Karimunnisa S. Shaikh

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.

Studies on nonionic surfactant bilayer vesicles of ciclopirox olamine

Context: Niosomal delivery can prove an alternative to improve the poor skin penetration and residence of the topical antifungal drugs that account for the long treatment regimes in cutaneous mycosis. Objective: To investigate niosomes as carriers for dermal delivery of ciclopirox olamine (CPO), a broad spectrum antifungal drug. Materials and methods: Niosomes were prepared by ethanol injection method using Span 60, cholesterol, diacetyl phosphate according to 32 factorial design and evaluated for physicochemical parameters, in vitro and ex vivo deposition in skin and stability study. Results: Unilamellar CPO niosomes of size 170–280 nm, entrapment efficiency 38–68%, and sufficient electrokinetic stability were obtained. Percent drug deposition in artificial membrane varied from 12.75 to 92.74. Deposition of CPO into rat skin from niosomal dispersion and its gel was significantly higher than that of plain CPO solution and its marketed product. Obtained niosomes possessed sufficient stability on storage. Discussion: Increasing amounts of Span 60 and cholesterol increase the vesicle size probably because of entrapment of CPO-ionized molecules in the aqueous compartment and interaction of its unionized counterpart with the bilayer constituents leading to increase in bilayer thickness. Consequently, the percent entrapment efficiency also increased. However, increasing Span 60 levels decreased the in vitro percent drug deposition. This might be attributed to the larger size of vesicles produced by high amounts of surfactant that showed poor deposition. The optimized batch possessed sufficient stability. Conclusions: The results of this investigation suggest that niosomes are promising tools for cutaneous retention of CPO.

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.

Strategies for formulation development of andrographolide

Andrographolide (AN), a diterpenoid lactone, is one of the prime phytoconstituents of Andrographis paniculata. AN possesses various therapeutic benefits such as hepatoprotective, analgesic, anti-inflammatory, anti-tumor, anti-hyperglycemic, anti-oxidant activities. However, AN has not reached its milestone therapeutic potential as clinical studies have suggested that a conventional dosage form of AN showed low oral bioavailability (2.67%). The factors attributed to low bioavailability included specific site absorption, hydrolysis in weak alkaline environments, first pass metabolism, P-gp excretion in the terminal intestine, biliary excretion and poor aqueous solubility (3.29 μg mL−1). A successful AN therapy warrants an apt delivery system that will enhance its bioavailability. Current approaches for developing an improved delivery system for AN are mainly focused on overcoming solubility and toxicity issues. The path to identify new molecules with better therapeutic efficacy will continue to be an integral part of health care systems but here the authors have emphasized on ‘better delivery of drugs’, which is going to further refine therapy. The different formulation approaches investigated so far have shown much promise experimentally in improving the bioavailability of AN. However, a product for human use is still far away. Since its isolation and characterisation in 1911 several developments related to AN have occurred. This review is the first comprehensive account of the pharmaceutical aspects of AN with special emphasis on its delivery that have occurred over the last century.

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.

Investigation of ethyl cellulose microsponge gel for topical delivery of eberconazole nitrate for fungal therapy

BACKGROUND The aim of the study was to investigate ethyl cellulose microsponges as topical carriers for the controlled release and cutaneous drug deposition of eberconazole nitrate (EB). MATERIALS & METHOD EB microsponges were prepared using the quasiemulsion solvent diffusion method. The effect of formulation variables (drug:polymer ratio, internal phase volume and amount of emulsifier) and process variables (stirring time and stirring speed) on the physical characteristics of microsponges were investigated. The optimized microsponges were dispersed into a hydrogel and evaluated. RESULTS & DISCUSSION Spherical and porous EB microsponge particles were obtained. The optimized microsponges possessed particle size, drug content and entrapment efficiency of 24.5 µm, 43.31% and 91.44%, respectively. Microsponge-loaded gels demonstrated controlled release, nonirritancy to rat skin and antifungal activity. An in vivo skin deposition study demonstrated fourfold higher retention in the stratum corneum layer as compared with commercial cream. CONCLUSION Developed ethyl cellulose microsponges could be potential pharmaceutical topical carriers of EB in antifungal therapy.

Development of floating in situ gelling system as an efficient anti-ulcer formulation: in vitro and in vivo studies

The aim of the present work was to design gellan gum and calcium carbonate based floating in situ gel as an efficient anti-ulcer formulation using andrographolide (AG) as a model drug. A 32 factorial design was used to study the effect of gellan gum and calcium carbonate on characteristic of in situ gelling system. The formulations were evaluated in terms of in vitro, in vivo anti-ulcer and histopathological study in Wistar rats. Drug content and viscosity were found in the range of 74.3 ± 1.2–95.5 ± 1.8% and 67.7 ± 1.6 to 152.13 ± 1.1 cps, respectively. Formulation gelled within 2 s and floated more than 24 h in simulated gastric fluid; an initial burst release of 11.7 ± 0.9 to 32.4 ± 2.1% till 1 h followed by a sustained release was observed. In vivo, the AG floating in situ gel (AGFIG) demonstrated lower acid and protein level, high hemoglobin level and negligible ulcer index. Moreover, it preserved integrity and histological aspects of the gastric mucosa as compared to pure AG and ranitidine. Improved anti-ulcer activity of AGFIG was attributed to longer residence time of AG in the stomach which improved the activity of myeloperoxidase, lipid peroxide, mucin content and glutathione peroxidase on gastric mucosal surface leading to protection from alcohol induced erosion. The study concluded that such floating in situ gelling system can be translated for existing and established anti-ulcer drugs.