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Papers by Krutika Sawant

Iranian journal of pharmaceutical research : IJPR, 2018

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection ... more Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM). Male C57BL/6 mice were intranasally given 2.86 mg ibuprofen/kg/day for 2 consecutive weeks, which were pre-treated with four MPTP injections (20 mg/kg of body weight) at 2 h interval by intraperitoneal route and immunohistochemistry was performed. Globule size of optimal MMEI was 46.73 nm ± 3.11 with PdI value as 0.201 ± 0.19. Histological o...

Journal of Textile Science & Engineering

Critical Reviews in Therapeutic Drug Carrier Systems, 2016

A "submicron emulsion" is an isotropic mixture of drug, lipids, and surfactants... more A "submicron emulsion" is an isotropic mixture of drug, lipids, and surfactants, usually with hydrophilic cosolvents and with droplet diameters ranging from 10 to 500 nm. Submicron emulsions are of increasing interest in medicine due to their kinetic stability, high solubilizing capacity, and tiny globule size. Because of these properties, they have been applied in various fields, such as personal care, cosmetics, health care, pharmaceuticals, and agrochemicals. Submicron emulsions are by far the most advanced nanoparticulate systems for the systemic delivery of biologically active agents for controlled drug delivery and targeting. They are designed mainly for pharmaceutical formulations suitable for various routes of administration like parenteral, ocular, transdermal, and oral. This review article describes the marked potential of submicron emulsions for oral drug delivery owing to their numerous advantages like reduced first pass metabolism, inhibition of P-glycoprotein efflux system, and enhanced absorption via intestinal lymphatic pathway. To overcome the limitations of liquid dosage forms, submicron emulsions can be formulated into solid dosage forms such as solid self-emulsifying systems. This article covers various types of submicron emulsions like microemulsion, nanoemulsion, and self-emulsifying drug delivery system (SEDDS), and their potential pharmaceutical applications in oral delivery with emphasis on their advantages, limitations, and advancements.

Materials Science and Engineering: C, 2016

Polyethylenimine (PEI) has recently been widely studied for the design of nucleic acid delivery v... more Polyethylenimine (PEI) has recently been widely studied for the design of nucleic acid delivery vehicles. Gene delivery using PEI involves condensation of DNA into compact particles, uptake into the cells, release from the endosomal compartment into the cytoplasm, and uptake of the DNA into the nucleus. PEIs being positively charged, linear or branched polymers are able to form nanoscale complexes with small RNAs, leading to RNA protection, cellular delivery, and intracellular release. This review highlights the important properties of various PEIs with regard to their use for nucleic acid delivery. Brief discussion on cellular uptake mechanism of non-viral vector is included to understand its utility for gene delivery. Applications of modified PEI for increased efficacy, altered pharmacokinetic properties; improved biocompatibility and targeted delivery have also been discussed. An overview of simulation studies which can help in understanding the underlying complexation mechanism has also been included. The review provides a brief discussion about clinical trials and patents related to nucleic acid delivery using PEI based systems.

Materials Science and Engineering: C, 2016

In the present investigation, a Quality by Design strategy was applied for formulation and optimi... more In the present investigation, a Quality by Design strategy was applied for formulation and optimization of aripiprazole (APZ) loaded PCL nanoparticles (APNPs) using nanoprecipitation method keeping entrapment efficiency (%EE) and particle size (PS) as critical quality attributes. Establishment of design space was done followed by analysis of its robustness and sensitivity. Characterization of optimized APNPs was done using DSC, FT-IR, PXRD and TEM studies and was evaluated for drug release, hemocompatibility and nasal toxicity. PS, zeta potential and %EE of optimized APNPs were found to be 199.2±5.65nm, -21.4±4.6mV and 69.2±2.34% respectively. In vitro release study showed 90±2.69% drug release after 8h. Nasal toxicity study indicated safety of developed formulation for intranasal administration. APNPs administered via intranasal route facilitated the brain distribution of APZ incorporated with the AUC0→8 in rat brain approximately 2 times higher than that of APNPs administered via intravenous route. Increase in Cmax was observed which might help in dose reduction along with reduction in dose related side effects. The results of the study indicate that intranasally administered APZ loaded PCL NPs can potentially transport APZ via nose to brain and can serve as a non-invasive alternative for the delivery of APZ to brain.

Drug Development and Industrial Pharmacy, 2015

The present study is to investigate the neuroprotective effect of ibuprofen by intranasal adminis... more The present study is to investigate the neuroprotective effect of ibuprofen by intranasal administration of mucoadhesive microemulsion (MMEI) against inflammation-mediated by dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Ibuprofen-loaded polycarbophil-based MMEI was developed by using response surface methodology (RSM). Ibuprofen with dose of 2.86 mg/kg/day was administered intranasally to male C57BL/6 mice for two consecutive weeks which were pre-treated with four intraperitoneal injections of MPTP (20 mg/kg of body weight) at 2 h intervals. Immunohistochemistry was performed. Optimal MMEI was stable and non-ciliotoxic with 66.29 ± 4.15 nm as average globule size and -20.9 ± 3.98 mV as zeta potential. PDI value and transmission electron microscopy result showed the narrow globule size distribution of MMEI. The result showed that all three independent variables had a significant effect (p < 0.05) on the responses. Rota-rod and open-field test findings revealed the significant improvement in motor performance and gross behavioral activity of the mice. The results from in vivo study and immunohistochemistry showed that nasal administration of Ibuprofen significantly reduced the MPTP-mediated dopamine depletion. Furthermore TH neurons count in the substantia nigra and the density of striatal dopaminergic nerve terminals were found to be significant higher for ibuprofen treated groups. Findings of the investigation revealed that Ibuprofen through developed MMEI was shown to protect neurons against MPTP-induced injury in the Substantia nigra pars compacta (SNpc) and striatum and hence, could be a promising approach for brain targeting of Ibuprofen through intranasal route to treat PD.

PEC film for local delivery of antifungal agent, clotrimazole which; reduces the frequency of app... more PEC film for local delivery of antifungal agent, clotrimazole which; reduces the frequency of application of formulation, improve patient compliance, reduce amount of drug administered, reduces irritation related to cream base formulation, adhere to the skin for the require duration. Solution of sodium alginate was added drop wise to chitosan solution under constant stirring, formed coacervates pour and dry to form film in Petri dish. Chitosan alginate ratio of 1:1.5 showed complete reactions (viscosity of supernatant closer to solvent viscosity) and having a good swelling property in both distilled water and buffer (pH 5). PEC film of chitosan and sodium alginate film can be used for sustained drug delivery of potent anti microbial and antifungal drugs or in more sophisticated means by formulating it as a transdermal patch

International Journal of Drug Delivery, 2010

... atorvastatin and study its intestinal permeability in rats Surjyanarayan Mandal1*, Snigdha S.... more ... atorvastatin and study its intestinal permeability in rats Surjyanarayan Mandal1*, Snigdha S. Mandal1, Krutika K. Sawant2 *Corresponding author: Surjyanarayan Mandal 1Dept. ... References 1. Shah NH, Carvajal MT, Patel CI, Infeld MH, Malick AW. ...

Journal of Drug Targeting, 2010

The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres o... more The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. The microspheres were prepared by emulsification-cross-linking method and evaluated for size, shape, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The mucoadhesive properties were also evaluated by Freundlich and Langmuir adsorption isotherms. In vivo tests were carried out in rabbits. The microspheres were spherical with size of 20-50 µm, which is favorable for intranasal absorption. The EE was observed from 42% to 68% while percentage mucoadhesion was from 74% to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining adsorption with electrostatic interaction. The microspheres released around 75% of drug in 8 h. DSC and XRD studies revealed that CRV was molecularly dispersed. The absorption rate was rapid and the absolute bioavailability was high, 72.29%. The gamma scintigraphy indicated that the microspheres cleared slowly from the nasal cavity. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability.

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012

Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid... more Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid first pass metabolism and to improve bioavailability were prepared and evaluated. The microspheres were prepared by emulsification cross-linking method. Radiolabeling of CRV and its microspheres was performed by direct labeling with reduced technetium-99m ((99m) Tc). In vivo studies were performed on New Zealand white rabbits by administering the microspheres intranasally using monodose nasal insufflator. The radioactivity was measured in a well-type gamma scintillation counter. The noncompartmental pharmacokinetic analysis was performed. The pattern of deposition and clearance of the microspheres were evaluated using a radioactive tracer and the noninvasive technique of gamma scintigraphy. The clearance of alginate microsphere was compared with that of control lactose. The microspheres were nonaggregated, free flowing powders with spherical shape, and smooth surface. Pharmacokinetics study displayed an increase in area under the curve and hence in relative bioavailability when compared with intravenous administration of drug. The nasal bioavailability was 67.87% which indicates that nasal administration results in improved absorption of CRV. The results of gamma scintigraphy showed that the alginate microspheres had significantly reduced rates of clearance from the rabbit nasal cavity when compared with the control lactose.

Acta Biomaterialia, 2011

Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to centr... more Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to central dopamine D 2 and serotonin (5-HT 2c ) receptors. It has poor bioavailability due to hepatic first-pass metabolism and low permeability into the brain due to efflux by P-glycoproteins. The present investigation aimed to prepare a nanoparticulate drug delivery system of OZ using poly(lactic-co-glycolic acid) (PLGA) for direct nose-to-brain delivery to provide brain targeting and sustained release. PLGA nanoparticles (NP) were prepared by the nanoprecipitation technique and characterized by entrapment efficiency, particle size, zeta potential, modulated temperature differential scanning calorimetry (MTDSC) and X-ray diffraction (XRD) studies. The NP were evaluated for in vitro release, ex vivo diffusion, toxicity and pharmacokinetic studies. The NP were 91.2 ± 5.2 nm in diameter and had entrapment efficiency 68.91 ± 2.31%. MTDSC studies indicated broadening of the drug peak and a shift in the polymer peak, possibly due to physical interaction or H-bonding between the carbonyl groups of PLGA and the NH groups of OZ, and also due to the plasticization effect of OZ on PLGA. XRD studies indicated a decrease in the crystallinity of OZ or amorphization. In vitro drug release showed a biphasic pattern with initial burst release and, later, sustained release (43.26 ± 0.156% after 120 h), following the Fickian diffusion-based release mechanism. Ex vivo diffusion through sheep nasal mucosa showed 13.21 ± 1.59% of drug diffusion in 210 min from NP. Histopathological study of sheep nasal mucosa showed no significant adverse effect of OZ-loaded NP. In vivo pharmacokinetic studies showed 6.35 and 10.86 times higher uptake of intranasally delivered NP than OZ solution delivered through intravenous (IV) and intranasal (IN) route, respectively. These results proved that OZ could be transported directly to the brain after IN delivery of PLGA NP, enhanced drug concentration in the brain and would therefore be effective in improving the treatment of central nervous system disorders.

International journal of nanomedicine, 2018

Low-molecular-weight polyethylenimine has lower cytotoxicity than high molecular weight polyethyl... more Low-molecular-weight polyethylenimine has lower cytotoxicity than high molecular weight polyethylenimine, but it is not an efficient transfection agent because of limitations of DNA delivery into the cytoplasm. Therefore, in the present study, the hydrophobic modification of low-molecular-weight polyethylenimine (PEI 2 kDa [PEI2]) by cholic acid (ChA) was performed to form PEI2-ChA, and in vitro and in vivo studies were performed. Results indicate that the nanoplexes of PEI2-ChA with gWIZ-GFP have greater transfection efficiency (27%) in NT8e cell lines as evaluated by flow cytometry and also observed by fluorescence imaging. The present study concluded that the transferrin-containing nanoplexes of PEI2-ChA conjugates with plasmid p53 warrant clinical trials in humans after exhaustive animal studies for use as a novel gene delivery system.

Artificial Cells, Nanomedicine, and Biotechnology, 2017

Hydrophobic modification of low molecular weight polyethylenimine (PEI 2 kDa) by cholic acid (ChA... more Hydrophobic modification of low molecular weight polyethylenimine (PEI 2 kDa) by cholic acid (ChA) was done to obtain PEI2-ChA. The nanoplexes of PEI2-ChA with gWIZ-GFP demonstrated increase transfection efficiency (∼27%) in NT8e cell lines. The cell-cycle analysis of NT8e cells (p53 mutant) treated with transferrin containing nanoplexes showed increased apoptosis of cells. In vitro protein expression revealed expression of exogenous p53 protein. In vivo imaging of mice showed localized signal for GFP protein in brain region. The tumors of mice treated with transferrin containing nanoplexes of PEI2-ChA were ∼5 times smaller in size than the tumor of untreated animals.

International Journal of Pharmacy and Pharmaceutical Sciences, 2016

&... more <p><strong>Objective: </strong>The objective of the present investigation was to prepare gastro-resistant microspheres of esomeprazole magnesium trihydrate (EMT) to prevent its degradation in the acidic environment of the stomach and enhance its bioavailability via intestinal…

Journal of Nanoscience and Nanotechnology, Aug 1, 2011

Lipid matrix based carriers are able to provide sustained release, increase the drug transport in... more Lipid matrix based carriers are able to provide sustained release, increase the drug transport into cancer cells and overcome the drug resistance. Therefore, nanostructured lipid carriers (NLC) were prepared and coated with polysorbate 80 to overcome the blood brain barrier for achieving effective treatment of meningeal leukemia. NLC were prepared by melt emulsification followed by ultrasonication, producing particles of 90.7 +/- 4.28 nm size with appreciable amount of drug entrapment (49.5 +/- 2.24%), considering the hydrophilic nature of the drug. The polysorbate 80 coated cytarabine loaded NLC (Cyt-NLC) thus produced were non-aggregated and had almost spherical, smooth and uniform shape. Results of DSC and XRD studies indicated that Cyt was entrapped inside the lipid as molecular dispersion. In-vitro release pattern showed initial fast release (15.87 +/- 1.524% in 1 h) followed by sustained release upto 72 h (89.90 +/- 1.11%). In-vitro cell line studies demonstrated that blank NLC showed no significant cytotoxic effects on leukemic EL-4 cells whereas Cyt-NLC exhibited concentration dependent cytotoxicity. At 48 and 72 h, cytotoxicity of Cyt-NLC was found to be significantly more than that of Cyt solution and the percentage cell viability decreased with increasing concentration of Cyt-NLC. The lyophilized Cyt-NLC formulation was found to be stable with respect to size and total drug content at refrigerated condition (2-8 degrees C) for 3 months. These results suggest that polysorbate 80 coated Cyt-NLC can be explored for treatment of meningeal leukemia owing to their ability of sustained drug release and improved cytotoxic effect in leukemic EL-4 cell line.

Drug Delivery, 2016

Nanoparticles (NPs) can be absorbed via M cells of Peyer's patches after ... more Nanoparticles (NPs) can be absorbed via M cells of Peyer's patches after oral delivery leading to passive lymphatic targeting followed by systemic drug delivery. Hence, the study was aimed to formulate PLGA NPs of lopinavir. The NPs were prepared by nanoprecipitation, optimized by 3(3) factorial design and characterized by TEM, DSC, FTIR studies and safety was assessed by MTT assay. In vivo pharmacokinetic studies were performed in rats. The NPs were discrete spherical structures having particle size of 142.1 ± 2.13 nm and entrapment of 93.03 ± 1.27%. There was absence of drug-polymer interaction. Confocal images revealed the penetration and absorption of coumarin-loaded NPs in Caco-2 cells and intestine after oral delivery. There was 3.04 folds permeability and 13.9 folds bioavailability enhancement from NPs. The NPs can be promising delivery system for antiretroviral drug by delivering the drug to lymph (major HIV reservoir site) via direct absorption through intestine before reaching systemic circulation.

Pda Journal of Pharmaceutical Science and Technology, 2011

Approaches used to avoid uptake of the injected particles by the reticuloendothelial system inclu... more Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm ((99m)Tc-Eto-PLGA NP(105)) and 160 nm ((99m)Tc-Eto-PLGA NP(160)) on biodistribution and blood clearance were studied after intravenous administration of the radiolabeled formulations and compared to that of free drug ((99m)Tc-Eto). It was found that etoposide-loaded PLGA NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA NPs of size 160 nm and pure drug. Moreover, the pure drug ((99m)Tc-Eto) did not cross the blood-brain barrier, whereas (99m)Tc-Eto-PLGA NP(105) showed relatively high concentrations of 0.58% of injected dose in brain in 1 h (8-fold higher), 0.6% in 4 h (20-fold higher) and 0.22% in 24 h (10-fold higher) than the concentration of (99m)Tc-Eto-PLGA NP(160). In bone, concentration of (99m)Tc-Eto-PLGA NP(105) was about 7.2 times higher than the concentration of (99m)Tc-Eto in 24 h. The study concludes that NPs of size ∼100 nm can be used for long-term circulation without the need for surface modification. Such NPs could be exploited for use in leukemia therapy for providing sustained release of etoposide by long-term circulation. Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm and 160 nm on biodistribution studies after intravenous administration in mice and blood clearance studies after intravenous administration in rats was studied. It was found that etoposide-loaded PLGA-NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA-NP of size 160 nm and pure drug. Moreover, the NPs of size 105 nm had greater uptake in bone and brain, in which concentration of free drug and NPs of size 160 nm was negligible. The study concludes that NPs of size ∼100 nm can be used for long-term circulation without the need for surface modification.

Current Drug Delivery, 2008

Solid lipid nanoparticles (SLNs) loaded with Cyclosporine A using glyceryl monostearate (GMS) and... more Solid lipid nanoparticles (SLNs) loaded with Cyclosporine A using glyceryl monostearate (GMS) and glyceryl palmitostearate (GPS) as lipid matrices were prepared by melt-homogenization using high-pressure homogenizer. Various process parameters such as homogenization pressure, homogenization cycles and formulation parameters such as ratio of drug: lipid, emulsifier: lipid and emulsifier: co-emulsifier were optimized using particle size and entrapment efficiencies as the dependent variables. The mean particle size of optimized batches of the GMS SLN and GPS SLN were found to be 131 nm and 158 nm and their entrapment efficiencies were 83 +/- 3.08% and 97 +/- 2.59% respectively. To improve the handling processing and stability of the prepared SLNs, the SLN dispersions were spray dried and its effect on size and reconstitution parameters were evaluated. The spray drying of SLNs did not significantly alter the size of SLNs and they exhibited good redispersibility. Solid state studies such as Infra Red Spectroscopy and Differential Scanning Calorimetry indicated absence of any chemical interaction between Cyclosporine A and the lipids. Scanning Electron Microscopy of optimized formulations showed spherical shape with smooth and non porous surface. In vitro release studies revealed that GMS based SLNs released the drug faster (41.12% in 20 hours) than GPS SLNs (7.958% in 20 hours). Release of Cyclosporine A from GMS SLN followed Higuchi equation better than first order while release from GPS SLN followed first order better than Higuchi model.

Systemic and local immune response against Chitosan encapsulated tetanus toxoid (CS-TT) micropart... more Systemic and local immune response against Chitosan encapsulated tetanus toxoid (CS-TT) microparticles is studied, prepared by ionic cross-linking using Sodium Tripolyphosphate (STPP). Final formulation was evaluated in terms of release of TT in 0.1 N HCl and PBS (pH 7.4), sedimentation profile and stability. CS-TT microparticles, TT in PBS and plain CS microparticles were orally administered to mice and TT (adsorbed) was administered through intramuscular route. Sera were analyzed for anti-TT IgG and intestinal lavage, faeces, intestinal washings for anti-TT IgA levels using an ELISA. Entrapment efficiency of about 100% was obtained. A dose dependent immune response was observed in mice vaccinated with Chitosan-TT microparticles. A strong enhancement of the systemic and local immune response against TT were found when compared with oral feeding of TT in PBS. The study shows the efficacy of chitosan microparticle suspension system, containing a high molecular protein (TT), in inducing the IgA in intestine and IgG in systemic circulation. This demonstrates that chitosan microparticles can prove to be a promising oral vaccine delivery system for mucosal and systemic immunity.

Drug development and industrial pharmacy, Jan 7, 2015

Cefdinir (Cef) is an orally active Biopharmaceutics Classification System (BCS) class IV drug wit... more Cefdinir (Cef) is an orally active Biopharmaceutics Classification System (BCS) class IV drug with incomplete absorption and low bioavailability (16-21%). The aim of this investigation was to develop nanosuspensions (NS) of Cef to improve its oral bioavailability. Cef NS were prepared by the media milling technique using zirconium oxide beads as the milling media. Cef NS were characterized by particle size, Scanning Electron Microscopy, Differential Scanning Calorimetry, X-Ray Diffraction pattern and evaluated for saturation solubility, in vitro release studies, ex vivo permeability studies and in vivo bioavailability studies. The particle size and zeta potential were found to be 224.2 ± 2.7 nm and -15.7 ± 1.9 mV, respectively. Saturation solubility of NS was found to be 1985.3 ± 10.2 µg/ml which was 5.64 times higher than pure drug (352.2 ± 6.5 µg/ml). The DSC thermograms and XRD patterns indicated that there was no interaction between drug and excipients and that the crystallinity...

Iranian journal of pharmaceutical research : IJPR, 2018

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection ... more Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM). Male C57BL/6 mice were intranasally given 2.86 mg ibuprofen/kg/day for 2 consecutive weeks, which were pre-treated with four MPTP injections (20 mg/kg of body weight) at 2 h interval by intraperitoneal route and immunohistochemistry was performed. Globule size of optimal MMEI was 46.73 nm ± 3.11 with PdI value as 0.201 ± 0.19. Histological o...

Journal of Textile Science & Engineering

Critical Reviews in Therapeutic Drug Carrier Systems, 2016

A "submicron emulsion" is an isotropic mixture of drug, lipids, and surfactants... more A "submicron emulsion" is an isotropic mixture of drug, lipids, and surfactants, usually with hydrophilic cosolvents and with droplet diameters ranging from 10 to 500 nm. Submicron emulsions are of increasing interest in medicine due to their kinetic stability, high solubilizing capacity, and tiny globule size. Because of these properties, they have been applied in various fields, such as personal care, cosmetics, health care, pharmaceuticals, and agrochemicals. Submicron emulsions are by far the most advanced nanoparticulate systems for the systemic delivery of biologically active agents for controlled drug delivery and targeting. They are designed mainly for pharmaceutical formulations suitable for various routes of administration like parenteral, ocular, transdermal, and oral. This review article describes the marked potential of submicron emulsions for oral drug delivery owing to their numerous advantages like reduced first pass metabolism, inhibition of P-glycoprotein efflux system, and enhanced absorption via intestinal lymphatic pathway. To overcome the limitations of liquid dosage forms, submicron emulsions can be formulated into solid dosage forms such as solid self-emulsifying systems. This article covers various types of submicron emulsions like microemulsion, nanoemulsion, and self-emulsifying drug delivery system (SEDDS), and their potential pharmaceutical applications in oral delivery with emphasis on their advantages, limitations, and advancements.

Materials Science and Engineering: C, 2016

Polyethylenimine (PEI) has recently been widely studied for the design of nucleic acid delivery v... more Polyethylenimine (PEI) has recently been widely studied for the design of nucleic acid delivery vehicles. Gene delivery using PEI involves condensation of DNA into compact particles, uptake into the cells, release from the endosomal compartment into the cytoplasm, and uptake of the DNA into the nucleus. PEIs being positively charged, linear or branched polymers are able to form nanoscale complexes with small RNAs, leading to RNA protection, cellular delivery, and intracellular release. This review highlights the important properties of various PEIs with regard to their use for nucleic acid delivery. Brief discussion on cellular uptake mechanism of non-viral vector is included to understand its utility for gene delivery. Applications of modified PEI for increased efficacy, altered pharmacokinetic properties; improved biocompatibility and targeted delivery have also been discussed. An overview of simulation studies which can help in understanding the underlying complexation mechanism has also been included. The review provides a brief discussion about clinical trials and patents related to nucleic acid delivery using PEI based systems.

Materials Science and Engineering: C, 2016

In the present investigation, a Quality by Design strategy was applied for formulation and optimi... more In the present investigation, a Quality by Design strategy was applied for formulation and optimization of aripiprazole (APZ) loaded PCL nanoparticles (APNPs) using nanoprecipitation method keeping entrapment efficiency (%EE) and particle size (PS) as critical quality attributes. Establishment of design space was done followed by analysis of its robustness and sensitivity. Characterization of optimized APNPs was done using DSC, FT-IR, PXRD and TEM studies and was evaluated for drug release, hemocompatibility and nasal toxicity. PS, zeta potential and %EE of optimized APNPs were found to be 199.2±5.65nm, -21.4±4.6mV and 69.2±2.34% respectively. In vitro release study showed 90±2.69% drug release after 8h. Nasal toxicity study indicated safety of developed formulation for intranasal administration. APNPs administered via intranasal route facilitated the brain distribution of APZ incorporated with the AUC0→8 in rat brain approximately 2 times higher than that of APNPs administered via intravenous route. Increase in Cmax was observed which might help in dose reduction along with reduction in dose related side effects. The results of the study indicate that intranasally administered APZ loaded PCL NPs can potentially transport APZ via nose to brain and can serve as a non-invasive alternative for the delivery of APZ to brain.

Drug Development and Industrial Pharmacy, 2015

The present study is to investigate the neuroprotective effect of ibuprofen by intranasal adminis... more The present study is to investigate the neuroprotective effect of ibuprofen by intranasal administration of mucoadhesive microemulsion (MMEI) against inflammation-mediated by dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Ibuprofen-loaded polycarbophil-based MMEI was developed by using response surface methodology (RSM). Ibuprofen with dose of 2.86 mg/kg/day was administered intranasally to male C57BL/6 mice for two consecutive weeks which were pre-treated with four intraperitoneal injections of MPTP (20 mg/kg of body weight) at 2 h intervals. Immunohistochemistry was performed. Optimal MMEI was stable and non-ciliotoxic with 66.29 ± 4.15 nm as average globule size and -20.9 ± 3.98 mV as zeta potential. PDI value and transmission electron microscopy result showed the narrow globule size distribution of MMEI. The result showed that all three independent variables had a significant effect (p < 0.05) on the responses. Rota-rod and open-field test findings revealed the significant improvement in motor performance and gross behavioral activity of the mice. The results from in vivo study and immunohistochemistry showed that nasal administration of Ibuprofen significantly reduced the MPTP-mediated dopamine depletion. Furthermore TH neurons count in the substantia nigra and the density of striatal dopaminergic nerve terminals were found to be significant higher for ibuprofen treated groups. Findings of the investigation revealed that Ibuprofen through developed MMEI was shown to protect neurons against MPTP-induced injury in the Substantia nigra pars compacta (SNpc) and striatum and hence, could be a promising approach for brain targeting of Ibuprofen through intranasal route to treat PD.

PEC film for local delivery of antifungal agent, clotrimazole which; reduces the frequency of app... more PEC film for local delivery of antifungal agent, clotrimazole which; reduces the frequency of application of formulation, improve patient compliance, reduce amount of drug administered, reduces irritation related to cream base formulation, adhere to the skin for the require duration. Solution of sodium alginate was added drop wise to chitosan solution under constant stirring, formed coacervates pour and dry to form film in Petri dish. Chitosan alginate ratio of 1:1.5 showed complete reactions (viscosity of supernatant closer to solvent viscosity) and having a good swelling property in both distilled water and buffer (pH 5). PEC film of chitosan and sodium alginate film can be used for sustained drug delivery of potent anti microbial and antifungal drugs or in more sophisticated means by formulating it as a transdermal patch

International Journal of Drug Delivery, 2010

... atorvastatin and study its intestinal permeability in rats Surjyanarayan Mandal1*, Snigdha S.... more ... atorvastatin and study its intestinal permeability in rats Surjyanarayan Mandal1*, Snigdha S. Mandal1, Krutika K. Sawant2 *Corresponding author: Surjyanarayan Mandal 1Dept. ... References 1. Shah NH, Carvajal MT, Patel CI, Infeld MH, Malick AW. ...

Journal of Drug Targeting, 2010

The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres o... more The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. The microspheres were prepared by emulsification-cross-linking method and evaluated for size, shape, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The mucoadhesive properties were also evaluated by Freundlich and Langmuir adsorption isotherms. In vivo tests were carried out in rabbits. The microspheres were spherical with size of 20-50 µm, which is favorable for intranasal absorption. The EE was observed from 42% to 68% while percentage mucoadhesion was from 74% to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining adsorption with electrostatic interaction. The microspheres released around 75% of drug in 8 h. DSC and XRD studies revealed that CRV was molecularly dispersed. The absorption rate was rapid and the absolute bioavailability was high, 72.29%. The gamma scintigraphy indicated that the microspheres cleared slowly from the nasal cavity. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability.

Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012

Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid... more Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid first pass metabolism and to improve bioavailability were prepared and evaluated. The microspheres were prepared by emulsification cross-linking method. Radiolabeling of CRV and its microspheres was performed by direct labeling with reduced technetium-99m ((99m) Tc). In vivo studies were performed on New Zealand white rabbits by administering the microspheres intranasally using monodose nasal insufflator. The radioactivity was measured in a well-type gamma scintillation counter. The noncompartmental pharmacokinetic analysis was performed. The pattern of deposition and clearance of the microspheres were evaluated using a radioactive tracer and the noninvasive technique of gamma scintigraphy. The clearance of alginate microsphere was compared with that of control lactose. The microspheres were nonaggregated, free flowing powders with spherical shape, and smooth surface. Pharmacokinetics study displayed an increase in area under the curve and hence in relative bioavailability when compared with intravenous administration of drug. The nasal bioavailability was 67.87% which indicates that nasal administration results in improved absorption of CRV. The results of gamma scintigraphy showed that the alginate microspheres had significantly reduced rates of clearance from the rabbit nasal cavity when compared with the control lactose.

Acta Biomaterialia, 2011

Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to centr... more Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to central dopamine D 2 and serotonin (5-HT 2c ) receptors. It has poor bioavailability due to hepatic first-pass metabolism and low permeability into the brain due to efflux by P-glycoproteins. The present investigation aimed to prepare a nanoparticulate drug delivery system of OZ using poly(lactic-co-glycolic acid) (PLGA) for direct nose-to-brain delivery to provide brain targeting and sustained release. PLGA nanoparticles (NP) were prepared by the nanoprecipitation technique and characterized by entrapment efficiency, particle size, zeta potential, modulated temperature differential scanning calorimetry (MTDSC) and X-ray diffraction (XRD) studies. The NP were evaluated for in vitro release, ex vivo diffusion, toxicity and pharmacokinetic studies. The NP were 91.2 ± 5.2 nm in diameter and had entrapment efficiency 68.91 ± 2.31%. MTDSC studies indicated broadening of the drug peak and a shift in the polymer peak, possibly due to physical interaction or H-bonding between the carbonyl groups of PLGA and the NH groups of OZ, and also due to the plasticization effect of OZ on PLGA. XRD studies indicated a decrease in the crystallinity of OZ or amorphization. In vitro drug release showed a biphasic pattern with initial burst release and, later, sustained release (43.26 ± 0.156% after 120 h), following the Fickian diffusion-based release mechanism. Ex vivo diffusion through sheep nasal mucosa showed 13.21 ± 1.59% of drug diffusion in 210 min from NP. Histopathological study of sheep nasal mucosa showed no significant adverse effect of OZ-loaded NP. In vivo pharmacokinetic studies showed 6.35 and 10.86 times higher uptake of intranasally delivered NP than OZ solution delivered through intravenous (IV) and intranasal (IN) route, respectively. These results proved that OZ could be transported directly to the brain after IN delivery of PLGA NP, enhanced drug concentration in the brain and would therefore be effective in improving the treatment of central nervous system disorders.

International journal of nanomedicine, 2018

Low-molecular-weight polyethylenimine has lower cytotoxicity than high molecular weight polyethyl... more Low-molecular-weight polyethylenimine has lower cytotoxicity than high molecular weight polyethylenimine, but it is not an efficient transfection agent because of limitations of DNA delivery into the cytoplasm. Therefore, in the present study, the hydrophobic modification of low-molecular-weight polyethylenimine (PEI 2 kDa [PEI2]) by cholic acid (ChA) was performed to form PEI2-ChA, and in vitro and in vivo studies were performed. Results indicate that the nanoplexes of PEI2-ChA with gWIZ-GFP have greater transfection efficiency (27%) in NT8e cell lines as evaluated by flow cytometry and also observed by fluorescence imaging. The present study concluded that the transferrin-containing nanoplexes of PEI2-ChA conjugates with plasmid p53 warrant clinical trials in humans after exhaustive animal studies for use as a novel gene delivery system.

Artificial Cells, Nanomedicine, and Biotechnology, 2017

Hydrophobic modification of low molecular weight polyethylenimine (PEI 2 kDa) by cholic acid (ChA... more Hydrophobic modification of low molecular weight polyethylenimine (PEI 2 kDa) by cholic acid (ChA) was done to obtain PEI2-ChA. The nanoplexes of PEI2-ChA with gWIZ-GFP demonstrated increase transfection efficiency (∼27%) in NT8e cell lines. The cell-cycle analysis of NT8e cells (p53 mutant) treated with transferrin containing nanoplexes showed increased apoptosis of cells. In vitro protein expression revealed expression of exogenous p53 protein. In vivo imaging of mice showed localized signal for GFP protein in brain region. The tumors of mice treated with transferrin containing nanoplexes of PEI2-ChA were ∼5 times smaller in size than the tumor of untreated animals.

International Journal of Pharmacy and Pharmaceutical Sciences, 2016

&... more <p><strong>Objective: </strong>The objective of the present investigation was to prepare gastro-resistant microspheres of esomeprazole magnesium trihydrate (EMT) to prevent its degradation in the acidic environment of the stomach and enhance its bioavailability via intestinal…

Journal of Nanoscience and Nanotechnology, Aug 1, 2011

Lipid matrix based carriers are able to provide sustained release, increase the drug transport in... more Lipid matrix based carriers are able to provide sustained release, increase the drug transport into cancer cells and overcome the drug resistance. Therefore, nanostructured lipid carriers (NLC) were prepared and coated with polysorbate 80 to overcome the blood brain barrier for achieving effective treatment of meningeal leukemia. NLC were prepared by melt emulsification followed by ultrasonication, producing particles of 90.7 +/- 4.28 nm size with appreciable amount of drug entrapment (49.5 +/- 2.24%), considering the hydrophilic nature of the drug. The polysorbate 80 coated cytarabine loaded NLC (Cyt-NLC) thus produced were non-aggregated and had almost spherical, smooth and uniform shape. Results of DSC and XRD studies indicated that Cyt was entrapped inside the lipid as molecular dispersion. In-vitro release pattern showed initial fast release (15.87 +/- 1.524% in 1 h) followed by sustained release upto 72 h (89.90 +/- 1.11%). In-vitro cell line studies demonstrated that blank NLC showed no significant cytotoxic effects on leukemic EL-4 cells whereas Cyt-NLC exhibited concentration dependent cytotoxicity. At 48 and 72 h, cytotoxicity of Cyt-NLC was found to be significantly more than that of Cyt solution and the percentage cell viability decreased with increasing concentration of Cyt-NLC. The lyophilized Cyt-NLC formulation was found to be stable with respect to size and total drug content at refrigerated condition (2-8 degrees C) for 3 months. These results suggest that polysorbate 80 coated Cyt-NLC can be explored for treatment of meningeal leukemia owing to their ability of sustained drug release and improved cytotoxic effect in leukemic EL-4 cell line.

Drug Delivery, 2016

Nanoparticles (NPs) can be absorbed via M cells of Peyer's patches after ... more Nanoparticles (NPs) can be absorbed via M cells of Peyer's patches after oral delivery leading to passive lymphatic targeting followed by systemic drug delivery. Hence, the study was aimed to formulate PLGA NPs of lopinavir. The NPs were prepared by nanoprecipitation, optimized by 3(3) factorial design and characterized by TEM, DSC, FTIR studies and safety was assessed by MTT assay. In vivo pharmacokinetic studies were performed in rats. The NPs were discrete spherical structures having particle size of 142.1 ± 2.13 nm and entrapment of 93.03 ± 1.27%. There was absence of drug-polymer interaction. Confocal images revealed the penetration and absorption of coumarin-loaded NPs in Caco-2 cells and intestine after oral delivery. There was 3.04 folds permeability and 13.9 folds bioavailability enhancement from NPs. The NPs can be promising delivery system for antiretroviral drug by delivering the drug to lymph (major HIV reservoir site) via direct absorption through intestine before reaching systemic circulation.

Pda Journal of Pharmaceutical Science and Technology, 2011

Approaches used to avoid uptake of the injected particles by the reticuloendothelial system inclu... more Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm ((99m)Tc-Eto-PLGA NP(105)) and 160 nm ((99m)Tc-Eto-PLGA NP(160)) on biodistribution and blood clearance were studied after intravenous administration of the radiolabeled formulations and compared to that of free drug ((99m)Tc-Eto). It was found that etoposide-loaded PLGA NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA NPs of size 160 nm and pure drug. Moreover, the pure drug ((99m)Tc-Eto) did not cross the blood-brain barrier, whereas (99m)Tc-Eto-PLGA NP(105) showed relatively high concentrations of 0.58% of injected dose in brain in 1 h (8-fold higher), 0.6% in 4 h (20-fold higher) and 0.22% in 24 h (10-fold higher) than the concentration of (99m)Tc-Eto-PLGA NP(160). In bone, concentration of (99m)Tc-Eto-PLGA NP(105) was about 7.2 times higher than the concentration of (99m)Tc-Eto in 24 h. The study concludes that NPs of size ∼100 nm can be used for long-term circulation without the need for surface modification. Such NPs could be exploited for use in leukemia therapy for providing sustained release of etoposide by long-term circulation. Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm and 160 nm on biodistribution studies after intravenous administration in mice and blood clearance studies after intravenous administration in rats was studied. It was found that etoposide-loaded PLGA-NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA-NP of size 160 nm and pure drug. Moreover, the NPs of size 105 nm had greater uptake in bone and brain, in which concentration of free drug and NPs of size 160 nm was negligible. The study concludes that NPs of size ∼100 nm can be used for long-term circulation without the need for surface modification.

Current Drug Delivery, 2008

Solid lipid nanoparticles (SLNs) loaded with Cyclosporine A using glyceryl monostearate (GMS) and... more Solid lipid nanoparticles (SLNs) loaded with Cyclosporine A using glyceryl monostearate (GMS) and glyceryl palmitostearate (GPS) as lipid matrices were prepared by melt-homogenization using high-pressure homogenizer. Various process parameters such as homogenization pressure, homogenization cycles and formulation parameters such as ratio of drug: lipid, emulsifier: lipid and emulsifier: co-emulsifier were optimized using particle size and entrapment efficiencies as the dependent variables. The mean particle size of optimized batches of the GMS SLN and GPS SLN were found to be 131 nm and 158 nm and their entrapment efficiencies were 83 +/- 3.08% and 97 +/- 2.59% respectively. To improve the handling processing and stability of the prepared SLNs, the SLN dispersions were spray dried and its effect on size and reconstitution parameters were evaluated. The spray drying of SLNs did not significantly alter the size of SLNs and they exhibited good redispersibility. Solid state studies such as Infra Red Spectroscopy and Differential Scanning Calorimetry indicated absence of any chemical interaction between Cyclosporine A and the lipids. Scanning Electron Microscopy of optimized formulations showed spherical shape with smooth and non porous surface. In vitro release studies revealed that GMS based SLNs released the drug faster (41.12% in 20 hours) than GPS SLNs (7.958% in 20 hours). Release of Cyclosporine A from GMS SLN followed Higuchi equation better than first order while release from GPS SLN followed first order better than Higuchi model.

Systemic and local immune response against Chitosan encapsulated tetanus toxoid (CS-TT) micropart... more Systemic and local immune response against Chitosan encapsulated tetanus toxoid (CS-TT) microparticles is studied, prepared by ionic cross-linking using Sodium Tripolyphosphate (STPP). Final formulation was evaluated in terms of release of TT in 0.1 N HCl and PBS (pH 7.4), sedimentation profile and stability. CS-TT microparticles, TT in PBS and plain CS microparticles were orally administered to mice and TT (adsorbed) was administered through intramuscular route. Sera were analyzed for anti-TT IgG and intestinal lavage, faeces, intestinal washings for anti-TT IgA levels using an ELISA. Entrapment efficiency of about 100% was obtained. A dose dependent immune response was observed in mice vaccinated with Chitosan-TT microparticles. A strong enhancement of the systemic and local immune response against TT were found when compared with oral feeding of TT in PBS. The study shows the efficacy of chitosan microparticle suspension system, containing a high molecular protein (TT), in inducing the IgA in intestine and IgG in systemic circulation. This demonstrates that chitosan microparticles can prove to be a promising oral vaccine delivery system for mucosal and systemic immunity.

Drug development and industrial pharmacy, Jan 7, 2015

Cefdinir (Cef) is an orally active Biopharmaceutics Classification System (BCS) class IV drug wit... more Cefdinir (Cef) is an orally active Biopharmaceutics Classification System (BCS) class IV drug with incomplete absorption and low bioavailability (16-21%). The aim of this investigation was to develop nanosuspensions (NS) of Cef to improve its oral bioavailability. Cef NS were prepared by the media milling technique using zirconium oxide beads as the milling media. Cef NS were characterized by particle size, Scanning Electron Microscopy, Differential Scanning Calorimetry, X-Ray Diffraction pattern and evaluated for saturation solubility, in vitro release studies, ex vivo permeability studies and in vivo bioavailability studies. The particle size and zeta potential were found to be 224.2 ± 2.7 nm and -15.7 ± 1.9 mV, respectively. Saturation solubility of NS was found to be 1985.3 ± 10.2 µg/ml which was 5.64 times higher than pure drug (352.2 ± 6.5 µg/ml). The DSC thermograms and XRD patterns indicated that there was no interaction between drug and excipients and that the crystallinity...