Topical phenytoin nanostructured lipid carriers: design and development

Phenytoin (PHT) is an antiepileptic drug that was reported to exhibit high wound healing activity. Nevertheless, its limited solubility, bioavailability, and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop, characterize nanostructured lipid carriers (NLCs), and evaluate their potential in topical delivery of PHT to improve the drug entrapment efficiency and sustained release. The NLCs were prepared by hot homogenization followed by ultra sonication method using 2³ factorial design. NLC formulations were characterized regarding their particle size (PS), zeta potential (ZP), entrapment efficiency percent (%EE), surface morphology, physicochemical stability, and in vitro release studies. The optimized NLC (F7) was further incorporated in 1%w/v carbopol gel and then characterized for appearance, pH, viscosity, stability, and in vitro drug release. The prepared NLCs were spherical in shape and possessed an average PS of 121.4–258.2?nm, ZP of (?15.4)–(–32.2)?mV, and 55.24–88.80 %EE. Solid-state characterization revealed that the drug is dispersed in an amorphous state with hydrogen bond interaction between the drug and the NLC components. NLC formulations were found to be stable at 25?°C for six months. The stored F7-hydrogel showed insignificant changes in viscosity and drug content (p>.05) up to six?months at 25?°C that pave a way for industrial fabrication of efficient PHT products. In vitro release studies showed a sustained release from NLC up to 48?h at pH 7.4 following non-Fickian Higuchi kinetics model. These promising findings encourage the potential use of phenytoin loaded lipid nanoparticles for future topical application.     

QbD-driven development and evaluation of nanostructured lipid carriers (NLCs) of Olmesartan medoxomil employing multivariate statistical techniques

Purpose: This research work entails quality by design (QbD)-based systematic development of nanostructured lipid carriers (NLCs) of Olmesartan medoxomil (OLM) with improved biopharmaceutical attributes.

Methods: Quality target product profile (QTPP) was defined and critical quality attributes (CQAs) were earmarked. Solubility of drug was performed in various lipids for screening of them. NLCs were prepared by hot-microemulsion method using solid lipids, liquid lipids and surfactants with maximal solubility. Failure mode and effect analysis (FMEA) was carried out for identifying high risk formulation and process parameters. Further, principal component analysis (PCA) was applied on high risk parameters for evaluating the effect of type and concentration of lipids and surfactants on CQAs. Further, systematic optimization of critical material attributes (CMAs) was carried out using face centered cubic design and optimized formulation was identified in the design space.

Results: FMEA and PCA suggested suitability of stearic acid, oleic acid and Tween 80 as the CMAs for NLCs. Response surface optimization helped in identifying the optimized NLC formulation with particle size ～250?nm, zeta potential <25?mV, entrapment efficiency >75%, in vitro drug release >80% within 6?h. Release kinetic modeling indicated drug release through Fickian-diffusion mechanism.

Conclusions: Overall, these studies indicated successful development of NLCs using multivariate statistical approaches for improved product and process understanding.     

Nanostructured lipid carriers loaded with simvastatin: effect of PEG/glycerides on characterization,stability, cellular uptake efficiency and in vitro cytotoxicity

Objective: The aim of this study is to evaluate the use of PEG/glycerides of different HLB; oleoyl macrogol-6-glycerides (Labrafil^® M 1944 CS) and caprylocaproylmacrogol-8-glycerides (Labrasol^®), compared to Labrafac lipophile^® as PEG-free glyceride in the preparation of nanostructured lipid carriers (NLCs). PEG/glycerides are suggested to perform a dual function; as the oily component, and as the PEG-containing substrate required for producing the PEGylated carriers without physical or chemical synthesis.

Methods: Lipid nanocarriers were loaded with simvastatin (SV) as a promising anticancer drug. An optimization study of NLC fabrication variables was first conducted. The effect of lyophilization was investigated using cryoprotectants of various types and concentrations. The prepared NLCs were characterized in terms of particle size (PS), size distribution (PDI), zeta potential (ZP), drug entrapment, in vitro drug release, morphology and drug–excipient interactions. The influence of glycerides?±?PEG on the cytotoxicity of SV was evaluated on MCF-7 breast cancer cells, in addition to the cellular uptake of fluorescent blank NLCs.

Results: The alteration between different oil types had a significant impact on PS, ZP and drug release. Both sucrose and trehalose showed the lowest increase in PS and PDI of the reconstituted lyophilized NLCs. The in vitro cytotoxicity and cellular uptake studies indicated that SV showed the highest antitumor effect on MCF-7 cancer cells when loaded into Labrasol^® NLCs demonstrating a high cellular uptake as well.

Conclusion: The study confirms the applicability of PEG/glycerides in the development of NLCs. Encapsulating SV in Labrasol^®-containing NLC could enhance the antitumor effect of the drug.     

pH-Sensitive and mucoadhesive microspheres for duodenum-specific drug delivery system

Particulate systems that could deliver drug specifically to duodenum have not yet been reported. The aim of this study was to develop a novel duodenum-specific drug delivery system based on thiolated chitosan and hydroxypropyl methylcellulose acetate maleate (HPMCAM) for the duodenal ulcer application. Berberine hydrochloride was used as model drug. Thiolated chitosan was synthesized and further used for the preparation of mucoadhesive microspheres. HPMCAM, which is insoluble below pH 3.0 was synthesized and used for the coating of thiolated chitosan microspheres (TCM). The resulting thiolated chitosan immobilized on chitosan was 268.21?±?18 μmol/g. In vitro mucoadhesion study showed that the mucoadhesion property of TCM was better than that of chitosan microspheres. Morphological observation showed that the HPMCAM coating would maintain its integrity in simulated gastric fluid (SGF) for 2?h and dissolved quickly in simulated pathological duodenal fluid (SPDF; pH 3.3). In vitro drug release studies showed that only 4.75% of the drug was released in SGF for 2?h, while nearly 90% of the drug was released within 6?h after transferring into SPDF.     

Formulation design,in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles

Context: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability.

Objective: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability.

Materials and methods: Rational blends of Softisan^®154 and Phospholipon^®90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice.

Results: Stable, smooth and spherical particles with sizes ranging from 4.2?±?0.02 to 9.3?±?0.8?µm were formed. EE% of 92.2–97.3% and 30.2–84.7% and pH of 3.0?±?0.02 to 4.9?±?0.12 and 3.0?±?0.02 to 5.8?±?0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p?Conclusion: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.     

Hyaluronic acid-coated,prodrug-based nanostructured lipid carriers for enhanced pancreatic cancer therapy

Abstract

Context: Gemcitabine (GEM) and Baicalein (BCL) are reported to have anti-tumor effects including pancreatic cancer. Hyaluronic acid (HA) can bind to over-expressed receptors in various kinds of cancer cells.

Objective: The aim of this study is to develop prodrugs containing HA, BCL and GEM, and construct nanomedicine incorporate GEM and BCL in the core and HA on the surface. This system could target the cancer cells and co-deliver the drugs.

Methods: GEM-stearic acid lipid prodrug (GEM-SA) and hyaluronic acid-amino acid-baicalein prodrug (HA-AA-BCL) were synthesized. Then, GEM and BCL prodrug-based targeted nanostructured lipid carriers (HA-GEM-BCL NLCs) were prepared by the nanoprecipitation technique. The in vitro cytotoxicity studies of the NLCs were evaluated on AsPC1 pancreatic cancer cell line. In vivo anti-tumor effects were observed on the murine-bearing pancreatic cancer model.

Results: HA-GEM-BCL NLCs were effective in entering pancreatic cancer cells over-expressing HA receptors, and showed cytotoxicity of tumor cells in vitro. In vivo study revealed significant tumor growth inhibition ability of HA-GEM-BCL NLCs in murine pancreatic cancer model.

Conclusion: It could be concluded that HA-GEM-BCL NLCs could be featured as promising co-delivery, tumor-targeted nanomedicine for the treatment of cancers.     

Effect of liquid-to-solid lipid ratio on characterizations of flurbiprofen-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for transdermal administration

The aim of this study is to evaluate the effect of liquid-to-solid lipid ratio on properties of flurbiprofen-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), and to clarify the superiority of NLCs over SLNs for transdermal administration. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, differential scanning calorimetry, X-ray diffractometry, in vitro percutaneous permeation profile, and stability of SLNs and NLCs were compared. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, and in vitro percutaneous permeation amount of the developed NLCs were all <200?nm, 78%, >35, and >240?μg/cm², respectively, however, for SLNs were 280?nm,??29.11?mV, 63.2%, 32.54, and 225.9?μg/cm², respectively. After 3 months storage at 4?°C and 25?°C, almost no significant differences between the evaluated parameters of NLCs were observed. However, for SLNs, particle size was increased to higher than 300?nm (4?°C and 25?°C), drug encapsulation efficiency was decreased to 51.2 (25?°C), in vitro occlusion factor was also decreased to lower than 25 (4?°C and 25?°C), and the cumulative amount was decreased to 148.9?μg/cm² (25?°C) and 184.4?μg/cm² (4?°C), respectively. And DSC and XRD studies indicated that not only the crystalline peaks of the encapsulated flurbiprofen disappeared but also obvious difference between samples and bulk Compritol® ATO 888 was seen. It could be concluded that liquid-to-solid lipid ratio has significant impact on the properties of SLNs and NLCs, and NLCs showed better stability than SLNs. Therefore, NLCs might be a better option than SLNs for transdermal administration.     

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.     

A synergistic approach of adapalene-loaded nanostructured lipid carriers,and vitamin C co-administration for treating acne

Abstract

The present study documents the fabrication and characterization of a topically applicable gel loaded with nanostructured lipid carriers (NLCs) of adapalene (ADA) and vitamin C (ascorbyl-6-palmitate [AP]). The NLCs were prepared by high pressure homogenization (HPH) method followed by incorporation into AP loaded gel. The fabricated system was characterized for size, poly dispersity index, entrapment efficiency (EE) and in vitro drug release properties, and was further investigated for skin compliance, skin transport characteristics (skin permeation and bio-distribution), rheological behavior, texture profile analysis and anti-acne therapeutic potential against testosterone-induced acne in male Wistar rats. The NLC-based formulation improved targeting of the skin epidermal layer and reducing systemic penetration. The co-administration of vitamin C led to an adjunct effect in acne therapy in physiological conditions. In brief, the present results suggest the potential of NLCs as a novel carrier for the dermal delivery of ADA and also the synergistic effect of vitamin C in topical therapeutics.     

Development and evaluation of intestinal targeted mucoadhesive microspheres of Bacillus coagulans

Background: Intestinal targeted mucoadhesive microsphere of probiotics may provide numerous associated health benefits.

Aim: To develop mucoadhesive microspheres that will deliver viable probiotic cells into gut protectively against harsh environmental conditions of stomach for extended period.

Materials and methods: Core mucoadhesive microspheres of Bacillus coagulans were prepared using hypromellose, following coacervation and phase separation technique and were then coated with hypromellose phthalate to achieve their site-specific release. Microspheres were evaluated for percent yield, entrapment efficiency, surface morphology, particle size and size distribution, flow property, swelling property, mucoadhesion property by the in vitro wash-off and the ex vivo mucoadhesive strength tests, in vitro release profile and release kinetic, in vivo probiotic activity, and stability. The values for kinetic constant and regression coefficient of model-dependent approaches and the difference factor, the similarity factor, and the Rescigno index of model-independent approaches were determined for accessing and comparing in vitro performance.

Results: Microsphere formulation batches have percent yield value between 56.26% and 69.13% and entrapment efficiency value between 66.95% and 77.89%. Microspheres were coarser with spherical shape having mean particle size from 28.03 to 48.31 μm. In vitro B. coagulans release profile follows zero-order kinetics and depends on the grade of hypromellose and the B. coagulans-to-hypromellose ratio. Experimental microspheres rendered adequate stability to B. coagulans at room temperature.

Conclusion: Microspheres had delivered B. coagulans in simulated intestinal condition following zero-order kinetics, protectively in simulated gastric condition, exhibiting appreciable mucoadhesion in intestinal condition, which could be useful to achieve site-specific delivery for extended period.     

Design and characterization of enteric-coated controlled release mucoadhesive microcapsules of Rabeprazole sodium

The objectives of present work was to design and characterize the rabeprazole sodium loaded microcapsules prepared by solvent evaporation technique using ethyl cellulose (EC) based various mucoadhesive polymer, followed by a triple coating with Eudragit L100. The Box-behnken design (BBD) was applied for optimization of formulations containing EC, HPMCK100M and Eudragit L100 as factors for selected responses like entrapment efficiency, mucoadhesive property and drug release in 24 h. The prepared microcapsules were characterized for particle size, drug content, swelling index, mucoadhesive strength, and in vivo antiulcer activity. FT-IR studies revealed that there was no drug-polymer interaction. SEM studies revealed that microcapsules were non-aggregated, spherical shape and smooth appearance. In vitro drug release data from microcapsules was fitted to different kinetic models to explain release profiles. The correlation coefficient value (r²) indicated that the drug release followed Higuchi model. Analysis of variance (ANOVA) showed significant difference in the release of drug from all formulations at p < 0.05 level. Accelerated stability study of optimized formulation (F4) upto 6 months showed there was no change in drug content and release characteristics during storage. In vivo antiulcer activity showed that the optimized microcapsules were able to protect rat stomach against ulcer formation vis-à-vis aqueous solution of the drug showed only negligible and minimum effect.     

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.     

Metronidazole-loaded nanostructured lipid carriers to improve skin deposition and retention in the treatment of rosacea

The objective of the present investigation was to improve the skin deposition and retention of metronidazole (MTZ) in rosacea therapy by incorporating it into nanostructured lipid carriers (NLCs). The main challenge in this endeavor was the partial hydrophilicity of MTZ, which mandated careful selection of excipients, including solid and liquid lipids, surfactants, and their ratios in combination. NLCs were produced by the phase inversion temperature method and finally converted into a gel for topical application. The prepared nanoparticles were evaluated for their particle size, zeta potential, entrapment efficiency, solid-state characteristics, surface morphology, in vitro drug release, and permeation through excised skin. The gel was additionally characterized for its pH, drug content, viscosity, and spreadability. The prepared nanoparticles were spherical in shape and of size less than 300?nm. Incorporation of judiciously chosen excipients made possible a relatively high entrapment efficiency of almost 40%. The drug release was found to be biphasic, with an initial burst release followed by sustained release up to 8?hours. In comparison to the plain drug gel, which had a tissue deposition of 11.23%, the NLC gel showed a much superior and desirable deposition of 26.41%. The lipophilic nature of the carrier, its size, and property of occlusion enabled greater amounts of drug to enter and be retained in the skin, simultaneously minimizing permeation through the skin, i.e. systemic exposure. The results of the study suggest that NLCs of anti-rosacea drugs have the potential to be used in the therapy of rosacea.     

Doxorubicin- and cisplatin-loaded nanostructured lipid carriers for breast cancer combination chemotherapy

Context: Combination anticancer therapy is promising to generate synergistic anticancer effects, to maximize the treatment effect and to overcome multi-drug resistance. Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers.

Objective: The aim of this study is to construct novel NLCs as nanocarriers for co-delivery of doxorubicin (DOX) and cisplatin (CDDP) to treat breast cancer.

Methods: DOX and CDDP loaded NLCs (D–C-NLCs) were prepared by the solvent diffusion method. The in vitro cytotoxicity and synergistic studies of different formulations were evaluated on human breast cancer cells (doxorubicin resistant) (MCF-7/ADR cells). In vivo anti-tumor effects were observed on the murine bearing MCF-7/ADR cells model.

Results: D–C-NLCs showed the highest cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. The in vivo study revealed the greatest anti-tumor activity than the other formulations in the breast cancer model.

Conclusion: The constructed NLCs could be used as a novel carrier for co-delivery of DOX and CDDP for breast cancer therapy. D–C-NLCs could be a promising targeted and combinational therapy nanomedicine.     

Fabrication and in vitro evaluation of bidirectional release and stability studies of mucoadhesive donut-shaped captopril tablets

Objective: To obtain controlled release of captopril in the stomach, coated, mucoadhesive donut-shaped tablets were designed.

Materials and methods: Donut-shaped tablet were made of different ratios of diluents to polymer or combination of polymers by direct compression method. Top and bottom portions of the tablet were coated with water-insoluble polymer followed by mucoadhesive coating. Time of water penetration, measurement of tensile strength, mucoadhesion studies (static ex vivo and ex vivo wash-off) were taken into account for characterization of respective films. In vitro study has been performed at different dissolution mediums. Optimized batches were also prepared by wet granulation. Stability studies of optimized batches have been performed.

Results: The results of time of water penetration and tensile strength indicated positive response against water impermeation. Mucoadhesive studies showed that film thickness of 0.12?mm was good for retention of tablet at stomach. At pH 1.2, optimized batch of tablet made with hydroxypropyl methyl cellulose (HPMC) E15 as binder showed 80% w/w drug release within 4–5?h with maximum average release of 97.49% w/w. Similarly, maximum average releases of 96.36% w/w and 95.47% w/w were obtained with nearly same dissolution patterns using combination of HPMC E5 and HPMC E50 and sodium salt of carboxy methyl cellulose (NaCMC) 500–600 cPs instead of HPMC E15. The release profiles in the distilled water and pH 4.5 followed the above pattern except deviation at pH 6.8. Stability studies were not positive for all combinations.

Conclusion: Coated, mucoadhesive donut-shaped tablet is good for controlled release of drug in the stomach.     

Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery

Aim: In this study, self-emulsifying drug delivery system (SEDDS) for oral delivery of opioid peptide dalargin were developed and characterized in vitro.

Methods: Dalargin lipophilicity was increased by O-esterification of tyrosine OH group, hydrophobic ion pairing, or a combination thereof. Distribution coefficients (log?D) of lipidized dalargin derivatives were determined. Then, dalargin was incorporated in chosen SEDDS, namely SEDDS-1, composed of 50% Capmul 907, 40% Cremophor EL, and 10% propylene glycol and comparatively more lipophilic SEDDS-2 composed of 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL, and 10% propylene glycol. Additionally, SEDDS were characterized regarding droplet size, polydispersity index (PDI), cloudy point, physical stability and stability against pancreatic lipase. Furthermore, mucus permeating properties of SEDDS and their ability to protect the incorporated dalargin against proteolysis by trypsin, α-chymotrypsin, elastase, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) were evaluated.

Results: The highest dalargin drug payload of 4.57% in SEDDS-2 was achieved when dalargin palmitate (pDAL) was ion paired with sodium dodecyl sulfate (SDS) in molar ratio 1:1. Moreover, SEDDS-1 and SEDDS-2 had a narrow droplet size distribution with average droplet sizes of 42.1 and 33.1?nm with PDI of 0.042 and 0.034, respectively. Lipolysis study showed that within 30?min 78.5% of SEDDS-1 and 92.1% of SEDDS-2 were digested. In addition, both SEDDS exhibited mucus permeating properties as well as a protective effect against enzymatic degradation by trypsin, α-chymotrypsin, elastase, SGF and SIF.

Conclusion: The results of this study suggest that the developed SEDDS could be considered for oral opioid peptide delivery.     

Atorvastatin-loaded lipid nanoparticles: antitumor activity studies on MCF-7 breast cancer cells

Atorvastatin is a synthetic statin commonly used in the treatment of hypercholesterolemia. Apart from this, statins appear to have pleiotropic effects, including modulation of cell growth, apoptosis. Through modulation of these pathways, statins have the potential to influence a wide range of disease processes, including cancer. However, poor aqueous solubility (0.1?mg/mL) and poor oral bioavailability has limited therapeutic application of atorvastatin. Present work is an attempt to improve tumor targeting of atorvastatin by incorporating in nanostructured lipid carriers (NLCs) and studying its anticancer activity on MCF-7 cell lines. NLCs of atorvastatin were formulated by high-speed homogenization followed by probe sonication method. The optimized batch of NLCs had a mean size of 130.02?±?3.1?nm and entrapment efficiency of 90.42?±?3.7%. The in vitro drug release study by dialysis method indicated that drug entrapped in the NLCs remains entrapped at acidic pH as well as in phosphate buffer of pH 7.4 for a prolonged period of time as compared to plain drug. In vitro cytotoxicity studies on MCF-7 (mammary adenocarcinoma human cell lines) cell lines showed that concentration of drug required for total growth inhibition (TGI) and 50% growth inhibition (GI50) of MCF-7 cells was found to be 27.4?µg/mL and <10?µg/mL respectively, in case of atorvastatin- NLCs which is less than that required in case of plain atorvastatin and almost similar to that of adriamycin. All these findings reinforce the fact that atorvastatin loaded NLCs are promising novel delivery system for treating breast cancer.     

Nanostructured lipid carriers engineered for intranasal delivery of teriflunomide in multiple sclerosis: optimization and in vivo studies

Background: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS).

Objective: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS).

Methods: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box–Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data.

Results: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82?±?1.36?nm), zeta potential (?22.29?±?1.8?mV) and % entrapment efficiency (83.39?±?1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830?±?7.6 and 651?±?9.8?µg/cm², respectively. Whereas, TFM-MNLC shows around 2.0-folds more J_ss than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control.

Conclusions: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.     

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine

Objective: The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg).

Significance: The IPN microbeads were optimized by Box–Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle.

Methods: Ionotropic gelation method utilizing metal ion calcium (Ca²⁺) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box–Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively.

Results: The particle size and % drug entrapment of the optimized batch was 494.37?±?1.4?µm and 81.39?±?2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12?h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP.

Conclusion: Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.