Formulation,optimization, hemocompatibility and pharmacokinetic evaluation of PLGA nanoparticles containing paclitaxel

Objective: Paclitaxel (PTX)-loaded polymer (Poly(lactic-co-glycolic acid), PLGA)-based nanoformulation was developed with the objective of formulating cremophor EL-free nanoformulation intended for intravenous use.

Significance: The polymeric PTX nanoparticles free from the cremophor EL will help in eliminating the shortcomings of the existing delivery system as cremophor EL causes serious allergic reactions to the subjects after intravenous use.

Methods and results: Paclitaxel-loaded nanoparticles were formulated by nanoprecipitation method. The diminutive nanoparticles (143.2?nm) with uniform size throughout (polydispersity index, 0.115) and high entrapment efficiency (95.34%) were obtained by employing the Box–Behnken design for the optimization of the formulation with the aid of desirability approach-based numerical optimization technique. Optimized levels for each factor viz. polymer concentration (X1), amount of organic solvent (X2), and surfactant concentration (X3) were 0.23%, 5?ml %, and 1.13%, respectively. The results of the hemocompatibility studies confirmed the safety of PLGA-based nanoparticles for intravenous administration. Pharmacokinetic evaluations confirmed the longer retention of PTX in systemic circulation.

Conclusion: In a nutshell, the developed polymeric nanoparticle formulation of PTX precludes the inadequacy of existing PTX formulation and can be considered as superior alternative carrier system of the same.     

Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization,in vitro,in situ and in vivo evaluation

Context: Nanosuspensions (NSs) of poorly water-soluble drugs are known to increase the oral bioavailability.

Objectives: The purpose of this study was to develop NS of efavirenz (EFV) and to investigate its potential in enhancing the oral bioavailability of EFV.

Materials and methods: EFV NS was prepared using the media milling technique. The Box–Behnken design was used for optimization of the factors affecting EFV NS. Sodium lauryl sulfate and PVP K30 were used to stabilize the NS. Freeze-dried NS was completely re-dispersed with double-distilled filtered water.

Results: Mean particle size and zeta potential of the optimized NS were found to be 320.4?±?3.62?nm and –32.8?±?0.4 mV, respectively. X-ray diffraction and differential scanning calorimetric analysis indicated no phase transitions. Rate and extent of drug dissolution in the dissolution medium for NS was significantly higher compared to marketed formulation. The parallel artificial membrane permeability assay revealed that NS successfully enhanced the permeation of EFV. Results of in situ absorption studies showed a significant difference in absorption parameters such as K_a, t_1/2 and uptake percentages between lyophilized NS and marketed formulation of EFV. Oral bioavailability of EFV in rabbits resulting from NS was increased by 2.19-fold compared to the marketed formulation.

Conclusion: Thus, it can be concluded that NS formulation of EFV can provide improved oral bioavailability due to enhanced solubility, dissolution velocity, permeability and hence absorption.     

Implementation of two different experimental designs for screening and optimization of process parameters for metformin-loaded carboxymethyl chitosan formulation

Abstract

Metformin (MET) was effectively encapsulated into O-carboxymethyl chitosan (O-CMC) polymeric formulation using an experimental design method. Six factors Plackett–Burman (PB) design was utilized to find the significant process parameters. Linear equations used to study the effect of each process parameters on particle size (PS), encapsulation efficiency (EE), and zeta potential (ZP) and the most influential three factors decided for further optimization. Optimization was carried out by implementing three-factor three-level Box–Behnken (BB) design. Mathematical models were generated by regression analysis for responses of PS, EE, and ZP. Two-step experimental design took into account for the preparation of optimized formulation with maximum %EE (72.78?±?9.7%) and minimum PS (225.67?±?5.53?nm) at optimum process conditions with a ZP of –5.22?mV for the nano-polymeric formulation in an economical matter by reduction chemical use and formulation time. Furthermore, the biological activity of the final formulation was determined by in vitro cytotoxicity study compared to free MET. The cytotoxicity result reveals that both pure drug and nano-formulation biocompatible with MCF10A non-tumorigenic cell line and lethal for the MCF7 cell line. These in vitro results were the first helpful step to further investigate O-CMC loaded MET nanoparticles in diagnostic and therapeutic applications of breast cancer.     

Nanosized nasal emulgel of resveratrol: preparation,optimization, in vitro evaluation and in vivo pharmacokinetic study

Abstract

Nano-emulgel has become one of the most significant controlled release systems, which has the advantages of both gels and nano-emulsions. This work aims at the formulation of nasal nano-emulgel for resveratrol, employing carbopol 934 and poloxamer 407 as the gelling agents. The optimum nano-emulsion was determined through further characterization of the selected system. The nasal nano-emulgel was prepared and tested for the in vitro release, the release kinetics, FTIR, ex vivo permeation, nasal mucosa toxicity, and in vivo pharmacokinetic study. The optimum nano-emulsion consisted of Tween 20, Capryol 90, and Transcutol at a ratio of (54.26: 23.81: 21.93%v/v), and it exhibited transmittance of 100%, resveratrol solubility of 159.9?±?6.4?mg/mL, globule size of 30.65?nm. The in vitro resveratrol released from nano-emulsion and nasal nano-emulgel was 96.17?±?4.43% and 78.53?±?4.7%, respectively. Ex vivo permeation was sustained during 12?h up to 63.95?±?4.7%. The histopathological study demonstrated that the formula is safe and tolerable to the nasal mucosa. C_max and AUC _(0–∞) of resveratrol obtained after nasal administration of nasal nano-emulgel was 2.23 and 8.05 times, respectively. Similarly, T_max was increased up to 3.67?±?0.82?h. The optimized nasal nano-emulgel established intranasal safety and bioavailability enhancement so it is considered as a well-designed system to target the brain.     

Design and evaluation of mucoadhesive microemulsion for neuroprotective effect of ibuprofen following intranasal route in the MPTP mice model

Background: The present study is to investigate the neuroprotective effect of ibuprofen by intranasal administration of mucoadhesive microemulsion (MMEI) against inflammation-mediated by dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease (PD).

Methods: Ibuprofen-loaded polycarbophil-based MMEI was developed by using response surface methodology (RSM). Ibuprofen with dose of 2.86 mg/kg/day was administered intranasally to male C57BL/6 mice for two consecutive weeks which were pre-treated with four intraperitoneal injections of MPTP (20?mg/kg of body weight) at 2?h intervals. Immunohistochemistry was performed.

Results: Optimal MMEI was stable and non-ciliotoxic with 66.29?±?4.15?nm as average globule size and??20.9?±?3.98?mV as zeta potential. PDI value and transmission electron microscopy result showed the narrow globule size distribution of MMEI. The result showed that all three independent variables had a significant effect (p?<?0.05) on the responses. Rota-rod and open-field test findings revealed the significant improvement in motor performance and gross behavioral activity of the mice. The results from in vivo study and immunohistochemistry showed that nasal administration of Ibuprofen significantly reduced the MPTP-mediated dopamine depletion. Furthermore TH neurons count in the substantia nigra and the density of striatal dopaminergic nerve terminals were found to be significant higher for ibuprofen treated groups.

Conclusion: Findings of the investigation revealed that Ibuprofen through developed MMEI was shown to protect neurons against MPTP-induced injury in the Substantia nigra pars compacta (SNpc) and striatum and hence, could be a promising approach for brain targeting of Ibuprofen through intranasal route to treat PD.     

Preparation and optimization of a novel microbead formulation to improve solubility and stability of curcumin

Curcumin is an active ingredient which is poorly water-soluble, leading to a low oral bioavailability. The aim of this research was to prepare a novel microbead formulation, and to solubilize, solidify, and improve storage stability of curcumin. Firstly, curcumin was solubilized with Kolliphor^TM RH40 and then microencapsulated by cross linking of sodium alginate with calcium chloride. A three-factor, three-level Box–Behnken design was employed to acquire the optimum microbead formulation, namely the best entrapment efficiency and in vitro curcumin release. The independent variables were sodium alginate concentration, calcium chloride concentration, and the weight of curcumin solution, while the dependent variables were entrapment efficiency and in vitro curcumin release. The optimized microbead formulation was 2.06% sodium alginate, 24.33% calcium chloride, and 1.28 g curcumin solution (containing curcumin and RH40 with a ratio of 1:22, g/g). Results showed that high concentrations of sodium alginate and calcium chloride could increase the entrapment efficiency. In vitro curcumin release decreased with increasing of sodium alginate as well as decreasing of calcium chloride. In conclusion, the optimum microbead formulation increased the solubility of curcumin and enhanced its stability, and achieved a high entrapment efficiency and in vitro curcumin release.     

7-Ethyl-10-hydroxycamptothecin proliposomes with a novel preparation method: optimized formulation,characterization and in-vivo evaluation

Context:?The proliposomes were used to solve the stability of the ordinary liposomes. Objective: 7-ethyl-10-hydroxycamptothecin (SN-38) proliposomes for intravenous (i.v.) administration were prepared successfully by a new method.

Materials and methods:?SN-38 liposomes solution was reconstituting automatically from proliposomes on contact with the acetic acid buffer solution (0.2 M, pH 2.6). The formulation was optimized by the Box–Behnken design. The physicochemical characteristics of the SN-38 proliposomes were studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The stability studies were also carried on. The FLU–HPLC system was served to study the concentration of SN-38 in the plasma of Sprague Dawley (SD) rats.

Results:?The optimized formulation was SN-38: 0.03 g; Soybean phospholipid (SP): 0.6 g; dextrose: 3.00 g. The entrapment efficiency of the optimized formulation was >85% and the mean particle size was about 231 nm. The stability studies showed that SN-38 proliposomes were stable in dark at 20–25°C for 6 months at least. The pharmacokinetic parameters of i.v. administration demonstrated that the half-life of SN-38 loaded in the liposomes was prolonged in vivo.

Discussion and conclusion:?The SN-38 proliposomes was prepared successful by the analysis of TEM, SEM, DSC and XRD, and SN-38 liposomes could be reconstituted on contact with the hydration medium. SN-38 liposomes circulated for a longer time in the blood circulating system than SN-38 solution, which contributed to maintaining the drug action.     

Process,optimization, and characterization of budesonide-loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease

The major challenge involved in the treatment of inflammatory bowel disease is targeted delivery of the drug at the site of inflammation. As nanoparticles possess the ability to accumulate at the site of inflammation, present investigation aims at development of Budesonide-loaded nanostructured lipid carrier systems (BDS-NLCs) for the treatment of inflammatory bowel disease. BDS-NLCs were prepared by employing a high pressure homogenization technique. Various preliminary trials were performed for optimization of the NLCs in which different processes, as well as formulation parameters, were studied. The BDS-NLCs was optimized statistically by applying a 3-factor/3-level Box–Behnken design. Drug concentration, surfactant concentration, and emulsifier concentration were selected as independent variables, and % entrapment efficiency and particle size were selected as dependent variables. The best batch comprises of 10%, 7%, and 20% w/w concentration of drug, surfactant, and emulsifier, respectively, with % entrapment efficiency of 92.66?±?3.42% and particle size of 284.0?±?4.53?nm. Further, in order to achieve effective delivery of nanoparticulate system to colonic region, the developed BDS-NLCs were encapsulated in Eudragit^® S100-coated pellets. The drug release studies of pellets depict intactness of BDS-NLCs during palletization process, with f₂ value of 75.879. The in vitro evaluation of enteric-coated pellets revealed that a coating level of 15% weight gain is needed in order to impart lag time of 5?h (transit time to reach colon). The results of the study demonstrate that the developed BDS-NLCs could be used as a promising tool for the treatment of inflammatory bowel disease.     

Design,characterization, and evaluation of intranasal delivery of ropinirole-loaded mucoadhesive nanoparticles for brain targeting

Context: Parkinson disease (PD) is a common, progressive neurodegenerative disorder, characterized by marked depletion of striatal dopamine and degeneration of dopaminergic neurons in the substantia nigra.

Objective: The purpose of the present study was to investigate the possibility of targeting an anti-Parkinson’s drug ropinirole (RH) to the brain using polymeric nanoparticles.

Materials and methods: Ropinirole hydrochloride (RH)-loaded chitosan nanoparticles (CSNPs) were prepared by an ionic gelation method. The RH-CSNPs were characterized for particle size, polydispersity index (PDI), zeta potential, loading capacity, entrapment efficiency in vitro release study, and in vivo distribution after intranasal administration.

Results and discussion: The RH-CSNPs showed sustained release profiles for up to 18?h. The RH concentrations (% Radioactivity/g) in the brain following intranasal administration (i.n.) of RH-CSNPs were found to be significantly higher at all the time points compared with RH solution. The concentration of RH was highest in the liver (7.210?±?0.52), followed by kidneys (6.862?±?0.62), intestine (4.862?±?0.45), and lungs (4.640?±?0.92) in rats following i.n. administration of RH-CSNPs. Gamma scintigraphy imaging in rats was performed to ascertain the localization of drug in the brain following intranasal administration of formulations. The brain/blood ratios obtained (0.251?±?0.09 and 0.386?±?0.57 of RH (i.n.) and RH-CSNPs (i.n.), respectively) at 0.5?h are indicative of direct nose to brain transport, bypassing the blood–brain barrier (BBB).

Conclusion: The novel formulation showed the superiority of nose to brain delivery of RH using mucoadhesive nanoparticles compared with other delivery routes reported earlier.     

Formulation,optimization, and characterization of rifampicin-loaded solid lipid nanoparticles for the treatment of tuberculosis

Abstract

Mycobacterium tuberculosis, being the causative infectious agent, is the leading cause of death worldwide amongst the infectious disease. The low bioavailability of rifampicin (RIF), one of the vital constituent of antitubercular therapy, instigates an urge to develop nanocarrier, which can prevent its degradation in the acidic pH of the stomach. Solid lipid nanoparticles (SLNs) have been proven to be promising versatile platform for oral delivery of lipophilic drugs. Therefore, the current investigation demonstrates development of RIF-loaded solid lipid nanoparticles (RIF-SLNs) using high-pressure homogenization technique by employing a three-level, three-factor Box–Behnken design. Concentration of drug, concentration of emulsifier, and homogenization pressure were selected as an independent variables, and %drug loading (%DL), %entrapment efficiency (%EE), and particle size were selected as dependent variables. The developed RIF-SLNs were characterized for particle size, polydispersity index, zeta potential, %EE, %DL, differential scanning calorimetry, X-ray diffraction, and TEM analysis. The mean diameter of RIF-SLNs was found to be 456?±?11?nm, %EE of 84.12?±?2.78%, and %DL of 15.68?±?1.52%. The in vitro lipolysis experiments revealed that RIF-SLNs stabilized using poloxamer 188, exhibited antilipolytic effect. Furthermore, the in vitro GI stability studies (at pH 1.2, pH 4.5, pH 6.8, and pH 7.4) revealed that the developed system could withstand various gastrointestinal tract media. The in vitro dissolution studies depicted biphasic drug release profile for drug-loaded SLNs revealing best fit with Weibull model. The accelerated stability studies for 6?months does not revealed any significant change in characteristics of developed RIF-SLNs.     

Chitosan nanoparticles for the oral delivery of tenofovir disoproxil fumarate: formulation optimization,characterization and ex vivo and in vivo evaluation for uptake mechanism in rats

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption.

Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption.

Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles.

Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156?±?5?nm with an entrapment efficiency of 48.2?±?1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir.

Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways.     

SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation,optimization and efficacy evaluation

One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle (NP) core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to NPs prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol^®F127 in order to maximize SN-38 loading and obtain NPs with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank NPs. Increased in vitro efficacy of drug-loaded NPs compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4?h.     

Chitosan based mucoadhesive nanoparticles of ketoconazole for bioavailability enhancement: formulation,optimization, in vitro and ex vivo evaluation

Purpose: The conventional dosage form of Ketoconazole (KZ) shows poor absorption due to rapid gastric emptying. Chitosan based mucoadhesive nanoparticles (NPs) of KZ were developed to efficiently release drug at its absorption window i.e. stomach and the site of action i.e. esophagus.

Method: The NPs were prepared by ionic gelation method. Concentration of polymer, cross-linking agent and ratio of drug/polymer as well as polymer/cross linking agent were optimized.

Results: NPs had 69.16?±?5.91% mucin binding efficiency, particle size of 382.6?±?2.384?nm, ζ potential of +48.1?mv and entrapment efficiency of 59.84 ± 1.088%. DSC thermogram indicated absence of any drug polymer interaction. The drug release was by controlled, non-fickian diffusion mechanism. Ex vivo diffusion studies were performed by emptying the stomach contents after 2?h to simulate in vivo gastric emptying. The results showed that drug diffusion from the solution across stomach mucosa stopped after emptying whereas that from the NPs continued upto 5?h. Hence we could conclude that the NPs must have adhered to the stomach mucosa and thereby would have been retained at this absorption site even after gastric emptying.

Conclusion: The orally delivered KZ loaded mucoadhesive NPs can be used as an efficient carrier for delivering drug at its absorption window i.e. the stomach and the site of action i.e. esophagus even after gastric emptying.     

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization,in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² factorial design was done using Polyox WSR 303 (X₁) and HPMC K₄M (X₂) as independent variables and cumulative percentage drug released at 6?h (Q6h) as dependent variable.

Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12?h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6?h. In vivo pharmacokinetic studies in rabbits showed C_max of 189.96?±?13.04?ng/mL and T_max of 4?±?0.35?h for GFDDS. The difference for AUC_(0–T) and AUC_(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC_(0–T) and AUC_(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

Cubosomal based oral tablet for controlled drug delivery of telmisartan: formulation,in-vitro evaluation and in-vivo comparative pharmacokinetic study in rabbits

A nanoparticulate system; cubosomes has been suggested to support the controlled release of Telmisartan (TEL), a poorly water-soluble medication. Four distinctive formulae were selected according to the results of three estimated responses. The liquid cubosomes were successfully adsorbed onto Aerosil 380 to form granules. The formulae were evaluated for their flow properties. The best granules were compressed into tablets suitable for oral administration. The tablets were evaluated for its performance. The in vivo study of the best selected cubosomal tablets was checked after oral administration in the blood of albino rabbits utilizing an HPLC method. Results revealed that the highest EE was shown in formulae C5 (59.68?±?1.3). All the prepared formulae had particle size less than 500?nm with PDI < 0.5 and the highest zeta potential results were observed in C5, C7, C9, C11 and C12 (>30?mv). A7 and A9 prepared using Aerosil 380 showed a perfect flowability. After 1?h of dissolution testing, the commercial product showed a 66% drug release while the release of all cubosomal formulae didn’t exceed 35% during the first hour reaching a 85% of the drug released at the end of 24?h. A7 was selected for the in vivo study; T_max of TEL absorption is increased for cubosomal formula by three folds indicating sustained release pattern. The relative bioavailability is also increased by 2.6 fold. The investigation proposed the rationality of cubosome to figure an effective controlled release tablets to improve its bioavailability and expand its activity.     

Chitosan-TPP nanoparticles stabilized by poloxamer for controlling the release and enhancing the bioavailability of doxazosin mesylate: in vitro,and in vivo evaluation

Objective: Control the release and enhance the bioavailability of chitosan-doxazosin mesylate nanoparticles (DM-NPs).

Significance: Improve DM bioavailability for the treatment of benign prostatic hyperplasia and hypertension.

Methods: Plackett–Burman design was utilized to screen the variables affecting the quality of DM-NPs prepared by ionic gelation method. The investigated variables were initial drug load (X₁), chitosan percentage (X₂), tripolyphosphate sodium (TPP) percentage (X₃), poloxamer percentage (X₄), homogenization speed (X₅), homogenization time (X₆) and TPP addition rate (X₇). The prepared DM-loaded NPs have been fully evaluated for particle size (Y₁), Zeta potential (Y₂), production yield (Y₃), entrapment efficiency (Y₄), loading capacity (Y₅), initial burst (Y₆), and cumulative drug release (Y₇). Finally, DM pharmacokinetic has been investigated on healthy albino male rabbits by means of non-compartmental analysis.

Results: The combination of variables showed variability of Y₁, Y₂, and Y₃ equal to 122–710?nm, 3.49–23.63?mV, and 47.31–92.96%, respectively. While Y₄ and Y₅, reached 99.87%, and 8.53%, respectively. The prepared NPs revealed that X₂, X₃, and X₄ are the variables that play the important role in controlling the release behavior of DM from the NPs. The in vivo pharmacokinetic results indicated the enhancement in bioavailability of DM by 7 folds compared to drug suspension and the mean residence time prolonged to 23.72?h compared to 4.7?h of drug suspension.

Conclusion: The study proved that controlling the release of DM from NPs enhance its bioavailability and improve the compliance of patients with hypertension or benign prostatic hyperplasia.     

Non-ionic surfactant based vesicular drug delivery system for topical delivery of caffeine for treatment of cellulite: design,formulation, characterization,histological anti-cellulite activity,and pharmacokinetic evaluation

Cellulite is a common topographical alteration where skin acquires an orange peel or mattress appearance with alterations in adipose tissue and microcirculation. This work aims to develop and evaluate a topical niosomal gel formulae with good permeation to reach the subcutaneous fat layer. Several caffeine niosomal dispersions were prepared and incorporated into gel formulae using Carbopol 940 polymer, chemical penetration enhancers, and iontophoresis, then the prepared gels were applied onto the skin of rats and anticellulite activity of caffeine from the prepared gels compared to that of the commercial product Cellu Destock^® was evaluated by histological study of the skin and measurement of plasma level of caffeine passing through the skin using liquid chromatography (LC/MS–MS). Results of histology revealed reduction of size and thickness of fatty layer of rat skin in the following order: FVII?>?FXIV?>?Cellu Destock^®?>?FVII?+?Iontophoresis?>?FXIV?+?Iontophoresis. Pharmacokinetic results of caffeine in plasma revealed that C_max, T_max, and AUC_0–12h decreased in the following order: FXIV?>?FVII?>?Cellu Destock^®. These results conclude that incorporation of caffeine niosomal dispersion into gel matrix with penetration enhancers and iontophoresis resulted in improvement in penetration of caffeine through the skin into the underlying fatty layer in treatment of cellulite.     

Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design,in vitro and in vivo evaluation

The prevalence of hyperuricemia is relatively high worldwide, and a great number of patients are suffering from its complications. 6-shogaol, an alkylphenol compound purified from the root of ginger (Zingiber officinale Roscoe), has been proved to possess diverse pharmacological activities. However, its poor aqueous solubility usually leads to low bioavailability, and further clinical applications will be greatly discounted. The current study aimed to formulate a 6-shogaol-loaded-Self Microemulsifying Drug Delivery System (SMEDDS) to amend low aqueous solubility and bioavailability orally, as well as, potentiate the hyperuricemic activity of the 6-shogaol. SMEDDS was developed with central composite design established on a two system components viz., 18.62% W/W ethyl oleate (oil phase) and ratio of tween 80 (surfactant) to PEG 400 (co-surfactant) (1.73:1, W/W). Based on quadratic model, the navigation of the design space could generate spherically-shaped and homogenous droplets with respective mean particle diameter, polydispersity and of 20.00?±?0.26?nm and 0.18?±?0.02. The 6-shogaol-SMEDDS showed significant elevation of cumulative release compared with the free 6-shogaol and more importantly a 571.18% increment in the relative oral bioavailability of the drug. The predominant accumulation of 6-shogaol-SMEDDS in the liver suggested hepatic-targeting potentiality of the drug. Oral administration of 6-shogaol-SMEDDS in hyperuricemic rats also significantly decreased uric acid level and xanthine oxidase activity. Histological studies confirmed formulation groups indeed could provide better protection of kidney than free drug groups. Collectively, these findings indicated that the SMEDDS hold much promise in enhancing the oral delivery and therapeutic efficacy of 6-shogaol.