Ultra rapidly dissolving repaglinide nanosized crystals prepared via bottom-up and top-down approach: influence of food on pharmacokinetics behavior.

The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly water-soluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus® was used as a stabilizer and Kolliphor™ E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p < 0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively).

Engineering of polymer-surfactant nanoparticles of doxycycline hydrochloride for ocular drug delivery.

CONTEXT: Physiologic barriers of the eye, short precorneal drug residence time and poor corneal penetration are the few reasons for reduced ocular bioavailability. OBJECTIVE: This study was aimed to develop novel polymer-surfactant nanoparticles of hydrophilic drug doxycycline hydrochloride (DXY) to improve precorneal residence time and drug penetration. MATERIALS AND METHODS: Nanoparticles were formulated using emulsion cross-linking method and the formulation was optimized using factorial design. The prepared formulation was characterized for particle size, ζ potential, encapsulation efficiency, in vitro drug release and ex vivo drug diffusion studies. The antibacterial activity studies were also carried out against Escherichia coli and Staphylococcus aureus using the cup-plate method. In vivo eye irritation study was carried out by a modified Draize test in rabbits. RESULTS AND DISCUSSION: The particle size was found to be in the range of 331-850 nm. About 45-80% of the drug was found to be encapsulated in the nanoparticles. In vitro release demonstrated sustained release profile. Lower flux values in case of nanoparticles as compared to DXY pure drug solution in ex vivo diffusion studies confirmed the sustained release. The nanoparticles were found to be significantly effective (p < 0.001) than DXY aqueous solution due to sustained release of doxycycline from nanoparticles in both the E. coli and S. aureus strains. The formulation was found to be stable over entire stability period. CONCLUSION: The developed formulation is safe and suitable for sustained ocular drug delivery.

Quality by design approach to understand the process of optimization of iloperidone nanostructured lipid carriers for oral bioavailability enhancement.

CONTEXT: The current work was carried out by exploring the principles of quality by design approach to develop an optimized nanostructured lipid carrier (NLC) formulation of poorly water soluble active iloperidone (ILO) through systematic statistical study. The potential of NLC for improving the oral bioavailability of ILO was also evaluated. OBJECTIVE: To understand the effect of formulation variables (critical parameters) on the performance characteristics (critical quality attributes) of NLC. MATERIALS AND METHODS: A 3-factor, 3-level Box-Behnken factorial design was explored to predict the responses such as particle size (Y1) and % entrapment efficiency (EE) (Y2) when concentration of lipid (X1), concentration of drug (X2) and concentration of surfactant (X3) were selected as independent variables. RESULTS AND DISCUSSION: Particle size analysis revealed that all the batches were within the nanometer range. The % EE was found to be between 63% and 96%. In-vitro release study demonstrated sustained release profile of ILO NLC. The pharmacokinetic study in Wistar rats over the period of 24 h demonstrated 8.30-fold increase in oral bioavailability of ILO NLC as compared with ILO pure drug suspension. CONCLUSION: The NLC formulation remarkably improved the oral bioavailability of ILO and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs.

Assessment of novel iloperidone- and idebenone-loaded nanostructured lipid carriers: brain targeting efficiency and neuroprotective potential.

BACKGROUND: To evaluate the outcome of combining iloperidone with idebenone in the form of brain-targeted nanostructured lipid carrier (NLC) on the expression of endogenous antioxidant enzymes present in the brain, and hence establish the neuroprotective activity. RESULTS: The combination NLC demonstrated good targeting potential (>85%) as compared with pure iloperidone (22.21%). The levels of various endogenous antioxidant enzymes present in the brain were reduced significantly (p < 0.001) in case of 28 days repeated administration of pure iloperidone, while administration of the combination NLC helped to restore the levels of these enzymes. CONCLUSION: Combining iloperidone with idebenone and converting into NLC has contributed in effectively reducing oxidative stress in the brain and helped in reversing the catalepsy induced by repeated iloperidone administration.

Pioglitazone solid dispersion system prepared by spray drying method: in vitro and in vivo evaluation.

OBJECTIVE: Pioglitazone is a thiazolidinedion antidiabetic agent which decreases insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is insoluble in water and has a low dissolution rate. The objective of the current work was to improve aqueous solubility of pioglitazone by the solid dispersion approach using the spray drying technique. DESIGN: In this study, various hydrophilic polymers such as PVP K17, PVP K30, and HPMC E3 were used to prepare pioglitazone solid dispersion by the spray drying method. MAIN OUTCOME MEASURES: Characterization of solid dispersion included solubility, particle size, surface area analysis, differential scanning calorimetry, infrared spectroscopy, x-ray diffraction, and dissolution test. In vivo hypoglycaemic activity was studied in Swiss albino mice. RESULTS: RESULTS showed that there was significant improvement in solubility and dissolution rate in solid dispersion containing PVP K17 than in that of the pure drug. This in turn resulted in improved pharmacodynamic activity, giving 2 fold mean percentage glucose inhibition as compared to the pure drug; thus the solid dispersion strategy proved to be potentially beneficial for improving the in vivo hypoglycaemic activity of pioglitazone. CONCLUSION: Increase in pioglitazone solubility and in vitro dissolution in solid dispersion was followed by improved in vivo hypoglycaemic activity. LAY ABSTRACT: The aim of the present study was to prepare and evaluate solid dispersion of pioglitazone by the spray drying method. Various hydrophilic polymers were used for preparation of solid dispersion. Pioglitazone is an oral antidiabetic agent effective for reactive hypoglycaemia and aggravated glycaemic metabolism associated with insulin resistance. The prepared solid dispersion was evaluated for saturation solubility, drug content, differential scanning calorimetry, x-ray diffraction, infrared spectroscopy, and stability as per International Conference on Harmonisation guidelines. The glucose-lowering response of the optimized formulation was also studied in Alloxan-induced diabetic Swiss Albino mice. The formulation containing hydrophilic polymers showed a satisfactory drug release pattern compared to the pure drug. Further, when in vivo hypoglycaemic response of pure drug, prepared solid dispersion, and marketed formulation was compared, the optimized solid dispersion batch revealed significant improvement in hypoglycaemic activity. Hence, the present study reveals that the formulation of solid dispersion of pioglitazone with hydrophilic polymer exhibits good release properties as well as in vivo antihyperglycemic activity.

Bicalutamide nanocrystals with improved oral bioavailability: in vitro and in vivo evaluation.

CONTEXT: Bicalutamide (BCT) is an antiandrogenic compound belonging to Biopharmaceutics Classification System (BCS) class II drug. Thus it has limited aqueous solubility and hence limited oral bioavailability. OBJECTIVE: The purpose of the present investigation was to obtain stable nanocrystals of BCT with improved kinetic solubility, dissolution and pharmacokinetic profiling. MATERIALS AND METHODS: BCT nanocrystals were prepared by antisolvent precipitation method using Soluplus, a novel amphiphilic polymer. Nanocrystals were characterized for particle size, powder X-ray diffraction analysis (PXRD), in vitro dissolution, in vivo pharmacokinetic profile and stability. RESULTS AND DISCUSSION: The obtained nanocrystals had particle size of 168 nm and were spherical in shape. The nanocrystals exhibited fivefold increase in kinetic solubility as compared to pure drug and 85% dissolution in 60 min. PXRD studies established the retention of crystalline polymorphic form II. The in vivo pharmacokinetic study demonstrated that the Cmax and AUC of nanosized BCT were about 3.5 times higher as compared to pure drug. CONCLUSION: Nanosizing of BCT significantly improved the pharmacokinetic profile of the drug administered to rats. Prepared nanocrystals were found to be stable over the entire stability period. Thus the use of amphiphilic polymer like Soluplus singularly helped in efficient size reduction and stabilization of the drug.

Ternary complexation of carvedilol, beta-cyclodextrin and citric acid for mouth-dissolving tablet formulation.

The purpose of this study was to improve the solubility and dissolution rate of carvedilol by forming a ternary complex with beta-cyclodextrin and citric acid and to formulate its mouth-dissolving tablets. The rationale for preparing mouth-dissolving tablet of carvedilol was to make the drug available in a soluble form in the mouth, which would facilitate its absorption from the buccal cavity. This would help to overcome its first-pass metabolism and thereby improve bioavailability. Phase solubility studies revealed the ability of beta-cyclodextrin and citric acid to complex with carvedilol and significantly increase its solubility. Ternary complexation of carvedilol was carried out with beta-cyclodextrin and citric acid by physical mixing, kneading and spray drying methods and the prepared complexes were characterized by Fourier transform infra red spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and complexation efficiency. The complex obtained by the spray drying method resulted in highest complexation efficiency and a 110-fold increase in the solubility of carvedilol. The mouth-dissolving tablets formulated using the spray dried complex with suitable excipients showed 100 % dissolution within five minutes. Accelerated stability studies of mouth-dissolving tablets carried out as per ICH guidelines revealed that the tablets were stable.

Studies on formulation development of mouth dissolving tablets of Carvedilol.

Carvedilol a poorly water soluble drug undergoes extensive first pass metabolism, which reduces its bioavailability to 25-30%. Mouth dissolving tablets of Carvedilol were prepared with the purpose of delivering the drug directly into the systemic circulation and bypassing the hepatic first pass metabolism with a concomitant increase in bioavailability. The solubility of Carvedilol was improved by forming inclusion complex with cyclodextrin which was then further used for the formulation of mouth dissolving tablet. Differential scanning calorimetry and Infrared spectroscopy results indicated no incompatibilities between drug-excipient mixtures. Effect of three different superdisintegrants on disintegration was studied. The formulations were evaluated for drug content, content uniformity, friability, disintegration time and in-vitro dissolution. Tablets containing Carvedilol-beta-cyclodextrin complex exhibited good tablet properties, with 90% drug dissolved within 5 min. This demonstrated the effectiveness of using various superdisintegrants and Carvedilol-beta-cyclodextrin complex in formulation of mouth dissolving tablet.