Extensive First-pass Metabolism Research Articles

Fabrication and characterisation of nabumetone transferosomal gel for effective topical delivery

Nabumetone is a lipophilic drug with a log P value of 3.2 and belongs to BCS class II due to its poor water solubility. When administered orally, it undergoes extensive first-pass metabolism, shows low bioavailability, and has unfavourable side effects that cause discomfort. Topical route has gain importance by delivering therapeutic agents via this route due to its safety and convenience of drug administration and as of there are no any gel formulations available for it. The present investigation aimed to prepare, optimise, and characterise Nabumetone-loaded transferosomes (Nb-TF) using 32 factorial designs. Transferosomes were prepared by the thin-film hydration method. The optimised formulation was incorporated into gel form (Nb-TG) and evaluated for its mechanical characteristics, in-vitro release, ex-vivo permeation, skin irritancy test, anti-inflammatory activity, and stability studies. The Nb-TF 5 transferosomal formulation was optimised based on vesicle size and entrapment efficiency and incorporated into the gel base. Both normal (Nb-gel) and transferosome-loaded (Nb-TG) gel pH was within the range of topical skin pH. The viscosities of Nb-gel and Nb-TG were 1262 ± 54 cP and 1327 ± 12 cP, respectively. The drug content of both gels was found to be 96.31 ± 1.16 and 97.18 ± 0.94, respectively. Nb-TG showed higher diffusion and drug permeation than Nb-gel. The skin irritancy test indicates that there was no sign of any edema or erythema observed. Nb-TG showed a curative and preventive anti-inflammatory effect. Gels were found stable at both refrigerator and room temperature. Nb-TFs were proven to be potential carriers for transdermal controlled delivery of Nabumetone as it has deep penetration in the dermis layer which directly goes into the systemic circulation, enhances the bioavailability and reduced toxicities.

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations.

Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients. We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug. Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention. In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.

Enhancing the bioavailability of clozapine through microwave-assisted formulation of a stable β-cyclodextrin inclusion complex

The low oral bioavailability of clozapine due to its poor aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism poses a challenge to the effective treatment of psychiatric disorders. The objective of the current research was to address the above issues by developing a clozapine inclusion complex (CLZ-IC) using the microwave irradiation method. To optimize the formulation and processing variables, namely the molar ratio of CLZ to β-CD (X1) and the irritation reaction time (X2), a 32 factorial design was performed. The phase solubility study revealed the formation of a stable inclusion complex with a stoichiometry of 1:1, suggesting that β-cyclodextrin could effectively solubilize clozapine. The characterization data confirmed the formation of the inclusion complex of clozapine in β-cyclodextrin. The optimized inclusion complex showed a solubility of 342 ± 26 µg/ml and a percentage dissolution of 91.1 ± 3.4% after four hours. The inclusion-complex tablets exhibited excellent physical properties and showed an improved in vitro dissolution profile, with 80% of the drug being released within 100 minutes, compared to marketed tablets (80% release in 300 min). In vivo pharmacokinetic studies conducted in a rat model demonstrated an increase in Cmax, area under the curve (AUC), and relative bioavailability by a factor of 2.26 with the optimized formulation, indicating a significant improvement in drug absorption compared to the marketed tablet. The techno-economic analysis suggests a cost-benefit ratio of 25.08 after 7 years, indicating the suitability for large-scale production. Overall, using Design of Experiment, in silico, and in vivo studies proved effective in optimizing the inclusion-complex formation and enhancing the bioavailability of clozapine. In conclusion, the optimized clozapine-β-cyclodextrin inclusion complex prepared using a time-saving (90 sec) and cost-effective microwave irradiation method exhibited excellent physical properties and demonstrated significant improvements in the drug's solubility, dissolution rate, and pharmacokinetic performance.

A Study on the Attitude, Abuse and Addiction to Tramadol among Sudanese University Students in Khartoum State, Sudan

Aim: This research was designed to study addiction to the drug Tramadol among university students in Khartoum State.&#x0D; Introduction: Tramadol is an atypical opioid that binds to μ-opioid receptors on neurons. It has a bioavailability of 70% and undergoes extensive first-pass metabolism in the liver. In most countries, it is a prescription-only medicine. Tramadol abuse has increased recently in the last few years between private universities in Khartoum state, Sudan. Common adverse effects of opioids are nausea, vomiting, relaxation, itching, mental confusion, delirium, urinary retention, sweating.&#x0D; Methodology: A study was conducted on 176 university students in Khartoum from August to September 2018. Ethical approval was obtained from sudan international university research commette and permission from each academic institution. A questionnaire sheet was developed to collect data related to drug abuse among students, including Sociodemographic data and knowledge about drug use without prescription. The collected data were statistically analyzed using ANOVA - IBM - Statistical Package for the Social Science version 16 programs-2008.&#x0D; Results: A study of 176 university students found that most were male (79.5%) and female (20.5%), with an age range of 21-25. Most were medical students, with a minority in engineering, literacy, and computing fields. Most were aware of tramadol analgesic "pain killer" effect, but only 53.7% knew its hallucinogenic effect. Most abusers used tramadol for less than a year, with most starting in university life. Most abusers consumed various doses, with most consuming daily. Adverse effects of tramadol included physical symptoms, psychological symptoms, and attempts at quitting. Reasons for failure to quit were mainly compliance.&#x0D; Conclusion: Tramadol abuse is prevalent among medical students in Sudan. Reasons for initiation include elation desire, avoidance of life conflicts, and curiosity.

Addressing the ADME Challenges of Compound Loss in a PDMS-Based Gut-on-Chip Microphysiological System.

Microphysiological systems (MPSs) are promising in vitro technologies for physiologically relevant predictions of the human absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates. However, polydimethylsiloxane (PDMS), a common material used in MPSs, can both adsorb and absorb small molecules, thereby compromising experimental results. This study aimed to evaluate the feasibility of using the PDMS-based Emulate gut-on-chip to determine the first-pass intestinal drug clearance. In cell-free PDMS organ-chips, we assessed the loss of 17 drugs, among which testosterone was selected as a model compound for further study based on its substantial ad- and absorptions to organ chips and its extensive first-pass intestinal metabolism with well-characterized metabolites. A gut-on-chip model consisting of epithelial Caco-2 cells and primary human umbilical vein endothelial cells (HUVECs) was established. The barrier integrity of the model was tested with reference compounds and inhibition of drug efflux. Concentration-time profiles of testosterone were measured in cell-free organ chips and in gut-on-chip models. A method to deduce the metabolic clearance was provided. Our results demonstrate that metabolic clearance can be determined with PDMS-based MPSs despite substantial compound loss to the chip. Overall, this study offers a practical protocol to experimentally assess ADME properties in PDMS-based MPSs.

Mirtazapine loaded polymeric micelles for rapid release tablet: A novel formulation-In vitro and in vivo studies.

Major depression is a prevalent disorder characterized by sadness, lack of interest or pleasure, interrupted sleep or food, and impaired concentration. Mirtazapine (MTZ), a tetracyclic antidepressant drug, is commonly used to treat moderate to severe depression. MTZ is classified as a BCS class II drug that has shown bioavailability of 50% due to extensive first-pass metabolism. The aim of this research is to develop a delivery platform with enhanced solubility and oral bioavailability of MTZ through formulating polymeric micelles modeled in a rapid release tablet. Mirtazapine loaded polymeric micelles (MTZ-PMs) were formulated to enhance the solubility. Solutol® HS 15 and Brij 58 were used as combined surfactants in a ratio of (20:1) to MTZ in addition to Transcutol® P as a penetration enhancer. The following in vitro tests were performed: particle size, PDI, zeta potential, solubility factor, stability index, and transmission electron microscopes. Afterward, MTZ-PMs were converted to dry free flowable powder through loading on the adsorptive surface of Aerosil 200; then, the powder mixture was directly compressed (MTZ-PMs-RRT) into 13 mm tablets. MTZ-PMs-RRT was further investigated using in vitro evaluation tests of the tablets, namely, weight variation, thickness, diameter, hardness, friability, disintegration time, drug content, and in vitro dissolution test, which complied with the pharmacopeial limits. The pharmacokinetic parameters of MTZ-PMs-RRT compared to Remeron® tablet were further investigated in rabbits. The results showed enhanced solubility of MTZ with improved percentage relative bioavailability to 153%. The formulation of MTZ in the form of MTZ-PMs-RRT successfully improved the solubility, stability, and bioavailability of MTZ using a simple and scalable manufacturing process.

Versatile Nanoparticulate Systems as a Prosperous Platform for Targeted Nose-Brain Drug Delivery.

The intranasal route has proven to be a reliable and promising route for delivering therapeutics to the central nervous system (CNS), averting the blood-brain barrier (BBB) and avoiding extensive first-pass metabolism of some drugs, with minimal systemic exposure. This is considered to be the main problem associated with other routes of drug delivery such as oral, parenteral, and transdermal, among other administration methods. The intranasal route maximizes drug bioavailability, particularly those susceptible to enzymatic degradation such as peptides and proteins. This review will stipulate an overview of the intranasal route as a channel for drug delivery, including its benefits and drawbacks, as well as different mechanisms of CNS drug targeting using nanoparticulate drug delivery systems devices; it also focuses on pharmaceutical dosage forms such as drops, sprays, or gels via the nasal route comprising different polymers, absorption promoters, CNS ligands, and permeation enhancers.

Emerging Phytochemical Formulations for Management of Rheumatoid Arthritis: A Review.

Rheumatoid arthritis (RA) is a T-cell-mediated chronic inflammatory disorder affecting 0.5-1% of the global population. The disease with unknown etiology causes slow destruction of joints, advancing to significant deterioration of an individual's quality of life. The present treatment strategy comprises the use of disease-modifying anti-rheumatic drugs (DMARDs) coupled with or without nonsteroidal anti-inflammatory drugs or glucocorticoids. Additionally, involves co-therapy of injectable biological DMARDs in case of persistent or recurrent arthritis. The availability of biological DMARDs and the implementation of the treat-to-target approach have significantly improved the outcomes for patients suffering from RA. Nevertheless, RA requires continuous attention due to inadequate response of patients, development of tolerance and severe side effects associated with long-term use of available treatment regimens. An estimated 60-90% of patients use alternative methods of treatment, such as herbal therapies, for the management of RA symptoms. Over the past few decades, researchers have exploring natural phytochemicals to alleviate RA and associated symptoms. Enormous plant-origin phytochemicals such as alkaloids, flavonoids, steroids, terpenoids and polyphenols have shown anti-inflammatory and immunomodulatory activity against RA. However, phytochemicals have certain limitations, such as high molecular weight, poor water solubility, poor permeability, poor stability and extensive first-pass metabolism, limiting absorption and bioavailability. The use of nanotechnology has aided to extensively improve the pharmacokinetic profile and stability of encapsulated drugs. The current review provides detailed information on the therapeutic potential of phytochemicals. Furthermore, the review focuses on developed phytochemical formulations for RA, with emphasis on clinical trials, regulatory aspects, present challenges, and future prospects.

Determination of alkaloid-inspired molecule vindeburnol in rabbit plasma by UPLC–HRMS and its application to pharmacokinetic studies and preliminary metabolite identification

The eburnamine-vincamine alkaloids exhibit a range of pharmacological activities. There is a limited understanding of the pharmacokinetics and pharmacodynamics of vindeburnol, a synthetic derivative of this chemical class of alkaloids. A fast and reliable UPLC-HRMS method was developed and validated to quantify vindeburnol in Soviet Chinchilla rabbit plasma from pharmacokinetics studies. An ultra-performance liquid chromatography system equipped with a Waters Acquity UPLC HSS T3 column was used for chromatographic separation by gradient elution with 0.1% (v/v) formic acid in water and acetonitrile. An Impact II QqTOF high-resolution mass spectrometer equipped with an Apollo II electrospray ionization source was used for analysis in positive mode; the ions [M+H]+m/z 269.1648 ± 0.003 and m/z 351.2067 ± 0.003 were monitored for vindeburnol and internal standard (vinpocetine), respectively. Preliminary metabolite profiling was also performed, and the pharmacokinetics of the identified metabolites were evaluated. The mean retention times for vindeburnol and vinpocetine were 2.0 and 3.5 min. The UPLC–HRMS method was validated with accuracy and precision within the 15% acceptance limit (8.2% and 11.0%, respectively). The mean extraction recovery value of vindeburnol from rabbit plasma was 77%. Pharmacokinetic evaluation of vindeburnol revealed that the compound is distributed rapidly with a short elimination half-life. Vindeburnol undergoes extensive first-pass metabolism and is metabolized into hydroxyvindeburnol and vindeburnol glucuronide.

Enhancing Pharmacokinetics and Pharmacodynamics of Rosuvastatin Calcium through the Development and Optimization of Fast-Dissolving Films.

Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed tablet to address this issue. The formulation process involved optimizing the thickness, disintegration time, and folding durability. All formulations were assessed for in vitro disintegration, thickness, folding endurance, in vitro dissolution, weight, and content uniformity. The study's results revealed that the optimized RSV-FDF displayed a significantly faster time to maximum plasma concentration (tmax) of 2 h, compared to 4 h for the marketed tablet. The maximum plasma concentration (Cmax) for the RSV-FDF (1.540 µg/mL ± 0.044) was notably higher than that of the marketed tablet (0.940 µg/mL ± 0.017). Additionally, the pharmacodynamic assessment in male Wistar rats demonstrated that the optimized RSV-FDF exhibited an improved lipid profile, including reduced levels of low-density lipoproteins (LDLs), elevated high-density lipoproteins (HDLs), decreased triglycerides (TGs), and lower very-low-density lipoproteins (VLDLs) compared to the conventional tablet. These findings underscore the potential of RSV-FDFs as a promising alternative to enhance the bioavailability and therapeutic efficacy of rosuvastatin in treating dyslipidemia. The faster onset of action and improved lipid-lowering effects make RSV-FDFs an attractive option for patients requiring efficient cholesterol management.

Comparison of Berberine Bioavailability between Oral and Rectal Administrations in Rats.

The oral bioavailability of berberine is quite low due to extensive first-pass metabolism. To increase the bioavailability of berberine (BBR), the efficacy of rectal administration that can avoid intestinal and hepatic first-pass metabolism partly was evaluated using BBR sulfate in rats. BBR sulfate was administered intravenously (1 mg/kg as BBR), orally (10 mg/kg as BBR) and rectally (1, 3, or 10 mg/kg as BBR) using Witepsol® H15 suppository base to evaluate bioavailability in rats. Concentrations of BBR in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). When BBR sulfate was administered orally, the average oral bioavailability was 0.26%. When BBR sulfate was administered rectally, the average bioavailabilities were 17.0% at 1 mg/kg, 24.3% at 3 mg/kg, and 12.3% at 10 mg/kg as BBR, respectively. Thus, rectal administration of BBR sulfate greatly increased the bioavailability of BBR as compared with oral administration, which would also increase the pharmacological activities of BBR in vivo.

QbD assisted development of inhalable spray-dried erlotinib procubosomal system for the effective management of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common and leading cause of cancer deaths worldwide. Erlotinib (ERL), an epidermal growth factor receptor (EGFR) kinase inhibitor, has been used as a primary prescription for the effective treatment of metastatic NSCLC. However, it has poor aqueous solubility, extensive first-pass metabolism, oral administration-related toxicities, and inconveniences for cancer patients with gastrointestinal tract (GIT) disorders that limit its therapeutic potential. To resolve the above challenges, inhalable ERL-loaded spray-dried procubosomal powder (ERL-SDPP) was developed employing a Box-Behnken design that exhibit impressive characteristics including a device removal efficiency (DRE) of 84.7 ± 2.37 %, aerosolization efficiency (AE) of 18.1 ± 0.75, fine particle fraction (FPFTSI) of 33.7 ± 1.28 %, drug content (DC) of 93.6 ± 3.9 %, and a reconstituted cubosome size (PS) of 453.87 ± 14.65 nm. During in-vitro characterization, the optimized inhalable ERL-SDPP formulation was found to have 96.2 ± 3.98 % entrapment efficiency, −28.6 ± 1.38 mV zeta potential, and 3.29 ± 0.53 μm mass median aerodynamic diameter (MMAD). In-vitro drug release studies revealed sustained release behavior of ERL from ERL-SDPP lasting up to 36 h, demonstrating the increased dissolution profile and stability of ERL-SDPP in simulated lung fluids compared to pure ERL. In-vitro cytotoxicity studies utilizing A549 cell lines uncovered the greater potential of ERL-SDPP formulation, with a ∼1.5-fold reduction in IC50 compared to pure ERL, after 24 h treatment. In-vivo pharmacokinetic parameters revealed that inhalable ERL-SDPP exhibited a 1.76-fold and 6.25-fold higher AUC than oral and intravenous administered ERL, respectively. Organ distribution studies confirmed enhanced retention and accumulation of ERL in lungs after administration of inhalable ERL-SDPP compared to oral ERL, thereby reducing the dose and related systemic toxicities. Thus, the developed inhalable ERL-SDPP has shown promise to improve therapeutic potential against NSCLC through a site-specific sustained drug delivery system as it requires lower doses and limits systemic side effects.

Formulation and Characterization of Nanoparticulate Drug Carrier System for Lacidipine.

Lacidipine, a calcium channel antagonist, is primarily used to treat hypertension. It is classified as a Biopharmaceutics Classification System Class II drug and exhibits an oral bioavailability of 10% due to its extensive hepatic first-pass metabolism. This research study focused on formulating lacidipine-loaded cubosomal nanovesicles developed into rapidly dissolving oral films as an alternative to overcome the downsides faced by conventional antihypertensive therapy. Lacidipine-loaded cubosomes were prepared utilizing a top-down technique using lipid and surfactant and were further developed into fast dissolving oral films. Box-Behnken design was used for the optimization of process variables to achieve minimum particle size and greater entrapment efficiency of the nanovesicles, and response data were statistically evaluated. The optimized cubosomal dispersions upon characterization reported particle size within nanorange (116.8-341 nm) and an entrapment efficiency of 88.15%-97.1%, with 91.72% of total drug content. Morphological studies revealed uniformly dispersed vesicles with cubic to spherical shape. Oral rapidly dissolving films, after evaluation, were reported to have transparent to opaque appearance with a highly porous nature, which was confirmed by scanning electron microscopic imaging and displayed uniformity in weight and thickness and reported optimum mechanical strength and considerable flexibility, with disintegration time of 37.67 ± 3.68 s and exhibited 91.44% ± 1.65% in vitro drug release after 6 min. Short-term stability studies conducted on films at 25°C ± 2°C and 60% ± 5% relative humidity for 3 months demonstrated no significant variation in morphological and mechanical properties. Therefore, lacidipine-loaded cubosomal rapid dissolving oral films may be a promising formulation approach for the management of hypertension.

A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation.

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro.

Development and optimization of Ropinirole loaded self-nanoemulsifying tablets

BackgroundThe present research work aims to develop a Ropinirole-loaded self-Nanoemulsifying Drug Delivery system. Ropinirole has limited oral bioavailability due to substantial first-pass metabolism, which ultimately results in poor oral bioavailability and reduces plasma drug concentration and an overall reduction in therapeutic effects. Avoiding hepatic first-pass metabolism by increasing lymphatic uptake is the goal of the creation of the Ropinirole Self-NanoEmulsifying System. The solvent system for the liquid Self-NanoEmulsifying Drug Delivery System (SNEDDS) was optimized using Box-Behnken Design, where the concentration of oil(X1), surfactant (X2), and co-surfactant(X3) were taken as independent variables. The formulated liquid SNEDDS were then converted into solid SNEDDS by the adsorption method for improving patient compliance.ResultsThe obtained mean droplet size of the formulated SNEDDS was 96.71 nm, and the rate of emulsification was 22 s. Liquid SNEDDS was converted into solid SNEDDS using Syloid 244 FP as adsorbent. Scanning Electron Microscopy (SEM) study shows well-separated particles adsorbed on Syloid 244 FP. In vitro drug release studies show better release from solid and liquid SNEDDS when compared to pure suspension.ConclusionsRopinirole-loaded SNEDDS can be a better option for reducing the extensive first-pass metabolism associated with Ropinirole.

Formulation and optimization of novel vesicular elastic carrier for transdermal delivery of lercanidipine for the treatment of hypertension

The blood pressure drug lercanidipine hydrochloride (LCP) is also prescribed to lower the risk of cardiovascular disease and heart attacks. However, it could be more bioavailable due to extensive first-pass metabolism. In this research study, bilosomes (BS) loaded with lercanidipine hydrochloride (BS-LCP) for transdermal drug delivery were developed and studied to increase bioavailability and patient compliance through high tissue penetration. The thin-film hydration method was used to formulate BS-LCP was optimized using Box-Behnken statistical design. Entrapment efficiency (%) was 82.36 ± 0.64%, mean vesicle size was 126.34 ± 1.28 nm, polydispersity index was 0.43 ± 0.1, and zeta potential was −52.74 ± 0.37 mV for the optimized bilosomal formulation. In 24 h, the amounts of LCP released from LCP-bilosomal preparation (BS-LCP) and LCP-bilosomal gel (BS-LCPG) were 97.53 ± 3.0% and 76.49 ± 4.0%, respectively. However, after 4 h, 98.724% was released from the LCP solution. Drug release from BS-LCPG was noticeably lower than that from LCP-bilosomes. The optimized BS-LCP vesicles were found to be perfectly round, with smooth surfaces and no aggregation, according to scanning electron microscopy (SEM) analysis. The Transmission electron microscopy (TEM) setup verified that the vesicles were round and had a restricted size distribution, indicating no irregularly shaped cysts were present. Inin-vitropermeation studies, bilosomal Gel (BSG) significantly outperformed the LCP solution and a commercially available formulation. Bilosomes are potential drug-delivery vesicles because they can avoid problems with the multiple-dose regime and limited oral bioavailability via the transdermal route.

Quality by design endorsed fabrication of Ibrutinib-loaded human serum albumin nanoparticles for the management of leukemia

Ibrutinib (IB), a BCS class II drug suffers from limited aqueous solubility, short half-life and extensive first-pass metabolism. In this project, we aim to recruit the desirable properties of human serum albumin (HSA) as a biocompatible drug carrier to circumvent nanoparticle-associated drawbacks. Quality by design and multivariate analysis was used for the optimization of IB-NPs. Cell culture studies performed on the K562 cell line revealed that the Ibrutinib-loaded HSA NPs demonstrated improved cytotoxicity, drug uptake, and reactive oxygen species generation in the leukemic K562 cells. Cell cycle analysis revealed G2/M phase retention of the leukemia cells. In vitro protein corona and hemolysis studies revealed superior hematological stability compared to the free drug which showed greater than 40 % hemolysis. In vitro drug release studies showed prolonged release profile till 48 h. Pharmacokinetic studies demonstrated a 2.31-fold increase in AUC and an increase in half-life from 0.43 h to 2.887 h with a tremendous reduction in clearance and elimination rate indicating prolonged systemic circulation which is desirable in leukemia. Hence, we conclude that IB-loaded albumin nanoparticles could be a promising approach for the management of leukemia.

Formulation, optimization, in-vivo biodistribution studies and histopathological safety assessment of duloxetine HCl-loaded ultra-elastic nanovesicles for antidepressant effect after intranasal and transdermal delivery

Duloxetine hydrochloride (DUL) is a BCS class-II antidepressant drug, acting via serotonin and norepinephrine reuptake inhibition. Despite high oral absorption, DUL suffers limited bioavailability due to extensive gastric and first-pass metabolism. To improve DUL's bioavailability; DUL-loaded elastosomes were developed, via full factorial design, utilizing various span®60: cholesterol ratios, edge activator types and amounts. Entrapment efficiency (E.E.%), particle size (PS), zeta potential (ZP) and in-vitro released percentages after 0.5 h (Q0.5h) and 8 h (Q8h) were evaluated. Optimum elastosomes (DUL-E1) were assessed for morphology, deformability index, drug crystallinity and stability. DUL pharmacokinetics were evaluated in rats following intranasal and transdermal application of DUL-E1 elastosomal gel. DUL-E1 elastosomes [comprising span®60 and cholesterol (1:1) and brij S2 (edge activator; 5 mg)] were optimum with high E.E.% (81.5 ± 3.2%), small PS (432 ± 13.2 nm), ZP (−30.8 ± 3.3 mV), acceptable Q0.5h (15.6 ± 0.9%), and high Q8h (79.3 ± 3.8%). Intranasal and transdermal DUL-E1 elastosomes revealed significantly higher Cmax (251 ± 18.6 and 248 ± 15.9 ng/mL) at Tmax (2 and 4 h) and improved relative bioavailability (≈ 2.8 and 3.1 folds) respectively, in comparison to oral DUL aqueous solution. In-vivo histopathological studies were conducted to ensure the safety of DUL-E1. Elastosomes are promising novel nano-carriers, capable of enhancing the bioavailability of DUL via various routes of administration.

Chitosan-based buccal mucoadhesive patches to enhance the systemic bioavailability of tizanidine

Tizanidine hydrochloride (TZN) is a muscle relaxant used to treat a variety of disorders such as painful muscle spasms and chronic spasticity. TZN has low oral bioavailability due to extensive first-pass metabolism and is used orally at a dose of 6–24 mg per day. In the present study, buccal patches were prepared by solvent casting method using chitosan glutamate (Chi-Glu) and novel chitosan azelate (Chi-Aze) which was synthesised in-house for the first time, to enhance the bioavailability of TZN by bypassing first-pass metabolism. The characterisation, mucoadhesion and drug release studies were performed. Chi-Aze patches retained their integrity longer in the buccal medium and showed higher ex vivo drug permeability compared to that prepared with Chi-Glu. In vivo studies revealed that buccal formulation fabricated with Chi-Aze (3%) showed approx 3 times more bioavailability than the orally administered commercial product. Results of the studies indicate that Chi-Aze, prepared by conjugation of chitosan and a fatty acid, the patch formulation is a promising buccal mucoadhesive system due to the physical stability in buccal medium, the good mucoadhesiveness and the high TZN bioavailability. Moreover, Chi-Aze patch might be an alternative to oral formulations of TZN to reduce the dose and frequency of drug administration.

Development of Tea Tree Oil Based Nanoemulgel Loaded with Azithromycin for Enhancing the Antibacterial Activity

Azithromycin (AZ) is an azalide macrolide antibiotic that is frequently employed for treating bacterial skin infections. It suffers from limited oral bioavailability, which results from incomplete absorption or extensive first-pass metabolism. Therefore, preparing azithromycin formulations for topical administration is highly recommended to avoid first-pass metabolism and to boost the concentration of the drug on the skin. The objective of our investigation was to formulate and evaluate the efficacy of AZ-loaded nanoemulgel as an antimicrobial drug. The physical appearance, spreadability, viscosity, particle size, in vitro drug release, ex vivo permeation investigations, and antimicrobial efficiency of the prepared formulations were evaluated. The prepared formulation loaded with AZ exhibited good physical quality. AZ-loaded nanoemulgel had a greater ex vivo drug permeation across rabbit skin than other formulations (AZ-loaded gel and AZ-loaded emulgel), revealing improved drug permeation and greater transdermal flux in addition to enhanced antibacterial efficacy (p &lt; 0.05). Overall, our findings imply that tea-tree-oil-based nanoemulgel would be a promising delivery system for enhancing the antimicrobial efficiency of azithromycin.