C. Bothiraja

Evaluation of molecular pharmaceutical and in-vivo properties of spray-dried isolated andrographolide-PVP.

Objectives Andrographolide, a natural lipophilic molecule, has a wide range of pharmacological actions. However, due to low aqueous solubility, it has low oral bioavailability. The purpose of the study was to increase the solubility and dissolution rate of isolated andrographolide by formulating its solid dispersion.

Development of plumbagin-loaded phospholipid–Tween® 80 mixed micelles: formulation, optimization, effect on breast cancer cells and human blood/serum compatibility testing

BACKGROUND Phospholipid and Tween(®) 80 mixed micelles were investigated as injectable nanocarriers for the natural anticancer compound, plumbagin (PBG), with the aim to improve anticancer efficiency. PBG-loaded mixed micelles were fabricated by self-assembly; composition being optimized using 3(2) factorial design. RESULTS & DISCUSSION Optimized mixed micelles were spherical and 46 nm in size. Zeta potential, drug loading and encapsulation efficiency were 5.04 mV, 91.21 and 98.38% respectively. Micelles demonstrated sustained release of PBG. Micelles caused a 2.1-fold enhancement in vitro antitumor activity of PBG towards MCF-7 cells. Micelles proved safe for intravenous injection as PBG was stable at high pH; micelle size and encapsulation efficiency were retained upon dilution. CONCLUSION Developed mixed micelles proved potential nanocarriers for PBG in cancer chemotherapy.

Fisetin-loaded nanocochleates: formulation, characterisation, in vitro anticancer testing, bioavailability and biodistribution study

Background: The natural flavonoid fisetin has shown anticancer properties but its in vivo administration remains challenging due its poor aqueous solubility and extensive in vivo metabolism. This juncture demands an effective, controlled release and safe formulation of fisetin would be a significant advance for the treatment of cancer. Objectives: Nanocochleates are unique lipid-based supramolecular assemblies composed of a negatively charged phospholipid and a divalent cation. The aim was to develop and evaluate fisetin-loaded nanocochleates to improve its therapeutic efficacy. Using the trapping method, fisetin-loaded dimyristoylphosphatidylcholine liposomal vesicles were converted into nanocochleates by the action of Ca2+ ions. These nanocochleates were further evaluated for physicochemical, in vitro anticancer and haemolysis, pharmacokinetics and tissue distribution study in mice. Results: Stable rolled-up layers as well as elongated structure of nanocochleates possessing particle size and encapsulation efficiency (EE) of 275 + 4 nm and 84.31 ± 2.52%, respectively were obtained. Nanocochleates demonstrated safety and a sustained release of fisetin at physiological pH. A 1.3-fold improvement in vitro anticancer towards human breast cancer MCF-7 cells was observed. Pharmacokinetics studies in mice revealed that nanocochleates injected intraperitonially showed a 141-fold higher relative bioavailability. Moreover, a low tissue distribution was observed. Conclusion: Developed nanocochleates markedly improved anticancer efficacy, bioavailability and safety of fisetin. The nanocochleates technology would facilitate the administration of this flavonoid in the clinical setting. Areas covered: In this research article, we focused on lipid-based supramolecular assembly ‘nanocochleates’ composed of negatively charged phospholipids and divalent cation as drug carrier for systemic delivery system and discussed their formulations, optimisation, characterization, in vitro and in vivo performance.

Formulation and Evaluation of Optimized Oxybenzone Microsponge Gel for Topical Delivery

Background. Oxybenzone, a broad spectrum sunscreen agent widely used in the form of lotion and cream, has been reported to cause skin irritation, dermatitis, and systemic absorption. Aim. The objective of the present study was to formulate oxybenzone loaded microsponge gel for enhanced sun protection factor with reduced toxicity. Material and Method. Microsponge for topical delivery of oxybenzone was successfully prepared by quasiemulsion solvent diffusion method. The effects of ethyl cellulose and dichloromethane were optimized by the 32 factorial design. The optimized microsponges were dispersed into the hydrogel and further evaluated. Results. The microsponges were spherical with pore size in the range of 0.10–0.22 µm. The optimized formulation possesses the particle size and entrapment efficiency of 72 ± 0.77 µm and 96.9 ± 0.52%, respectively. The microsponge gel showed the controlled release and was nonirritant to the rat skin. In creep recovery test it had shown highest recovery indicating elasticity. The controlled release of oxybenzone from microsponge and barrier effect of gel result in prolonged retention of oxybenzone with reduced permeation activity. Conclusion. Evaluation study revealed remarkable and enhanced topical retention of oxybenzone for prolonged period of time. It also showed the enhanced sun protection factor compared to the marketed preparation with reduced irritation and toxicity.

Novel solvent‐free gelucire extract of Plumbago zeylanica using non-everted rat intestinal sac method for improved therapeutic efficacy of plumbagin

INTRODUCTION Various shortcomings of the available methods of extraction of plumbagin from Plumbago zeylanica using non-edible organic solvents coupled with the poor aqueous solubility and low bioavailability called for extracting plumbagin in a water soluble form via a single step technique using hydrophilic lipid Gelucire 44/14. METHODS Gelucire extract of P. zeylanica (GPZ) was prepared and evaluated for extraction efficiency, High-performance thin layer chromatography (HPTLC) and thermal analysis. In vitro intestinal absorption and bioavailability of plumbagin from GPZ in comparison with that of aqueous (APZ), ethanolic extract (EPZ) and standard plumbagin studied using non-everted rat intestinal sac model. RESULTS The GPZ showed significantly higher extraction efficiency (3.24±0.12% w/w) compared to ethanolic (EPZ) and aqueous (APZ) extraction, 2.48±0.16% w/w and 0.07±0.02% w/w respectively. GPZ displayed significantly higher Q(30min) (cumulative percentage absorption of plumbagin in 30 min) and lower t(40%) (time required for 40% w/w drug absorption). The flux and apparent permeability coefficient in duodenum and ileum were 2, 3 and 6 fold higher than EPZ, standard plumbagin and APZ respectively. DISCUSSION Improved therapeutic efficacy of plumbagin may be due to the micellar solubilization and consequent enhanced partitioning of plumbagin through intestinal by Gelucire which was reflected in the in vivo anti-inflammatory study conducted in rats. CONCLUSION Thus extraction using Gelucire can be proclaimed as an efficient, economic and solvent-free technique for extraction of plumbagin and can be utilized for various clinically important water insoluble phytoconstituents in order to improve their biopharmaceutical properties.

Development of photostable gastro retentive formulation for nifedipine using low-density polypropylene microporous particles

The aim of this study was to develop photostable gastro retentive formulation for nifedipine loading into low-density polypropylene microporous particles (Accurel MP 1000®) by a solvent evaporation technique using the 32 factorial design. Yield, drug loading, surface topography, thermal properties, crystal characteristics, photostability and in vitro drug release were studied. Optimized microparticles formulated into a capsule were evaluated for the dissolution study and compared with marketed formulation. Higher values of T50%, time required for 50% degradation of drug with threefold and 1.5-fold decrease in degradation rate constant (K) under UV and fluorescent lamp were observed for the microparticles, respectively, as compared to pure nifedipine indicated remarkable improved photostability. Microparticles showed good floating ability in 0.1N HCl with initial burst release (16–29%) followed by the zero-order drug release up to 8 h. The capsule formulation followed the ideal modified release pattern.

An insight into cochleates, a potential drug delivery system

Cochleates, a type of lipid based drug delivery system, are solid particulates made up of large continuous lipid bilayer sheets rolled up in a spiral structure with little or no internal aqueous phase. These nano-sized or sub-micron sized structures are generated on fusion of negatively charged liposomes with metal cations. They are efficient in encapsulating drug molecules that are hydrophobic and hydrophilic; positively charged as well as negatively charged. The interior of a cochleate structure remains substantially intact irrespective of outer harsh environmental conditions or enzymes. Cochleate technology is applicable for administration through parenteral, topical as well as oral routes and can be formulated in liquid or powder form. Cochleates have been reported to improve the oral bioavailability; improve the safety of the drugs by decreasing side effects and increasing drug efficacy; all of which lead to enhanced patient compliance. This review article highlights the important aspects of cochleates such as their structure, properties, methods of preparation, stability, advantages, applications and current status. The information provided herein should help formulators in judiciously selecting cochleate technology for delivery of drugs.

Enhanced hepatoprotective activity of andrographolide complexed with a biomaterial.

Abstract Context: Humic acid (HA), a natural organic matter is recently being investigated for pharmaceutical purposes. Andrographolide (AGP), a potent hepatoprotective, possesses low aqueous solubility which results in a low bioavailability after oral administration, inappropriate tissue localization and consequently poor therapeutic application. Objective: The present study investigates the complexation of AGP with HA to increase its solubility and hepatoprotective efficacy. Materials and methods: Complexes prepared by solvent evaporation in various weight ratios were characterized using differential scanning calorimetry, Fourier Transform InfraRed spectroscopy, X-ray diffraction, and scanning electron microscopy. Results and discussion: The complexed AGP demonstrated improved solubility, dissolution, and permeation across rat intestine. It also displayed better hepatoprotection against carbontetrachloride-induced liver toxicity than the free drug in rats. Conclusion: Complexation with HA is a valuable technique to improve solubility and bioavailability of pharmaceuticals.

Improved pharmaceutical properties of surface modified bioactive plumbagin crystals

Plumbagin recrystallised by cold crystallisation technique using a variety of polar and non-polar solvents was investigated for pharmaceutical properties. Different solvents gave varying sized and shaped plumbagin. Powder X-ray diffraction, differential scanning calorimetery and fourier transform infrared spectroscopy too confirmed differing crystal habit. Platy crystals, the most significant forms, obtained from cyclohexane possessed small size (62.93 ± 3.74 μm), higher bulk density (0.108 ± 0.014 g/ml) and lower enthalpy of fusion (∆H 62.62 ± 3.67 J/g). These demonstrated approximately two-fold increase in saturation solubility (155.01 ± 3.86 μg/ml), higher Q5min (cumulative percentage dissolution in 5 min) and lower t65% (time required for 65% dissolution) owing to greater surface area. In-vivo anti-inflammatory study in Wistar rats demonstrated improvement in therapeutic efficacy of recrystallised plumbagin. In conclusion surface modification led to enhanced efficacy of plumbagin; an approach capable of improving the bioavailability and clinical efficacy of other poorly water soluble phytomedicine.

Development of fisetin-loaded folate functionalized pluronic micelles for breast cancer targeting

Abstract The natural flavonoid fisetin (FS) has shown anticancer properties but its in-vivo administration remains challenging due to its poor aqueous solubility. The aim of the study was to develop FS loaded pluronic127 (PF)-folic acid (FA) conjugated micelles (FS-PF-FA) by the way of increasing solubility, bioavailability and active targetability of FS shall increase its therapeutic efficacy. FA-conjugated PF was prepared by carbodiimide crosslinker chemistry. FS-PF-FA micelles were prepared by thin-film hydration method and evaluated in comparison with free FS and FS loaded PF micelles (FS-PF). The smooth surfaces with spherical in shape of FS-PF-PF micelles displayed smaller in size (103.2 ± 6.1 nm), good encapsulation efficiency (82.50 ± 1.78%), zeta potential (−26.7 ± 0.44 mV) and sustained FS release. Bioavailability of FS from FS-PF-PF micelles was increased by 6-fold with long circulation time, slower plasma elimination and no sign of tissue toxicity as compared to free FS. Further, the FS-PF-FA micelles demonstrated active targeting effect on folate overexpressed human breast cancer MCF-7 cells. The concentration of the drug needed for growth inhibition of 50% of cells in a designed time period (GI50) was 14.3 ± 1.2 µg/ml for FS while it was greatly decreased to 9.8 ± 0.78 µg/ml, i.e. a 31.46% decrease for the FS-PF. Furthermore, the GI50 value for FS-PF-FA was 4.9 ± 0.4 µg/ml, i.e. a 65.737% decrease compared to FS and 50% decrease compare to FS-PF. The results indicate that the FS-PF-FA micelles have the potential to be applied for targeting anticancer drug delivery.