In-vivo Pharmacokinetic Study Research Articles

Activated charcoal dispersion of carbon monoxide prodrugs for oral delivery of CO in a pill

A novel orally bioavailable solid formulation to deliver a gaseous signaling molecule, carbon monoxide (CO), was developed by adsorbing oxalyl saccharin, a newly developed organic CO prodrug, in activated charcoal (AC). The resulting solid dispersion formulation addresses key developability issues of this CO prodrug. By taking advantage of the large surface area of AC, the paradoxical problem of low water solubility of the prodrug and the requirement of hydrolysis to release CO is resolved, and the need for an organic cosolvent is completely circumvented. The AC formulation also mitigates the adverse effect of low pH on the CO release yield, allowing steady CO release in simulated gastric and intestine fluids. This formulation allows encapsulation in normal and enteric-coated gel capsules, which enables controllable CO delivery to the upper or lower GI system. It also features an advantage of trapping CO prodrug and CO release product in the AC, therefore lowering systemic absorption of these chemicals. Through in-vivo pharmacokinetic studies in mice, the AC formulation showed better efficiency of delivering CO through oral administration compared to the prodrug dosed with an organic cosolvent. The AC formulation has also been applied to address similar developability issues of another cheletropic reaction-based CO prodrug. We envision the wide applicability of this formulation in facilitating the future development of CO-based therapeutics.

SOLID LIPID NANOPARTICLES OF REBAMIPIDE: FORMULATION, CHARACTERIZATION AND IN VIVO PHARMACOKINETIC EVALUATION

Objective: Rebamipide (REB) is a gastroprotective agent used to treat ulcers and gastritis throughout the stomach. Rebamipide is a BCS class IV drug with low oral bioavailability of less than 10%. The objective of this study was to develop an REB-SLNs formulation for oral administration to improve the bioavailability of rebamipide. Methods: The hot homogenization and ultrasonication methods were used to prepare the REB-SLNs. Lipids are dynasan 114, dynasan 116, dynasan 114, imwitor 900 P. Non-ionic surfactants are poloxamer 188, polysorbate 80, and lipoid E 80 act as an amphoteric stabilizing agent used in the formulation. Developed SLNs were evaluated for particle size, PDI, zeta potential, entrapment efficiency, drug content, in vitro release, stability studies, and in vivo pharmacokinetic profile. Results: The optimized REB SLNs (F9) formulation prepared with Dynassan 114 contains an average particle size of 234±3.5 nm, PDI of 0.228±0.05, ZP of-24.58±2.63mV, drug content of 99.89±0.04%, and entrapment efficiency of 96.15±0.32%. DSC studies revealed that no interactions occurred between drugs and excipients. SEM studies showed that SLNs were nearly spherical. In vitro drug release of the optimized formulation, F9 was 91.61% in 24 h as sustained drug release. The optimized formulation was stable under refrigeration and room temperature for three months. Invivo pharmacokinetic studies of optimized formulation (F9) exhibited higher Cmax and AUC values relative to the coarse suspension. Conclusion: Compared to the reference standard coarse suspension, the relative bioavailability of the developed formulation of REB-SLNs of dynasan 114 and combination of poloxamer 188 and polysorbate 80 (F9) was increased by 3.87 times.

Formulation and optimization of cilnidipine loaded nanosuspension for the enhancement of solubility, dissolution and bioavailability

The present investigation involves preparation, optimization, and evaluation of the Cilnidipine (CLN) nanosuspension to enhance the dissolution rate and bioavailability. CLN nanosuspension was formulated by precipitation-ultrasonication method. The factors affecting the formulation of CLN nanosuspension were screened by Plackett–Burman design. The screened parameters (concentration of drug, agitation speed, and concentration of Tween 80) were used to optimize the CLN loaded nanosuspension using Box Behnken (BB) design. Optimized formulation was evaluated for particle size (nm), zeta potential (mV), PDI, entrapment efficiency (%), and in-vitro dissolution study. Compatibility studies of the optimized formulation were carried out by Fourier transform-infrared spectroscopy, powdered x-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Further, in-vivo performance of the optimized formulation was investigated and was compared with the marketed product. The optimized formulation demonstrated desirable results for particle size (280.1 ± 3.7 nm), PDI (0.176), zeta potential (−13.9 ± 0.9 mV), percent entrapment efficiency (92.14 ± 0.97%), and in-vitro dissolution at 40 min (100.23 ± 1.63%). The compatibility studies demonstrated no interactions between drug and excipients. Scanning electron microscopy and transmission electron microscopy analysis illustrated the spherical shape of the particle with uniform distribution. Further, In-vivo pharmacokinetic study indicated significant increase (P<0.005) in Cmax (23.67 ± 1.50 ng/ml), tmax (0.25 h), and AUC (0–t) (94.26 ± 2.19 ng.h ml−1) when compared to the CLN and marketed formulation. In conclusion, the present investigation of the nanosuspension approach can enhance the solubility and dissolution of the poorly water-soluble drug with improved bioavailability, resulting into better oral absorption than the conventional dosage form and pure drug.

Bioanalytical Method Development and Validation of Cilnidipine and Metoprolol Succinate by RP-HPLC: Its Pharmacokinetic Application

Background: Cilnidipine and Metoprolol Succinate are antihypertensive agents used in the treatment of hypertension. Methods: A pharmacokinetic study of Cilnidipine and Metoprolol Succinate in rat plasma was carried out using the chromatographic method. Methods: The chromatographic method involved a reverse phase C18 column, using acetonitrile and pH 4.0 water in the ratio of 80:20 v/v as mobile phase, a flow rate of 1.2 ml/min, and UV detection at 231 nm. In-vivo pharmacokinetic studies were performed on rats. Rats were treated with Cilnidipine (1mg/kg) and Metoprolol Succinate (1 mg/kg) orally, and blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 12 and 24 h post-treatment. Results: The retention time of Plasma, Cilnidipine and Metoprolol Succinate was found to be 2.3, 3.1 and 5.5 min, respectively. Linearity was acceptable in the concentration range of 2-10 and 10- 50 for Cilnidipine and Metoprolol Succinate, respectively. The intra-day and inter-day variances were found to be less than 2. The mean recovery of Cilnidipine and Metoprolol Succinate was 100.12 and 100.15, respectively. The assay was successfully applied to a pharmacokinetic study in rat after oral administration. After oral administration, maximal concentration (Cmax) of Cilnidipine and Metoprolol Succinate was found to be 460.01 and 642.13 (μg g/mL), and the halflife was found at 2.0 and 3.904 hours, respectively. Conclusion: The present method was successfully applied to the pharmacokinetic study of Cilnidipine and Metoprolol Succinate in rat plasma after oral administration.

Mechanistic evaluation of lymphatic targeting efficiency of Atazanavir sulfate loaded lipid nanocarriers: In-vitro and in-vivo studies

In the present study, Atazanavir sulfate-loaded solid lipid nanoparticles (ATZ-SLNs) were developed and characterized for oral bioavailability enhancement and lymphatic absorption. ATZ-SLNs were formulated by emulsion-solvent evaporation technique using hydrogenated castor oil and sodium oleate. The optimized formulation had a mean particle size of 190.1 ± 2.45 nm, the zeta potential of −42.63 ± 2.46 mV and entrapment efficiency of 94.26 ± 2.12%. Transmission electron microscopy and Field emission-scanning electron microscopy morphology indicated discrete and round structures without aggregation. In-vitro drug release study showed controlled drug release of 80.36% in 12 h in simulated intestinal fluid. Cell-line study in Caco-2 cells showed increased permeability upon SLN formulation and mode of cellular uptake of SLN as clathrin and caveoli mediated endocytosis. In-vivo pharmacokinetic study in rats indicated increased oral bioavailability using ATZ-SLNs by 200% compared to suspension formulation. A lymphatic transport study revealed that SLNs were transported via lymphatic vessels. In organ biodistribution study, peyer's patch region showed a 4.5 fold higher uptake of ATZ through ATZ-SLNs formulation than non-peyer's patch region and high accumulation in spleen and brain. This delivery approach could maximize the drug concentrations to the lymphatic system leading to effective therapy for HIV.

Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

In-vivo Pharmacokinetic Study, in-vitro Cytotoxic, Cell Cycle Arresting and Proapoptotic Characteristics of Multiple Emulsions for the Co-delivery of Simvastatin and Alendronate Sodium

Abstract: Purpose: Development of nanocarriers that can provide efficient co-delivery of immiscible hydrophilic/ hydrophobic drugs with established technology for industrial production is crucial. Due to this reason, multiple emulsions (MEs) were selected as the desired carriers to achieve the co-delivery ability of many drugs and the improvement of cancer therapeutic effect. MEs could entrap the drug in the inner oil phase and hence avoid the drug leaking and co-deliver the drugs into the tumor sites. Therefore, in the present study, an attempt is made to develop w/o/w multiple emulsion for co-delivery of lipophilic Simvastatin (SVS) and hydrophilic Alendronate Sodium (ADS) with improved oral pharmacokinetics. Methods: The MEs were formulated by the use of Poloxamer-407, TPGS and Soyabean Oil. Tween 80 and Span 80 were used as surfactant and co-surfactant respectively. The MEs was prepared by the process of primary and secondary emulsification and evaluated in terms of visual assessment, turbidity, viscosity, particle size and zeta potential. The optimized batch was evaluated in terms of TEM analysis, X-Ray diffraction, FTIR study, in-vitro release and screened for cytotoxicity study, cell cycle arresting, apoptosis study and quantification of SVS and ADS in Rat Plasma. Results: The MEs treatment inhibited the cell growth with low IC50 value against all cells (A549: 0.030±0.014 μg/mL, MDAMB-231: 0.088±0.013 μg/mL, PC-3: 0.019±0.002 μg/mL).The AUC in case of ADS and SVS was found to be 710.01 ng/mL and 14.413 ng/mL respectively by oral administration and 42.308 ng/mL and 28.902 ng/mL in 12 and 1 hr respectively by IV administration. Conclusion: This strategy has improved simultaneous oral bioavailability of very poorly bio-available both ADS and SVS and thus improved the oral therapeutic efficacy of this combination therapy. Key words: Simvastatin, Alendronate Sodium, In-vivo Pharmacokinetic Study, Cytotoxicity Study, Cell cycle arresting, Apoptosis Study.

Development and in-vitro in-vivo characterization of in-situ gelling sustained-release nevirapine suspension

Nevirapine is a BCS class-II drug used in the treatment and prevention of HIV/AIDS, specifically HIV-1. This study was aimed to develop and evaluate a novel pH-responsive in-situ gelling sustained-release nevirapine pediatric suspension (SRNPS) for treatment and prevention of mother-to-child transmission of HIV. SRNPS can reduce the number of doses administered with subsequent improvement of patient compliance. Nevirapine anhydrous (NA) is unstable in the suspension formulation which leads to the formation of clusters. So here, initially, nevirapine hemihydrate (NH) was synthesized using NA. Both NA and NH forms were later evaluated for differential scanning calorimetry (DSC), Fourier transforms infrared spectroscopy (FTIR) and Powder X-Ray diffraction (pXRD). Furthermore, for the preparation of SRNPS NH form was selected. The developed novel SRNPS was compared with marketed immediate-release nevirapine suspension (Viramune®). Further, both suspensions were evaluated for in-vitro drug release studies and in-vivo pharmacokinetic studies using a rat model. SRNPS has shown good in-situ gelling behavior and results have shown sustained drug release for 8 h. The pharmacokinetic studies in rats also demonstrate an increase in the Cmax, Tmax and AUC for SRNPS compared to Viramune®. The observed Cmax for Viramune® and SRNPS is 0.548 ± 0.16 ng/mL and 0.670 ± 0.22 ng/mL respectively, observed Tmax is 3 ± 0.2 h and 6 ± 0.5 h respectively, while, AUC0-∞ for Viramune® and SRNPS is 26.61 ± 4.26 μg/ml*h and 59.23 ± 5.87 μg/ml*h respectively. The study thus supports the claim that development of SRNPS would minimize the dosing frequency along with sustained action.

Monodispersed magnetographene quantum dot nanocomposites for delivery of silibinin

Silibinin shows multi-applications and therapeutic activities such as anticancer, antioxidant, hypocholesterolemic, cardioprotective, neuroprotective and hepatoprotective but exhibits limited clinical applications due to poor oral bioavailability and in-vitro in-vivo biological correlation. The present study focused on the characterization of magnetic graphene quantum dot nanocomposites for silibinin delivery with a specific interest in kidney cancer treatment optimized by a central composite design. The effect of the composition of polylactic-co-glycolic acid (PLGA), polyvinyl alcohol (PVA) and silibinin on the mean particle size and encapsulation efficiency was studied. The properties of the synthesized magnetic graphene nanocomposites by using silibinin magnetic nanoparticles determined by central composite design method revealed particle size below 300 nm, high encapsulation efficiency (81.27 %) and cumulative in-vitro drug release exhibited in sustained manner. In vitro cellular uptake studies with kidney cancer cell line (A-498) demonstrated that the magnetic graphene quantum dot nanocomposites presented higher cellular uptake of silibinin and cytotoxicity than graphene quantum dots. The in-vivo pharmacokinetic study demonstrated a significant improvement in drug bioavailability with better mean residence time due to prolong exposure in systemic circulation. Therefore, monodispersed magnetic graphene quantum dot nanocomposites are considered as an interesting alternative for silibinin delivery against kidney cancer cell line A-498.

Fabrication of alginate based microgels for drug-sustained release: In-vitro and in-vivo evaluation

The current study was conducted to evaluate and analyze the effect of alginate, itaconic acid, and N,N′-methylene bisacrylamide in formulation of a novel alginate based microgels for sustained release of theophylline. The fabricated microgels were characterized by PXRD, SEM, FTIR, TGA and DSC respectively. FTIR revealed that alginate reacted with itaconic acid during polymerization reaction and confirmed the overlapping of itaconic acid on the backbone of alginate. TGA and DSC depicted high thermal stability of the fabricated microgels as compared to pure unreacted polymer and monomer. Likewise, dynamic swelling and percent drug release studies were carried out at different pH media i.e., pH 1.2, 4.6 and 7.4 respectively. Greater dynamic swelling and percent drug release was observed at higher pH 7.4 as compared to lower pH 4.6 and 1.2 due to the deprotonation of COOH groups of both alginate and itaconic acid respectively. The drug release mechanism from the fabricated microgels could be described by first order model. In-vivo pharmacokinetic study was performed on rabbits and exhibited sustained release in rabbits. Hence, the developed microgels indicated higher potential as the delivery system for the sustained delivery of theophylline.

Nose to Brain Delivery of Phenytoin Sodium Loaded Nano Lipid Carriers: Formulation, Drug Release, Permeation and In Vivo Pharmacokinetic Studies.

An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic agent for the immediate treatment of status epilepticus. Phenytoin sodium formulated as nanolipid carriers (NLCs) seems to be promising as an intranasal delivery system for controlling acute seizures. Three different nanosized phenytoin sodium loaded NLCs (<50 nm, 50–100 nm and >100 nm) were prepared by melt emulsification and was further characterised. In vitro drug release studies showed immediate drug release from phenytoin sodium loaded NLCs of <50 nm size, which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation from <50 nm sized NLC through the olfactory epithelium compared to thecontrol drug solution. Invivo pharmacokinetic studies revealed higher drug concentration in CSF/brain within 5 min upon intranasal administration of <50 nm sized phenytoin sodium NLCs than the control drug solution and marketed IV phenytoin sodium, indicating direct and rapid nose to brain drug transport through the olfactory epithelium. The study has shown that formulation strategies can enhance olfactory uptake, and phenytoin sodium NLCs of desired particle sizes (<50 nm) offer promising potential for nose to brain direct delivery of phenytoin sodium in treating acute epileptic seizures.

Hepatoprotective, antioxidant and anti-inflammatory potentials of Vit-E/C@SeNPs in rats: Synthesis, characterization, biochemical, radio-biodistribution, molecular and histopathological studies

This study aimed to synthesize a nano-structure between selenium, Vit. C, and Vit. E (Vit-E/C@SeNPs) as a promising protective and therapeutic agent for hepatocellular carcinoma. Vit-E/C@SeNPs were characterized using TEM and DLS and its zetapotential was measured to evaluate its stability. DPPH assay and SRB test were performed to estimate its antioxidant capacity and cytotoxicity, respectively. A radiosynthesis of 99mTc-Vit-E/C@SeNPs was done for further in-vivo pharmacokinetic studies on normal and solid tumor induced mice. Further, in-vivo studies were conducted to investigate Vit-E/C@SeNPs efficacy against hepatocellular damage in Wistar albino rats induced by diethylnitrosamine (DEN) / Carbon Tetra chloride (CCl4). The synthesis results showed spherical Vit-E/C@SeNPs with core size of 50 nm, radical scavenging activity (%RSC) of 75.9%, and IC50 of 27.9 µg/ml. The biochemical analysis results showed that the lower liver function biomarker values (ALT, AST, ALP, total bilirubin and GGT) has gone for the Vit-E/C@SeNPs prevention and treated group, which also showed significant depletion of liver tissue l-MDA, and obvious increase in GSH concentration and CAT activity and marked improvement in the histological feature of liver tissue. Additionally, a significant up-regulation of mRNA gene expression levels of inflammatory gene (TGFβ1, NFκB, iNOS, PPAR-γ and TNFα) and Apoptotic gene (P53) were determined by using Quantitative real-time PCR (qPCR). The values down regulate and tend to normal in prevention and control group. All of these introduce Vit-E/C@SeNPs as a promising agent as protective and therapeutic agent against DEN/ CCl4-induced hepatocellular damage (Hepatocellular carcinoma).

Fabrication of novel bio-compatible cefixime nanoparticles using chitosan and Azadirachta indica fruit mucilage as natural polymers

Polymeric nanoparticles were found to be an effective drug delivery system to improve the bioavailability of drugs by increasing their solubility and circulation half-life in comparison with pure cefixime. In the current investigation, cefixime was used as a model drug and orally administered polymeric nanoparticles were developed using chitosan and Azadirachta indica fruit mucilage as natural polymers to achieve enhanced permeation, solubility and sustained release of therapeutically active agent. As a result, improved half-life, bioavailability and better therapeutic index of cefixime can be achieved when compared to pure cefixime. Polymeric cefixime nanoparticles were formulated using modified coacervation technique and then evaluated for various physico-chemical parameters such as average particle size, percentage entrapment efficiency and in-vitro drug release behavior, in-vitro antimicrobial efficiency and in-vivo animal studies (i.e., pharmacokinetics, acute toxicity and the efficacy studies) in comparison to the pure cefixime. The formulations were found to have a mean particle size range of 85.6 ± 4.5 to 250.6 ± 9.3 nm, and percentage entrapment efficiency was found to be in the range of 76.2 ± 1.3% to 90.4 ± 1.5%. The in-vitro drug release data showed an initial burst release of drug followed by a sustained up to 28 h. The in-vitro antimicrobial efficiency studies for the selected formulation revealed that the formulations found to have an improved zone of inhibition with lower minimum inhibitory concentration compared to the pure cefixime. The in-vivo pharmacokinetic study of formulation revealed sustained release of cefixime into the blood stream with a 14.59-fold increase in oral bioavailability and one fold increase in half-life compared to the pure cefixime when administered orally in rats (20 mg/kg weight). The acute toxicity study revealed that the formulation was found to be safe up to 2000 mg/kg with improved efficacy. Therefore, the developed formulation might be a novel carrier that improves the oral bioavailability of cefixime and thereby improved therapeutic activity can be achieved when compared to pure cefixime.

Bioadhesive chitosan nanoparticles: Dual targeting and pharmacokinetic aspects for advanced lung cancer treatment

The chitosan-folate conjugate was synthesized initially and confirmed by FTIR and NMR spectroscopic studies. Following, docetaxel (DXL) loaded non-targeted, single receptor and dual receptor (folate and EGFR) targeted chitosan nanoparticles were prepared and their shape, particle size, zeta-potential, surface morphology and texture were screened by SEM, TEM, AFM analyses. Surface chemistry analysis by XPS indeed confirmed the successful conjugation of folate and cetuximab on the targeted formulations. In-vitro analysis of dual-targeted chitosan nanoparticles has revealed their superior cytotoxicity against A-549 cells. The IC50 of dual receptor-targeted chitosan NP was almost 34 times lower than DXL control. In-vivo pharmacokinetic study on Wistar rats has demonstrated improved relative bioavailability of all NP in comparison to DXL control. The results illustrated that EGFR and folate dual targeted NP enhanced the cytotoxicity of DXL towards A-549 lung cancer cells and substantially improved DXL pharmacokinetics in rats.

Injectable niclosamide nanohybrid as an anti-SARS-CoV-2 strategy

COVID-19 is a rapidly evolving emergency, which necessitates scientific community to come up with novel formulations that could find quick relief to the millions affected around the globe. Remdesivir being the only injectable drug by FDA for COVID-19, it initially showed promising results, however, later on failed to retain its claims, hence rejected by the WHO. Therefore, it is important to develop injectable formulation that are effective and affordable. Here in this work, we formulated poly ethylene glycol (PEG) coated bovine serum albumin (BSA) stabilized Niclosamide (NIC) nanoparticles (NPs) (∼BSA-NIC-PEG NPs) as an effective injectable formulation. Here, serum albumin mediated strategy was proposed as an effective strategy to specifically target SARS-CoV-2, the virus that causes COVID-19. The in-vitro results showed that the developed readily water dispersible formulation with a particle size <120 nm size were well stable even after 3 weeks. Even though the in-vitro studies showed promising results, the in-vivo pharmaco-kinetic (PK) study in rats demands the need of conducting further experiments to specifically target the SARS-CoV-2 in the virus infected model. We expect that this present formulation would be highly preferred for targeting hypoalbuminemia conditions, which was often reported in elderly COVID-19 patients. Such studies are on the way to summarize its potential applications in the near future.

Exploration of a transdermal nanoemulgel as an alternative therapy for postmenopausal osteoporosis

The study investigated the ability of a transdermal nanoemulgel formulation to enhance the bioavailability and anti-osteoporotic efficacy of raloxifene hydrochloride (RH) using recent techniques such as micro-CT, SEM-EDX analysis. The ex-vivo permeation, histopathology, SEM, DSC and CLSM studies were carried out to determine the mechanistics of permeation. The in-vivo pharmacokinetic and pharmacodynamic studies were performed after establishing osteoporosis model using ovariectomy surgery. The biocompatibility of the developed nanoemulgel was tested as per OECD TG 439 protocol. The permeation of RH enhanced by 13 fold compared to plain drug gel. DSC and SEM examination showed change in microstructure of the skin which is the foundation for improved permeation. The pharmacokinetic study suggested 26 fold improved bioavailability of RH compared to per-oral marketed treatment. The micro-CT study demonstrated 202% enhanced bone mineral density. Improved pharmacokinetic and pharmacodynamic performance supported our claim of a successful delivery system. Our formulation is proposed to be safe, patient compliant and therapeutically effective alternative to the available marketed product.

Electrospray technology as a probe for single step fabrication of glipizide loaded nanocochleates with enhanced bioavailability

Nanocochleates (NCs) are amongst the nanoformulations gaining wide popularity owing to their ability to improve biopharmaceutical performance of drug molecules remarkably. However, biggest drawback of this nanocarrier is that it requires minimum two steps for synthesis which limits its industrial scalability. Considering the same, the present work was designed with an objective to assess suitability of electrospray technique in the preparation of biomaterial based NCs. Glipizide (GPZ) was chosen as a model drug for preparation of NCs. Briefly, GPZ, phosphatidylcholine and cholesterol were dissolved in methanol and co-axially sprayed into a pool of CaCl2 solution. Factorial design (22) approach was used for batch optimization. The optimized batch was evaluated for surface morphology, FTIR, DSC, zeta potential, in-vitro drug release study and in-vivo evaluation in male wistar rats. FESEM images confirmed formation of NCs using electrospray technique. Negative zeta potential (-14.36 ± 0.55 mV) of optimized batch reflected high stability of the sample. GPZ was released in a controlled manner from the optimized GPZNC. In-vivo pharmacokinetic study demonstrated significant increase in Cmax (2-fold) and AUC (3-fold) upon entrapment of GPZ into NCs. Thus, the present work unfolded suitability of electrospray technology toward single step preparation of Phosphatidylcholine and Cholesterol biomaterial based nanocochleates over currently used two step preparation techniques.

Chitosan-alginate core-shell-corona shaped nanoparticles of dimethyl fumarate in orodispersible film to improve bioavailability in treatment of multiple sclerosis: Preparation, characterization and biodistribution in rats

Dimethyl fumarate (DMF) is used for the treatment of relapsing forms of multiple sclerosis and causes undesired adverse effects in patients such as gastroenteritis, dyspepsia, low bioavailability, gastritis, nausea and flushing. The aim of this study was to develop oral film containing biocompatible and biodegradable chitosan-alginate nanoparticles of DMF to improve oral bioavailability in multiple sclerosis treatment. The film formulations containing DMF were optimized through design of experiments using full factorial design, and impact of varying levels of independent factors on critical quality attributes of films were studied. The orodispersible film of chitosan-alginate core-shell-corona shaped nanoparticles of DMF was prepared by ionotropic pre-gelation of alginate core followed by chitosan polyelectrolyte complexation, the obtained colloidal nanosuspension was added to the optimized polymer matrix composition by simple process integration and then cast to films by solvent casting process. The films were characterized for their critical quality attributes like pH, tensile strength, disintegration time, in-vitro drug release, ex-vivo permeation study through porcine buccal mucosa and in-vivo pharmacokinetic study in wistar rats. The in-vitro drug release profile from chitosan-alginate core-shell-corona shaped nanoparticles in film evidenced a sustained release with initial 18.39% release in 30 min followed by sustained release up to 6 h in comparison to DMF oral film formulations which released more than 80% drug within 15 min. The in-vivo pharmacokinetic study confirmed that nanoparticles of DMF in orodispersible films (DMF051) were 0.6-fold more bioavailable even at very low drug concentration (2 mg/film) in comparison to conventional oral film formulation (DMF023) (30 mg of drug/film). The Cmax values obtained for DMF023 was 19.21 ± 0.46 μg/ml in comparison to 21.90 ± 0.38 μg/ml for DMF051 and 1.02 μg/ml for drug suspension, Tmax values obtained for DMF023 was 4.00h in comparison to 2.00 h for DMF051, t1/2 values 3.81 ± 0.03 for DMF023 in comparison to 6.59 ± 0.36 for DMF051, AUC 0-t values for DMF023 was 142.02 ± 1.17 μg/ml*h in comparison to 231.49 ± 3.49 μg/ml*h for DMF051 and AUC 0-inf_obs values 153.67 ± 1.27 μg/ml*h for DMF023 in comparison to 251.21 ± 3.48 μg/ml*h for DMF051. The study indicates enhanced bioavailability from this promising dosage form, prompting dose reduction and reduced side effects.

In-vivo Pharmacokinetic Study of Matrix Tablets of Atenolol Prepared by Sintering Technique

In-vivo Pharmacokinetic Study of Matrix Tablets of Atenolol Prepared by Sintering Technique

Design, development and in-vitro/in-vivo evaluation of intranasally delivered Rivastigmine and N-Acetyl Cysteine loaded bifunctional niosomes for applications in combinative treatment of Alzheimer’s disease

The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7% for RIV and 85.9% for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4–8 °C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.