Design and Development of Gastro-retentive Drug Delivery System for Trazodone Hydrochloride: a Promising Alternative to Innovator's Controlled-Release Tablet.

Trazodone hydrochloride (TZN) is a serotonin reuptake inhibitor that treats a major depressive disorder. It exhibits a short plasma half-life of 4.1 h and shows pH-dependent solubility. Above its pKa (6.74), solubility of TZN is very low, affecting its dissolution in the lower part of GIT. Hence, the present work aimed to develop gastro-retentive floating tablet of TZN. Central composite design was employed to optimize the formulation. Formulation variables like the concentration of HPMC-K100M, Polyox WSR 303 Leo, and sodium bicarbonate were evaluated for the responses like floating lag time and drug release. X-ray imaging study was performed on rabbits to determine the in vivo gastric retention of the optimized formulation. The accelerated stability study was conducted on optimized tablets as per ICH guidelines. Floating lag time and f2 value of the optimized formulation were found to be 2.51±0.02 min and 62.79, respectively. X-ray imaging studies in rabbits determined the in vivo gastro retention time. After 12 h of administration, tablet remained in the gastric region, indicating better retentive power. Accelerated stability studies showed sufficient formulation stability even after 3 months of storage. All these studies depict that the floating gastro-retentive system could be used as an alternative to the innovator formulation.

Mannose-Anchored Nano-Selenium Loaded Nanostructured Lipid Carriers of Etravirine for Delivery to HIV Reservoirs.

The present investigation aims to develop and explore mannosylated lipid-based carriers to deliver an anti-HIV drug, Etravirine (TMC) and Selenium nanoparticles (SeNPs), to the HIV reservoirs via the mannose receptor. The successful mannosylation was evaluated by the change in zeta potential and lectin binding assay using fluorescence microscopy. Electron microscopy and scattering studies were employed to study the structure and surface of the nanocarrier system. The presence of selenium at the core-shell of the nanocarrier system was confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray analysis. Further, the in vitro anti-HIV1 efficacy was assessed using HIV1 infected TZM-bl cells followed by in vivo biodistribution studies to evaluate distribution to various reservoirs of HIV. The results exhibited higher effectiveness and a significant increase in the therapeutic index as against the plain drug. The confocal microscopy and flow cytometry studies exhibited the efficient uptake of the coumarin-6 tagged respective formulations. The protective effect of nano selenium toward oxidative stress was evaluated in rats, demonstrating the potential of the lipidic nanoparticle-containing selenium in mitigating oxidative stress in all the major organs. The in vivo biodistribution assessment in rats showed a 12.44, 8.05 and 9.83-fold improvement in the brain, ovary, and lymph node biodistribution, respectively as compared with plain TMC. Delivery of such a combination via mannosylated nanostructured lipid carriers could be an efficient approach for delivering drugs to reservoirs of HIV while simultaneously reducing the oxidative stress induced by such long-term therapies by co-loading Nano-Selenium.

Pickering Dry Emulsion System for Improved Oral Delivery of Fenofibrate.

The current study reports a Pickering dry emulsion (PDE) system for improved oral delivery of fenofibrate, a poorly water-soluble model drug. The silica nanoparticles were modified by surface modifiers and explored as a stabilizer for emulsion. The wetting property of modified silica nanoparticles was evaluated by contact angle study. Emulsion was spray-dried to obtain PDE. PDE was evaluated for particle size analysis, drug loading, TGA, DSC, XRPD, FEG-SEM, in vitro dissolution study, and in vivo pharmacodynamic study. The particle size of liquid emulsion was found within the range of 0.3-0.6 µm; after spray drying, the particles agglomerated and exhibited an increase in particle size (1.5 µm). The high drug loading (13% w/w) was found in PDE. DSC and XRD study confirmed the amorphous form of fenofibrate. SEM study showed the formation of a spherical porous microcapsule structure. In vitro dissolution exhibited significant enhancement in drug release for the PDE system as compared to plain fenofibrate. The PDE significantly lowered serum lipid level as compared to plain fenofibrate in a Triton-based hypercholesterolemia model in rats, which ultimately confirmed the enhancement in bioavailability. Thus, the PDE system has good potential in the drug delivery area.

Long-acting microspheres of Human Chorionic Gonadotropin hormone: In-vitro and in-vivo evaluation.

Human Chorionic Gonadotropin (hCG) hormone is used to cause ovulation, treat infertility in women, and increase sperm count in men. Conventional hCG solution formulations require multiple administration of hCG per week and cause patient noncompliance. The long-acting PLGA depot microspheres (MS) approach with hCG can improve patient compliance, increase the efficacy of hCG with a lower total dose and improve quality of life. Therefore, hCG was encapsulated by a modified double emulsion solvent evaporation technique within PLGA MS by high-speed homogenizer and industrially scalable in-line homogenizer, respectively. MS was characterized for particle size, encapsulation efficiency (EE), surface morphology, and in-vitro release. The spherical, dense, non-porous microspheres were obtained with a size of 58.88 ± 0.18 µm. Microspheres showed high EE (77.4% ± 5.9%) with low initial burst release (12.82% ± 2.07%). Circular Dichroism and SDS-PAGE analysis indicated good stability and structural integrity of hCG in the microspheres. Its bioactivity was proven further by a bioassay study in immature Wistar rats. Pharmacokinetic analysis showed that the hCG PLGA MS maintained serum hCG concentration up to 13 days compared to multiple injections of a marketed conventional parenteral injectable formulation of hCG. Thus, it can be ascertained that the hCG PLGA MS may have great potential for clinical use in long-term therapy.

Multi-organ targeting of HIV-1 viral reservoirs with etravirine loaded nanostructured lipid carrier: An in-vivo proof of concept.

The inadequate bioavailability and toxicity potential of antiretroviral therapy limit their effectiveness in the complete eradication of HIV from viral reservoirs. The penetration of these drugs into the brain is challenging because of the unfavorable physicochemical properties required to cross the membranes, limiting the transport of the drugs. Thus, in the current study, the authors report a nanocarrier-based drug delivery of a highly hydrophobic drug to overcome the existing limitations of the conventional therapies. An explicitly simple approach was used to overcome the limitations of existing anti-HIV therapies. The monophasic hot homogenized solution of lipid, drug, and solubilizer was diluted with the predetermined hot surfactant solution followed by the ultrasonication to generate the polydisperse nanoparticles with the size range of 50-1000 nm. The anti-HIV1 potential of nanostructured lipid carriers of Etravirine on HIV-infected cell lines showed efficacy with an appreciable increase in the therapeutic index as compared with the plain drug. Further, the results obtained from confocal microscopy along with flow cytometry exhibited efficient uptake of the nanocarrier loaded with coumarin-6 in cells. The pharmacokinetics of Etravirine nanostructured carriers was significantly better in all aspects compared to the plain drug solution, which could be attributed to molecular dispersion in the lipid matrix of the nanocarrier. A significant enhancement of Etravirine concentration of several-fold was also observed in the liver, ovary, lymph node, and brain, respectively, as compared to plain drug solution when assessed by biodistribution studies in rats. In conclusion, ETR-NLC systems could serve as a promising approach for simultaneous multi-site targeting and could provide therapeutic benefits for the efficient eradication of HIV/AIDS infections.

Etravirine-loaded dissolving microneedle arrays for long-acting delivery.

A key challenge of HIV treatment with multiple antiretroviral drugs is patient adherence. Thus, there is an urgent need for long-acting depot systems for delivering drugs over an extended duration. Although the parenteral route is preferred for depot systems, it is associated with obvious drawbacks, such as painful injections, potentially-contaminated sharps waste, and the necessity of trained healthcare personnel for administration. Amongst a small number of alternatives in development microneedles are versatile delivery systems enabling systemic drug delivery and potentially improving patient adherence due to their capacity for self-administration. We have developed dissolving microneedle (DMNs) embedded with etravirine nanosuspension (ETR NS) as a long-acting HIV therapy to improve patient adherence. The ETR NS prepared by sonoprecipitation yielded particle sizes of 764 ± 96.2 nm, polydispersity indices of of 0.23 ± 0.02, and zeta potentials of -19.75 ± 0.55 mV. The DMNs loaded with ETR NS demonstrated 12.84 ± 1.33% ETR deposition in ex-vivo neonatal porcine skin after 6 h application. In in vivo rat pharmacokinetic studies, the Cmax exhibited by DMNs loaded with ETR powder and ETR NS were 158 ± 10 ng/mL and 177 ± 30 ng/mL, respectively. DMN groups revealed a higher t1/2, Tmax, and mean residence time compared to intravenous ETR solutions, suggesting the long-acting potential of etravirine delivered intradermally using DMNs.

Chitosan oligosaccharide enhances binding of nanostructured lipid carriers to ocular mucins: Effect on ocular disposition.

The objective of the study was to assess the effect of enhanced mucoadhesion of a cationic mucoadhesive nanostructured lipid carrier (NLC) on its ocular disposition after topical administration. The NLC was made mucoadhesive by surface coating with chitosan oligosaccharide (COS), a low molecular weight derivate of chitosan which is more suitable for drug delivery applications as compared to the native chitosan. The NLC was characterised by surface evaluating techniques like SANS and XPS for confirming coating of COS over the surface of NLC. In order to assess the effect of COS coating on in vivo ocular mucoadhesion, coumarin loaded NLC were topically administered to rats and the sagittal sections of the eyes were imaged using confocal microscopy. The COS coated NLC were seen to adhere more around the ocular surface than the uncoated NLC during the 4-h study. The improved ocular retention for COS-NLC reflected on the content of Etoposide within the eye, which showed a higher concentration of Etoposide, as compared to the uncoated NLC. The NLC was also assessed for any ocular irritancy in rabbits and repeat dose toxicity in rats and found to be relatively non-irritant and non-toxic as compared to appropriate controls. Thus, the study asserts that to achieve higher concentration of therapeutics within the eye, the formulations like NLC are not just required to be permeating but also retentive on the surface of the eye to achieve appreciable concentrations.

Synthesis, Characterization, and Drug Delivery Application of Self-assembling Amphiphilic Cyclodextrin.

The main aim of the research was to synthesize amphiphilic cyclodextrin (AMCD) by substituting C12 alkyl chain to a ß-cyclodextrin (ßCD) in a single step and to study its self-assembly in an aqueous medium. The drug delivery application of the AMCD was also evaluated by encapsulating tamoxifen citrate as a model hydrophobic drug. AMCD was able to self-assemble in aqueous media, forming nanovesicles of size < 200 nm, capable of encapsulating tamoxifen citrate (TMX). Molecular docking and MD simulation studies revealed the interaction between TMX and AMCD which formed a stable complex. TEM and AFM studies showed that nanovesicles were perfectly spherical having a smooth surface and a theoretical AMCD bilayer thickness of ~ 7.2 nm as observed from SANS studies. XRD and DSC studies revealed that TMX was amorphized and molecularly dispersed in AMCD bilayer which was released slowly following Fickian diffusion. AMCD has excellent hemocompatibility as opposed to ßCD and no genotoxicity. IC50 of TMX against MCF-7 cell lines was significantly reduced from 11.43 to 7.96 µg/ml after encapsulation in nanovesicle because of nanovesicles being endocytosed by the MCF-7 cells. AMCD was well tolerated by IV route at a dose of > 2000 mg/kg in rats. Pharmacokinetic profile of TMX after encapsulation was improved giving 3-fold higher AUC; extended mean residence time is improving chances of nanovesicle to extravasate in tumor via EPR effect.

Selectivity Enhancement of Paclitaxel Liposome Towards Folate Receptor-Positive Tumor Cells by Ligand Number Optimization Approach.

The present work aims to develop folate-targeted paclitaxel liposome (F-PTX-LIP), which will selectively target tumor cells overexpressing folate receptor (FR) and leave normal cells. Liposomes were prepared by thin-film hydration method followed by post-insertion of synthesized ligand 1,2-distearoyl-sn-glycero-phosphoethanolamine-polyethyleneglycol 2000-folic acid (DSPE-PEG2000-FA) on the outer surface of the liposome. The synthesized ligand was evaluated for in vivo acute toxicity in Balb/c mice. Developed liposomal formulations were characterized using transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). We have investigated the effect of ligand number on cell uptake and cytotoxicity by confocal laser scanning microscopy (CLSM), competitive inhibition and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Compared to lung adenocarcinoma cells (A549), uptake in human ovarian carcinoma cells (SKOV3) was 2.2- and 1.2-fold higher for liposome with 480 and 240 ligand number respectively. Competitive inhibition experiment shows that prior incubation of SKOV3 cells with free folic acid significantly reduced the cell uptake of F-PTX-LIP with 480 ligand number (480 F-PTX-LIP) by 2.6-fold. 480 F-PTX-LIP displays higher cytotoxicity than free drug and PTX liposome. Moreover, it specifically targets the cells with higher folate receptor expression. Optimized 480 F-PTX-LIP formulation can be potentially useful for the treatment of folate receptor-positive tumors.

Exploring molecular dynamics simulation to predict binding with ocular mucin: An in silico approach for screening mucoadhesive materials for ocular retentive delivery systems.

In recent times, molecular dynamic (MD) simulations have been applied in the area of drug delivery, as an in silico tool to predict the behaviour of nanoparticles with respect to their interaction with larger biological entities like bilayer membranes, DNA and dermal surface. However, the predictions must be systematically evaluated by extensive studies with actual biological entities in order to deem the in silico models accurate. Thus, in the present study, MD simulation was used to screen ligands with respect to ocular mucoadhesion. Mucin-4, a cell surface-associated mucin was selected as the substrate for the in silico study due to its abundance across the ocular surface. The ligands were then incorporated into a delivery system like nanostructured lipid carriers (NLC) and assessed for mucoadhesion by relevant in vitro and in vivo techniques. The in silico study suggested chitosan oligosaccharide (COS) to have an extensive mucoadhesive potential towards ocular mucin followed by stearylamine (STA) and cetrimonium bromide (CTAB) which showed intermediate and low mucoadhesion respectively. The corresponding in vitro assessment by spectrophotometry and nanoparticle tracking analysis showed a similar outcome wherein COS was found to be extensively mucoadhesive, followed by both STA and CTAB, which showed mucoadhesion to a nearly equal extent. The findings of in vivo confocal imaging following topical administration to rats showed that while COS and STA adhered extensively to the ocular surface, CTAB showed negligible adhesion. MD simulation was thus found to accurately predict interactions critical to mucoadhesion and the same could be fairly correlated well by relevant mucoadhesion studies both in vitro and in vivo.

Novel nanosuspension-based dissolving microneedle arrays for transdermal delivery of a hydrophobic drug.

A nanosuspension (NS) was formulated from the lipophilic molecule cholecalciferol (CL) for enhanced transdermal delivery by embedding this NS into hydrophilic polymer-based dissolving microneedles (DMNs). First, the NS was prepared by sonoprecpitation with different molecular weights of poly (vinyl alcohol) and poly (vinyl pyrrolidone) as stabilizers and using two different solvents for particle size and zeta potential optimization. DMN arrays were then prepared by centrifugation-assisted micromoulding and subsequently dried. Poly (vinyl alcohol) (10 kDa) produced a NS with the lowest particle size ( ~ 300 nm). These particles yielded DMN with good mechanical properties when combined with aqueous blends of high molecular weight poly (vinyl pyrrolidone) (360 kDa). The particle size remained similar before and after MN preparation, as confirmed by scanning electron microscope. The CL was in the amorphous state in the free particles as well as in the DMN and, hence, no characteristic CL peak was observed in differential scanning calorimetry or X-ray diffraction. DMN arrays were found to be strong enough to bear a 32 N force, showed efficient skin insertion, and penetrated down to the third layer (depth ≈ 375 µm) of the validated skin model Parafilm M®. An ex vivo porcine skin permeation study using Franz diffusion cells compared the permeation of CL from CL-NS-loaded DMN arrays and MN-free CL-NS patches. It was observed that CL-NS-loaded DMN arrays showed significantly higher (498.19 µg ± 89.3 µg) ex vivo skin permeation compared with MN-free CL-NS patches (73.2 µg ± 26.5 µg) over 24 h. This is the first time a NS of a hydrophobic drug has been successfully incorporated into dissolving MN and suggest that NS-containing DMN systems could be a promising strategy for transdermal delivery of hydrophobic drugs.

Liposils: An effective strategy for stabilizing Paclitaxel loaded liposomes by surface coating with silica.

The present work aims at improving stability of paclitaxel (PTX) loaded liposomes by its coating with silica on the surface by a modified sol-gel method. Effect of various components of liposomes such as phosphatidylcholine to cholesterol ratio (PC:CH), PTX and stearylamine on entrapment efficiency (% EE) and particle size were systematically investigated and optimized using central composite design on Design-Expert®. The optimized liposomes were utilized as a template for silica coating to prepare surface coated PTX liposils. Physical stability of liposomes and liposils was evaluated with Triton X-100 and the results indicated that liposils were much more stable as compared to liposomes and the same has been reiterated in stability study performed over 6 months. In vitro cytotoxicity study on B16F10 tumor cells showed cytotoxicity of PTX liposils was not significantly different than PTX liposomes, whereas both were less cytotoxic as compared to the commercial Taxol®. In vivo pharmacokinetics on rats, exhibited increased T1/2 of liposils when compared to liposomes and Taxol®, thus releasing the drug over a longer duration. The enhanced physicochemical stability as well as controlled release of PTX in liposils developed in this study could be an effective alternative to Taxol® and PTX liposomes.

Rational Design of Cholesterol Derivative for Improved Stability of Paclitaxel Cationic Liposomes.

PURPOSE: This work explores synthesis of novel cholesterol derivative for the preparation of cationic liposomes and its interaction with Paclitaxel (PTX) within liposome membrane using molecular dynamic (MD) simulation and in-vitro studies. METHODS: Cholesteryl Arginine Ethylester (CAE) was synthesized and characterized. Cationic liposomes were prepared using Soy PC (SPC) at a molar ratio of 77.5:15:7.5 of SPC/CAE/PTX. Conventional liposomes were composed of SPC/cholesterol/PTX (92:5:3 M ratio). The interaction between paclitaxel, ligand and the membrane was studied using 10 ns MD simulation. The interactions were studied using Differential Scanning Calorimetry (DSC) and Small Angle Neutron Scattering analysis. The efficacy of liposomes was evaluated by MTT assay and endothelial cell migration assay on different cell lines. The safety of the ligand was determined using the Comet Assay. RESULTS: The cationic liposomes improved loading efficiency and stability compared to conventional liposomes. The increased PTX loading could be attributed to the hydrogen bond between CAE and PTX and deeper penetration of PTX in the bilayer. The DSC study suggested that inclusion of CAE in the DPPC bilayer eliminates Tg. SANS data showed that CAE has more pronounced membrane thickening effect as compared to cholesterol. The cationic liposomes showed slightly improved cytotoxicity in three different cell lines and improved endothelial cell migration inhibition compared to conventional liposomes. Furthermore, the COMET assay showed that CAE alone does not show any genotoxicity. CONCLUSIONS: The novel cationic ligand (CAE) retains paclitaxel within the phospholipid bilayer and helps in improved drug loading and physical stability. Graphical Abstract ᅟ.

Novel bilayer dissolving microneedle arrays with concentrated PLGA nano-microparticles for targeted intradermal delivery: Proof of concept.

Polymeric microneedle (MN) arrays continue to receive growing attention due to their ability to bypass the skin's stratum corneum barrier in a minimally-invasive fashion and achieve enhanced transdermal drug delivery and "targeted" intradermal vaccine administration. In this research work, we fabricated biodegradable bilayer MN arrays containing nano - microparticles for targeted and sustained intradermal drug delivery. For this study, model drug (vitamin D3, VD3)-loaded PLGA nano- and microparticles (NMP) were prepared by a single emulsion solvent evaporation method with 72.8% encapsulation of VD3. The prepared NMP were directly mixed 20% w/v poly(vinyl pyrrolidone) (PVP) gel, with the mixture filled into laser engineered micromoulds by high-speed centrifugation (30min) to concentrate NMP into MN shafts. The particle size of PLGA NMP ranged from 300nm to 3.5µm and they retained their particle size after moulding of bilayer MN arrays. The relatively wide particle size distribution of PLGA NMP was shown to be important in producing a compact structure in bilayer conical, as well as pyramidal, MN, as confirmed by scanning electron microscopy. The drug release profile from PLGA NMP was tri-phasic, being sustained over 5days. The height of bilayer MN arrays was influenced by the weight ratio of NMP and 20% w/v PVP. Good mechanical and insertion profiles (into a skin simulant and excised neonatal porcine skin) were confirmed by texture analysis and optical coherence tomography, respectively. Ex vivo intradermal neonatal porcine skin penetration of VD3 NMP from bilayer MN was quantitatively analysed after cryostatic skin sectioning, with 74.2±9.18% of VD3 loading delivered intradermally. The two-stage novel processing strategy developed here provides a simple and easy method for localising particulate delivery systems into dissolving MN. Such systems may serve as promising means for controlled transdermal delivery and targeted intradermal administration.

Supercritical processed starch nanosponge as a carrier for enhancement of dissolution and pharmacological efficacy of fenofibrate.

In current study, supercritical processed starch nanosponge (SSNS) used as a carrier for poorly water soluble drug (fenofibrate) to enhance its in-vitro and in-vivo performance. SSNS was prepared by using sol- gel method and effective supercritical drying technique. Fenofibrate was loaded into the SSNS by using solvent immersion method with selected and optimized organic solvent. BET surface area of SSNS was evaluated by nitrogen adsorption/desorption analysis. SSNS and drug loaded SSNS were characterized by DSC, XRPD, FTIR, SEM, Contact angle study and evaluated for in-vitro, in-vivo studies. The results revealed that the formed SSNS material has high surface area (180m2/gm) with pore size (40 nm to 200nm). The DSC and XRPD study revealed the amorphization of drug within a SSNS. SEM study showed the continuous porous structure with differ nanosized pores of SSNS. Contact angle study showed improvement in aqueous wetting property of drug within a SSNS. In-vitro drug release study showed remarkable dissolution enhancement of SSNS formulation as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) showed SNSS based formulation significantly improved the bioavailability of drug. Thus SSNS carrier system has good potential to be explored as a delivery system for poorly water soluble drugs.

Dodecylamine Template-Based Hexagonal Mesoporous Silica (HMS) as a Carrier for Improved Oral Delivery of Fenofibrate.

The aim of present investigation was the preparation of dodecylamine template-based hexagonal mesoporous silica (HMS) as a carrier for poorly water-soluble drug (fenofibrate). HMS material has distinctive characteristics such as easy synthesis, high surface area and wormhole pores. These characteristics are highly admirable to make use of it as a carrier in drug delivery system. HMS was prepared by pH and temperature-independent process. Fenofibrate was loaded into the HMS by solvent immersion method using organic solvent. The BET surface area of HMS was evaluated by nitrogen adsorption/desorption analysis. HMS and drug-loaded HMS were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and contact angle study. The HMS-based system was also evaluated for in vitro and in vivo study as compared to plain drug. The BET surface area of HMS was found 974 m2/g with a narrow pore size average of 2.6 nm. The DSC and XRD study confirmed the amorphization of drug within the HMS. SEM and TEM study showed morphological features of HMS as well as revealed the wormhole porous structure. Contact angle study showed improvement in aqueous wetting property of drug within the HMS (contact angle 46°). The In vitro drug release study showed a remarkable dissolution enhancement in HMS-based system as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) exhibited HMS-based formulation was significantly improved the bioavailability of fenofibrate. Thus, HMS has admirable properties; makes it a potential carrier for delivery system of poorly water-soluble drugs.

Effect of Lipid Composition in Propofol Formulations: Decisive Component in Reducing the Free Propofol Content and Improving Pharmacodynamic Profiles.

Current endeavor was aimed towards studying significance of lipid composition on free propofol concentration in aqueous phase and associated pain on injection. Three different nanoformulations, namely long-chain triglyceride (LCT)/medium-chain glyceride (MCG)-based nanoemulsion (ProNano), MCG-based self-nanoemulsifying formulation (PSNE), and lipid-free nanoformulation (PNS) were accessed for the same. In vitro and in vivo performances of developed formulations were compared with Diprivan®. ProNano showed minimum free propofol concentration (0.13%) and hence lower pain on injection (rat paw-lick test, 6 ± 2 s) compared to Diprivan®, PSNE, and PNS (0.21%, 0.23%, and 0.51% free propofol, respectively, and rat paw-lick test; 12 ± 3, 14 ± 2, and 22 ± 3 s, respectively). These results conjecture the role of MCG in effective encapsulation of propofol. Anesthetic action assessed by measuring duration of loss of righting reflex (LORR), which was found similar in case of ProNano and PSNE (14 ± 3 and 15 ± 3 min, respectively) compared to Diprivan® (13 ± 3 min). In case of lipid-free formulation, PNS, extended anesthetic action (21 ± 2 min) was observed which may be due to sustained release of propofol from nanosponges. Studies on effect of lipoproteins on propofol release highlighted significance of HDL (100% release with maximum concentration of about 1.2 µg/ml of HDL) from all three formulations.

Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery.

In the current research work, rivastigmine (RV)-loaded in situ gelling nanostructured lipid carriers (NLCs) were developed for nose to brain delivery. NLCs were fabricated by ethanol injection method using glyceryl monosterate, Capmul MCM C8, Lecithin and Tween 80. NLCs showed average particle size of 123.2 ± 2.3 nm with entrapment efficiency of 68.34 ± 3.4%. DSC, XRD and IR studies showed complete amorphization and incorporation of the drug into nanoparticles. NLCs were incorporated into an in situ gelling system using 0.8% gellan gum and 15% Lutrol F 127. RV in situ gel showed excellent elasticity, rheology, mucoadhesion and adhesiveness to facilitate its adhesion to the upper nasal mucosa. NLC-based in situ gel showed a 2-fold increase in nasal permeation of the drug over plain RV solution. In situ gelling NLCs showed a 3-fold increase in enzyme inhibition efficacy.

Novel L-lactide-depsipeptide polymeric carrier for enhanced brain uptake of rivastigmine in treatment of Alzheimer's disease.

The present study discusses possibility of targeting an anti-Alzheimer's drug rivastigmine tartarate (RT) to the brain using novel synthesized L-lactide-depsipeptide polymeric nanoparticles (NPs). Single emulsion-solvent evaporation technique was used for preparation of NPs. The mean particle size, zeta potential and entrapment efficiency of drug loaded NPs were found to be 142.2 +/- 21.3 nm, +4.85 mV and 60.72 +/- 3.72% respectively. Pharmacodynamic study showed faster regain of memory loss in amnesic rat with RT loaded NPs as compared to RT solution. In pharmacokinetic study, total concentration and mean residence time was increased up to 3.79 fold and 2 fold respectively while clearance was decreased to 1.91 fold on intravenous administration of RT loaded NPs as compared to RT solution. The biodistribution study demonstrated 5.45 fold and 2 fold increase in brain concentration of drug after administration of RT loaded NPs (i.v; 10.52 +/- 1.31 ng/ml) as compared to plain RT solution by oral (1.93 +/- 1.23 ng/ml) and intravenous (5.34 +/- 1.22 ng/ml) route, respectively. Therefore, RT loaded L-lactide-depsipeptide polymeric NPs might be a potential drug delivery system in treatment of Alzheimer's disease.

Naltrexone-loaded poly[La-(Glc-Leu)] polymeric microspheres for the treatment of alcohol dependence: in vitro characterization and in vivo biocompatibility assessment.

The poly[La-(Glc-Leu)] copolymer was applied in the present investigation as polymeric carrier to fabricate naltrexone (NTX)-loaded poly[La-(Glc-Leu)] microspheres in the single emulsion solvent evaporation technique for the long-term treatment of alcohol dependence. Newly synthesized poly[La-(Glc-Leu)] copolymer exhibited diminished crystallanity, good biocompatibility and favorable biodegradability to be explored for drug delivery application. Scanning Electron Microscopy study revealed smooth and spherical-shaped NTX-loaded polymeric microspheres with a mean size of 10-90 µm. Influence of various decisive formulation variables such as amount of polymer, stabilizer concentration, homogenization speed, homogenization time, drug loading and organic-to-aqueous phase ratio on particle size, and entrapment efficiency was studied. Differential scanning calorimeter and X-ray diffractometry study confirmed the drug entrapment within polymer matrix into the microsphere environment. In vitro drug release showed the sustained drug release of formulation for the period of 28 d giving biphasic release pattern. Histological examination of NTX-loaded poly[La-(Glc-Leu)] microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that NTX-loaded microspheres were biocompatible. Insignificant increase in the serum creatine phosphokinase level (p < 0.05) as compared with the normal value revealed good muscle compatibility of the poly[La-(Glc-Leu)] microsphere system. Biocompatible nature and sustained drug-release action of poly[La-(Glc-Leu)] microspheres may have potential application in depot therapy.