Intranasal delivery of topiramate nanoemulsion: Pharmacodynamic, pharmacokinetic and brain uptake studies.

Epilepsy is the noncommunicable and chronic central nervous system disorder characterized by frequent, unprovoked seizures, or electrical disturbances in the brain. Topiramate is used as an antiepileptic drug for the treatment of partial onset seizures, generalized seizures and Lennox-Gastaut Syndrome. Topiramate, a BCS class II drug, has a relatively low bioavailability. It is also a substrate of P-glycoprotein and Blood Brain Barrier restricts its entry into the brain. This investigation was aimed to prepare O/W nanoemulsion delivery system of topiramate to improve its brain bioavailability. Topiramate loaded nanoemulsion was prepared by phase titration method. It was consisting of 2% w/w Capmul MCM C8, 32% w/w Tween 20:Carbitol (2:1) and 66% w/w water. It was characterized for globule size, viscosity, polydispersibility index, zeta potential, pH, conductivity values, transmittance and TEM. Pharmacodynamic, pharmacokinetic and brain drug uptake study was carried out using wistar albino rats post intranasal and oral administration. Topiramate loaded nanoemulsion was having a globule size of 4.73 ± 0.52 nm. It was stable for six months. Brain uptake of topiramate post intranasal administration of topiramate loaded nanoemulsion was significantly (P < 1.86 × 10-8) higher when it was compared with oral administration of topiramate loaded nanoemulsion. This study indicates that intranasal administration of topiramate containing nanoemulsion could be an encouraging approach for the treatment of epilepsy to minimize the dose of topiramate in direction to avoid dose related adverse events.

Targeted delivery of mannosylated-PLGA nanoparticles of antiretroviral drug to brain.

Mannosylated polymeric nanoparticles (NPs) enable improvement of brain bioavailability and reduction of dosing due to efficient drug delivery at the target site. Mannose receptors are present on the surface of macrophages, and therefore, in this study, it is expected that mannosylated NPs of anti-human immunodeficiency virus drug may target the macrophages, which may improve the therapeutic outcome and reduce the toxicity of antiretroviral bioactives. Poly(lactic-co-glycolic acid) (PLGA) and mannosylated-PLGA NPs (Mn-PLGA NPs) were prepared and administered by intravenous route in a dose of 10 mg/kg. After predetermined time period, the pharmacokinetics and biodistribution of NPs were analyzed using high-performance liquid chromatography and confocal microscopy, respectively. Results of this study indicated that Mn-PLGA NPs would be a promising therapeutic system for efficient delivery of the drug into brain macrophages.

HPTLC Method for Estimation of Topiramate in Solubility Studies, Diffusion Studies, Plasma, Brain Homogenate and Pharmaceutical Formulation.

Topiramate, 2,3:4,5-bis-O-(1-methylethylidene)-ß-d-fructopyranose, is an anticonvulsant drug indicated in the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures in adults and children. An economic and rapid high-performance thin-layer chromatographic (HPTLC) method was developed and was validated for the quantitative determination of topiramate in plasma, brain homogenate and pharmaceutical formulation. The simple extraction method was used for the isolation of topiramate from formulation, plasma and brain homogenate samples. HPTLC separation was achieved on an aluminum-backed layer of silica gel 60F254 plates using toluene : acetone (5.0 : 2.0, v/v) as mobile phase. Spots of developed plates were visualized by spraying of reagent [3.0% phenol in the mixture of ethanol : sulfuric acid (95 : 5, v/v)]. Quantitation was achieved by densitometric analysis at 340 nm over the concentration range of 1,000-5,000 ng/spot. The method was found to give compact spot for the drug (Rf: 0.61 ± 0.018). The regression analysis data for the calibration plots showed good relationship with a correlation coefficient of 0.9983. The minimum detectable amount was found to be 165 ng/spot, whereas the limit of quantitation was found to be 500 ng/spot. Statistical analysis of the data showed that the method is precise, accurate, reproducible and selective for the analysis of topiramate. The developed method was successfully employed for the estimation of topiramate in samples of equilibrium solubility study, diffusion study, microemulsion formulation and suspension formulation (developed in-house), rat plasma and rat brain homogenate samples.

Nanoemulsions for Intranasal Delivery of Riluzole to Improve Brain Bioavailability: Formulation Development and Pharmacokinetic Studies.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease (MND), is a progressive neurodegenerative disorder characterized by the deterioration of both upper and lower motor neurons. Only one drug (riluzole) has been approved for the treatment of ALS. Riluzole is a BCS class II drug having 60% absolute bioavailability. It is a substrate of P-glycoprotein and BBB restricts its entry in brain. OBJECTIVE: This investigation was aimed to develop O/W nanoemulsion system of riluzole to improve its brain bioavailability. METHODS: Riluzole loaded nanoemulsion was prepared by phase titration method. It was consisting of 3% w/w Sefsol 218, 28.3% w/w Tween 80:Carbitol (1:1) and 68.7% w/w water. It was characterized for drop size, drop size distribution, transmittance, viscosity, pH, zeta potential, conductivity and nasal ciliotoxicity study. Thermodynamic stability and room temperature stability of prepared nanoemulsion formulation were evaluated. Pharmacokinetic and brain uptake study was carried out using albino rats (wistar) post intranasal and oral administration. RESULTS: Riluzole loaded nanoemulsion was having a drop size of 23.92±0.52 nm. It was free from nasal ciliotoxicity and stable for three months. Brain uptake of riluzole post intranasal administration of riluzole loaded nanoemulsion was significantly (P <4.10 × 10-6) higher when it was compared with oral administration of riluzole loaded nanoemulsion. CONCLUSION: This study indicates that nanoemulsion of riluzole for intranasal administration could be a promising approach for the treatment of ALS to minimize the dose of riluzole in order to avoid dose related adverse events.

Development of oral sustained release rifampicin loaded chitosan nanoparticles by design of experiment.

Objective. The main objective of the present investigation was to develop and optimize oral sustained release Chitosan nanoparticles (CNs) of rifampicin by design of experiment (DOE). Methodology. CNs were prepared by modified emulsion ionic gelation technique. Here, inclusion of hydrophobic drug moiety in the hydrophilic matrix of polymer is applied for rifampicin delivery using CN. The 2(3) full-factorial design was employed by selecting the independent variables such as Chitosan concentration (X 1), concentration of tripolyphosphate (X 2), and homogenization speed (X 3) in order to achieve desired particle size with maximum percent entrapment efficiency and drug loading. The design was validated by checkpoint analysis, and formulation was optimized using the desirability function. Results. Particle size, drug entrapment efficiency, and drug loading for the optimized batch were found to be 221.9 nm, 44.17 ± 1.98% W/W, and 42.96 ± 2.91% W/W, respectively. In vitro release data of optimized formulation showed an initial burst followed by slow sustained drug release. Kinetic drug release from CNs was best fitted to Higuchi model. Conclusion. Design of Experiment is an important tool for obtaining desired characteristics of rifampicin loaded CNs. In vitro study suggests that oral sustained release CNs might be an effective drug delivery system for tuberculosis.

Self-nanoemulsifying drug delivery system of glimepiride: design, development, and optimization.

The objective of the present investigation was to develop and characterize the self-nanoemulsifying drug delivery system (SNEDDS) of glimepiride, a poorly soluble drug. Solubility of glimepiride in various vehicles was determined, and ternary phase diagrams were constructed using a suitable oil, surfactant, and cosurfactant system to find out the efficient self-emulsification system. A three factor, three level Box-Behnken statistical design was employed to explore the main and interaction effect of independent variables, namely X1 (amount of Capmul MCM), X2 (amount of Acrysol K 140), and X3 (amount of Transcutol P). Percent transmittance value (Y1), droplet diameter (Y2), and percent drug released at 5 min (Y3) were the dependent variables. Formulation optimization was carried out to optimize the droplet diameter and percent drug dissolved at 5 min. The batch prepared according to the optimized formulation showed a close agreement between observed and predicted values. Box-Behnken statistical design allowed us to understand the effect of formulation variables on the rapid dissolution of drug from SNEDDS and to optimize the formulation to obtain a rapid drug dissolution at 5 min. LAY ABSTRACT: A self-nanoemulsifying drug delivery system of glimepiride has been design, developed, and optimized. A three factor, three level Box-Behnken statistical design was employed to explore the main and interaction effect of independent variables, namely X1 (amount of Capmul MCM), X2 (amount of Acrysol K 140), and X3 (amount of Transcutol P). Percent transmittance value (Y1), droplet diameter (Y2), and percent drug released at 5 min (Y3) were the dependent variables. The Capmul MCM-Akcrysol K 140-Transcutol system was found to be the suitable ternary system that was able to release almost 80% of drug within the first 5 min. The improved dissolution of glimepiride might improve patient compliance.

Preparation and characterization of co-grinded mixtures of aceclofenac and neusilin US2 for dissolution enhancement of aceclofenac.

The present study was carried out with a view to enhance the dissolution of poorly water-soluble BCS-class II drug aceclofenac by co-grinding with novel porous carrier Neusilin US(2.) (amorphous microporous granules of magnesium aluminosilicate, Fuji Chemical Industry, Toyama, Japan). Neusilin US(2) has been used as an important pharmaceutical excipient for solubility enhancement. Co-grinding of aceclofenac with Neusilin US(2) in a ratio of 1:5 was carried out by ball milling for 20 h. Samples of co-ground mixtures were withdrawn at the end of every 5 h. and characterized for X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. The analysis revealed the conversion of crystalline aceclofenac to its amorphous form upon milling with Neusilin US(2). Further, in vitro dissolution rate of aceclofenac from co-ground mixture was significantly higher compared to pure aceclofenac. The accelerated stability study of co-ground mixture was carried out at 40 degrees C/75%RH for 4 weeks, and it showed that there was no reversion from amorphous to crystalline form. Thus, it is advantageous to use a porous carrier like Neusilin US(2) in improvement of dissolution of poorly soluble drugs.

Process optimization and characterization of poloxamer solid dispersions of a poorly water-soluble drug.

The objective of the present investigation was to improve the dissolution rate of Rofecoxib (RXB), a poorly water-soluble drug by solid dispersion technique using a water-soluble carrier, Poloxamer 188 (PXM). The melting method was used to prepare solid dispersions. A 3(2) full factorial design approach was used for optimization wherein the temperature to which the melt-drug mixture cooled (X(1) ) and the drug-to-polymer ratio (X(2) ) were selected as independent variables and the time required for 90% drug dissolution (t(90)) was selected as the dependent variable. Multiple linear regression analysis revealed that for obtaining higher dissolution of RXB from PXM solid dispersions, a low level of X(1) and a high level of X(2) were suitable. The differential scanning calorimetry and x-ray diffraction studies demonstrated that enhanced dissolution of RXB from solid dispersion might be due to a decrease in the crystallinity of RXB and PXM and dissolution of RXB in molten PXM during solid dispersion preparation. In conclusion, dissolution enhancement of RXB was obtained by preparing its solid dispersions in PXM using melting technique. The use of a factorial design approach helped in identifying the critical factors in the preparation and formulation of solid dispersion.

Formulation and optimization of piroxicam proniosomes by 3-factor, 3-level Box-Behnken design.

The aim of this study was to investigate the combined influence of 3 independent variables in the preparation of piroxicam proniosomes by the slurry method. A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation and construct contour plots to predict responses. The independent variables selected were molar ratio of Span 60:cholesterol (X(1)), surfactant loading (X(2)), and amount of drug (X(3)). Fifteen batches were prepared by the slurry method and evaluated for percentage drug entrapment (PDE) and vesicle size. The transformed values of the independent variables and the PDE (dependent variable) were subjected to multiple regression to establish a full-model second-order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full-model equation to derive a reduced-model polynomial equation to predict the PDE of proniosome-derived niosomes. Contour plots were constructed to show the effects of X(1), X(2) and X(3) on the PDE. A model was validated for accurate prediction of the PDE by performing checkpoint analysis. The computer optimization process and contour plots predicted the levels of independent variables X(1), X(2), and X(3) (0, -0.158 and -0.158 respectively), for maximized response of PDE with constraints on vesicle size. The Box-Behnken design demonstrated the role of the derived equation and contour plots in predicting the values of dependent variables for the preparation and optimization of piroxicam proniosomes.

Two-stage optimization process for formulation of chitosan microspheres.

The objective of the present study was to optimize the concentration of a chitosan solution, stirring speed, and concentration of drugs having different aqueous solubility for the formulation of chitosan microspheres. Chitosan microspheres (unloaded and drug loaded) were prepared by the chemical denaturation method and were subjected to measurement of morphology, mean particle size, particle size distribution, percentage drug entrapment (PDE), drug loading, and drug release (in vitro). Morphology of the microspheres was dependent on the level of independent process parameters. While mean particle size of unloaded microspheres was found to undergo significant change with each increase in concentration of chitosan solution, the stirring rate was found to have a significant effect only at the lower level (ie, 2000 to 3000 rpm). Of importance, spherical unloaded microspheres were also obtained with a chitosan solution of concentration less than 1 mg/mL. Segregated unloaded microspheres with particle size in the range of 7 to 15 microm and mean particle size of 12.68 microm were obtained in the batch prepared by using a chitosan solution of 2 mg/mL concentration and stirring speed of 3000 rpm. The highest drug load ( microg drug/mg microspheres) was 50.63 and 13.84 for microspheres containing 5-fluorouracil and methotrexate, respectively. While the release of 5-fluorouracil followed Higuchi's square-root model, methotrexate released more slowly with a combination of first-order kinetics and Higuchi's square-root model. The formation of chitosan microspheres is helped by the use of differential stirring. While an increase in the concentration of water-soluble drug may help to increase PDE and drug load over a large concentration range, the effect is limited in case of water-insoluble drugs.

Poly(D,L-lactide-co-glycolide) microspheres containing 5-fluorouracil: optimization of process parameters.

The objective of this research was to optimize the processing parameters for poly(D,L-lactide-co-glycolide) (PLGA) microspheres of 5-fluorouracil (5-FU) and to mathematically relate the process parameters and properties of microspheres. Microspheres were prepared by a water-in-oil-in-water emulsion solvent evaporation technique. A 3(2) factorial design was employed to study the effect of the volume of the internal phase of the primary emulsion and the volume of the external phase of the secondary emulsion on yield, particle size, and encapsulation efficiency of microspheres. An increase in the volume of the internal phase of the primary emulsion resulted in a decrease in yield and encapsulation efficiency and an increase in particle size of microspheres. When the volume of the external phase of the secondary emulsion was increased, a decrease in yield, particle size, and encapsulation efficiency was observed. Microspheres with good batch-to-batch reproducibility could be produced. Scanning electron microscopic study indicated that microspheres existed as aggregates.