Naringin nano-ethosomal novel sunscreen creams: Development and performance evaluation.

Long term exposure of skin to UV rays produces detrimental effects such as premature skin-ageing and skin cancer. Although, zinc oxide (ZnO) and titanium dioxide (TiO2) are good sunscreen agents, they do not provide highly efficient UV radiation protection and antioxidant and anti-aging effects. The present study was aimed at developing and characterizing ethosomes loaded with naringin and then to incorporate them into sunscreen creams containing nano-ZnO and -TiO2 to achieve adequate skin penetration and skin retention so as to scavenge the free radicals by virtue of naringin's antioxidant property. Ethosomes were prepared and optimized with respect to concentrations of ethanol and cholesterol, time of sonication, drug and lipid ratio and amount of drug. The ethosomes were evaluated for size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency and surface morphology. Ethosomal sunscreen creams were evaluated for physicochemical tests, spreadability, antioxidant, cytotoxicity and skin permeation studies. Optimized ethosomal formulation exhibited average vesicle size, PDI, ZP and drug encapsulation efficiency of 142.5 ± 5.6 nm, 0.199 ± 0.007, -72.5 ± 2.9 mV and 33.79 ± 1.35%, respectively. Naringin ethosomes showed enhanced retention in the skin (403.44 ± 15.33 µg/cm2) compared to naringin suspension (202.81 ± 9.45 µg/cm2). The optimized sunscreen cream exhibited SPF of 21.21 ± 0.62 with negligible permeation of naringin across the skin. Ethosomes showed pronounced skin permeation for naringin and optimized cream containing naringin ethosomes along with nano- ZnO and TiO2 showed good skin retention for naringin.

Surface engineered nanoliposomal platform for selective lymphatic uptake of asenapine maleate: In vitro and in vivo studies.

Asenapine maleate (ASPM) is an antipsychotic drug prescribed for the treatment of schizophrenia and bipolar disorder. ASPM possesses low oral bioavailability due to extensive hepatic metabolism. Therefore, RGD peptide conjugated liposomes loaded with ASPM were prepared to target Peyer's patches in the intestine which in-turn get access into intestinal lymphatic system thereby increasing the oral bioavailability of the drug. Liposomes were evaluated for size, zeta potential, differential scanning calorimetry (DSC), FTIR spectroscopy, X-ray diffraction (XRD), shape and morphology, in vitro drug release, cell line studies, everted intestinal uptake, pharmacodynamics, pharmacokinetics, tissue distribution, targetability and stability studies. In vitro drug release study showed the sustained release of drug from the formulations. Optimized liposomes (size <110 nm) showed greater permeability across the Caco2 + Raji B co-culture model in vitro and everted rat ileum ex vivo. Liposomes showed increase in bioavailability and high efficacy in reducing the L-DOPA-carbidopa induced locomotor count compared to plain drug. Liposomes also showed high concentration of drug in the brain after their oral administration. Imaging studies showed that RGD peptide conjugated liposomes were successful in targeting the Peyer's patches, both in vivo and ex vivo. The study successfully demonstrated the improved pharmacokinetics and efficacy profile of ASPM by using a ligand conjugated targeted liposomal system.

Asenapine maleate-loaded nanostructured lipid carriers: optimization and in vitro, ex vivo and in vivo evaluations.

AIM: To prepare nanostructured lipid carriers (NLCs) loaded with asenapine maleate (ASPM) to increase its oral bioavailability by intestinal lymphatic uptake. MATERIALS & METHODS: ASPM-NLCs were prepared by ultrasound dispersion technique, by adopting Design of Experiment approach, and characterized. RESULTS: The optimized formulation exhibited good physicochemical parameters. Differential scanning calorimetry and x-ray diffraction studies indicated the amorphized nature of ASPM in lipid matrix. In vitro drug release study indicated the sustained release of drug from NLCs. ASPM-NLCs showed greater permeability across Caco2 cells and everted rat ileum. ASPM-NLCs showed greater cellular uptake, superior preclinical oral bioavailability and higher efficacy in reducing the L-DOPA-carbidopa-induced locomotor count compared with plain drug. CONCLUSION: ASPM-NLCs were successfully developed that showed enhanced performance both in vitro and in vivo.

Long circulating PEGylated-chitosan nanoparticles of rosuvastatin calcium: Development and in vitro and in vivo evaluations.

The aim of this study was to improve the pharmacokinetics and pharmacodynamics profile of rosuvastatin calcium by formulating long-circulating PEGylated chitosan nanoparticles (NPs). Chitosan was PEGylated by a carbodiimide mediated reaction, using a carboxylic acid derivative of PEG (polyethylene glycol). The NPs were optimised for particle size, polydispersity index, zeta potential and drug entrapment efficiency. In vitro drug release, pharmacokinetic and pharmacodynamics studies of the optimized nanoparticles were performed. PEGylation of chitosan was confirmed by FTIR analysis. Drug-excipient compatibility was studied by differential scanning calorimetry and FTIR analyses. Two batches of nanoparticles were optimized with particle size of <200nm and entrapment efficiency of ≈14%. In vitro drug release studies revealed cumulative release of 14.07±0.57% and 22.02±0.81% of rosuvastatin over the period of 120h, indicating appreciable sustained release of drug. TEM analysis showed the spherical structure of nanoparticles. Pharmacokinetic studies indicated that optimized NPs showed prolonged drug release over a period of 72h. Pharmacodynamics studies in hyperlipidemic rat model demonstrated greater lipid-lowering capability of rosuvastatin nanoparticles in comparison with plain rosuvastatin. The nanoparticles demonstrated substantial prolonged delivery of the drug in vivo along with better therapeutic action, which could be potential drug delivery modality for 'statins'.

Sunscreen creams containing naringenin nanoparticles: Formulation development and in vitro and in vivo evaluations.

BACKGROUND: The aim of this study was to develop sunscreen creams containing polymeric nanoparticles (NPs) of naringenin for photoprotective and antioxidant effects. METHODS: Polymeric NPs of naringenin were prepared and optimized. The NPs were incorporated into sunscreen creams and evaluated for in vitro and in vivo skin retention. RESULTS: The optimized naringenin NPs showed a size of 131.2 nm, zeta potential -25.4 mV, and entrapment efficiency 32.45%. The absence of drug-excipient interaction was confirmed by Fourier transform infrared spectroscopy and differential scanning calorimetry. X-Ray diffraction analysis demonstrated the amorphization of naringenin in nanoparticles. Transmission electron microscopy showed the sphericity of the NPs with the size of <200 nm. Cytotoxicity assessment in HaCaT cells indicated non-toxic nature of naringenin NPs. In vitro skin permeation studies demonstrated that higher amount of naringenin permeated at the end of 12 hours (Q12 hours  = 184.03 ± 3.37 µg/cm2 ) and deposited in the skin (10.38 ± 0.48 µg/cm2 ) from NPs as compared to plain naringenin. Sunscreen creams (SC1-SC5) containing plain naringenin or NPs with/without nano-zinc oxide and nano-titanium dioxide were prepared and evaluated. Optimized cream (SC5) containing naringenin NPs showed highest SPF value and enhanced skin retention of naringenin in comparison with NPs in suspension form and other cream formulations. CONCLUSION: Optimized nanoparticulate sunscreen cream exhibited highest skin retention and negligible skin permeation of naringenin besides showing excellent SPF value.

Preclinical pharmacokinetics and biodistribution studies of asenapine maleate using novel and sensitive RP-HPLC method.

AIM: Asenapine maleate (ASPM) is a newer antipsychotic drug available as a sublingual tablet in the market. EXPERIMENTAL: To investigate the pharmacokinetic and tissue distribution study of ASPM following oral administration in rats, reversed-phase HPLC method was developed and validated. RESULTS: ASPM was extracted from plasma and tissue matrix by liquid-liquid extraction technique and analyzed using mobile phase consisted of phosphate buffer pH 3.0 and acetonitrile (65:35% v/v). The method showed good linearity (10-500 ng/ml) with recovery 83-102%. In pharmacokinetics study, half-life was 32.74 ± 7.51 h due to slow elimination of drug. The biodistribution study indicated preferential distribution of ASPM to highly perfused organs. CONCLUSION: The current method can be successfully applied for estimating the drug in various biological matrices.

Development and Validation of a Stability-Indicating RP-HPLC Method by a Statistical Optimization Process for the Quantification of Asenapine Maleate in Lipidic Nanoformulations.

A stability-indicating RP-HPLC method was developed for quantification of asenapine maleate (ASPM) in lipid nanoformulations. The proposed method was used to assess intrinsic stability of ASPM by conducting force degradation study. The results indicated no considerable degradation of ASPM on subjecting it to hydrolytic, oxidative, thermal and photolytic stresses. The method was validated according to ICH Q2(R1) guidelines by employing Full factorial design using Design-Expert(®) software. ASPM was precisely and accurately quantified in nanoparticles by separating it on Hyperclone BDS C18 using 80-20% v/v mixture of potassium phosphate solution containing 0.1% v/v triethylamine and acetonitrile. The effect of flow rate, pH, acetonitrile content and column temperature was assessed on method responses. The current method was linear in the range of 0.1-20 µg/mL with limit of detection (LOD) and limit of quantification (LOQ) of 29 and 89 ng/mL, respectively. The method was precise and accurate in the determination of ASPM with peak area RSD and recovery of <1.0% and 97-101% in bulk drug solution and of <1.0% and 92-104% in nanoformulations, respectively. Analysis of variance indicated the significance (P < 0.0001) of a statistical model in validating the method with respect to change in independent chromatographic factors. The developed method was successfully employed in determining ASPM content in bulk and lipid nanoformulations.

Development of fast dissolving oral films containing lercanidipine HCl nanoparticles in semicrystalline polymeric matrix for enhanced dissolution and ex vivo permeation.

Lercanidipine is a vasoselective dihydropyridine calcium antagonist, mainly used for the treatment of hypertension and angina pectoris. However, it suffers from food dependent absorption, poor solubility, low permeability and considerable first pass metabolism, resulting in highly variable and low bioavailability of 10%. Nanoparticles of lercanidipine were incorporated in fast dissolving oral films (FDO) via preparation of nanosuspension by evaporative antisolvent precipitation method. Prepared nanosuspensions were incorporated in FDO without lyophilizing or spray drying. Two nanosuspensions containing PEG 400 and TPGS 1000 as stabilizers, were selected further for incorporation in FDO. Physicochemical and mechanical properties of the optimized films were observed to be within acceptance criteria. SEM images as well as FTIR chemical images of oral films show uniform distribution of nanoparticles in polymeric matrix. The DSC and XRD results proved the poorly crystalline nature of lercanidipine. However thermal processing of film induces crystallinity in hypromellose which results in embedding of amorphous drug nanoparticles in semicrystalline polymeric matrix. Superior dissolution and permeability properties of nanoparticles were confirmed by in vitro dissolution studies and about 4.5-folds higher ex vivo drug permeation was observed from formulation through porcine buccal mucosa. This may give the clue for enhancement of bioavailability in vivo via improving orotransmucosal absorption.

Development and performance evaluation of novel nanoparticles of a grafted copolymer loaded with curcumin.

Inflammatory bowel disease (IBD) is an inflammatory condition with mucosal ulceration, edema and hemorrhage of gastrointestinal tract. Curcumin has been shown to mitigate colitis in animal models. However, its usefulness is reduced due to poor pharmacokinetic behavior and low oral bioavailability. To address this, novel pH-sensitive hydrolyzed polyacrylamide-grafted-xanthan gum (PAAm-g-XG) nanoparticles (NPs) loaded with curcumin were prepared for colonic delivery. Optimized nanoparticles (CN20) were spherical, with an average size of 425 nm. A negligible amount of curcumin (≈8%) was released from CN20 NPs in pH 1.2 and 4.5 solutions. When the pH was increased to 7.2, curcumin release was comparatively faster than that observed with pH 1.2 and 4.5 collectively. In pH 6.8 solution, excellent release of curcumin was observed. Highest curcumin release was observed when rat caecal contents were incorporated in pH 6.8 solution, indicating microflora-dependent drug release property of NPs. In acetic acid-induced IBD in rats, curcumin NPs reduced myeloperoxidase and nitrite levels, prevented weight loss and attenuated colonic inflammation. Curcumin was better absorbed systemically in nanoparticulate form with increased Cmax (∼3 fold) and AUC (∼2.5 fold) than when delivered as free curcumin. We demonstrate successful development of grafted co-polymeric NPs containing drug suitable for colon targeting.

Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations.

CONTEXT: Asenapine maleate (ASPM) is an antipsychotic drug for the treatment of schizophrenia and bipolar disorder. Extensive metabolism makes the oral route inconvenient for ASPM. OBJECTIVE: The objective of this study is to increase ASPM bioavailability via transdermal route by improving the skin permeation using combined strategy of chemical and nano-carrier (transfersomal) based approaches. MATERIALS AND METHODS: Transfersomes were prepared by the thin film hydration method using soy-phosphatidylcholine (SPC) and sodium deoxycholate (SDC). Transfersomes were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, and in vitro skin permeation studies. Various chemical enhancers were screened for skin permeation enhancement of ASPM. Optimized transfersomes were incorporated into a gel base containing suitable chemical enhancer for efficient transdermal delivery. In vivo pharmacokinetic study was performed in rats to assess bioavailability by transdermal route against oral administration. RESULTS AND DISCUSSION: Optimized transfersomes with drug:SPC:SDC weight ratio of 5:75:10 were spherical with an average size of 126.0 nm, PDI of 0.232, ZP of -43.7 mV, and entrapment efficiency of 54.96%. Ethanol (20% v/v) showed greater skin permeation enhancement. The cumulative amount of ASPM permeated after 24 h (Q24) by individual effect of ethanol and transfersome, and in combination was found to be 160.0, 132.9, and 309.3 µg, respectively, indicating beneficial synergistic effect of combined approach. In vivo pharmacokinetic study revealed significant (p < 0.05) increase in bioavailability upon transdermal application compared with oral route. CONCLUSION: Dual strategy of permeation enhancement was successful in increasing the transdermal permeation and bioavailability of ASPM.

Full factorial design for optimization, development and validation of HPLC method to determine valsartan in nanoparticles.

High performance liquid chromatographic method was optimized, developed and validated as per the ICH guidelines. In this study the 20 mM ammonium formate and acetonitrile in the 57:43 ratio were used as mobile phase for the analysis of valsartan. Full factorial design was used to optimize the effect of variable factors. The responses were peak area, tailing factor and number of theoretical plates. The quadratic effect of flow rate and wavelength individually as well as in interaction were most significant (p < 0.0001 and p < 0.0086, respectively) on peak area; the quadratic effect of pH of buffer was also most significant effect (p < 0.0001) on tailing factor (5%) whereas the quadratic effect of flow rate and wavelength individually was significant (p = 0.0006 and p = 0.0265, respectively) on the number of theoretical plates. The high-performance liquid chromatographic separation was performed at the flow rate 1.0 min/mL, UV detector wavelength 250 nm and pH of the buffer 3.0 as optimized parameters using design of experiments. The retention time values of valsartan were found to be 10.177 min. Percent recovery in terms of accuracy for the prepared valsartan nanoparticles was found in the range of 98.57-100.27%.

Development and validation of reversed phase high-performance liquid chromatography method for estimation of lercanidipine HCl in pure form and from nanosuspension formulation.

AIM: Quantitative estimation of lercanidipine HCl in bulk material as well as from nanosuspension formulations via a developed reverse phase HPLC method. MATERIALS AND METHODS: Optimized chromatographic condition was used to achieve separation on a Kromasil (100-5c18 250 × 4.6 mm) column using Shimadzu HPLC system. The mobile phase consisted of a mixture of acetate buffer (20 mM pH 4.5) and acetonitrile in the ratio of 10:90, v/v. It is pumped through the chromatographic system at a flow rate of 1 ml/min. The detection was carried out at 240 nm using ultraviolet-visible spectrophotometry detector. The method was validated as per Q2 (R1) guidelines, and suitability of the developed method was established by optimized nanosuspension formulation. RESULTS: The method is specific to lercanidipine (RT: 7.7 min), and has ability to resolve the analyte peak from excipient interferences. It is linear (regression coefficient: 0.9993), accurate (average recovery: 100%), and passed all the system suitability requirements. CONCLUSION: Developed method was found applicable for evaluation of drug content, content uniformity, and analyzing samples of dissolution studies of nanosuspension.