In situ evaluation of the impact of metformin or verapamil coadministration with vildagliptin on its regional absorption from the rabbit's intestine.

This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an in situ rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P-gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P-gp, but the observations suggest that P-gp is significant in reducing vildagliptin absorption. Verapamil co-perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co-administration showed a non-significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site-dependent and may be related to the intestinal P-glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug-drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P-glycoprotein level.

Nanomedicines as enhancers of tumor immunogenicity to augment cancer immunotherapy.

The potential of cancer immunotherapy is hampered by the poor immunogenicity of cancer cells. Strategies to enhance tumor immunogenicity are imperative to enhance T cell-mediated anti-tumor immunity. Although conventional therapeutics can increase tumor antigen expression or stimulate the release of danger signals to promote immunogenic cell death (ICD), they face challenges relating to efficacy and tumor-specific delivery. Nanomedicines can efficiently deliver tumor antigens, immune adjuvants, epigenetic modulators, or ICD inducers through targeted drug delivery with minimal off-target effects. Collectively, nanomedicines can overcome biological barriers to immunotherapy through targeted antigen delivery, induction of ICD, or epigenetic remodeling, resulting in increased tumor immunogenicity.

Lactosylated Chitosan Nanoparticles Potentiate the Anticancer Effects of Telmisartan In Vitro and in a N-Nitrosodiethylamine-Induced Mice Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide. Telmisartan (TLM), a BSC class II drug, has been reported to have antiproliferative activity in HCC. However, its therapeutic activity is limited by poor bioavailability and unpredictable distribution. This work aimed to enhance TLM's liver uptake for HCC management through passive and active targeting pathways utilizing chitosan nanoparticles decorated with lactose (LCH NPs) as a delivery system. In vitro cell cytotoxicity and cellular uptake studies indicated that TLM-LCH NPs significantly (p < 0.05) enhanced the antiproliferative activity and cellular uptake percentage of TLM. In vivo bioavailability and liver biodistribution studies indicated that TLM-LCH NPs significantly (p < 0.05) enhanced TLM concentrations in plasma and the liver. The relative liver uptake of TLM from TLM-LCH NPs was 2-fold higher than that of unmodified NPs and 5-fold higher than that of plain TLM suspension. In vivo studies of a N-nitrosodiethylamine-induced HCC model revealed that administration of TLM through LCH NPs improved liver histology and resulted in lower serum alpha-fetoprotein (AFP), matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF) levels, and liver weight index compared to plain TLM and TLM-loaded unmodified NPs. These results reflected the high potentiality of LCH NPs as a liver-targeted delivery system for TLM in the treatment of HCC.

Application of Design of Experiment in the Optimization of Apixaban-Loaded Solid Lipid Nanoparticles: In Vitro and In Vivo Evaluation.

Solid lipid nanoparticles (SLnPs) are usually utilized as lipid-based formulations for enhancing oral bioavailability of BCS class IV drugs. Accordingly, the objective of this work was to investigate the effect of formulation and processing variables on the properties of the developed SLnPs for oral delivery of apixaban. Randomized full factorial design (24) was employed for optimization of SLnPs. With two levels for each independent variable, four factors comprising both formulations and processing factors were chosen: the GMS content (A), the Tween 80 content (B), the homogenization time (C), and the content of poloxamer 188 used (D). The modified hot homogenization and sonication method was employed in the formulation of solid lipid nanoparticles loaded with apixaban (APX-SLnPs). The size of APX-SLnPs formulations was measured to lie between 116.7 and 1866 nm, polydispersity index ranged from 0.385 to 1, and zeta potential was discovered to be in the range of - 12.6 to - 38.6 mV. The entrapping efficiency of APX-SLnPs formulations was found to be in the range of 22.8 to 96.7%. The optimized formulation was evaluated in vivo after oral administration to rats. Oral administration of APX-SLnPs resulted in significant prolongation in bleeding time compared with both positive and negative control. This indicates the ability of this system to enhance drug therapeutic effect either by increasing intestinal absorption or trans-lymphatic transport. So, this study highlighted the capability of SLnPs to boost the pharmacological effect of apixaban.

Chitosan coated clove oil-based nanoemulsion: An attractive option for oral delivery of leflunomide in rheumatoid arthritis.

Rheumatoid arthritis (RA), a distressing inflammatory autoimmune disease, is managed mainly by Disease-modifying antirheumatic drugs (DMARDs), e.g. leflunomide (LEF). LEF (BCS class II) has limited solubility and adverse effects following its systemic exposure. The appealing antirheumatic properties of both clove oil and chitosan (CS) were exploited to design oral leflunomide (LEF)-loaded nanoemulsion (NE) system to augment the therapeutic action of LEF and decrease its systemic side effects as well. Different LEF-NEs were prepared using clove oil, Tween® 20 (surfactant), and PEG 400(co-surfactant) and characterized by thermodynamic stability, percentage transmittance, cloud point, size analysis, and drug content. Optimized LEF-NE was subjected to CS coating forming LEF-CS-NE that exhibited nanometric size range, prolonged drug release, and good physical stability. In vivo anti-rheumatic activity of pure LEF, market LEF, and LEF-CS-NE was assessed utilizing a complete Freund's adjuvant (CFA) rat model. Treatment with LEF-CS-NE reduced edema rate (48.68% inhibition) and caused a marked reduction in interleukin-6 (IL-6) (510.9 ± 2.48 pg/ml), tumor necrosis factor- α (TNF-α) (397.3 ± 2.53 pg/ml), and rheumatoid factor (RF) (42.58 ± 0.49 U/ml). Furthermore, LEF-CS-NE reduced serum levels of glutamic pyruvic transaminase (GPT) to (83.19%) and glutamic oxaloacetic transaminase (GOT) to (40.68%) compared to the control + ve group. The effects of LEF-CS-NE were also superior to both pure and market LEF and showed better results in histopathological studies of paws, liver, kidney, lung, and heart. The remarkable therapeutic and safety profile of LEF-CS-NE makes it a potential oral system for the management of RA.

Telmisartan-Loaded Lactosylated Chitosan Nanoparticles as a Liver Specific Delivery System: Synthesis, Optimization and Targeting Efficiency.

Hepatocellular carcinoma (HCC) has a significant economic impact and a high mortality rate. Telmisartan (TLM) is a potential therapy for HCC, but it has a limited scope in drug delivery due to unpredictable distribution and poor bioavailability. The objective of this study was to prepare, design, and in vitro evaluate lactose-modified chitosan nanoparticles (LCH NPs) as a liver-targeted nanocarrier for TLM with the potential to offer a promising HCC therapy. The combination of chitosan with lactose was successfully attained using the Maillard reaction. TLM-LCH NPs were prepared, characterized, and optimized with the developed 23 full factorial design. The optimized formulation (F1) was in vitro and in vivo characterized. LCH was synthesized with an acceptable yield of 43.8 ± 0.56%, a lactosylation degree of 14.34%, and a significantly higher aqueous solubility (6.28 ± 0.21 g/L) compared to native chitosan (0.25 ± 0.03 g/L). In vitro characterization demonstrated that, F1 had a particle size of 145.46 ± 0.7 nm, an entrapment efficiency of 90.21 ± 0.28%, and a surface charge of + 27.13 ± 0.21 mV. In vitro TLM release from F1 was most consistent with the Higuchi model and demonstrated significantly higher release at pH 5.5. Moreover, a significantly higher ratio of liver to plasma concentration was observed with TLM-LCH NPs compared to plain TLM and unmodified TLM-NPs. The obtained results nominate TLM-LCH NPs as a promising carrier for enhancing liver targeting of TLM in treatment of HCC.

Recent advances in polymer shell oily-core nanocapsules for drug-delivery applications.

Polymeric nanocapsules are vesicular drug-delivery systems composed of an inner oily reservoir surrounded by polymeric membranes. Nanocapsules have various advantages over other nanovesicular systems such as providing controlled drug release properties. We discuss the recent advances in polymeric shell oily-core nanocapsules, illustrating the different types of polymers used and their implementation. Nanocapsules can be utilized for many purposes, especially encapsulation of highly lipophilic drugs. They have been shown to have variable applications, especially in cancer therapy, due to the ability of the polymeric shell to direct the loaded drugs to their target sites, as well as their high internalization efficacy. Those productive applications guaranteed their high potential as drug-delivery systems. However, their clinical development is still in an early stage.

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity.

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano-vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification-solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl-lactic-co-glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP-PLGA-NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP-PLGA-NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma-aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme-linked immunosorbent assay. The maximal electroshock-induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP-loaded NPs. The prepared ZP-PLGA NPs were negatively charged spherical particles with an average size of 120-300 nm. Optimized ZP-PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42-fold augmentation in oral drug bioavailability in comparison to ZP-marketed products. Moreover, parenteral administration of ZP-NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP-PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.

Formulation of lyophilized oily-core poly-Ɛ-caprolactone nanocapsules to improve oral bioavailability of Olmesartan Medoxomil.

Objective: This study aims to detect the enhancement in the oral bioavailability of a poorly water-soluble antihypertensive drug Olmesartan Medoxomil (OM) due to the formulation of lyophilized oily-core nanocapsules.Significance: A comparative pharmacokinetic study in rats was conducted for oily-core polymeric nanocapsules (ONC) after formulation and lyophilization against market tablet products to show the significant improvement in oral absorption of OM.Materials and methods: OM loaded ONC were prepared using poly-Ɛ-caprolactone (0.5% w/v) as a polymer and an oily core of Labrafac PG® by applying a well-controlled nanoprecipitation technique in terms of injection rate (80 mL/h) and magnetic stirring rate (300 rpm). The prepared lyophilized ONC were in-vitro characterized after reconstitution and evaluated in-vivo for oral bioavailability after a single OM oral dose (20 mg/kg) of reconstituted lyophilized ONC dispersion was administered to rats.Results: The prepared lyophilized ONC containing 10% w/v mannitol showed an average particle size of 158 nm, polydispersity index of 0.37, negative zeta potential value equals 33.9 and entrapment efficiency of 90%. The dissolution profile for OM from lyophilized ONC powder filled into hard gelatin capsules (HGC) showed a 1.8-fold increase in dissolution rate as compared to the pure drug. In-vivo pharmacokinetic study in rats revealed a significant enhancement in the oral bioavailability of OM with 1.6-fold increase for AUC0-24 and a 1.9-fold increase for Cmax as compared to marketed product.Conclusion: It is concluded that the formulation of lyophilized ONC for OM can significantly enhance its oral bioavailability and consequently, its therapeutic efficacy and patient compliance.

Formulation of acyclovir-loaded solid lipid nanoparticles: design, optimization, and in-vitro characterization.

The goal of this study was to design, optimize, and characterize Acyclovir-loaded solid lipid nanoparticles (ACV-SLNs) concerning particle size, zeta potential, entrapment efficiency, and release profile. Full factorial design (23) was applied and the independent variables were surfactant type (Tween 80 and Pluronic F68), lipid type (Stearic acid and Compritol 888 ATO), and co-surfactant type (Lecithin and Sodium deoxycholate). The microemulsion technique was used followed by ultrasonication. The ACV-SLNs had a particle size range of about 172-542 nm. The polydispersity index (PDI) was found to be between 0.193 and 0.526. Zeta potential was in the range of -25.7 to -41.6 mV indicating good physical stability. Entrapment efficiency values were in the range of 56.3-80.7%. The drug release kinetics of the prepared formulations was best fitted to Higuchi diffusion model. After storing ACV-SLNs at refrigerated condition (5 ± 3 °C) and room temperature (25 ± 2 °C) for 4 weeks; we studied the change in the particle size, PDI, and zeta potential. The selected optimized formulation (F4) was containing Compritol, Pluronic F68, and Lecithin. These results indicated the successful application of this design to optimize the ACV-SLNs as a promising delivery system.

Formulation of acyclovir-loaded solid lipid nanoparticles: 2. Brain targeting and pharmacokinetic study.

Acyclovir (ACV) is widely used in the treatment of herpes encephalitis. The present study was conducted to prepare chitosan-tween 80 coated solid lipid nanoparticles (SLNs) as a delivery system for brain targeting of ACV in rabbits. The SLNs were prepared and coated in one step by microemulsion method using a coating solution containing chitosan (0.1% w/v) and tween 80 (2% w/v) for loading sustained release ACV. In vitro characterization was performed for coated ACV-SLNs. Concerning in vivo experiments; a single intravenous bolus dose of coated ACV-SLNs was given versus free ACV solution to rabbits (62 mg/kg). Plasma pharmacokinetic parameters were calculated from the ACV concentration-time profiles in plasma using the two compartmental analysis. The values of AUC0-∞ and MRT of coated ACV-SLNs were higher than free drug by about twofold, 233.36 ± 41.56 µg.h/mL and 1.81 ± 0.36 h, respectively. The noncompartmental analysis was conducted to estimate the brain pharmacokinetic parameters. The AUC0-∞ brain/AUC0-∞ plasma ratio for coated ACV-SLNs and free ACV was 0.22 and 0.12, respectively. These results indicated the effectiveness of using coated ACV-SLNs for brain targeting.

Regional difference in intestinal drug absorption as a measure for the potential effect of P-glycoprotein efflux transporters.

OBJECTIVES: The aim of this research was to assess regional difference in the intestinal absorption of ranitidine HCl as an indicator for the potential effect of P-glycoprotein (P-gp) efflux transporters. METHODS: In situ rabbit intestinal perfusion was used to investigate absorption of ranitidine HCl, a substrate for P-gp efflux from duodenum, jejunum, ileum and colon. This was conducted both in the presence and absence of piperine as P-gp inhibitor. KEY FINDINGS: Ranitidine HCl was incompletely absorbed from rabbit intestine. The length normalized absorptive clearance (PeA/L) of ranitidine HCl was ranked as colon > duodenum > jejunum > ileum. This is the reverse order of the magnitude of P-gp expression. Coperfusion of piperine with ranitidine HCl significantly increased the PeA/L of ranitidine HCl from jejunum and ileum with no significant change on the absorption from duodenum and colon. This was confirmed by significant reduction in the length required for complete ranitidine HCl absorption from jejunum and ileum in presence piperine. CONCLUSIONS: The results indicate that P-gp transporters play a major role in determining regional difference in intestinal absorption of ranitidine HCl. Thus, the regional absorption of drugs may be taken as an indirect indication for the role of P-gp in intestinal absorption.

Lactoferrin-tagged quantum dots-based theranostic nanocapsules for combined COX-2 inhibitor/herbal therapy of breast cancer.

AIM: Herein, tumor-targeted quantum dots (QDs)-based theranostic nanocapsules (NCs) coloaded with celecoxib and honokiol were developed. Materials & methodology: The anionic CD44-targeting chondroitin sulfate and cationic low density lipoprotein (LDL)-targeting lactoferrin (LF) were sequentially assembled onto the surface of the positively charged oily core. As an imaging probe, highly fluorescent mercaptopropionic acid-capped cadmium telluride QDs were coupled to LF. RESULTS: In vitro, fluorescence of QDs was quenched (OFF state) due to combined electron/energy transfer-mediated processes involving LF. After intracellular uptake of NCs, fluorescence was restored (ON state), thus enabled tracing their internalization. The NCs demonstrated enhanced cytotoxicity against breast cancer cells as well as superior in vivo antitumor efficacy. CONCLUSION: We propose these multifunctional nanotheranostics for imaging and targeted therapy of breast cancer.

Layer-by-layer gelatin/chondroitin quantum dots-based nanotheranostics: combined rapamycin/celecoxib delivery and cancer imaging.

Aim: Nanotheranostics consisting of highly-fluorescent quantum dots coupled with gelatin/chondroitin layer-by-layer assembled nanocapsules were developed. Materials & methods: The hydrophobic drugs celecoxib (CXB) and rapamycin (RAP) were co-loaded into the oily core of nanocapsules (NCs) to enable synergistic growth inhibition of breast cancer cells. To overcome the nonspecific binding of actively targeted CS-NCs with normal cells, a matrix metalloproteinase (MMP-2)-degradable cationic gelatin layer was electrostatically deposited onto the surface of the negatively-charged CS-NCs. Results: The prepared nanocarriers displayed strong fluorescence which enabled tracing their internalization into cancer cells. An enhanced cytotoxicity of the NCs against breast cancer cells was demonstrated. In vivo, the nanoplatforms displayed superior antitumor efficacy as well as nonimmunogenic response. Conclusion: Therefore, these multifunctional nanoplatforms could be used as potential cancer theranostics.

Enhanced cutaneous wound healing in rats following topical delivery of insulin-loaded nanoparticles embedded in poly(vinyl alcohol)-borate hydrogels.

Insulin plays an important role in the wound healing process, but its method of delivery to the wound bed and subsequent effect on rate of healing is less well investigated. In this study, we evaluated the therapeutic effectiveness of topical human insulin delivery using a nanoparticulate delivery system suspended in a structured hydrogel vehicle. Poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) of 202.6 nm diameter and loaded with 33.86 µg insulin per milligram of polymer were formulated using a modified double-emulsion solvent evaporation technique and dispersed in a dilatant hydrogel (poly(vinyl alcohol)-borate). Importantly, this hydrogel formulation was used to achieve ultimate contact with the wound bed. A comparison of wound healing rates following local administration of insulin in the free and nanoencapsulated forms was performed in diabetic and healthy rats. In non-diabetic rats, there was no significant difference between healing observed in control and wounds treated with free insulin (p > 0.05), whereas treatment with insulin encapsulated within PLGA NP showed a significant difference (p < 0.001). In diabetic cohorts, both free insulin and nanoencapsulated insulin induced significant improvement in wound healing when compared to controls, with better percentage wound injury indices observed with the colloidal formulation. At day 10 of the experiment, the difference between percentage wound injury indices of insulin-PLGA NP and free insulin comparing to their controls were 29.15 and 12.16%, respectively. These results support strongly the potential of insulin-loaded colloidal carriers for improved wound healing when delivered using dilatant hydrogel formulations.

Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice.

Biodegradable PLGA nanoparticles, loaded with 5-fluorouracil (5FU), were prepared using a double emulsion method and characterised in terms of mean diameter, zeta potential, entrapment efficiency and in vitro release. Poly (vinyl alcohol) was used to modify both internal and external aqueous phases and shown have a significant effect on nanoparticulate size, encapsulation efficiency and the initial burst release. Addition of poly (ethylene glycol) to the particle matrix, as part of the polymeric backbone, improved significantly the encapsulation efficiency. 5FU-loaded NPs were spherical in shape and negatively charged with a size range of 185-350 nm. Biological evaluation was performed in vivo using a solid Ehrlich carcinoma (SEC) murine model. An optimised 5FU-loaded formulation containing PEG as part of a block copolymer induced a pronounced reduction in tumour volume and tumour weight, together with an improved percentage tumour growth inhibition. Drug-loaded nanoparticles showed no significant toxicity or associated changes on liver and kidney function in tested animals, whereas increased alanine aminotransferase, aspartate aminotransferase and serum creatinine were observed in animals treated with free 5FU. Histopathological examination demonstrated enhanced cytotoxic action of 5FU-loaded nanoparticles when compared to the free drug. Based on these findings, it was concluded that nano-encapsulation of 5FU using PEGylated PLGA improved encapsulation and sustained in vitro release. This leads to increased anti-tumour efficacy against SEC, with a reduction in adverse effects.

Xylitol as a potential co-crystal co-former for enhancing dissolution rate of felodipine: preparation and evaluation of sublingual tablets.

Dissolution enhancement is a promising strategy for improving drug bioavailability. Co-crystallization of drugs with inert material can help in this direction. The benefit will become even greater if the inert material can form co-crystal while maintaining its main function as excipient. Accordingly, the objective of the current study was to investigate xylitol as a potential co-crystal co-former for felodipine with the goal of preparing felodipine sublingual tablets. Co-crystallization was achieved by wet co-grinding of the crystals deposited from methanolic solutions containing felodipine with increasing molar ratios of xylitol (1:1, 1:2 and 1:3). The developed co-crystals were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) before monitoring drug dissolution. These results reflected the development of new crystalline species depending on the relative proportions of felodipine and xylitol with complete co-crystallization of felodipine being achieved in the presence of double its molar concentration of xylitol. This co-crystal formulation was compressed into sublingual tablet with ultrashort disintegration time with subsequent fast dissolution. Co-crystal formation was associated with enhanced dissolution with the optimum formulation producing the fastest dissolution rate. In conclusion, xylitol can be considered as a co-crystal co-former for enhanced dissolution rate of drugs.

Development and optimization of a novel drug free nanolipid vesicular system for treatment of osteoarthritis.

OBJECTIVE: The goal of this study is to improve the transdermal delivery of phosphatidylcholine (PC) via constructing a novel nanolipid vesicular system (NLVS) with high level of permeability through the stratum corneum (SC). SIGNIFICANCE: In our study, a novel drug free NLVS was developed. The system depends on PC boundary cartilage lubrication to relieve osteoarthritic pain without developing gastrointestinal problems associated with anti-inflammatory drug. MATERIALS AND METHODS: A full two-level (23) factorial design is applied to optimize the quality of the prepared NLVS. The selected independent variables are the concentration of PC, the concentration of edge activator (EA), and EA type. The developed NLVS was evaluated for in-vitro, ex-vivo as well as in-vivo efficacy in rat animal model. RESULTS: Based on the factorial design, the selected formulation variables significantly affect the tested responses. The prepared NLV formulations have a particle size (PS)in the range of 10.34 to 496.3 nm, polydispersity index (PdI) values less than one, and negative zeta potential (ZP) range of -1.42 to -32.01 mV. In-vitro and ex-vivo study results reveal that the designed NLVS is effective in sustaining PC release and enhancing its transdermal permeation over 24 h. The optimal permeation flux through ex-vivo study is 0.415 mg/cm2/h following zero-order kinetics. Moreover, in-vivo study of the optimized formulations demonstrated remarkable reduction in inflammatory mediators associated with osteoarthritis (OA). CONCLUSION: The results indicate that the optimized drug free NLVS significantly augment transdermal delivery of PC and have a potential role in treatment of OA without the risk of systemic side effects.

Effect of poly(ethylene glycol) on insulin stability and cutaneous cell proliferation in vitro following cytoplasmic delivery of insulin-loaded nanoparticulate carriers - A potential topical wound management approach.

We describe the development of a nanoparticulate system, with variation of poly(ethylene glycol) (PEG) content, capable of releasing therapeutic levels of bioactive insulin for extended periods of time. Recombinant human insulin was encapsulated in poly(d,l-lactide-co-glycolide) nanoparticles, manufactured with variation in poly(ethylene glycol) content, and shown to be stable for 6days using SDS-PAGE, western blot and MALDI MS. To determine if insulin released from this sustained release matrix could stimulate migration of cell types normally active in dermal repair, a model wound was simulated by scratching confluent cultures of human keratinocytes (HaCaT) and fibroblasts (Hs27). Although free insulin was shown to have proliferative effect, closure of in vitro scratch fissures was significantly faster following administration of nano-encapsulated insulin. This effect was more pronounced in HaCaT cells when compared to Hs27 cells. Variation in PEG content had the greatest effect on NP size, with a lesser influence on scratch closure times. Our work supports a particulate uptake mechanism that provides for intracellular insulin delivery, leading to enhanced cell proliferation. When placed into an appropriate topical delivery vehicle, such as a hydrogel, the extended and sustained topical administration of active insulin delivered from a nanoparticulate vehicle shows promise in promoting tissue healing.

Niosomes for oral delivery of nateglinide: in situ-in vivo correlation.

Niosomes have been claimed to enhance intestinal absorption and to widen the absorption window of acidic drugs. This was reported after monitoring the intestinal absorption in situ. Accordingly, the aim of this work was to investigate the effect of niosomal encapsulation on intestinal absorption and oral bioavailability of nateglinide. This was conducted with the goal of correlation between in situ intestinal absorption and in vivo availability. The drug was encapsulated into proniosomes. The niosomes resulting after hydration of proniosomes were characterized with respect to vesicle size and drug entrapment efficiency. The in situ rabbit intestinal absorption of nateglinide was monitored from its aqueous solution and niosomes. Streptozotocin was used to induce diabetes in albino rats which were then used to assess the hypoglycemic effect of nateglinide after oral administration of aqueous dispersion and niosomal systems. The prepared vesicles were in the nanoscale with the recorded size being 283 nm. The entrapment efficiency depended on the pH of the formulation. The in situ intestinal absorption reflected non-significant alteration in the membrane transport parameters of the drug after niosomal encapsulation compared with the free drug solution. In contrast, niosomes showed significant improvement in the rate and extent of the hypoglycemic effect compared with the unprocessed drug. This discrepancy can be attributed to different transport pathway for the drug after niosomal inclusion with the vesicles undergoing translymphatic transport which can minimize presystemic metabolism. However, this requires confirmatory investigations. In conclusion niosomes can enhance oral bioavailability of nateglinide with the absorption being through nontraditional pathway.