Advanced stability-indicating RP-HPLC method for the quantification of Lurasidone Hydrochloride in bulk and PLGA based in-situ implant formulation.

OBJECTIVES: The aims of the present investigation was to develop and validate stability-indicating RP-HPLC method for the estimation of Lurasidone hydrochloride (LURA-H) followed by its drug product, LURA-H encapsulated poly-D,L lactic-glycolic acid (PLGA) based in-situ depot forming implant (LURA-H-PLGA-ISI). METHODS: The LURA-H-PLGA-ISI formulation was developed by simple mixing method. According to international conference on harmonization guidelines, RP-HPLC method was developed and validated using Waters 2695 and discovery C18, 5µ, 250×4.6 mm ID column. Force degradation studied were performed by various degradation techniques. RESULTS: The chromatographic separations of LURA-H as well as LURA-H-PLGA-ISI with good resolutions have been achieved using the mobile phase 0.1% orthophosphoric acid and acetonitrile (50:50). The linearity in the range of 25-150 µg/mL of developed method. LOD and LOQ limits for LURA-H were found to be 0.07µg/mL and 0.22 µg/mL, respectively. The % RSD was found to be <2% showing the precision of developed method. The accuracy of developed method was demonstrated which is close to 100±2%. Little modifications in the chromatographic conditions indicated robustness of the developed method. Further, solution stability of LURA-H and LURA-H-PLGA-ISI was stable at room temperature. Furthermore, force degradation studies demonstrated LURA-H was unaffected and stable under thermal, photodegradation and neutral (hydrolytic) stress conditions. AGREE and GAPI assessment demonstrated the developed method is environmentally sustainable. CONCLUSION: The developed method is simple, robust, precise, accurate and sensitive which can be utilized for the regular analysis of LURA-H in quality control laboratories of bulk drug substance and PLGA containing formulations of LURA-H.

Biomimicking dual drug eluting twisted electrospun nanofiber yarns for post-operative wound healing.

The morbidity rate following a surgical procedure increasing rapidly in the cases associated with surgical site infections. Traditional sutures lack the ability to deliver drugs as the incorporation of the drug in their structure would hamper their mechanical properties. To prevent such infections, we developed an extracellular matrix mimicking electrospun nanofibrous yarns of poly-(D,L)-lactic acid and polyvinyl alcohol loaded with vancomycin and ferulic acid, prepared by uniaxial electrospinning technique.In-vitrocharacterization such as scanning electron microscopy, Fourier transform infrared spectroscopy, x-ray diffraction, tensile strength testing, degradation studies, and antimicrobial studies along within-vivoevaluation done with help of incision wound healing rat model and simultaneous testing of microbial load in the incised tissue. Thein-vitrostudies indicated the nanofiber yarns have size range 200-300 nm with a tensile strength of 7.54 ± 0.58 MPa. The dual drug-loaded yarn showed sustained drug release over a period of 48 h.In-vitrowater uptake and biodegradation data indicated optimum results suitable for suturing applications. Antimicrobial study showed excellent antimicrobial activity against bothS. aureus and E. coli.Results obtained fromin-vivostudy suggested excellent wound healing potential of nanofiber yarns as compared with commercial silk sutures. The histopathological studies confirmed restoring ability of nanofiber yarn to the normal skin structure. Enzyme-linked immunosorbent assay (ELISA) study revealed the downregulation of inflammatory markers i.e. TNF-alpha and IL-6, making nanofibers sutures suitable for surgical wound healing applications. Overall, the present study may conclude that the developed dual drug-loaded nanofiber yarns have excellent potential in surgical wound healing applications.

Formulation design, optimization and in vivo evaluation of oral co-encapsulated resveratrol-humic acid colloidal polymeric nanocarriers.

The study aims at formulation and optimization of resveratrol and humic acid co-encapsulated colloidal polymeric nanocarriers to improve stability, oral bioavailability, and antiradical activity of water-insoluble, resveratrol. The eudragit E100 polymeric material was used to fabricate resveratrol and humic acid co-encapsulated oral colloidal polymeric nanocarriers (Res-HA-co-CPNs) using emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for oral bioavailability as well as for antiradical potential. Optimized Res-HA-co-CPNs demonstrated spherical and smooth surface including mean particle size, 120.56 ± 18.8 nm; polydispersity index, 0.122; zeta potential, +38.25 mV; and entrapment efficiency, 82.37 ± 1.49%. Solid-state characterization confirmed the amorphous characteristic of optimized Res-HA-co-CPNs. In vitro release profile of Res-HA-co-CPNs showed sustained release behavior up to 48 h and CPNs were found to remain stable at the refrigerated condition for 6 months. In vivo pharmacokinetic studies revealed significant (p < 0.05) improvement of ∼62.76-fold in oral bioavailability. The radical-scavenging activity was found to be increased with time and after 72 h, it was analogous to pure Res. IC50 values were reported to be decreased with time. Henceforth, developed Res-HA-co-CPNs was proven to be a proficient dosage form to increase stability, oral bioavailability, and antiradical activity of resveratrol.HighlightsResveratrol-humic acid co-encapsulated colloidal polymeric nanocarriers (Res-HA-co-CPNs) were fabricated by emulsification-diffusion-evaporation method and optimized by Taguchi orthogonal array design.The Res-HA-co-CPNs revealed favorable mean particle size and percent encapsulation efficiency with a spherical and smooth surface.The Res-HA-co-CPNs showed diffusion-controlled release of Res and were found to be stable at the refrigerated condition for 6 months.The optimized Res-HA-co-CPNs demonstrated significantly (p < 0.05) higher oral bioavailability with respect to pure Res and PM.The optimized Res-HA-co-CPNs demonstrated higher radical-scavenging activity with respect to time.

Mannose-conjugated curcumin-chitosan nanoparticles: Efficacy and toxicity assessments against Leishmania donovani.

Aim was to fabricate and optimize CUR-loaded mannose-functionalized chitosan nanoparticles (Cur-MCN) which overcome the limitations of drugs to reach the intracellular locations and to establish its therapeutic potential in visceral leishmaniasis by targeting of CUR to macrophages. Cur-MCN were developed by mannose-conjugated chitosan and have been tested for their efficacy and toxicit. In vivo antileishmanial activity in hamsters has shown significantly greater suppression of parasite replication in the spleen with Cur-MCN than unconjugated chitosan nanoparticles. The in vitro cytotoxicity study against the J774A.1 cell line demonstrated its comparative non-toxicity towards the macrophage cells. The potential of Cur-MCN was also confirmed by minimal observed cytotoxicity in our in vivo studies.

Potential of Cationic-Polymeric Nanoparticles for Oral Delivery of Naringenin: In Vitro and In Vivo Investigations.

The objective of the study was to improve the bioavailability and anticancer potential of naringenin (NRG) by developing a drug-loaded polymeric nanodelivery system. NRG-loaded eudragit E100 nanoparticle (NRG-EE100-NPs) system was developed and physicochemically characterized. In vivo pharmacokinetic and in vitro cytotoxicity abilities of the NRG-EE100-NPs were investigated. In vivo anticancer activity was evaluated in murine BALB/c mice-bearing colorectal tumor. The NRG-EE100-NPs had an optimum mean particle size (430.42 ± 5.78 nm), polydispersity index (0.283 ± 0.089) with percent entrapment efficiency (68.83 ± 3.45%). The NRG-EE100-NPs demonstrated significant higher bioavailability (∼96-fold; p <0.05) as well as cytotoxicity (∼16-fold; p <0.001) as compared to free NRG. Furthermore, NRG-EE100-NPs indicated significant tumor suppression (p <0.01) subsequently improvement in survival rate compared to free NRG in vivo. Thus, the physicochemical properties and colorectal cancer efficacy of NRG were improved by successful encapsulating in cationic-polymeric nanoparticle system.

Oral naringenin nanocarriers: Fabrication, optimization, pharmacokinetic and chemotherapeutic efficacy assessments.

AIM: To enhance oral bioavailability and chemotherapeutic efficacy of naringenin (NG) by fabricating the NG-encapsulated Soluthin-maltodextrin-based nanocarrier (NC) system. MATERIALS & METHODS: NG-encapsulated nanocarriers (NG/NCs) were developed, and in vitro physicochemically characterized. Furthermore, Wistar rats were used to evaluate the pharmacokinetic profile. Furthermore, in vitro and in vivo colorectal cancer efficacy was evaluated in BALB/c mice-bearing colon-26 cells. RESULTS: The NG/NCs demonstrated favorable mean particle size (176 ± 2.35 nm) and percent entrapment efficiency (70.83 ± 4.55%), respectively. The oral bioavailability was found to be approximately 116-fold higher and in vitro cytotoxicity exhibited approximately 21-fold reduction as compared with pure NG. Moreover, optimized NG/NCs demonstrated significant tumor suppression compared with pure NG in vivo. CONCLUSION: The NG/NCs would be an efficient formulation for enhancing oral bioavailability and chemotherapeutic efficacy of NG.

Performance evaluation of non-ionic surfactant based tazarotene encapsulated proniosomal gel for the treatment of psoriasis.

The study aims to explore the potential of non-ionic surfactant based proniosomal gel (PNG) in improving the topical delivery of tazarotene by in vitro and in vivo studies. The PNG was prepared using coacervation phase separation method composed of span, stearylamine, cholesterol, and lecithin. The PNG demonstrated favorable vesicle size (3.26±0.22µm) and percent encapsulation efficiency (49.50±2.3%). The PNG was evaluated for viscosity which indicated that the ratio of span:cholesterol:stearylamine (64.5:30.5:5mM) demonstrated no any fluctuations in viscosity. The scanning electron micrographs exhibited spherical vesicles with sharp boundaries. The in vitro drug release through cellulose membrane and rat's skin were found to be in the following order of the formulation code A2>A4>A3>A5 and A4>A2>A3>A5, respectively, which showed the prolonged release of entrapped tazarotene. Further, in vitro drug permeation and retention studies revealed that formulations A2 and A4 showed the higher percent of drug permeation whereas formulations A3 and A5 showed the higher percent of drug retention through rat's skin. Moreover, PNG A2 and A4 formulations demonstrated good stability characteristics at different temperature conditions. The stability in the presence of detergent revealed that no any abrupt change in turbidity. The skin irritation studies performed with formulations A2 and A4 showed no erythema compared with the plain PNG. The male Albino NMRI mice tail model was used to performed in vivo skin histological examination which revealed that an increase in the orthokeratosis strengthened. Thus, all the results concluded that surfactant, Span 60 based PNG formulations have shown a good ability to increase drug accumulation in the various skin layers and more potential carrier for topical delivery of tazarotene for an effective therapy of psoriasis.

3-month parenteral PLGA microsphere formulations of risperidone: Fabrication, characterization and neuropharmacological assessments.

The study aims at formulation and characterization of three months parenteral risperidone loaded polymeric microspheres (p-RLPMs) as a sustained delivery system and established their in vitro and in vivo assessments. The p-RLPMs formulations were prepared by solvent extraction and diffusion method. The optimized p-RLPMs (batch RPLGA-1) formulation demonstrated favorable different physicochemical properties such as mean particle size (104±5.34µm), percent porosity (44.56±3.11%) and percent drug loading (38.42±2.67%). The physical state characterization, Fourier transformed infrared spectroscopy analysis showed no changes in the chemical structure of risperidone (RPD) in the batch RPLGA-1 formulation and differential scanning calorimetry study confirmed, pure RPD retained its crystallinity in the batch RPLGA-1 formulation. The SEM micrographs of the all p-RLPMs formulations revealed the irregular shapes and indentations. The GC/MS results showed that the residual organic solvent content in the batch RPLGA-1 formulation was below the limits. Pharmacokinetic parameters revealed that optimized RPLGA-1 formulation exhibited an initial burst followed by an excellent sustained release as compared to pure RPD as well as other formulations. Furthermore, in vivo studies of the batch, RPLGA-1 formulation showed an antipsychotic effect that was significantly prolonged over that of pure RPD solution for up to 72h with fewer extrapyramidal side effects. Thus, results of this study prove the suitability of using poly(lactic-co-glycolic acid) copolymer to develop sustained release p-RLPMs formulations that can tailor in vivo behavior and enhance the pharmacological effectiveness of the RPD.

Design of novel chemotherapeutic delivery systems for colon cancer therapy based on oral polymeric nanoparticles.

Oral delivery of cancer chemotherapeutic drugs (CCDs) is subject matter in the 21st century, which changes the dosage regimens of oncotherapy with enhancement in patient's life and deducts the cost of therapy. The present report explored on the nano-oncology such as polymeric nanoparticles (PNPs) as an oral CCDs delivery vehicle, showing great potential for colon cancer treatment. Proof-of-concept in vitro and in vivo results for delivery of CCDs using various oral PNPs are included in this review from the literatures. Subsequently, the gastrointestinal barriers for oral chemotherapy have been highlighted. Furthermore, PNPs achieving better accumulation in the cancer region by desirable quality of their passive- and active-targeting phenomena have also been highlighted.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability.

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS-SLNs were engineered by double emulsification method (W1/O/W2) and optimised by using Box-Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24 hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ∼2.96-fold increase in permeability of CS by presentation as SLNs (p < 0.05). Further, in-vivo pharmacokinetic study exhibited ∼2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.

Cromolyn sodium encapsulated PLGA nanoparticles: An attempt to improve intestinal permeation.

High hydrophilicity curtails the intestinal permeation of cromolyn sodium (CS) which in turn compels to compromise with its multiple biological activities. Hence, the present research was intended with an objective to develop CS encapsulated polylactide-co-glycolide (PLGA) nanoparticles (CS-PNs) for enhancing intestinal permeation. The CS-PNs were prepared by double emulsification solvent evaporation method (W1/O/W2). The "Quality by Design" approach using box-behnken experimental design was employed to enhance encapsulation of CS inside CS-PNs without compromising with particle size. The polymer concentration, surfactant concentration and organic/aqueous phase ratio significantly affected the physicochemical properties of CS-PNs. The optimized CS-PNs were subjected to various solid-state and surface characterization studies using FTIR, DSC, XRD, TEM and AFM, which pointed towards the encapsulation of CS inside the spherical shaped nanoparticles without any physical as well as chemical interactions. Ex-vivo intestinal permeation study demonstrated ∼4 fold improvements in CS permeation by forming CS-PNs as compared to pure CS. Further, in-vivo intestinal uptake study performed using confocal microscopy, after oral administration confirmed the permeation potential of CS-PNs. Thus, the findings of the studies suggest that CS-PNs could provide a superior therapeutic carrier system of CS, with enhanced intestinal permeation.

Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies.

CONTEXT: Curcumin (CUR), can inhibit proliferation and induce apoptosis of tumor cells, its extreme insolubility and limited bioavailability restricted its clinical application. OBJECTIVE: An innovative polymeric nanoparticle of CUR has been developed to enhance the bioavailability and anti-cancer efficacy of CUR, in vitro and in vivo. MATERIALS AND METHODS: Cationic copolymer Eudragit E 100 was selected as carrier, which can enhance properties of poor bioavailable chemotherapeutic drugs (CUR). The CUR-loaded Eudragit E 100 nanoparticles (CENPs) were prepared by emulsification-diffusion-evaporation method. The in vitro cytotoxicity study of CENPs was carried out using sulphorhodamine B assay. Pharmacokinetic and anti-cancer efficacy of CENPs was investigated in Wister rats as well as colon-26 tumor-bearing mice after oral administration. RESULTS: CENPs showed acceptable particle size and percent entrapment efficiency. In vitro cytotoxicity studies in terms of 50% cell growth inhibition values demonstrated ∼19-fold reduction when treated with CENPs as compared to pure CUR. ∼91-fold increase in Cmax and ∼95-fold increase in AUC0-12h were observed indicating a significant enhancement in the oral bioavailability of CUR when orally administered as CENPs compared to pure CUR. The in vivo anti-cancer study performed with CENPs showed a significant increase in efficacy compared with pure CUR, as observed by tumor volume, body weight and survival rate. CONCLUSIONS: The results clearly indicate that the developed polymeric nanoparticles offer a great potential to improve bioavailability and anticancer efficacy of hydrophobic chemotherapeutic drug.

Lipopolysaccharide based oral nanocarriers for the improvement of bioavailability and anticancer efficacy of curcumin.

Soluthin MD(®), a unique phosphatidylcholine-maltodextrin based hydrophilic lipopolysaccharide, which exhibits superior biocompatibility and bioavailability enhancer properties for poorly water soluble drug(s). Curcumin (CUR) is a potential natural anticancer drug with low bioavailability due to poor aqueous solubility. The study aims at formulation and optimization of CUR loaded lipopolysaccharide nanocarriers (C-LPNCs) to enhance oral bioavailability and anticancer efficacy in colon-26 tumor-bearing mice in vitro and in vivo. The Optimized C-LPNCs demonstrated favorable mean particle size (108 ± 3.4 nm) and percent entrapment efficiency (65.29 ± 1.0%). Pharmacokinetic parameters revealed ∼130-fold increase in oral bioavailability and cytotoxicity studies demonstrated ∼23-fold reduction in 50% cell growth inhibition when treated with optimized C-LPNCs as compared to pure CUR. In vivo anticancer study performed with optimized C-LPNCs showed significant increase in efficacy compared with pure CUR. Thus, lipopolysaccharide nanocarriers show potential delivery strategy to improve oral bioavailability and anticancer efficacy of CUR in the treatment of colorectal cancer.