Poonam Parashar

Development of an α-linolenic acid containing soft nanocarrier for oral delivery: in vitro and in vivo evaluation

The oral bioavailability of simvastatin (SIM) a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor is about 5%. That may be due to low intestinal permeability and hepatic first pass metabolism (FPM). The objective of the present investigation was to increase the therapeutic efficacy of SIM via developing a soft nanocarrier i.e. a microemulsion to enhance the intestinal permeability in addition to bioavailability. α-Linolenic acid (ALA) was used in the oil phase with Kolliphor EL 40 as surfactant and Transcutol HP as cosurfactant. A microemulsion formulation was developed for the oral delivery of SIM and characterized for physicochemical parameters. The SIM-loaded microemulsion (MES) was investigated for pharmacodynamic and pharmacokinetic parameters to investigate its suitability as a potential drug delivery system for the treatment of Hyperlipidemia in albino Wistar rats. In pharmacodynamic studies, significant differences in parameters were found between the optimized and marketed formulations. Optimized MES showed significantly higher (P < 0.05) Cmax (107.84 ± 8.95 ng ml−1) than marketed tablets (57.65 ± 4.48 ng ml−1). It was found that AUClast obtained from the optimized MES (409.6 ± 22.54 ng h ml−1) was significantly higher (P < 0.01) than the marketed tablet (155.4 ± 12.78 ng h mL−1). The relative bioavailability (Fr) of the optimized formulation was about 263.5% higher than that of the marketed tablets. Optimized MES exhibited no cytotoxicity. Cellular uptake studies confirmed payload delivery to a cellular site (J774.A1 cell line). The results prove that the prepared microemulsion formulation is an improved and effective oral delivery of SIM for the management of lipid levels.

Oral delivery of allopurinol niosomes in treatment of gout in animal model

Abstract Context: Gout is a painful disorder which does not have an efficient delivery system for its treatment. Objective: Development and in vitro, in vivo evaluation of allopurinol-loaded nonionic surfactant-based niosomes was envisaged. Materials and methods: Niosomes were prepared with Span 20 and Tween 20 (1:1 molar ratio) using ether injection method. The formulations were screened for entrapment efficiency, particle size analysis, zeta potential, release kinetics, in vivo activity, and stability studies. Result: Stable, spherical vesicles of average particle size 304 nm with zeta-potential and entrapment efficiency of 22.2 mV and 79.44 ± 0.02%, respectively, were produced. In vitro release study revealed 82.16 ± 0.04% release of allopurinol within 24 h. The niosomal formulation was further evaluated for its antigout potential in monosodium urate (MSU) crystal induced gout animal model. The formulation demonstrated significant uric acid level reduction and enhanced antigout activity when compared with the pure allopurinol. Discussion: The better antigout activity displayed by niosomal formulation could be attributed to sustained release of drug, higher drug solubility within biological fluids, better membrane interaction, smaller size, and presence of cholesterol and surfactant. Conclusions: This study reveals that niosomes can be an efficient delivery system for the treatment of gout.

Hyaluronic Acid Decorated Naringenin Nanoparticles: Appraisal of Chemopreventive and Curative Potential for Lung Cancer

Lung carcinoma is the most common cancer in men and second in women (preceded by breast cancer) worldwide. Around 1 in 10 of all cancers diagnosed in men, lung cancer contributed to a total fraction of 20% cancer deaths. Naringenin (NAR) is well known for its chemopreventive properties since ancient times but lacks an appropriate delivery carrier. The objective of present study was to expand the functionality of naringenin loaded poly caprolactone (PCL) nanoparticles in terms of release, chemoprevention and therapeutics. Polymeric nanoparticles such as PCL lack target specificity; hence, surface modification was attempted using layer by layer technique (LBL) to achieve improved and desired delivery as well as target specificity. The designing of Hyaluronic acid (HA) decorated PCL nanoparticles were prepared by utilizing self-assembling LBL technique, where a polycationic layer of a polymer was used as a linker for modification between two polyanionic layers. Additionally, an attempt has been made to strengthen the therapeutic efficacy of PCL nanocarriers by active targeting and overcoming the extracellular matrix associated barriers of tumors using HA targeting cluster determinant 44 receptor (CD44). Cell cytotoxicity study on A549 cells and J774 macrophage cells depicted enhanced anticancer effect of NAR-HA@CH-PCL-NP with safe profile on macrophages. Uptake study on A549 cells advocated enhanced drug uptake by cancer cells. Cell cycle arrest analysis (A549 cell lines) demonstrated the superior cytotoxic effect and active targeting of NAR-HA@CH-PCL-NP. Further chemopreventive treatment with NAR-HA@CH-PCL-NP was found effective in tumor growth inhibitory effect against urethane-induced lung cancer in rat. In conclusion, developed formulation possesses a promising potential as a therapeutic and chemopreventive agent against urethane-induced lung carcinoma in albino wistar rats.

Colloidal Vesicular System of Inositol Hexaphosphate to Counteract DMBA Induced Dysregulation of Markers Pertaining to Cellular Proliferation/Differentiation and Inflammation of Epidermal Layer in Mouse Model

Cancer is a global health problem and chemoprevention is a promising approach for reducing cancer burden. Inositol hexaphosphate (IP6), a natural bioactive constituent of cereals, legumes, etc., has momentous potential as an antiangiogenic agent, that specifically affects malignant cells. The shortcoming is its quick absorption on oral/topical administration. Niosomes are flexible carriers for topical drug delivery. The central venture of current research was to optimize and characterize niosomal delivery system of IP6 for treatment of skin cancer. Thin film hydration method was utilized to prepare IP6 niosomes, and these were dispersed as a suspension in a suitable base. Developed formulations were analyzed for various physicochemical and pharmacological parameters such as particle size, encapsulation efficiency, morphology, drug release, texture analysis, irritability, cell line studies, Western blotting, RT-PCR, and histopathology. IP6 niosomal suspension and IP6 in acetone displayed IC50 value at the concentration of 0.96 mM (0.63 mg/mL) and 1.39 mM (0.92 mg/mL), respectively. IP6 niosomal suspension showed significantly higher (p < 0.05) activity and showed cytotoxic effect in SK-MEL-2 cancer cell line. Crucial events of cellular proliferation and differentiation, like expression of ornithine decarboxylase (ODC), proliferating cell nuclear antigen (PCNA), cycloxygenase-2 (COX-2) and Cyclin D1 were initiated from the fourth hour through application of 7,12-dimethylbenzanthracene (DMBA) on albino mice. The DMBA altered expression of aforesaid enzymes was significantly (P < 0.001) prevented by concomitant application of niosomal formulations. Results of cell line study, Western blotting, RT-PCR, and histopathology suggested that IP6 niosomal suspension could constitute a promising approach for prevention of cellular proliferation as well as DMBA induced dysregulation of cellular proliferation/differentiation and inflammation.

Development of an α-linolenic acid containing a soft nanocarrier for oral delivery-part II: buccoadhesive gel

The objective of the present research was to develop and characterize a Carbopol 71G (CP 71G) buccoadhesive gel encompassing an optimized simvastatin-loaded microemulsion (MES4) containing α-linolenic acid as an oil phase for buccal delivery. Crosslinking of the gelling agent was done by adjusting the pH with a neutralizing agent triethanolamine (TEA). The formulations, namely, the drug suspension, the MES4, and the microemulsion based buccal gel containing 4% w/v (MEBG4), 5% w/v (MEBG5) and 6% w/v (MEBG6) CP 71G respectively, were optimized on the basis of the permeation flux of simvastatin (SIM), which was found to be in the range of 0.132–0.482 mg cm−2 h−1, calculated from an ex vivo permeation study. The optimized buccal gel (MEBG4) showed a significantly higher (P < 0.001) permeation flux (J = 0.443 ± 0.062 mg cm−2 h−1) compared to the drug suspension (J = 0.132 ± 0.044 mg cm−2 h−1). The permeation enhancement ratio of MEBG4 was found to be 3.36 fold higher than that of the aqueous suspension. The Cmax value (131.208 ± 21.563 ng ml−1) of the buccoadhesive gel (MEBG4) was found to be significantly higher (P < 0.001) when compared to the same dose administered by an oral route (Cmax – 68.513 ± 9.821 ng ml−1). The relative bioavailability (Fr) of the optimized MEBG4 buccal gel was about 385.3% higher than that of the oral marketed tablet. The MEBG4 gel followed the Korsmeyer–Peppas equation implying that the gel showed a diffusion type of drug release, due to polymer relaxation or erosion (Case II transport). The texture profile in terms of spreadability (0.8 mJ), adhesiveness (2.9 g), firmness (11.0 g) and extrudability (35.2 mJ) of MEBG4 was evaluated and showed good spreadability and adhesiveness. A rheological study revealed the pseudoplastic behavior of the gel. In conclusion, a consistent and effective buccoadhesive gel with a SIM-loaded microemulsion and improved buccal permeation and pharmacokinetics parameters was developed successfully.

Genipin crosslinked soy-whey based bioactive material for atorvastatin loaded nanoparticles: preparation, characterization and in vivo antihyperlipidemic study

The aim of the present study was to explore the lipid lowering potential of soy protein isolate (SPI) and whey protein concentrate (WPC) for the development of novel bioactive material as a drug delivery system for encapsulation of atorvastatin (ATR) in nanoparticles (NPs) and to enhance the antihyperlipidemic potential. SPI-WPC crosslinks were synthesized through amine–amine crosslinking reaction using genipin and characterized by FTIR, mass analysis and degree of crosslinking. ATR loaded NPs were prepared by desolvation process and the optimized formulation (ATR/SPI-WPC NPs-10) was selected on the basis of least particle size (158.1 ± 3.8 nm), zeta potential (−33.5 ± 2.6 mV), maximum EE (81.23 ± 1.1%) and DL (31.5 ± 2.9%). X-ray diffractometry spectra confirmed the encapsulation of ATR into NPs, whereas Transmission electron microscopy revealed that NPs were spherical in shape. Additionally, the ATR/SPI-WPC NPs significantly reduced cholesterol level as compare to SPI and WPC, individually. The results of internalization and MTT assay revealed efficient cellular uptake and cytocompatibility of the formulation. The results confirmed that SPI and WPC based bioactive material can be considered as promising biomaterial for encapsulation and enhancement of the therapeutic efficiency of ATR.

A synergistic Approach for management of lung carcinoma through Folic acid Functionalized Co-therapy of Capsaicin and Gefitinib Nanoparticles: Enhanced Apoptosis and Metalloproteinase-9 Down-Regulation

BACKGROUND Lung cancer is one of the most lethal cancers and lacks effective treatment strategy. Therapeutic efficacy can be improved through active targeting approach utilizing surface engineered nanoparticles (NPs) for cancer therapy. PURPOSE The present study envisioned development of Folic acid (FA) functionalized NPs for co-administration of gefitinib (Gnb) and capsaicin (Cap) respectively to enhance the therapeutic outcome by disabling the barriers related to tumors extracellular matrix. RESEARCH METHODS AND PROCEDURE The FA conjugated Gnb/Cap polymeric (PLGA-PEG) NPs were prepared using oil in water emulsion technique and methodically developed using Quality by Design (QbD) concept employing central composite design. The developed formulations were subjected to various in vitro (A549 cell lines) and in vivo evaluations in urethane-induced lung cancer. RESULTS The modified NPs displayed particle sizes of 217.0 ± 3.2 nm and 213.0 ± 5.2 nm and drug release of 85.65 ± 3.21% and 81.43 ± 4.32% for Gnb and Cap respectively. Higher cellular uptake and lower cell viability in A549 cell line was displayed by functionalized NPs compared to free drug. Co administration of Gnb and Cap NPs displayed significant targeting potential, reduction in tumor volume while restoring the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels when compared with toxic group. Significant down regulation was observed for anti-apoptotic proteins (MMP-9) and up regulation of pro-apoptotic proteins (caspase-3, caspase-9 and MMP-9) with co-therapy of Gnb and Cap NPs, when compared with individual therapy through Gnb/Cap. CONCLUSION Potentiation of the action of Gnb when co administered with Cap NPs can be a promising breakthrough for developing safe, effective and targeted delivery for lung carcinoma therapy.

Biotinylated naringenin intensified anticancer effect of gefitinib in urethane-induced lung cancer in rats: favourable modulation of apoptotic regulators and serum metabolomics

Abstract Co-therapy through biotin modified nanoparticles (NPs) of gefitinib (Gnb) and naringenin (Nar) was investigated for its therapeutic and synergistic potential against lung cancer. The biotin-conjugated polymeric NPs (bty-Nar/Gnb) were developed using oil in water emulsion technique and optimized using central composite design. The formulations were subjected to various in vitro (A549 cell lines) and in vivo evaluations in urethane-induced lung cancer. Co-administration of Gnb and Nar NPs displayed a significant reduction in tumour volume while restoring the biochemical parameters and serum metabolites to normal levels. Significant down-regulation of anti-apoptotic proteins (P-16, MMP-9 and Bcl-2) and up-regulation of pro-apoptotic proteins (caspase-9 and BAX) was displayed with co-therapy. This investigation demonstrated the superiority of co-therapy over individual therapy for improved therapeutic efficacy and is favourable for developing a safe, effective and targeted delivery for lung carcinoma therapy. Graphical Abstract