A modified spontaneous emulsification solvent diffusion method for the preparation of curcumin-loaded PLGA nanoparticles with enhanced in vitro anti-tumor activity

To improve the anti-tumor activity of hydrophobic drug curcumin, we prepared curcumin-loaded PLGA nanoparticles （PLGA-Cur NPs） through a modified spontaneous emulsification solvent diffusion （modified-SESD） method. The influence of main preparation parameters was investigated, such as the volume ratio of binary organic solvents and the concentration of surfactant. Results indicated that the synthesized regular spherical PLGA NPs with the average diameter of 189.7 nm exhibited relatively higher yield （58.9%）, drug loading （11.0% （w/w）） and encapsulation efficiency （33.5%）, and also a controllable drug release profile. In order to evaluate the in vitro cytotoxicity of the prepared NPs, MTT assay was conducted, and results showed that the NPs could effectively inhibit HL60 and HepG2 cells with lower IC50 values compared with free curcumin. Furthermore, confocal microscopy together with flow cytometry analysis proved the enhanced apoptosis-inducing ability of PLGA-Cur NPs. Polymeric NP formulations are potential to be used for hydrophobic drug delivery systems in cancer therapy.     

A fibrin gel loaded with chitosan nanoparticles for local delivery of rhEGF: preparation and in vitro release studies

Recombinant human epidermal growth factor (rhEGF) is known to stimulate cell proliferation and accelerate wound healing. Direct delivery of rhEGF at the wound site in a sustained and controllable way without loss of bioactivity would enhance its biological effects. The aim of this study was to prepare a novel local delivery system for the sustained and controllable release of rhEGF, a fibrin gel loaded with chitosan nanoparticles. First, rhEGF-loaded chitosan nanoparticles were prepared and characterized, and these showed an ability to protect rhEGF from proteolysis. The prepared nanoparticles were then incorporated into a fibrin gel matrix during polymerization. In vitro release studies showed that the fibrin gel loaded with rhEGF/chitosan nanoparticles could achieve a more sustained release of rhEGF than either chitosan nanoparticles or an unloaded fibrin gel. Additionally, the release rate could be controlled by altering the contents of fibrinogen and thrombin in this composite delivery system. The bioactivity of the released rhEGF was determined by assessing its ability to stimulate the proliferation of BALB/c 3T3 cells, and the results showed that rhEGF bioactivity was not affected during the preparation process and could be maintained for at least 7 days. This novel delivery system may have great potential applications in the local administration of rhEGF.     

Biodegradable PLGA85/15 nanoparticles as a delivery vehicle for Chlamydia trachomatis recombinant MOMP-187 peptide

Development of a Chlamydia trachomatis vaccine has been a formidable task partly because of an ineffective delivery system. Our laboratory has generated a recombinant peptide of C. trachomatis major outer membrane protein (MOMP) (rMOMP-187) and demonstrated that it induced at 20 μg ml(-1) maximal interleukin (IL)-6 and IL-12p40 Th1 cytokines in mouse J774 macrophages. In a continuous pursuit of a C. trachomatis effective vaccine-delivery system, we encapsulated rMOMP-187 in poly(d,l-lactic-co-glycolic acid) (PLGA, 85:15 PLA/PGA ratio) to serve as a nanovaccine candidate. Physiochemical characterizations were assessed by Fourier transform-infrared spectroscopy, atomic force microscopy, Zetasizer, Zeta potential, transmission electron microcopy and differential scanning calorimetry. The encapsulated rMOMP-187 was small (～200 nm) with an apparently smooth uniform oval structure, thermally stable (54?°C), negatively charged ( - 27.00 mV) and exhibited minimal toxicity at concentrations <250 μg ml (-1) to eukaryotic cells (>95% viable cells) over a 24-72 h period. We achieved a high encapsulation efficiency of rMOMP-187 (～98%) in PLGA, a loading peptide capacity of 2.7% and a slow release of the encapsulated peptide. Stimulation of J774 macrophages with a concentration as low as 1 μg ml (-1) of encapsulated rMOMP-187 evoked high production levels of the Th1 cytokines IL-6 (874 pg ml(-1)) and IL-12p40 (674 pg ml(-1)) as well as nitric oxide (8 μM) at 24 h post-stimulation, and in a dose-response and time-kinetics manner. Our data indicate the successful encapsulation and characterization of rMOMP-187 in PLGA and, more importantly, that PLGA enhanced the capacity of the peptide to induce Th1 cytokines and NO in vitro. These findings make this nanovaccine an attractive candidate in pursuit of an efficacious vaccine against C. trachomatis.     

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization,in vitro characterization,cell line studies and in vivo efficacy in schizophrenia

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration.

Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies.

Results: The LH-SLNs had PS of 139.8?±?5.5?nm, EE of 79.10?±?2.50% and zeta potential of ?30.8?±?3.5?mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia.

Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.     

Insulin nanoparticles for transdermal delivery: preparation and physicochemical characterization and in vitro evaluation

Aim: This work is aimed to study the feasibility of insulin nanoparticles for transdermal drug delivery (TDD) using supercritical antisolvent (SAS) micronization process. Methods: The influences of various experimental factors on the mean particle size (MPS) of insulin nanoparticles were investigated. Moreover, the insulin nanoparticles obtained were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric (TG) analyses. Results: Under optimum conditions, uniform spherical insulin nanoparticles with a MPS of 68.2?±?10.8 nm were obtained. The Physicochemical characterization results showed that SAS process has not induced degradation of insulin. Evaluation in vitro showed that insulin nanoparticles were accorded with the Fick's first diffusion law and had a high permeation rate. Conclusion: These results suggest that insulin nanoparticles can have a great potential in TDD systems of diabetes chemotherapy.     

Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro,ex vivo and in vivo characterizations

Objective: The purpose of this research was the development, in vitro, ex vivo and in vivo characterization of lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan.

Methods: Insulin nanoparticles were prepared from methylated N-(4-N,N-dimethylaminobenzyl), methylated N-(4 pyridinyl) and methylated N-(benzyl). Insulin nanoparticles containing non-modified chitosan and also trimethyl chiotsan (TMC) were also prepared as control. The effects of the freeze-drying process on physico-chemical properties of nanoparticles were investigated. The release of insulin from the nanoparticles was studied in vitro. The mechanism of the release of insulin from different types of nanoparticles was determined using curve fitting. The secondary structure of the insulin released from the nanoparticles was analyzed using circular dichroism and the cell cytotoxicity of nanoparticles on a Caco-2 cell line was determined. Ex vivo studies were performed on excised rat jejunum using Frantz diffusion cells. In vivo studies were performed on diabetic male Wistar rats and blood glucose level and insulin serum concentration were determined.

Results: Optimized nanoparticles with proper physico-chemical properties were obtained. The lyophilization process was found to cause a decrease in zeta potential and an increase in PdI as well as and a decrease in entrapment efficiency (EE%) and loading efficiency (LE%) but conservation in size of nanoparticles. Atomic force microscopy (AFM) images showed non-aggregated, stable and spherical to sub-spherical nanoparticles. The in vitro release study revealed higher release rates for lyophilized compared to non-lyophilized nanoparticles. Cytotoxicity studies on Caco-2 cells revealed no significant cytotoxicity for prepared nanoparticles after 3-h post-incubation but did show the concentration-dependent cytotoxicity after 24?h. The percentage of cumulative insulin determined from ex vivo studies was significantly higher in nanoparticles prepared from quaternized aromatic derivatives of chitosan. In vivo data showed significantly higher insulin intestinal absorption in nanoparticles prepared from methylated N-(4-N, N-dimethylaminobenzyl) chitosan nanoparticles compared to trimethyl chitosan.

Conclusion: These data obtained demonstrated that as the result of optimized physico-chemical properties, drug release rate, cytotoxicity profile, ex vivo permeation enhancement and increased in vivo absorption, nanoparticles prepared from N-aryl derivatives of chitosan can be considered as valuable method for the oral delivery of insulin.     

Preparation,characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting.

Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques.

Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67?±?6.43?nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100?nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p?Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.     

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation,optimization and in vivo evaluation

Objective: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery.

Materials and methods: Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug–excipients interactions, powder X-ray diffraction analysis and drug release in vitro.

Results and discussion: The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100?nm, PDI 0.291, zeta potential of ?23.4?mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration.

Conclusion: In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.     

Rapid preparation of pH-sensitive polymeric nanoparticle with high loading capacity using electrospray for oral drug delivery

Drug loading capacity is an important property for an ideal drug delivery system. However, the drug loading capacity of prepared pH-sensitive polymeric nanoparticles is usually low. To overcome this drawback, the electrospray method was used to prepare Eudragit L 100-55 nanoparticles with high drug loading capacity in one step. Omeprazole was selected as the model drug. The maximum loading capacity of nanoparticles was 43.21% by changing the mass ratio of drug to polymer, and the entrapment efficiency was nearly 100%. The prepared nanoparticle showed spherical or ellipsoidal morphology and the average diameter was about 300 nm. The pH-sensitive nanoparticle displayed pH-dependent release in vitro. In addition, a slight cytotoxicity was detected in the cytotoxicity study. The results indicated that electrospray is an easy, rapid and efficient technique for the preparation of high-loading pH-sensitive polymeric nanoparticles, and the pH-sensitive nanoparticle is a promising carrier for oral drug delivery.     

Preparation of PLGA nanoparticles using TPGS in the spontaneous emulsification solvent diffusion method

D-alpha-tocopheryl poly (ethylene glycol) 1000 succinate (TPGS) is a widely used form of vitamin E that has been used as a solubilizer, an emulsifier and as a vehicle for drug delivery formulations. In this study, poly lactide-co-glycolide (PLGA) nanoparticles were prepared by spontaneous emulsification solvent diffusion (SESD) method. TPGS as an emulsifier and further as a matrix material blended with PLGA was used to enhance the encapsulation efficiency and improve the drug release profile of nanoparticles. Rifampicin and estradiol valerate were used as model drugs with different water solubility. The effect of formulation parameters such as drug/polymer ratio, oil phase combination, volume and surfactant content was evaluated. The surface morphology and size of the nanoparticles were studied by scanning electron microscopy (SEM) and laser light scattering. Drug encapsulation efficiency and in vitro drug release profiles of nanoparticles were determined using high performance liquid chromatography (HPLC). The nanoparticles prepared in this study were spherical with size range of 150–250?nm. It was shown that TPGS was a good emulsifier for producing nanoparticles of hydrophobic drugs and improving the encapsulation efficiency and drug loading and drug release profile of nanoparticles. However, the drug loading efficiency of rifampicin, a slightly water-soluble molecule, was significantly lower than that of estradiol valerate, a water insoluble molecule.     

Oral insulin delivery by self-assembled chitosan nanoparticles: In vitro and in vivo studies in diabetic animal model

We have developed self-assembled chitosan/insulin nanoparticles for successful oral insulin delivery. The main purpose of our study is to prepare chitosan/insulin nanoparticles by self-assembly method, to characterize them and to evaluate their efficiency in vivo diabetic model. The size and morphology of the nanoparticles were analyzed by dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM). The average particle size ranged from 200 to 550 nm, with almost spherical or sub spherical shape. An average insulin encapsulation within the nanoparticles was ~ 85%. In vitro release study showed that the nanoparticles were also efficient in retaining good amount of insulin in simulated gastric condition, while significant amount of insulin release was noticed in simulated intestinal condition. The oral administrations of chitosan/insulin nanoparticles were effective in lowering the blood glucose level of alloxan-induced diabetic mice. Thus, self-assembled chitosan/insulin nanoparticles show promising effects as potential insulin carrier system in animal models.     

Surface-modified superparamagnetic nanoparticles for drug delivery: preparation, characterization, and cytotoxicity studies

Superparamagnetic iron oxide nanoparticles have been used for many years as magnetic resonance imaging (MRI) contrast agents or in drug delivery applications. In this study, a novel approach to prepare magnetic polymeric nanoparticles with magnetic core and polymeric shell using inverse microemulsion polymerization process is reported. Poly(ethyleneglycol) (PEG)-modified superparamagnetic iron oxide nanoparticles with specific shape and size have been prepared inside the aqueous cores of AOT/n-Hexane reverse micelles and characterized by various physicochemical means such as transmission electron microscopy (TEM), infrared spectroscopy, atomic force microscopy (AFM), vibrating sample magnetometry (VSM), and ultraviolet/visible spectroscopy. The inverse microemulsion polymerization of a polymerizable derivative of PEG and a cross-linking agent resulted in a stable hydrophilic polymeric shell of the nanoparticles. The results taken together from TEM and AFM studies showed that the particles are spherical in shape with core-shell structure. The average size of the PEG-modified nanoparticles was found to be around 40-50 nm with narrow size distribution. The magnetic measurement studies revealed the superparamagnetic behavior of the nanoparticles with saturation magnetization values between 45-50 electromagnetic units per gram. The cytotoxicity profile of the nanoparticles on human dermal fibroblasts as measured by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the particles are nontoxic and may be useful for various in vivo and in vitro biomedical applications.     

Enhanced efficacy of clindamycin hydrochloride encapsulated in PLA/PLGA based nanoparticle system for oral delivery

Clindamycin hydrochloride (CLH) is a clinically important oral antibiotic with wide spectrum of antimicrobial activity that includes gram‐positive aerobes (staphylococci, streptococci etc.), most anaerobic bacteria, Chlamydia and certain protozoa. The current study was focused to develop a stabilised clindamycin encapsulated poly lactic acid (PLA)/poly (D,L‐lactide‐co‐glycolide) (PLGA) nano‐formulation with better drug bioavailability at molecular level. Various nanoparticle (NPs) formulations of PLA and PLGA loaded with CLH were prepared by solvent evaporation method varying drug: polymer concentration (1:20, 1:10 and 1:5) and characterised (size, encapsulation efficiency, drug loading, scanning electron microscope, differential scanning calorimetry [DSC] and Fourier transform infrared [FTIR] studies). The ratio 1:10 was found to be optimal for a monodispersed and stable nano formulation for both the polymers. NP formulations demonstrated a significant controlled release profile extended up to 144 h (both CLH‐PLA and CLH‐PLGA). The thermal behaviour (DSC) studies confirmed the molecular dispersion of the drug within the system. The FTIR studies revealed the intactness as well as unaltered structure of drug. The CLH‐PLA NPs showed enhanced antimicrobial activity against two pathogenic bacteria Streptococcus faecalis and Bacillus cereus. The results notably suggest that encapsulation of CLH into PLA/PLGA significantly increases the bioavailability of the drug and due to this enhanced drug activity; it can be widely applied for number of therapies.Inspec keywords: drug delivery systems, biomedical materials, antibacterial activity, nanoparticles, nanomedicine, microorganisms, polymers, nanofabrication, differential scanning calorimetry, encapsulation, drugs, scanning electron microscopy, Fourier transform infrared spectraOther keywords: Streptococcus faecalis, Bacillus cereus, DSC, stable nanoformulation, monodispersed nanoformulation, pathogenic bacteria, FTIR spectra, molecular dispersion, thermal behaviour, controlled release profile, Fourier transform infrared spectra, differential scanning calorimetry, scanning electron microscopy, drug loading, encapsulation efficiency, polymer concentration, solvent evaporation method, molecular level, drug bioavailability, stabilised clindamycin encapsulated poly lactic acid‐poly (D,L‐lactide‐co‐glycolide) nanoformulation, protozoa, Chlamydia, anaerobic bacteria, gram‐positive aerobes, antimicrobial activity, oral antibiotics, oral delivery, PLA‐PLGA based nanoparticle system, clindamycin hydrochloride     

Cholesterol derivative-based liposomes for gemcitabine delivery: preparation,in vitro,and in vivo characterization

As an anti-tumor drug, gemcitabine (Gem) is commonly used for the treatment of non-small cell lung cancer and pancreatic cancer. However, there are several clinical drawbacks to using Gem, including its extremely short plasma half-life and side effects. To prolong its half-life and reduce its side effects, we synthesized a derivative of Gem using cholesterol (Chol). This derivative, called gemcitabine-cholesterol (Gem-Chol), was entrapped into liposomes by a thin-film dispersion method. The particle size of the Gem-Chol liposomes was 112.57?±?1.25?nm, the encapsulation efficiency was above 99%, and the drug loading efficiency was about 50%. In vitro studies revealed that the Gem-Chol liposomes showed delayed drug release and long-term stability at 4?°C for up to 2 months. In vivo studies also showed the superiority of the Gem-Chol liposomes, and compared with free Gem, the Gem-Chol liposomes had longer circulation time. Moreover, an anti-tumor study in H₂₂ and S180 tumor models showed that liposomal entrapment of Gem-Chol improved the anti-tumor effect of Gem. This study reports a potential formulation of Gem for clinical application.     

Development and in vitro evaluation of oxytetracycline‐loaded PMMA nanoparticles for oral delivery against anaplasmosis

Poly‐methyl methacrylate (PMMA) polymer with remarkable properties and merits are being preferred in various biomedical applications due to its biocompatibility, non‐toxicity and cost effectiveness. In this investigation, oxytetracycline‐loaded PMMA nanoparticles were prepared using nano‐precipitation method for the treatment of anaplasmosis. The prepared nanoparticles were characterised using dynamic light scattering (DLS), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The mean average diameter of the nanoparticles ranged between 190–240 nm and zeta potential was found to be −19 mV. The drug loading capacity and entrapment efficiency of nanoparticles was found varied between 33.7–62.2% and 40.5–60.0%. The in vitro drug release profile exhibited a biphasic phenomenon indicating controlled drug release. The uptake of coumarin‐6(C‐6)‐loaded PMMA nanoparticles in Plasmodium falciparum (Pf 3D7) culture model was studied. The preferential uptake of C‐6‐loaded nanoparticles by the Plasmodium infected erythrocytes in comparison with the uninfected erythrocytes was observed under fluorescence microscopy. These findings suggest that oxytetracycline‐loaded PMMA nanoparticles were found to be an effective oral delivery vehicle and an alternative pharmaceutical formulation in anaplasmosis treatment, too.Inspec keywords: nanoparticles, nanomedicine, conducting polymers, microorganisms, cellular biophysics, toxicology, drug delivery systems, light scattering, atomic force microscopy, differential scanning calorimetry, Fourier transform infrared spectra, bloodOther keywords: in vitro evaluation, oxytetracycline‐loaded PMMA nanoparticles, anaplasmosis, polymethyl methacrylate polymer, biocompatibility, toxicity, oxytetracycline‐nanoparticles, nanoprecipitation method, dynamic light scattering, atomic force microscopy, AFM, differential scanning calorimetry, DSC, Fourier transform infrared spectroscopy, FTIR spectroscopy, zeta potential, drug loading capacity, entrapment efficiency, in vitro drug release profile, biphasic phenomenon, coumarin‐6(C‐6)‐loaded PMMA nanoparticles, plasmodium falciparum culture model, preferential uptake, plasmodium infected erythrocytes, fluorescence microscopy, oral delivery vehicle, anaplasmosis treatment, size 190 nm to 240 nm     

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

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

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

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

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

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

Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation

Isradipine (ISR) is a potent calcium channel blocker with low oral bioavailability due to low aqueous solubility, extensive first-pass metabolism and P-glycoprotein (P-gp)-mediated efflux transport. In the present investigation, an attempt was made to develop isradipine-loaded self-nano emulsifying powders (SNEP) for improved oral delivery. The liquid self-nano emulsifying formulations (L-SNEF/SNEF) of isradipine were developed using vehicles with highest drug solubility, i.e. Labrafil® M 2125 CS as oil phase, Capmul® MCM L8 and Cremophor® EL as surfactant/co-surfactant mixture. The developed formulations revealed desirable characteristics of self-emulsifying system such as nano-size globules ranging from 32.7 to 40.2?nm, rapid emulsification (around 60?s), thermodynamic stability and robustness to dilution. The optimized stable self-nano emulsifying formulation (SNEF₂) was transformed into SNEP using Neusilin US2 (SNEP_N) as adsorbent inert carrier, which exhibited similar characteristics of liquid SNEF. The solid state characterization of SNEP_N by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopic studies shown transformation of crystalline drug into amorphous form or molecular state without any chemical interaction. The in vitro dissolution of SNEP_N compared to pure drug was indicated by 18-fold increased drug release within 5?min. In vivo pharmacokinetic studies in Wistar rats showed significant improvement of oral bioavailability of isradipine from SNEP_N with 3- and 2.5-fold increments in peak drug concentration (C_max), area under curve (AUC_0–∞) compared to pure isradipine. In conclusion, these results signify the improved oral delivery of isradipine from developed SNEP.     

Fabrication strategies and supramolecular interactions of polymer-lipid complex nanoparticles as oral delivery systems

Nano Research - Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug...     

Solid lipid nanoparticles incorporating melatonin as new model for sustained oral and transdermal delivery systems

melatonin (MT) is a hormone produced by the pineal gland at night, involved in the regulation of circadian rhythms. For clinical purposes, exogenous MT administration should mimic the typical nocturnal endogenous MT levels, but its pharmacokinetics is not favourable due to short half-life of elimination. Aim of this study is to examine pharmacokinetics of MT incorporated in solid lipid nanoparticles (SLN), administered by oral and transdermal route. SLN peculiarity consists in the possibility of acting as a reservoir, permitting a constant and prolonged release of the drugs included. In 7 healthy subjects SLN incorporating MT 3 mg (MT-SLN-O) were orally administered at 8.30 a.m. MT 3 mg in standard formulation (MT-S) was then administered to the same subjects after one week at 8.30 a.m. as controls. In 10 healthy subjects SLN incorporating MT were administered transdermally (MT-SLN-TD) by the application of a patch at 8.30 a.m. for 24 hours. Compared to MT-S, Tmax after MT-SLN-O administration resulted delayed of about 20 minutes, while mean AUC and mean half life of elimination was significantly higher (respectively 169944.7 +/- 64954.4 pg/ml x hour vs. 85148.4 +/- 50642.6 pg/ml x hour, p = 0.018 and 93.1 +/- 37.1 min vs. 48.2 +/- 8.9 min, p = 0.009). MT absorption and elimination after MT-SLN-TD demonstrated to be slow (mean half life of absorption: 5.3 +/- 1.3 hours; mean half life of elimination: 24.6 +/- 12.0 hours), so MT plasma levels above 50 pg/ml were maintained for at least 24 hours. This study demonstrates a significant absorption of MT incorporated in SLN, with detectable plasma level achieved for several hours in particular after transdermal administration. As dosages and concentrations of drugs included in SLN can be varied, different plasma level profile could be obtained, so disclosing new possibilities for sustained delivery systems.