient comorbidities, genetic makeup, and smoking status with the objective of improving the antiplatelet response of those taking clopidogrel. In summation, this review provides insight into multiple areas of research concerning clopidogrel and the smoker's paradox taking into account proposed mechanisms, genetics, other antiplatelet agents, and personalised dosing., Competing Interests: Declaration of Competing Interest The authors of the manuscript “Investigation of smoking on the antiplatelet response to clopidogrel: Unravelling the Smoker’s Paradox.”, submitted to the journal “Pathology – Research and Practice”, have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: To investigate extracts of the stem bark of Ziziphus jujuba (L.) Gaertn. var. hysudrica Edgew. ( Rhamnaceae ) for anti-inflammatory activity and isolate the active principle(s)., Methods: The dry powder was macerated separately in three types of solvents to prepare methanol extract (ME), ethyl acetate extract (EE), and chloroform extract (CE). Following in vitro anti-inflammatory screening, the most active extract was selected to isolate the active compound. Both, the active extract and isolated compound were further tested on rats using the carrageenan-induced inflammation model. The blood and paw tissue were subjected to qPCR, and histopathology, respectively., Key Findings: CE showed comparatively higher anti-inflammatory activity (85.0-95.0 %) in all in vitro assays, except the heat-induced membrane stabilization model ( p  < 0.05), and upon column chromatography, it yielded a pure crystalline compound. The compound was a pentacyclic triterpenoid (Lupane), named as hydroxymethyl (3 β )-3-methyl-lup-20(29)-en-28-oate (Hussainate). CE (500 mg/kg) and Hussainate (1.0 mg/kg) reduced edema in 5 h after carrageenan administration. The activity of Hussainate was found to be comparable to that of dexamethasone (standard). The possible activity mechanism was the downregulation of tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-II), NF-κB, and IL-1β., Conclusions: This study reveals that chloroform extract of the stem's bark of Z. jujuba may be used to prepare standardized anti-inflammatory herbal products using Hussainate as an active analytical marker. Hussainate may be used as a lead to develop anti-inflammatory drugs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: The pharmaceutical sector in Pakistan has grown over a period, however, there are several barriers in the framework governing the growth of the country's pharmaceuticals. The lack of academia-industry linkage (AIL) is among the critical barriers; hence the focus of the study is to find out the reasons for the lack in the above collaboration. Understanding barriers may help their redressal., Method: This qualitative phenomenology-based study has been conducted in the most prominent pharmacy institutes, located in Lahore, Islamabad, Peshawar, Sargodha, and Quetta. Academic participants, with a minimum experience of 10 years and designation of assistant professor or above were recruited with a two-stage selection process, purposive sampling and snowball sampling. The data were collected using semi-structured interviews with academic experts. Thematic content analysis was employed to conclude the data., Results: Analysis of data yielded 8 themes with 18 codes. The main reasons for neglected AIL were explained by a partial or complete lack of industrial research and development activities. Other key factors for the scarcity of AILs were the lack of positive attitude from both industry and academia, applied research in academics, and the research and development of the new molecules in the pharmaceutical industry. Support by the government and the drug regulatory authority of Pakistan in terms of regulatory and academic policies was also perceived to be absent. New horizons in research and development could be opened by providing applied research to industry, including but not limited to new molecule development., Conclusion: Academia-industry linkage could be boosted with government-backed funded projects and policies. Academia should focus on the industrial-demanded applied research., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a pharmacologically important bioflavonoid in vegetables and fruits, is important in treating cardiovascular comorbidities. QUE alters the bioavailability of drugs used concurrently by dual inhibition of P-glycoproteins (P-gp) and cytochrome (CYP) enzyme systems. The current study aimed to investigate the pre-treatment and co-administration effect of QUE on AMD pharmacokinetics in rats., Materials and Methods: Two separate animal trials (I and II) were planned to probe the effect of QUE on AMD pharmacokinetics by following previously cited studies. The pre-treatment group received oral doses of QUE for 14 days, and a single dose of AMD on the 15th day. Rats were administered single doses of QUE (20 mg/kg) and AMD (50 mg/kg) concurrently in a carboxymethylcellulose (CMC) in the co-administration study. Blood was collected at pre-determined time points. AMD was quantified by HPLC, and data was analyzed by PK solver software., Results: In the pre-treated group, peak plasma concentration (Cmax) and area under the curve (AUC0-∞) of AMD were increased by 45.52% and 13.70%, respectively, while time to achieve maximum concentration (tmax), half-life (t1/2) and clearance (CL) were declined by 35.72%, 16.75%, and 11.0% respectively compared to the control. In the co-administered group, compared to controls, Cmax and AUC0-∞ were elevated to 12.90% and 7.80%, respectively, while tmax, t1/2, and CL declined by 16.70%, 2.35%, and 13.40%. Further, AMD was increased in lung tissue of both treated groups, relative to the respective controls., Conclusions: A notable pharmacokinetic drug interaction between QUE and AMD was observed in rats and warrants possible drug interaction study in humans, suggesting AMD dose adjustment specifically in patients with arrhythmia having a pre-treatment history and simultaneous administration of QUE-containing products.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Gelatin-based hydrogels have shown good injectability and biocompatibility and have been broadly used for drug delivery and tissue regeneration. However, their low mechanical strengths and fast degradation rates must be modified for long-term implantation applications. With an aim to develop mechanically stable hydrogels, reactive anhydride-based oligomers were developed and used to fabricate gelatin-based crosslinked hydrogels in this study. A cascade of hydrophilic oligomers containing reactive anhydride groups was synthesized by free radical polymerization. These oligomers varied in degree of reactivity, comonomer composition, and showed low molecular weights (M n < 5 kDa). The reactive oligomers were utilized to fabricate hydrogels that differed in their mechanical strengths and degradation profiles. These formulations exhibited good cytocompatibility with human adipose tissue-derived stem cells (hADCs). In conclusion, the reactive MA-containing oligomers were successfully synthesized and utilized for the development of oligomer-crosslinked hydrogels. Such oligomer-crosslinked gelatin-based hydrogels hold promise as drug or cell carriers in various biomedical applications.

This research aimed to acquire doxorubicin loaded zinc oxide nanoflowers (DOX-ZnO-NFs) for intracellular drug cargo possessing a synergistic in-vitro anticancer activity with minimal toxicity. Zinc is the main inorganic metallic component of various enzyme systems and has the possibility of fabrication into the diverse nano-structural forms. An easy absorption and extensive tissue distribution of zinc have made it unique candidate for drug delivery system. Hence, the zinc oxide nanoflowers were prepared with sonochemical-precipitation. The developed system was characterized using the reported methods and was optimized employing design of experiment, coupled with artificial neural network approach. The optimized nanoflowers (DOX-ZnO-NFV) were anionic with particle size of 24 ± 0.05 nm, polydispersity index of <0.5, a zeta potential of -25.68 ± 0.16 mV, yield of 87.40% and encapsulation efficiency of 85.25%. DOX-ZNO-NFV depicted sustained DOX release, around 65.413% release in 30 h at pH 7.4 and assumed Weibull model with its derived parameters, a and b of 22.77 and 0.918, respectively. DOX-ZnO-NFV remained stable on storage for 3 months at 4° C/50% RH and 25° C/60% RH. DOX-ZnO-NFV displayed a zone of inhibition of 13.50 ± 1.25 mm and 25.50 ± 0.98 mm, respectively against gram-positive Staphylococcus aureus and gram-negative Escherichia coli strains, presenting the nanoflowers as self-preservative. DOX-ZnO-NFV exhibited higher in-vitro anticancer activity in Henrietta Lacks cell line, with least hemolysis compared to the free DOX and ZnO-NF. Thus, doxorubicin loaded zinc oxide nanoflowers envisioned to act as better chemotherapeutic cargos with the maximize anticancer activity and minimal toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Warfarin (WAR) is an anticoagulant with a narrow therapeutic index and is principally metabolized by CYP3A4 and CYP2C9 enzymes. The inhibitors of these enzymes may alter the systemic exposure to WAR. Quercetin (QUE), a bioflavonoid, may modify the bioavailability of drugs used concurrently by inhibiting CYP3A4, CYP2C8, CYP2C9, CYP1A2, and Pglycoprotein (P-gp)., Objective: The current study scrutinized the influence of QUE on WAR pharmacokinetics in rats., Method: QUE was orally administered to animals for 14 consecutive days, followed by WAR as a single oral dose on the 15 th day in the pre-treatment group. The co-administration group received a single dose of QUE and WAR concomitantly. Only carboxymethylcellulose (CMC) 0.5% was administered as a vehicle to control group., Results: In the pre-treated group, WAR's C max was increased by 30.43%, AUC 0-∞ by 62.94%, and t 1/2 by 10.54%, while Cl decreased by 41.35%, relative to control. In co-administered animals, WAR's C max increased by 10.98%, AUC 0-∞ by 20.20%, and t 1/2 by 8.87%, while Cl declined by 16.40%., Conclusion: QUE alters the pharmacokinetics of WAR, warranting possibly WAR dose adjustment after confirmatory clinical investigations, specifically in patients with thrombotic disorders and a pre-treatment history of QUE or its product., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Plant mucilages are commonly employed as excipients in pharmaceutical manufacturing. Ocimum basilicum (Lamiaceae family), a source of hydrophilic mucilage referred herein as Ocicum, was evaluated for the solubility enhancer of a model drug, aceclofenac, in solid dispersions prepared using different methods. Polymer was extracted from O. basilicum and solid dispersions of aceclofenac were fabricated with Ocicum or Poloxamer 407 using polymer-to-drug ratios of 1:1, 1:2 and 1:3 utilizing solvent evaporation, lyophilization and melt methods. Ocicum was evaluated for its safety via acute toxicity study including different biochemical and hematological parameters including liver and kidney profiles. Moreover, different characterization studies including melting-point, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and differential thermal analysis (TGA) were used for evaluation of polymer and solid dispersions. Furthermore, solubility and dissolution studies were performed to confirm solubility enhancement. Ocicum was found to be safer, and different characterization studies confirmed the purity of the compounds. In addition, Ocicum exhibited up to 6.27-fold enhanced solubility as compared to pure aceclofenac; similarly, 4.51-fold increased solubility by the synthetic polymer in their respective solid dispersions was shown. Furthermore, Ocicum-based solid dispersions showed substantial improvement in dissolution of aceclofenac. Therefore, it can be concluded from the above-mentioned results that Ocicum might be used as an economical natural oral delivery carrier alternative to the synthetic polymers.

Sumatriptan succinate and prochlorperazine maleate are a clinically proven combination for treating migraine and associated nausea and vomiting. Classical oral dosage forms are not frequently workable in migraine because of the associated nausea/vomiting, and no effective fixed dose combination is available. Thus, the aim of the study was to optimize a combined sumatriptan-prochlorperazine orodispersible film for rapid release of drugs. Orodispersible films were prepared by solvent casting method using varied amounts of polyvinyl alcohol and glycerol as film former and plasticizer, respectively, along with fixed levels of other ingredients employing central composite design. The optimum film (VF) demonstrated disintegration and total dispersion times as 21 s and 2.3 min, respectively. Tensile strength and Young's modulus were 8.86 ± 0.37 MPa and 24.15 ± 0.07 MPa, respectively. The in vitro T80% of both drugs from the ODF was achieved within 4 min. The film was palatable and disintegrated in 2 min in buccal cavity of human volunteers. Permeation study through goat mucosa demonstrated 100% permeation of both drugs within 15 min. X-Ray diffraction and differential scanning calorimetry supported drugs being amorphous and Fourier transform infrared demonstrated drug-excipient compatibility in optimized film. A judicious combination of sumatriptan succinate and prochlorperazine maleate could be prepared in orodispersible films for the possible relief of migraine., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The concomitant use of herbal products and synthetic drugs necessitates the assessment of their interaction potentials. The herbal hepatoprotective medicine, silybin A inhibits cytochrome P450 (CYP) 2C9 and 3A4 enzymes, thus, may interact with the drugs that are substrates of CYP2C9 and 3A4, such as losartan. The three most prominent genotypes, expressed by CYP2C9 are the CYP2C9*1/*1, CYP2C9*1/*2 and CYP2C9*1/*3. This study aimed to assess silybin A-losartan interaction in different CYP2C9 genotypes using physiological-based pharmacokinetic (PBPK) model approach. The individual PBPK models for silybin A and losartan were developed using PK-Sim®. Losartan pharmacokinetics was predicted with or without co-administration of silybin A in individuals of different CYP2C9 genotypes to find herbal-drug interaction. The predicted drug plasma curves and pharmacokinetic parameters were optimized using parameter identification tool and were compared with reported pharmacokinetic parameters from the published clinical studies for model validation. The silybin-losartan interactions were predicted by change in area under the curve (AUC) and peak systemic concentration (C max ). The co-treatment of silybin A, 420 mg/24 h (140 mg/8 h) with losartan 50 mg/24 h, exhibited a genotype-dependent change in the losartan's AUC and C max . In CYP 2C9*1/*1 genotype, AUC and C max of losartan were increased 1.16 and 1.37 folds, respectively falling in a range stipulated for negligible interaction. Increase in AUC and C max by 0.873 and 0.294 folds, respectively in CYP2C9*1/*3 after co-administration of silybin A exhibited a minor interaction with losartan. However, in individuals with CYP2C9*1/*2 genotype, the losartan's AUC and C max were decreased by 0.01 folds, manifesting a moderate interaction. Hence, in CYP2C9*1/*1 and CYP2C9*1/*3 genotypes, silybin A is a weak CYP inhibitor for losartan while in CYP2C9*1/*2 genotype, the co-administration of silybin consequents into a moderate pharmacokinetic interaction with losartan., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present study aimed to investigate the enzymetic, non-enzymetic toxicity and antioxidant potential of a drug candidate 5-Benzyl-1,3,4-Oxadiazole-2-Thiol(OXPA) using computational tools and in vivo models. The binding pattern of it, with different toxicity/oxidative enzymes was predicted using software pkCSM, Protox- II, LAZAR, Mcule 1-Click Docking 3D-Ligand binding Site and best score obtained used as an evaluating criterion. After acute oral toxicity, in vivo. antioxidant and hepato protective activity was investigated on male wistar rats, segregated into four groups as control (NS), toxic (INH-RIF), standard (Silymerin) and sample (OXPA, 100mg/Kg) for 21days. Level of antioxidant enzymes / histopathology and serum biochemical parameters in liver and blood of treated rats was assessed by using scientific tools. In silico study reveal no profound toxicity parameters however, LD50 found to be 560mg/Kg while in vivo study declared it safe till 1000mg/Kg, as having no toxicity symptoms. Molecular interaction score with GTH reductase, s-transferase and significant in vivo antioxidant effect on catalase, SOD, TBARS enzymes and histopathological assessment, declare OXPA a good antioxidant having significant (P< 0.05) hepato protective activity. Results of in silico, in vivo studies declare the propensity of 5-Benzyl-1, 3, 4-oxadiazole-2-thiol as potential antioxidant, for further investigations as a drug.

Background: The dissolution method for certain drugs needs specialized conditions. Dissolution testing for felodipine extended release (ER) tablets (Plendil® 5 mg) and amlodipine-indapamide fixed dose (Natrilam®, 5/1.5 mg) ER tablets requires the use of a stationary (felodipine) basket in USP Apparatus II., Objective: The study aimed to develop simple methods for Plendil® and Natrilam® without the use of a felodipine basket., Methods: The dissolution profiles obtained from different media and paddle speeds were used to compute miscellaneous dissolution parameters and were compared to those obtained from standard (existing) methods using a felodipine basket., Results: The f1, f2, and bootstrap f2 (5th % percentile) values for Plendil® 2.47, 88.17, and 54.62, respectively, and all other dissolution factors revealed similarity between standard and the selected test method with 1% Tween 20 at 50 rpm. For Natrilam®, f1 and f2 and bootstrap f2 5.13, 72.92, and 62.67, respectively, and all other dissolution parameters showed similarity of the standard and selected test method using 0.1N HCl media having 0.38 gm/L EDTA with a sinker at 100 rpm. Release of products assumed zero-order and Weibull model, respectively., Conclusion: Test dissolution methods for Plendil® and Natrilam® tablets produced equivalent dissolution profiles compared to their respective standard methods with stationary basket USP Apparatus II., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Liquid Semisolid Matrix (LSSM) technology involves the filling of drugmixed gel in hard gelatin capsules for different applications., Methods: In continuation of our previous work on LSSM technology, 10% (w/w) of practically insoluble model drug, mefenamic acid was incorporated in gels of different poloxamers with 8% (w/w) SiO 2 ., Results: Gels exhibited plasticity or pseudoplasticity along thixotropy at 2 and 24 h enabling their easy filling into hard gelatin capsules without content seepage. Mefenamic acid gels prepared with L64 and L92 maintained their apparent viscosities for the study period of one month. Around 100% mefenamic acid was released within 90 min from L64- and in 150 min from L92-SiO 2 gels, both with first-order kinetics. In 12 month long-term stability studies, only mefenamic acid-L64- SiO gel at 30°C/65% RH indicated dispersion stability with similar rheology and release pattern to that at 2, 24 and 30 days. No chemical drug-polymer interactions were found in FTIR., Conclusion: The release of practically insoluble mefenamic acid could be enhanced from gel formulated with L64 and SiO 2 ., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The study aimed at simultaneous quantification of sumatriptan succinate (SUM) and prochlorperazine maleate (PCP) in an orodispersible film using two validated spectroscopic methods viz. simultaneous equation (Method I) and the Q-absorption ratio (Method II). The Method I involved measurement of absorbances at λ max of both drugs while in Method II, absorbances were measured at isosbestic wavelength and λ max of one of the two components. Method validation were accomplished as per the ICH guidelines. A 1:1 mixture of the drugs and an orodispersible film (ODF) containing these drugs were assayed by both methods. The absorbance data of SUM and PCP in both methods were linear at respective wavelengths with correlation coefficient values >0.995. Both methods were precise as % RSD in repeatability, interday and intraday precision was less than 2. The estimation of SUM and PCP from the film dosage form by method I was104.74% and 98.34% and by method II was 103.45% and 98.85%, respectively, with a standard deviation <2. The study concluded that both the methods were simple, reliable and robust and can be applied successfully for the simultaneous quantification of SUM and PCP in mixture and orodispersible film dosage form.

The limited solubility of clarithromycin (CAM), coupled with low bioavailability and rapid elimination, are major shortcomings, needed to be addressed to achieve optimum therapeutic goals. Therefore, sustained-release (SR) tablets containing solid dispersion (SD) granules of CAM were prepared in this study. Initially, SD granules of CAM were prepared by hot melt extrusion (HME) technique using Kollidon VA64 as a hydrophilic carrier. The saturation solubility of SD showed almost 4.5-fold increase as compared to pure CAM in pH 6.8 medium. In vitro drug dissolution data indicated a substantial increase in the dissolution of SD as compared to that of pure CAM. The thermal stability of drug, carrier, and SD at elevated HME temperatures was evident from the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-ray diffraction (PXRD) data and scanning electron microscope (SEM) images revealed a decrease in the crystallinity and the uniform dispersion of drug, respectively. Moreover, Fourier transformed infrared spectroscopy (FT-IR) data confirmed the formation of hydrogen bond between the carbonyl group of drug and the hydroxyl group of carrier. SD loaded sustained-release (SD-SR) matrix tablets were prepared with hydrophobic polymers (Eudragit RS100 and Eudragit RL100). The pH-independent swelling and permeability of both polymers were responsible for the sustained drug release from SD-SR tablets. Pharmacokinetic (PK) studies suggested a 3.4-fold increase in the relative bioavailability of SD-SR tablets as compared to that of pure CAM., (© 2021. American Association of Pharmaceutical Scientists.)

Poor bioavailability is a major obstacle in the development of an effective dosage form of the poorly soluble drugs. The present study aimed to improve the dissolution rate of a poorly soluble drug oxcarbazepine (OXC) exploiting the approach of surface area enhancement by fabricating drug loaded microfibers via centrifugal melt spinning (CMS) technique. For the generation of OXC loaded fibers, a well-known cotton candy process was used and the prepared fibers were characterized using SEM, DSC, XPRD and FTIR. Drug loaded fibers were also pressed into tablets which were also subjected to various in-vitro and in-vivo characterizations. The results have shown the formations of stable, amorphous, micro sized fibers, with average diameter of 6.0 ± 2 μm, loading efficiency > 80% and overall yield > 85%. In-vitro dissolution of OXC from fibers was > 90% within two minutes, which is ~ 5 times faster than that of pure drug. Pharmacokinetic data showed an improvement of ~ 25% and 35% in C max and AUC, respectively with two hours earlier T max . In-vivo studies in human oral cavity showed quick disintegration (45 ± 5 s) with > 90% OXC dissolved. The study concludes that the OXC incorporated in microfibers showed rapid in-vitro and in-vivo (oral) dissolution which resulted in rapid systemic absorption and improved bioavailability parameters. Furthermore, the addition of PVP boosted the extrusion process and stability of fibers and the sucrose base of these fibers has masked the taste of OXC making such formulation palatable, especially for pediatric patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

To evaluate in-vivo antioxidant potential of fruit mucilage from Cucumis melo variety momordica (PM) and variety agrestis (KM) using rats as experimental animals, the fruits were collected, identified, dried and pulverized. Mucilages were isolated from the fruit powders by microwave-assisted method. Aqueous extracts obtained were filtered to remove fruit pulp. Each filtrate was centrifuged at 4000xg rpm for 15 min. Each supernatant was precipitated with 3 volumes of 95% ethanol and maintained overnight at 4°C. These precipitates were filtered and lyophilized. In vivo antioxidant activity was determined using rats for 14 days. Paracetamol (75mg/Kg, i.p.) for inducing oxidative stress and Vitamin C & Vitamin E (200mg/Kg each, p.o.) as standard treatment were used. PM and KM were given in 500mg/Kg and 1000mg/Kg, p.o. doses in separate groups. SOD, MDA, GSH and CAT levels were estimated in organs (liver, kidney, heart, brain) of all groups using standard procedures. Toxic control showed prominent toxicity in the liver. The levels of GSH, CAT and SOD were raised and MDA levels were reduced in all organs of test and standard groups. The levels of antioxidant biomarkers varied in all remaining groups. The overall results are significant suggesting strong antioxidant potential of PM and KM.

A simple, sensitive and precise high performance liquid chromatographic (HPLC) method was developed and validated for determination of flavoxate HCI in raw material, tablets and biological fluids. The method followed by using the Zorbax XDB-C18 column containing Di-isobutyl n-octadeceylsilane (4.6mm×150mm, 5μm). The mobile phase consisted of acetonitrile: methanol: 0.15M sodium perchlorate (17:35:48 v/v) having pH 3. UV detection was carried out at 229nm at 40°C. Results indicated that the method has successfully established and validated in accordance with ICH guidelines acceptance criteria for linearity (0.03-7.5μg), accuracy (101.18-101.28%), robustness of column age and column lot (peak area %CV<0.04, purity %CV< 0.006) and robustness of HPLC condition (%CV<0.02), precision (intra and inter day precision assay, %CV values for peak area and percent purity of flavoxate HCl<2%) and system suitability parameters. The average noise, theoretical LOD and LOQ were found to be 0.01 mAU, 0.03 mAU and 0.6ng, respectively. The Coefficient of determination (r2) ranging from 0.03μg to 7.5μg, 0.99 which was within acceptable criteria of r 2 & gt 0.99. The spiked recoveries of samples were 101.28, 101.18 and 101.18% respectively. All data revealed that this method can be used for in-vitro & in-vivo determination of flavoxate HCI in various pharmaceutical preparations.

In the present study nanotechnology approach, i.e., a cyclodextrin (CD) based carbonate nanosponge was used to improve the solubility and dissolution of ibuprofen. Solvent and ultrasound assisted methods were used to prepare nanosponges using two CDs (β-CD and 2-hydroxypropyl-β-CD (2HP-β-CD)) and a cross-linker (CL) diphenyl carbonate (DPC) in varying molar ratios. Nanosponges were investigated for their solubilizing efficiency and phase solubility studies. Structural analysis by Fourier transform infrared (FTIR) and powder X-ray diffraction (PXRD), thermo-analytical characterization by differential scanning calorimetry (DCS), morphology by scanning electron microscopy (SEM). In-vitro drug release followed by in-vivo analgesic and anti-inflammatory studies were performed. 2HP-β-CD based nanosponges (molar ratio 0.01:0.04) prepared by ultrasound assisted method showed the highest solubilizing efficiency (i.e., 4.28 folds). Stability constant values showed that all complexes were stable. Inclusion complexes of drug was confirmed by PXRD and DSC. SEM images showed porous structures confirming the formation of cross-linked network. Particle size was in the range of 296.8±64 to 611.7±32nm. In-vitro release studies showed enhanced dissolution profile from nanosponge formulation (~94% from I11) as compared to the pure drug (~45% Ibuprofen) in 120min. Significant (p<0.05) extent of pain inhibition and anti-inflammatory activity was observed for nanosponge formulation when compared with the pure drug. CD based carbonate nanosponges with better solubility, enhanced release profile, improved analgesic and anti-inflammatory activity were successfully formulated for ibuprofen.

Objectives: This study was conducted to assess the effect of microwave heating on the preparation of paracetamol cross-linked gelatin matrices by using the design of experiment (DoE) approach and explore the influence of the duration of microwave irradiation, the concentrations of crosslinker, and the amount of sodium bicarbonate (salt) on paracetamol release. These parameters were also compared with those of the matrices prepared via conventional heating., Materials and Methods: Twenty gel matrices were prepared with different durations of microwave irradiation, amounts of maize, and concentrations of sodium bicarbonate as suggested by Design Expert (DX ® ). The percentage drug release, the coefficient of variance (CV) in release, and the mean dissolution time (MDT) were the properties explored in the designed experimentation., Results: Target responses were dependent on microwave irradiation time, cross-linker amount, and salt concentration. Classical and microwave heating did not demonstrate statistically significant difference in modifying the percentage of drug released from the matrices. However, the CVs of microwave-assisted formulations were lower than those of the gel matrices prepared via classical heating. Thus, microwave heating produced lesser variations in drug release. The optimized gel matrices demonstrated that the observed percentage of drug release, CV, and MDT were within the prediction interval generated by DX ® . The release mechanism of the matrix formulations followed the Peppas-Korsmeyer anomalous transport model., Conclusion: The DoE-supported microwave-assisted approach could be applied to optimize the critical factors of drug release with less variation.

Objective: The present study was aimed to prepare and characterize new cocrystals of lornoxicam (LORX), a BCS class II drug employing 1,3-dimethyl urea (DMU) as a coformer to improve physicochemical, pharmaceutical, and pharmacokinetic performance., Methods: A screening study was conducted by employing three techniques viz. neat grinding, liquid-assisted grinding (LAG), and solvent evaporation (SE) using different drug-coformer molar ratios (1:1, 1:2, and 1:3). Samples were characterized by DSC, PXRD, ATR-FTIR, SEM, intrinsic dissolution rate (IDR) studies, compressional studies, and pharmacokinetic studies. In vitro dissolution and stability studies (25 °C/60%RH and 40 °C/75%RH for three months) were carried out for cocrystal tablets., Results: LAG and SE were found successful in ratio 1:3 and IDR showed approximately 28- and 19-fold increase, respectively in 0.1 N HCl (pH 1.2) and buffer (pH 7.4) as compared to pure LORX. The cocrystal exhibited good tabletability and was ∼2.5 times that of LORX at 6000 Psi. Dissolution profiles of tablets of cocrystal increased (56% and 100% at pH 1.2 and 7.4, respectively in contrast to those of physical mixture (PhyMix) (∼35% and ∼10%) and pure LORX (∼17% and ∼7%) within 60 min. The C max and AUC 0-∞ for the selected cocrystal were significantly increased ( p  < 0.05) which was 2.4 and 2.5 times, respectively, that of LORX in a single dose oral pharmacokinetic study executed in rabbits. Tablets of cocrystal were found stable at both conditions., Conclusion: The study indicates that cocrystallization with DMU can concomitantly improve tabletability, dissolution rate, and in vivo performance of dissolution limited drug LORX.

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC 0-∞ (37.87±1.3 μgh/ml) and C max (6.94±2.94 μg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced (p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.

Clinical success of effective gene therapy is mainly hampered by the insufficiency of safe and efficient internalization of a transgene to the targeted cellular site. Therefore, the development of a safe and efficient nanocarrier system is one of the fundamental challenges to transfer the therapeutic genes to the diseased cells. Polyamidoamine (PAMAM) dendrimer has been used as an efficient non-viral gene vector (dendriplexes) but the toxicity and unusual biodistribution induced by the terminal amino groups (-NH 2 ) limit its in vivo applications. Hence, a state of the art lipid modification with PAMAM based gene carrier (lipodendriplexes) was planned to investigate theirs in vitro (2D and 3D cell culture) and in vivo behaviour. In vitro pDNA transfection, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, cellular protein contents, live/dead staining and apoptosis were studied in 2D cell culture of HEK-293 cells while GFP transfection, 3D cell viability and live/dead staining of spheroids were performed in its 3D cell culture. Acute toxicity studies including organ to body index ratio, hematological parameters, serum biochemistry, histopathological profiles and in vivo transgene expression were assessed in female BALB/c mice. The results suggested that, in comparison to dendriplexes the lipodendriplexes exhibited significant improvement of pDNA transfection (p < 0.001) with lower LDH release (p < 0.01) and ROS generation (p < 0.05). A substantially higher cellular protein content (p < 0.01) and cell viability were also observed in 2D culture. A strong GFP expression with an improved cell viability profile (p < 0.05) was indicated in lipodendriplexes treated 3D spheroids. In vivo archives showed the superiority of lipid-modified nanocarrier system, depicted a significant increase in green fluorescent protein (GFP) expression in the lungs (p < 0.01), heart (p < 0.001), liver (p < 0.001) and kidneys (p < 0.001) with improved serum biochemistry and hematological profile as compared to unmodified dendriplexes. No tissue necrosis was evident in the animal groups treated with lipid-shielded molecules. Therefore, a non-covalent conjugation of lipids with PAMAM based carrier system could be considered as a promising approach for an efficient and biocompatible gene delivery system.

Vaccines are among the most vital interventions to control and reduce the morbidity and mortality worldwide. In accessing vaccines, pricing is usually the single most important deciding element. However, there is a scarcity of the literature on the vaccines pricing. The current study aims to review vaccine prices from the published literature and to evaluate factors that impact the pricing of vaccines. The literature (from 2015-2020) was reviewed to identify the original research articles. Systematic searches were conducted across the five databases including, Google Scholar, PubMed, Science Direct, Scopus and Springer Link. Literature search yielded 23,626 articles, of which 7351 were screened and 7310 articles were excluded based on title and abstracts relevance. The 41 studies were selected for full text review and 4 studies were found to meet the inclusion criteria. The included studies discussed vaccine prices for childhood vaccines, for Human Papilloma Virus (HPV) in US, China and in Europe. One study detailed the various scenarios of the HPV vaccines pricing. It was found that recently introduced vaccines have higher prices owing to the involvement of technology and research for their manufacture. However, prices tended to decrease over some maturation in price and by the involvement of Global Alliance for Vaccine Initiative (GAVI) and other allies. The prices of vaccines in China were much lower than the other high-income countries and the prices offered through United Nations Children's Fund (UNICEF), mainly due to the large scale of demand in China. The affordable prices of vaccines were related to delicate procedures involving multiple stakeholders and a shorter duration of contract. This review systematically evaluated the literature and identified key factors that could impact vaccines pricing. The prices were higher for the newly introduced vaccines into the market. However, with the price maturation, there was a decline in the pricing and affordable prices could be achieved through tender pricing and involvement of GAVI and other allies.

Objectives: The aim of this study was to prepare orally disintegrating, slow release tablets of naproxen sodium for prompt onset and sustained action required in many types of acute pain., Materials and Methods: Tablet formulations containing varying concentrations of croscarmellose sodium (a superdisintegrant) and Soluplus ® (as release modifier) were prepared by wet granulation method using a single punch tablet machine. The prepared granules were evaluated for their bulk properties and the tablets were evaluated for hardness, disintegration time, and drug release profiles., Results: The results showed that the granules so prepared have good flow and compressional properties. A disintegration time of tablets <30 s was achieved by selecting an optimum concentration of croscarmellose sodium. The drug release from the tablets was sustained for 2 h by incorporating a suitable amount of Soluplus ® ., Conclusion: This study examined the use of Soluplus ® (a novel solubilizer) for the first time as a release modifier of API from tablets., Competing Interests: Conflicts of interest: No conflict of interest was declared by the authors. The authors alone are responsible for the content and writing of the paper., (©Copyright 2020 Turk J Pharm Sci, Published by Galenos Publishing House.)

Background: This study aimed to assess the pediatric lisinopril doses using an adult physiological based pharmacokinetic (PBPK) model. As the empirical rules of dose calculation cannot calculate gender-specific pediatric doses and ignores the age-related physiological differences., Methods: A PBPK model of lisinopril for the healthy adult population was developed for oral (fed and fasting) and IV administration using PK-Sim MoBI® and was scaled down to a virtual pediatric population for prediction of lisinopril doses in neonates to infants, infants to toddler, children at pre-school age, children at school age and the adolescents. The pharmacokinetic parameters were predicted for the above groups at decremental doses of 20 mg, 10 mg, 5 mg, 2.5 mg, and 1.5 mg in order to accomplish doses producing the pharmacokinetic parameters, similar (or comparable) to that of the adult population. The above simulated pediatric doses were compared to the doses computed using the conventional four methods, such as Young's rule, Clark's rule, and weight-based and body surface area-based equations and the dose reported in different studies., Results: Though the doses predicted for all subpopulations of children were comparable to those calculated by Young's rule, yet the conventional methods overestimated the pediatric doses when compared to the respective PBPK-predicted doses. The findings of previous real time pharmacokinetic studies in pediatric patients supported the present simulated dose., Conclusion: Thus, PBPK seems to have predictability potential for pediatric dose since it takes into consideration the physiological changes related to age and gender.

Introduction: Most of the antibiotics currently used in pediatrics are either unlicensed or being prescribed outside the specifications of product label (off-label prescribing). The aim of this study was to assess the extent of off-label antibiotic use in pediatrics., Methodology: A six month longitudinal off-label antibiotic utilization survey was carried out from January to June, 2018. A structured questionnaire was designed to collect detailed information for each pediatric patient admitted to participating health center. The data included basic demographic and clinical diagnosis with details of prescribed antibiotics (formulation, dose, dosage, route of administration and indication for use). Data were analyzed using Social packages for Statistical Sciences (SPSS) version 21.0., Results: Of 1,810 admissions, 1,795 (99.2%) patients received antibiotics. Out of these, a total of 451 (25.1%) patients (326 patients admitted in the medical ward and 125 patients in ICUs) received at least one unlicensed/off-label antibiotic. Antibiotics were predominantly prescribed for the treatment of infections (n = 311, 69.0%). The majority of the pediatric patients who received off-label antibiotic suffered from respiratory tract infections (n = 223, 49.4%), skin and soft tissue infections (n = 53, 11.8%), gastrointestinal tract infections (n = 56, 12.4%) and other infections (n = 46, 10.2%). Co-amoxiclav (n = 190, 42.1%) was the most frequently off-label prescribed antibiotic to pediatric patients. An inappropriate dose for patients (n = 430, 95.3%) was the most frequent cause of prescribing off-label antibiotics., Conclusions: Further evaluation of health and economic outcomes of off-label prescribing and determinants influencing the drug choice is required., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Muhammad Hafeez, Zikria Saleem, Nasir Abbas Bukhari, Khalid Hussain, Rahat Shamim, Amjad Hussain, Nadeem Irfan Bukhari.)

Rosa brunonii L., a less investigated plant contains flavonoid glycosides and is used to treat stomach ailments, heart problems, and diabetes in folk. The crude extract of the plant possesses antioxidant activity. The current work was aimed to investigate the presence of phytochemicals, antioxidative stress and protective potential of chloroform extract of the Rosa brunonii L. fruits (RBFCE) against liver and kidney toxicity induced by anti-tuberculosis drugs, rifampicin/isoniazid (Rif/INH) in Wistar albino rats. Animals were divided into six groups, each comprising 6 rats and fed with a standard pelleted diet. Normal control group was given only a standard pelleted diet. The vehicle control group received 0.5% carboxymethylcellulose (CMC) aqueous solution (vehicle). Negative and positive control groups were given Rif/INH (50+50 mg/kg, p.o) and silymarin (SILM) (200 mg/kg, p.o) in 0.5% vehicle for 30 days, respectively. Extract treated groups received low and high doses of RBFCE (500 mg/kg, p.o and 1000 mg/kg, p.o respectively) in 0.5% vehicle for 30 days. At a higher dose, animals showed significantly reduced Rif/INH induced toxicity in liver and kidney tissues as indicated by the normalized serum biochemical markers and histopathological investigations. The present exploration reveals the presence of strong antioxidant phytochemical constituents, antioxidative stress and protective potential of RBFCE against Rif/INH induced hepatic and renal damage.

The purpose of this study was to investigate the application of piezoelectric inkjet technology in the preparation of custom-made indomethacin (IMC) films. Indomethacin solutions with and without PVP were printed onto polymeric sheets using a commercial inkjet printer. Drug loading was varied by selecting a machine parameter different dots per inches (DPIs). The printed patches were evaluated for particulate morphologies, drug loading, in vitro release and ex vivo skin permeation and anti-inflammatory effects using hind paw inflammation model. Calculated drug loaded in 2 × 2 cm 2 patches of IMC of 96, 300, and 600 DPIs were in the range of 40, 60, and 65 μg, respectively. Patches loaded with IMC alcoholic solution showed crystalline structures observed by scanning electron microscopy and the addition of PVP in solution turned it to amorphous form. The drug release profile showed 60-70% of total drug released in 3 h. Permeation studies showed 40-50% of total drug loaded permeated through rat skin using Franz cells. Patches with higher printing density 600 DPI showed anti-inflammatory effect in hind paw inflammation model studies. This study has shown the potential of personalized medicine in which a calculated amount of drug can be delivered to patients by piezoelectric technology.

The rhizomes of Bergenia ciliata ( B. ciliata , Family: Saxifragaceae ) are widely used for treating gastric ulcers in folk medicine in Asia. It was hypothesized that anti-ulcer activity of B. ciliata is due to its anti-Helicobacter pylori ( H. pylori) activity. The anti-H. pylori activity was investigated on six clinical bacterial isolates using agar well-diffusion and broth micro-dilution methods. The anti-H. pylori activity of amoxicillin (standard) was the highest (Zone of inhibition; ZI = 25 mm, minimum inhibitory concentration; MIC=0.125 µg/µL) whereas among all the extracts of the rhizomes, methanol extract showed the highest activity (ZI = 16 mm, MIC = 12.50 µg/µL). Bioassay guided isolation of methanol extract using chromatographic and crystallization techniques isolated bergenin (ZI = 21mm, MIC = 0.391µg/µL) as constituent responsible for anti-H. pylori activity. The present study describes for the first time anti-H. pylori activity and possible mechanism of anti-ulcer properties of rhizomes of B. ciliata.

Microneedle patch is a prominent strategy with minimal invasion and painless application to improve skin penetration of drug molecules. Herein, we report microneedle patch (MNP) as an alternative to the oral route for the systemic delivery of tacrolimus (TM), an immunosuppressant drug. Thiolated chitosan (TCS) based microneedle patch was fabricated and characterized in vitro and in vivo for its mechanical strength, skin penetration, drug release, and skin irritation. The MNP having 225 needles with 575 μm showed good mechanical properties in terms of tensile strength and percentage elongation. The skin penetration showed 84% penetration with no breakage. Histology of the mice skin after insertion showed the penetration of needles into the dermis. In vitro release and ex vivo permeation studies through Franz diffusion cell showed the sustained release (82.5%) of TM from the MNP with significantly higher (p < 0.05) skin permeation as compared with controls, respectively. Moreover, in vivo biocompatibility in rats showed the safety of the material and patch. Thus, the TCS microneedle patch has the potential to be developed as a transdermal delivery system for tacrolimus with improved bioavailability and sustained release over a longer period.