Oral self-nanoemulsifying drug delivery systems for enhancing bioavailability and anticancer potential of fosfestrol: In vitro and in vivo characterization.

PURPOSE: The objective of the current research work was to fabricate a fosfestrol (FST)-loaded self-nanoemulsifying drug delivery system (SNEDDS) to escalate the oral solubility and bioavailability and thereby the effectiveness of FST against prostate cancer. METHODS: 32 full factorial design was employed, and the effect of lipid and surfactant mixtures on percentage transmittance, time required for self-emulsification, and drug release were studied. The optimized solid FST-loaded SNEDDS (FSTNE) was characterized for in vitro anticancer activity and Caco-2 cell permeability, and in vivo pharmacokinetic parameters. RESULTS: Using different ratios of surfactant and co-surfactant (Km) a pseudo ternary phase diagram was constructed. Thirteen liquid nano emulsion formulations (LNE-1 to LNE-13) were formulated at Km = 3:1. LNE-9 exhibited a higher % transmittance (99.25 ± 1.82 %) and a lower self-emulsification time (24 ± 0.32 s). No incompatibility was observed in FT-IR analysis. Within 20 min the solidified FST loaded LNE-9 (FSTNE) formulation showed almost complete drug release (98.20 ± 1.30 %) when compared to marketed formulation (40.36 ± 2.8 %), and pure FST (32 ± 3.3 %) in 0.1 N HCl. In pH 6.8 phosphate buffer, the release profiles are found moderately higher than in 0.1 N HCl. FSTNE significantly (P < 0.001) inhibited the PC-3 prostate cell proliferation and also caused apoptosis (P < 0.001) compared to FST. The in vitro Caco-2 cell permeability study results revealed 4.68-fold higher cell permeability of FSTNE than FST. Remarkably, 4.5-fold rise in bioavailability was observed after oral administration of FSTNE than plain FST. CONCLUSIONS: FSTNE remarkably enhanced the in vitro anticancer activity and Caco-2 cell permeability, and in vivo bioavailability of FST. Thus, FST-SNEDDS could be utilized as a potential carrier for effective oral treatment of prostate cancer.

Pazopanib-laden lipid based nanovesicular delivery with augmented oral bioavailability and therapeutic efficacy against non-small cell lung cancer.

The present investigation deals with the pazopanib-loaded solid lipid nanoparticles (Pazo-SLNs) and their in-vitro and in-vivo assessments. Quality by design approach employing the Plackett-Burman and central composite design was used to identify the formulation variables, including drug/lipid ratio, organic/aqueous phase ratio, and surfactant concentration with a significant impact on the process and to fabricate a safe and efficacious novel oral dosage form of pazopanib. Particle size, drug loading, entrapment efficiency, and zeta potential of optimal Pazo-SLNs formulation were 210.03 ± 7.68 nm, 13.35 ± 0.95 %, 79.05 ± 2.55 % and -18.29 ± 1.89 mV (n = 3) respectively. FTIR study affirmed the absence of incompatibilities between the drug and the excipients. DSC and XRD measurements substantiated the amorphous form of pazopanib entrapped within the SLNs. Pazo-SLNs demonstrated high cellular uptake, showed substantial cytotoxicity to A-549 lung cancer cells due to apoptotic mode and inhibited tyrosine kinase in-vitro. Pazo-SLNs were found to be stable for three months. SLNs greatly ameliorated the pharmacokinetic behavior and bioavailability (9.5 folds) of pazopanib with a sustained-release pattern (92.67 ± 4.68 % within 24 h). A biodistribution study corroborated the lung targeting potential of Pazo-SLNs. Thus, SLNs could potentially boost the oral route efficacy of pazopanib against cancer cells.

1, 2-Dihexadecanoyl-sn-glycero-3-phosphoethanolamin (DPPE), doxorubicin and folic acid conjugated micelles for cancer management in tumor bearing BALB/c mice.

Aim of the present investigation was to assess and compare the in-vitro and in-vivo cancer targeting propensity of DPPE-FA-DOX Micelles and free DOX in tumor bearing BALB/c mice. The DOX was conjugated with 1, 2-Dihexadecanoyl-sn-glycero-3-phosphoethanolamin (DPPE) and folic acid using Di-cyclohexyl-carbodiimide, confirmed by Fourier transform infrared spectroscopy (FTIR) and proton NMR. DPPE-FA-DOX micelles were prepared using thin film method and evaluated for zeta potential, particle size, surface morphology, in- vitro drug release study etc. In-vitro anticancer activity and apoptosis assay was evaluated in breast cancer (MCF-7) cells using MTT assay and flow cytometer respectively. In-vivo biodistribution and toxicity assessment were evaluated in rats whereas antitumor activity in tumor bearing BALB/c mice. Prepared micelles were spherical with size and zeta potential of 295.6 + 84.4 nm and 0.8 ± 0.24 mV respectively. Apoptosis assay for DPPE-FA-DOX micelles treated cells using Annexin V/PI staining demonstrated 56.2% apoptotic cells. Remarkably, DPPE-FA-DOX micelles improved DOX bioavailability by 7 fold and diminished plasma elimination with no sign of tissue toxicity compared to free DOX. In-vivo biodistribution studies revealed that micelles facilitated higher accumulation of DOX in tumor than free DOX. DPPE-FA-DOX micelles treated mice survived for 62 days than Free DOX (40 days), revealed by Kaplan-Meier survival curve analysis. Histopathological examination of liver, kidney and heart tissues of micelles treated rat's corroborated reduced systemic toxicity than free DOX. Conclusively, DPPE-FA-DOX micelles could potentially facilitate the targeted delivery of DOX to tumors.

Capsaicin Loaded Solid SNEDDS for Enhanced Bioavailability and Anticancer Activity: In-Vitro, In-Silico, and In-Vivo Characterization.

In this investigation, the fabrication of capsaicin loaded self nano emulsifying drug delivery system (SNEDDS) was attempted to improve the effectiveness of capsaicin through the oral route. A pseudo-ternary phase diagram was constructed at different km values (1:1, 2:1, & 3:1). Nine liquid formulations (L-CAP-1 to L-CAP-9) were prepared at km = 3, evaluated & converted to solid free-flowing granules using neusilin® US2. L-CAP-3 comprising of 15% isopropyl myristate, 33.75% Labrafil, & 11.25% ethanol exhibited higher % transmittance (98.90 ± 1.24%) & lower self-emulsification time (18.19 ± 0.46 s). FT-IR spectra showed no incompatibility whereas virtual analysis confirmed hydrogen bond interaction between amino hydrogen in the capsaicin & oxygen of the neusilin. DSC & XRD study revealed the amorphization & molecular dispersion of capsaicin in S-SNEDDS. TEM analysis confirmed the nano-sized spherical globules. Within 15 min, L-SNEDDS, S-SNEDDS, & pure capsaicin showed 87.36 ± 3.25%, 85.19 ± 4.87%, & 16.61 ± 3.64% drug release respectively. S-CAP-3 significantly (P < 0.001) inhibited the proliferation of HT-29 colorectal cancer cells than capsaicin. Apoptosis assay involving Annexin V/PI staining for S-CAP-3 treated cells demonstrated a significant (P < 0.001) apoptotic rate. Remarkably, 3.6 fold increase in bioavailability was observed after oral administration of capsaicin-SNEDDS than plain capsaicin.

Acrylamide grafted neem (Azadirachta indica) gum polymer: Screening and exploration as a drug release retardant for tablet formulation.

The study was initiated with the intent to synthesize acrylamide grafted neem gum polymer (AAm-g-NG), and screen its drug release retardation ability both in vitro and in vivo. Different batches (NGP-1 to NGP-9) of tablet formulation were prepared by varying polymer concentration using propranolol HCl and compared with HPMC K100 M and marketed SR tablets. FTIR study proved the grafting phenomenon and showed no incompatibility between AAm-g-NG and propranolol HCl. AAm-g-NG showed significant swelling and water retention capacity than NG. AAm-g-NG was found to be biodegradable and exhibited no toxicity to Artemia salina. After 12 h, NGP-6 showed non-significant (p > 0.05; f2= ∼ 90) percent drug release (80.52 ±â€¯3.41%) compare to marketed formulation (79.65 ±â€¯4.08%). Significant swelling of the matrix caused slower diffusion of the drug. NGP-6 and marketed formulation in rabbits showed the non-significant difference between Cmax and Tmax, hence NGP-6 meets the requirement of sustained-release tablets.

Optimization of Thiazolidone Scaffolds Using Pocket Modeling for Development of Potential Secretory System Inhibitors of Mycobacterium tuberculosis.

OBJECTIVES: Mycobacterium tuberculosis is the causative organism of tuberculosis, which is the most lethal disease after cancer in the current decade. The development of multidrug and broadly drug-resistant strains is making the problem of tuberculosis more and more critical. In the last 40 years, only one molecule has been added to the treatment regimen. Generally, drug design and development programs target proteins whose function is known to be essential to the bacterial cell. M. tuberculosis possesses specialized protein export systems like the SecA2 export pathway and ESX pathways. MATERIALS AND METHODS: In the present communication, rational development of an antimycobacterial agent's targeting protein export system was carried out by integrating pocket modeling and virtual analysis. RESULTS: The 23 identified potential lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like infrared and nuclear magnetic resonance spectroscopy, and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds showed profound antimycobacterial activity. CONCLUSION: We found that Q30, M9, M26, U8, and R26 molecules had significant desirable biological activity and specific interactions with Sec of mycobacteria. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates with fewer side effects.