Evaluation of cilnidipine-loaded self-micro-emulsifying drug delivery system (SMEDDS) by quantification of comparative pharmacokinetic parameters using validated LC-ESI-MS/MS bioanalytical method and pharmacodynamic assessment.

OBJECTIVE: Regardless of having desired therapeutic properties many of the recently approved drugs are removed from the developmental pipeline for their clinical use due to low solubility and permeability. Conventional dosage forms are found relatively unsuitable for achieving desired pharmacokinetic and pharmacodynamics profiles. Cilnidipine is 1,4 dihydropyridine derivative calcium channel blocker used for the treatment of hypertension. METHOD: The aim and objective of this study was to develop a precise and significant method in LC-MS/MS for quantification of pharmacokinetic parameters of a cilnidipine-loaded self-micro-emulsifying drug delivery system in rat plasma and simultaneously assessed pharmacodynamic characters in comparison with the marketed cilnidipine tablet. Another potential aim of this study is to reduce the dose of the drug in order to counter the dose-dependent toxicities related to chronic use. In the present study, the parent and product ion of cilnidipine was m/z 491.3\237.1. RESULT: The plasma was extracted by protein precipitation technique. The calibration standard concentrations were 1.875, 3.75, 7.50, 15.00, 30.00, 60.00ng/mL and LLOQ, low-quality control, middle-quality control and high-quality control were 1.87, 5.62, 22.50, 45.00ng/mL, respectively. The mobile phase composition was 0.1% formic acid in Milli Q water with 10mM Ammonium acetate as an aqueous solvent and 0.1% formic acid in methanol as an organic solvent. Following oral administration of optimized formulation Cmax (peak plasma concentration) was achieved 21.02±3.17ng/mL at 0.866±0.11h (Tmax), whereas in the case of marketed tablet Cmax (peak plasma concentration) was achieved 10.16±0.89ng/mL at 0.93±0.11h (Tmax). DISCUSSION: The in-vivo characterizations of the optimized SMEDDS showed significantly better pharmacokinetic parameters in Wistar rats and showed almost 2.4 times enhanced relative bioavailability as compared to the marketed tablet of cilnidipine which was observed to be correlating to our findings with noninvasive blood pressure parameter of Wistar rats.

Shellac and locust bean gum coacervated curcumin, epigallocatechin gallate nanoparticle ameliorates diabetic nephropathy in a streptozotocin-induced mouse model.

Curcumin and epigallocatechin gallate have the disadvantage of low aqueous solubility and first-pass metabolism, resulting in limited bioavailability. This work aimed to enhance oral bioavailability by forming gastric pH-stable shellac nanoparticles containing curcumin and epigallocatechin gallate using locust bean gum by anti-solvent precipitation (CESL-NP). The nanoparticles were characterized by their particle size, morphology, zeta potential, gastric pH stability, release profile, drug loading, and entrapment efficiency. The findings showed that a network of hydrolyzed shellac, locust bean gum, curcumin, and epigallocatechin gallate successfully entrapped individual particles inside a complex system. The morphological investigation of the CESL-NP formulation using FESEM, TEM, and AFM revealed the presence of spherical particles. FTIR, DSC, and XRD analysis revealed that curcumin and epigallocatechin gallate were amorphous due to their bond interactions with the matrix. Streptozotocin-treated mice, upon treatment with CESL-NP, showed kidney and pancreatic improvements with normalized kidney hypertrophy index and histopathology, maintained biochemical parameters, increased beta cell count, and a 38.68-fold higher blood glucose level inhibition were observed when compared to free-(CUR + EGCG). This research affirms that the shellac-locust bean gum complex shows potential for the sustained oral delivery of curcumin and epigallocatechin gallate, specifically for treating diabetic nephropathy.

Carnosic acid attenuates doxorubicin-induced cardiotoxicity by decreasing oxidative stress and its concomitant pathological consequences.

This work aimed to reveal the protective mechanism of CA against Dox (doxorubicin)-induced cardiotoxicity. In isolated murine cardiomyocytes, CA showed a concentration-dependent cytoprotective effect against Dox. Dox treatment significantly (p < 0.01) increased the formation of reactive oxygen species (ROS), increased NO levels, activated NADPH oxidase, and inactivated the cellular redox defense mechanism in cardiac cells, resulting in augmented oxidative stress in cardiomyocytes and rat hearts. Dox-induced oxidative stress significantly (p < 0.01) upregulated several pathogenic signal transductions, which induced apoptosis, inflammation, and fibrosis in cardiomyocytes and murine hearts. In contrast, CA significantly (p < 0.05-0.01) reciprocated Dox-induced cardiac apoptosis, inflammation, and fibrosis by suppressing oxidative stress and interfering with pathological signaling events in both isolated murine cardiomyocytes and rat hearts. CA treatment significantly (p < 0.05-0.01) countered Dox-mediated pathological changes in blood parameters in rats. Histological examinations backed up the pharmacological findings. In silico chemometric investigations predicted potential interactions between CA and studied signal proteins, as well as the drug-like features of CA. Thus, it would be concluded that CA has the potential to be regarded as an effective agent to alleviate Dox-mediated cardiotoxicity in the future.

In-situ fast gelling formulation for oral sustained drug delivery of paracetamol to dysphagic patients.

Evaluation of the potential for oral sustained drug delivery of formulations with in-situ gelling properties is the main objective of the present investigation. Oral administration of aqueous dispersion of sodium alginate (1.5% w/v) containing calcium ions in complex form resulted in the formation of gel matrix as a consequence of the release of the calcium ions in the acidic environment of stomach fluid. Addition of methylcellulose, sodium chloride and polyethylene glycol improved the drug retention efficacy of the gel. In this investigation, the study on the influence of added excipients on the rheological and drug release properties of the formulations has been focused. In-vitro studies demonstrated diffusion-controlled release of paracetamol from the gels. The bioavailability of orally administered paracetamol from the in-situ gel F4 (composed of 1.5% sodium alginate, 1.5% methyl cellulose, 3% CaCO3, 2% NaCl 0.05% polyethylene glycol) administered in the stomach of rabbit, was more sustained as compared to the commercially available suspension Calpol® containing an identical dose of paracetamol.

Effect of gellan gum on the thermogelation property and drug release profile of Poloxamer 407 based ophthalmic formulation.

The effect of gellan gum on the gelation behavior and in-vitro release of a specific drug named pilocarpine hydrochloride from different ophthalmic formulations based on poloxamer 407 is examined. The mixture of 0.3wt% gellan gum and 18wt% poloxamer (PM) solutions show a considerable increase in gel strength in physiological condition. Gel dissolution rate from PM based formulation is significantly decreased due to the addition of gellan gum. FTIR spectra analysis witnesses an interaction in between OH groups of two polymers which accounts for lowering in gelation temperature of PM-gellan gum based formulations. It is also observed from the cryo-SEM study that the pore size of PM gel decreases with an addition of gellan gum and in-vitro release studies indicate that PM-gellan gum based formulation retain drug better than the PM solution alone. Therefore, the developed formulation has the potential to be utilized as an in-situ ophthalmic drug carrier.

Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations.

The effect of weight average molecular weight (Mw) of methyl cellulose (MC) on the gelation behavior of Poloxamer 407 (PM) and in vitro release of Ketorolac Tromethamine (KT) from different ophthalmic formulations based on PM is examined. A drop of gelation temperature of PM is observed using MC of various M(w) by test tube tilting method, UV-vis spectroscopy, viscometry and rheometry. It is also observed that the viscosity and gel strength of all the formulations are increased with the increase in Mw of MC. PM with highest Mw of MC provides best drug release property among all the formulations. It is evident from this investigation that there is a distinct effect of M(w) of MC on the gelation behavior of PM as well as on the drug release profile of KT from PM-MC based ophthalmic formulations.

Effect of xanthan gum and guar gum on in situ gelling ophthalmic drug delivery system based on poloxamer-407.

The aim of this investigation was to develop a novel in situ gelling formulation based on poloxamer-407 (PM) for the sustained release of an ophthalmic drug. In an attempt to reduce the concentration of PM without compromising the in situ gelling capability and also to increase the drug release time, xanthan gum (XG) and guar gum (GG) were added into PM to develop different formulations. At concentrations of 18% and above, the PM was able to undergo sol-gel transition below body temperature. It was found that XG and GG at a weight ratio of 3:7 were able to convert PM solution into gel below body temperature at PM concentrations below 18%. Both the in vitro and in vivo studies indicated that the PM with an XG-GG combination had a better ability to retain the drug than PM itself. The results indicated that the developed in situ gelling formulations containing PM with XG-GG may be a better alternative than a conventional eye drop.

Expedition of in vitro dissolution and in vivo pharmacokinetic profiling of sulfur nanoparticles based antimicrobials.

A comprehensive pharmacokinetic profiling of novel drugs and therapeutics is a definite prerequisite of drug discovery and development. The present study expedites the in vivo and in vitro pharmacokinetic properties of colloidal sulfur nanoparticles (SNPs). In vitro dissolution properties of SNPs have been demonstrated and compared with the in vivo pharmacokinetic parameters of rabbit (Oryctolagus cuniculus) serum sample. The present study was also aimed at developing levels of correlation between in vitro and in vivo pharmacokinetic parameters. Cumulative results of the proposed study also suggest good in vitro-in vivo correlation of these novel nanocolloids and suggest their immediate profiling as an antimicrobial drug.

Effect of PEG-salt mixture on the gelation temperature and morphology of MC gel for sustained delivery of drug.

Gelation temperature of MC was reduced from 59°C to 54°C with the addition of 10% PEG. Sodium tartrate (NaT) and sodium citrate (NaC) were added to the MC-PEG solution to further reduce the gelation temperature close to physiological temperature. Different techniques were used to measure the gelation temperature of all formulations. It was observed that NaC was more effective in reducing the gelation temperature of MC-PEG combination than NaT. Environmental scanning electron microscopy (ESEM) images of hydrogels containing NaC and NaT showed that NaC containing hydrogel having an interconnected microporous structure instead of the hollow rod like structure as in the case of NaT containing hydrogel. In vitro drug release studies showed that drug release time increased from 6 to 9h by only changing the type of salt from NaT to NaC in MC-PEG combination.

Effect of PVA on the gel temperature of MC and release kinetics of KT from MC based ophthalmic formulations.

The effect of molecular weight of poly(vinyl alcohol) (PVA) and sodium chloride on the gelation temperature of methylcellulose (MC) was studied with the objective to develop a MC based formulation for sustained delivery of ketorolac tromethamine a model ophthalmic drug. Pure MC showed sol-gel transition at 61.2 °C. In order to reduce the gelation temperature of MC and to increase the drug release time, PVA was used. Different techniques such as test tube tilting method, UV-vis spectroscopy, viscometry and rheometry were used to measure gelation temperature of all the binary combinations of MC and PVA. It was observed that the gelation temperature of MC was reduced with the addition of 4% PVA and also the extent of reduction of the gelation temperature of MC was dependent on the molecular weight of PVA. The strong interactions between MC and PVA molecules were established using Fourier transform infrared spectroscopy. To study the in vitro drug release properties of the MC-PVA binary combinations, 6% sodium chloride was used to reduce the gelation temperature further up to physiological temperature. It was observed that the drug release time increased from 5 to 8h with the increase of molecular weight of PVA from 9×10(3) to 1.3×10(5) and this was due to the higher viscosity, better gel strength and greater interactions between the drug and PVA molecules in case of PVA (1.3×10(5)) compared to PVA (9×10(3)). In order to have an idea about the nature of interactions between the functional moieties of the drug and the polymer unit of PVA, a theoretical study was carried out.

Attenuation of reactive nitrogen species by different flavonoids enriched fractions of Schima Wallichii

Objective: To investigate Schima wallichii (S. wallichii) Choisy (Ternstroemiaceae) which is a well known plant of Sikkim in the Himalayan region, India. Methods: Therefore three major flavonoid enriched fractions (FPet.Ether, FChloroform and FEthylacetate) were isolated by petroleum ether chloroform and ethyl acetate successively. The reactive nitrogen species scavenging activity of the flavonoid fractions was established using biochemical assay to measure scavenging of 2, 2 diphenyl picrylhydrazyl (DPPH), nitric oxide (NO) and peroxinitrite. Results: FEthylacetate showed maximum scavenging activity: their IC50 being (7.33 ± 3.32), (7.11 ± 2.21), and (6.67 ± 2.23)μg/mL in DPPH, NO, peroxinitrite radical respectively. Presence of (57.32 ± 2.31) and (163.4 ±2.22) μg of flavonoids and phenolic compound in 1 mg of extract is assumed to be responsible for free radical scavenging activity. Conclusion: Taken together S. wallichii has potent free radical scavenging property indicating its importance in food supplement as a rich source of active flavonoid and phenolic compounds in ethyl acetate fraction which is responsible for its free radical scavenging as well as antioxidant activity.

Study of thermo-sensitive in-situ gels for ocular delivery.

The aim of the present study was the development of thermo-sensitive in-situ gels for in-vitro evaluation of ophthalmic delivery systems of ketorolac tromethamine (KT), based on methylcellulose (MC) in combination with hydroxypropylmethyl cellulose (HPMC). The gel temperature of 1% MC solution was observed at 60°C. It was found that 6% oral rehydration salt without dextrose (ORS) was capable to reduce the gel temperature below physiological temperature. HPMC was added to increase viscosity and drug release time. The results indicated a large increase in viscosity at 37°C with addition of HPMC whch provided sustained release of the drug over a 4h period. From in-vitro release studies, it could be concluded that the developed systems were thus a better alternative to conventional eye drops.

Effect of salts on gelation and drug release profiles of methylcellulose-based ophthalmic thermo-reversible in situ gels.

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions may be overcome by the use of thermo-reversible in situ gel. The purpose of this study was to examine the influence of different salts on the gelation, rheology and drug release of in situ gel based on methylcellulose. The gel temperature of 1% w/v methylcellulose (MC) was 60?C. It was found that 5?7% w/v sodium chloride (NaCl), 8?9% w/v potassium chloride (KCl), or 5% w/v sodium bicarbonate (NaHCO(3)) was capable of decreasing the gel temperature below physiological temperature, i.e. 37?C. Rheological studies indicated a large increase in viscosity at 37?C with the addition of salts in MC solutions. The duration of drug release from MC solution was 1.5?h. The significant observation was that the duration of drug release increased from 1.5?h to 3?5?h from salted MC solutions depending on the concentration and the type of salt. So, it can be concluded that the salted MC solutions were a better alternative than the MC solution to enhance the ocular bioavailability of the drug.

Development and in vitro evaluation of Letrozole loaded biodegradable nanoparticles for breast cancer therapy / Desenvolvimento e avaliação in vitro de Letrozole carregado nanopartículas biodegradáveis para o tratamento do câncer de mama

The objectives of our study were to prepare and evaluate a biodegradable nanoparticulate system of Letrozole (LTZ) intended for breast cancer therapy. LTZ loaded poly(lactide-co-glycolide) nanoparticles (LTZ-PLGA-NPs) were prepared by emulsion-solvent evaporation method using methylene chloride and polyvinyl alcohol. Percentage of drug (with respect to polymer) was selected as formulation variable. LTZ-PLGA-NPs were characterized by particle size, zeta potential, infrared spectra, drug entrapment efficiency and in vitro release. Sonication was done with an ultrasound pulse sonicator at 70 W, 30 kHz for 90 sec to produce stable NPs of mean size range from 64 nm to 255 nm with high entrapment efficiency (68 percent to 82 percent). Percentage of drug significantly influenced particle size, entrapment efficiency and release (p <0.05). The system sustained release of LTZ significantly and further investigation could exhibit its potential usefulness in breast cancer therapy.

Os objetivos de nosso estudo foram preparar e avaliar o sistema de nanopartícula biodegradável de letrozol na terapia de câncer mamário. Nanopartículas de poli(lactídeo-co-glicolídeo) carregadas com LTZ (LTZ-PLGA-NPs) foram preparadas pelo método de emulsão-evaporação de solvente, utilizando dicloro metano e álcool polivinílico. A porcentagem do fármaco (com relação ao polímero) foi selecionada como variável da formulação. LTZ-PLGA-NPs foram caracterizadas pelo tamanho da partícula, potencial zeta, espectros no infravermelho, eficiência de inclusão e liberação in vitro. A sonicação foi realizada com sonicador de ultrassom, de pulso a 70W e 30 kHz por 90 segundos para produzir NPs estáveis, de faixa de tamanho médio de 64 nm a 266 nm, com alta eficiência de inclusão (68 por cento a 82 por cento). A porcentagem do fármaco foi significativamente influenciada pelo tamanho da partícula, eficiência de inclusão e liberação (p<0,05). O sistema controlou significativamente a liberação de LTZ e estudos posteriores poderiam mostrar sua utilidade potencial na terapia de câncer de mama.