Preparation and characterisation of self-emulsifying drug delivery system (SEDDS) for enhancing oral bioavailability of metformin hydrochloride using hydrophobic ion pairing complexation.

AIM: The aim of this study was preparation of a self-emulsifying drug delivery system (SEEDS) containing metformin hydrochloride. METHODS: Hydrophobic ion paired complexes were prepared by electrostatic interaction between metformin and sodium lauryl sulphate (SLS). The nanodroplets were optimised using two-level full factorial methodology and their morphology were examined. In vitro release of metformin from SEDDS was evaluated in simulated gastric and intestinal fluids. Finally, the ex-vivo efficacy of the optimised formulation in enhancing the intestinal permeability of metformin was evaluated using non-everted intestinal sac. RESULTS: The data revealed that in weight ratio 1:4(metformin: SLS), the highest recovery was achieved. The physico-chemical properties of the optimised nano-droplets including size, polydispersity index (PdI), zeta potential, and loading efficiency (%) were 192.33 ± 9.9 nm, 0.275 ± 0.051; -1.52 mV, and 93.75 ± 0.77% (w/w), respectively. CONCLUSIONS: The data obtained from the intestinal transport study demonstrated that SEDDS can significantly enhance the oral permeability of the compound.

Nano optical and electrochemical sensors and biosensors for detection of narrow therapeutic index drugs.

For the first time, a comprehensive review is presented on the quantitative determination of narrow therapeutic index drugs (NTIDs) by nano optical and electrochemical sensors and biosensors. NTIDs have a narrow index between their effective doses and those at which they produce adverse toxic effects. Therefore, accurate determination of these drugs is very important for clinicians to provide a clear judgment about drug therapy for patients. Routine analytical techniques have limitations such as being expensive, laborious, and time-consuming, and need a skilled user and therefore  the nano/(bio)sensing technology leads to high interest.

Hydrophobic ion pairing with cationic derivatives of α-, ß-, and γ-cyclodextrin as a novel approach for development of a self-nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin.

To enhance the oral bioavailability of heparin, a self-nano-emulsifying drug delivery system (SNEDDS) was developed using hydrophobic ion-pairing with cationic polymers of α-, ß-, and γ-cyclodextrins (CPCDs). Hydrophobic ion paired complexes were formed, and the recovery of heparin was determined in n-hexane and isopropyl myristate (IPM). The SNEDDSs were prepared and were optimized using D-optimal response surface methodology (RSM). The determination of the recovery of complexes in IPM revealed that in cationic α-cyclodextrin, the highest recovery was achieved at the heparin: CPCD weight ratio of 1:0.5. However, in cationic ß-cyclodextrin the highest recovery was obtained at the weight ratio of 1:4. Similar to CPßCD, for ealed that in c the highest recovery was obtained at 1:4 weight ratio. The size of optimized nano-droplets was found to be 127.00 ± 4.1, 184.00 ± 6.43, and 216.00 ± 5.43 nm; polydispersity index (PdI) values were reported as 0.372 ± 0.005, 0.163 ± 0.008, 0.236 ± 0.003; and calculated loading efficiency (LE%) were 84.60 ± 3.62, 91.06 ± 2.49, and 92.81 ± 0.70% for SNEDDS preparations incorporating cationic derivatives of α-, ß-, and γ-cyclodextrin, respectively. The in vitro release study revealed that SNEDDS preparations containing cationic γ-cyclodextrin posed the slowest release rate. Data achieved from cellular uptake study showed that the SNEDDS containing α-cyclodextrin had the highest cumulative uptake percentage after 6 h post-exposure; same results were obtained in the intestinal transport study demonstrating SNEDDS containing α-cyclodextrin posed the highest transport efficiency with Papp of 24.85 × 10-r ± 1.06 × 10-± cm.s-m.

Pharmacokinetics and brain distribution studies of perphenazine-loaded solid lipid nanoparticles.

BACKGROUND: Perphenazine (PPZ) is a typical antipsychotic that is mainly administrated for the treatment of schizophrenia. Due to its highly lipophilic nature and extensive hepatic first-pass metabolism, its oral bioavailability is low (40%). OBJECTIVE: The novel nanocarriers like solid lipid nanoparticles (SLN) have been reported to be highly effective for improving the therapeutic effect of drugs. Therefore the main scope of the present investigation was the evaluation of in vivo characteristics of PPZ-SLN in terms of pharmacokinetic parameters and brain distribution. METHODS: The PPZ-SLN was prepared by the solvent-emulsification and evaporation method. The storage stability of PPZ-SLN and empty SLN powders was studied for 3 months. In vivo pharmacokinetic studies and brain distribution evaluations were performed following a single oral dose administration of PPZ and PPZ-SLN suspensions on male Wistar rats. An HPLC method was established and validated for the quantitative determination of PPZ in plasma and brain samples. RESULTS: The storage stability studies revealed the good storage stability of the both PPZ-SLN and empty SLN at 4 °C. Compared to PPZ suspension, the relative bioavailability and the brain distribution of PPZ-SLN were increased up to 2-fold and 16-fold, respectively. Mean residence time (MRT) and half-life (t1/2) of PPZ-SLN were significantly (p value < 0.01) increased in both plasma and brain homogenate compared to PPZ suspension. CONCLUSION: The significant improvement in the pharmacokinetic properties of PPZ following one oral dose indicates that SLN is a promising drug delivery system for PPZ and shows a high potential for successful brain delivery of this antipsychotic.

Preparation, statistical optimization, in vitro characterization, and in vivo pharmacological evaluation of solid lipid nanoparticles encapsulating propolis flavonoids: a novel treatment for skin edema.

Propolis is a natural resinous product and exerts anti-inflammatory properties. The aim of this study is formulation and characterization of solid lipid nanoparticles (SLNs) encapsulating propolis flavonoids (PFs), intended for topical treatment of skin edema. The nanoparticles were prepared and statistically optimized using Box-Behnken response surface methodology. The in vitro release profile of the optimized nanoparticles was investigated. Cytotoxicity of nanoparticles on HSF-PI 18 cell line was determined. Permeation and penetration of nanoparticles across the incised skin were measured. Finally, the nanoparticles were incorporated into a pharmaceutical hydrogel formulation and the in vivo efficacy in reduction of skin edema was determined. The size, PdI, zeta potential, entrapment efficiency (EE%) and loading efficiency (LE %) of the optimized nanoparticles were 111.3 ± 19.35 nm, 0.34 ± 0.005, -24.17 ± 3.3 mV, 73.5 ± 0.86%, and 3.2 ± 0.27%, respectively. Data obtained through in vitro release study suggested a burst release followed by a prolonged release behavior up to 24 h post incubation time interval. The prepared SLNs exhibited no cytotoxicity on HSF-PI 18 cell line. Ex vivo permeation and penetration study of nanoparticles across the incised skin showed approximately a 2.5-fold and a 3-fold increase in cumulative amount of transport and cumulative amount of skin penetration, respectively. Finally, in vivo studies in rat models, showed a threefold reduction in volume of the edema in animals treated with SLNs. The obtained data revealed that the prepared SNs entrapping PFs, exert high skin targeting effects, prolonged anti-inflammatory properties and therefore high efficiency in treatment of skin edema.

Preparation and characterization of self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin using hydrophobic complexation by cationic polymer of ß-cyclodextrin.

OBJECTIVE: The aim of this study was the preparation of a self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin. SIGNIFICANCE: Preparation of hydrophobic complexes between heparin as the hydrophilic macromolecule and cationic polymer of ß-cyclodextrin (CPßCD) was considered for preparation of orally administered SNEDDS in which the drug incorporated in internal oil phase of O/W nano-droplets. METHODS: Hydrophobic complexes of heparin-CPßCD were prepared by electrostatic interaction. The lipophilic feature of complexes was characterized by determining their partition co-efficients. SNEDDS prototypes were prepared by mixing liquid paraffin, Tween 80, propylene glycol and ethanol, diluted 1:100 in an aqueous medium. Central composite response surface methodology was applied for statistical optimization. Independent variables were the amount of liquid paraffin and the amount of Tween 80, while responses were size and poly dispersity index (PdI). Optimized SNEDDS were studied morphologically using transmission electron microscopy (TEM). In vitro release of heparin was studied in the simulated gastric and simulated intestinal media. RESULTS: The data revealed that in molar ratio 1:3 (heparin:CPßCD), the n-octanol recovery was maximized and reached 67.6 ± 11.86%. Size, PdI, zeta potential, EE% in gastric medium and EE% in intestinal medium for optimized nano-droplets were reported as 307 ± 30.51 nm, 0.236 ± 0.02, +2.1 ± 0.66 mV, 90.2 ± 0.04 and 96.1 ± 0.73%, respectively. Microscopic images revealed spherical nano-droplets. The obtained data revealed no burst release of heparin from nano-droplets. CONCLUSIONS: The obtained results indicate that SNEDDS could be regarded as a good candidate for oral delivery of heparin as the hydrophilic macromolecule.

Preparation and optimization of N-trimethyl-O-carboxymethyl chitosan nanoparticles for delivery of low-molecular-weight heparin.

The aim of this study was preparation, optimization and in vitro characterization of nanoparticles composed of 6-[O-carboxymethyl]-[N,N,N-trimethyl] (TMCMC) for oral delivery of low-molecular-weight heparin. The chitosan derivative was synthesized. Nanoparticles were prepared using the polyelectrolyte complexation method. Box-Behnken response surface experimental design methodology was used for optimization of nanoparticles. The morphology of nanoparticles was studied using transmission electron microscopy. In vitro release of enoxaparin from nanoparticles was determined under simulated intestinal fluid. The cytotoxicity of nanoparticles on a Caco-2 cell line was determined, and finally the transport of prepared nanoparticles across Caco-2 cell monolayer was defined. Optimized nanoparticles with proper physico-chemical properties were obtained. The size, zeta potential, poly-dispersity index, entrapment efficiency and loading efficiency of nanoparticles were reported as 235 ± 24.3 nm, +18.6 ± 2.57 mV, 0.230 ± 0.03, 76.4 ± 5.43% and 12.6 ± 1.37%, respectively. Morphological studies revealed spherical nanoparticles with no sign of aggregation. In vitro release studies demonstrated that 93.6 ± 1.17% of enoxaparin released from nanoparticles after 600 min of incubation. MTT cell cytotoxicity studies showed no cytotoxicity at 3 h post-incubation, while the study demonstrated concentration-dependent cytotoxicity after 24 h of exposure. The obtained data had shown that the nanoparticles prepared from trimethylcarboxymethyl chitosan may be considered as a good candidate for oral delivery of enoxaparin.

Development and validation of a novel, simple, and accurate spectrophotometric method for the determination of lead in human serum.

The determination of blood lead levels is the most useful indicator of the determination of the amount of lead that is absorbed by the human body. Various methods, like atomic absorption spectroscopy (AAS), have already been used for the detection of lead in biological fluid, but most of these methods are based on complicated, expensive, and highly instructed instruments. In this study, a simple and accurate spectroscopic method for the determination of lead has been developed and applied for the investigation of lead concentration in biological samples. In this study, a silica gel column was used to extract lead and eliminate interfering agents in human serum samples. The column was washed with deionized water. The pH was adjusted to the value of 8.2 using phosphate buffer, and then tartrate and cyanide solutions were added as masking agents. The lead content was extracted into the organic phase containing dithizone as a complexion reagent and the dithizone-Pb(II) complex was formed and approved by visible spectrophotometry at 538 nm. The recovery was found to be 84.6 %. In order to validate the method, a calibration curve involving the use of various concentration levels was calculated and proven to be linear in the range of 0.01-1.5 µg/ml, with an R (2) regression coefficient of 0.9968 by statistical analysis of linear model validation. The largest error % values were found to be -5.80 and +11.6 % for intra-day and inter-day measurements, respectively. The largest RSD % values were calculated to be 6.54 and 12.32 % for intra-day and inter-day measurements, respectively. Further, the limit of detection (LOD) was calculated to be 0.002 µg/ml. The developed method was applied to determine the lead content in the human serum of voluntary miners, and it has been proven that there is no statistically significant difference between the data provided from this novel method and the data obtained from previously studied AAS.

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release.

It was the aim of this study to evaluate the impact of lipases on the release behaviour of a peptide drug from oral self-nanoemulsifying drug delivery systems. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate, oleate and dodecylsulphate. The lipophilic character of these complexes was characterised by determining the n-octanol/buffer pH 7.4 partition coefficient. In the following the most hydrophilic complex was incorporated in a likely lipase degradable self-nanoemulsifying drug delivery systems (SNEDDS) formulation containing a triglyceride (olive oil; Pharm.Eur.) and in a likely not lipase degradable SNEDDS containing lipids and surfactants without any ester bonds. After 1:100 dilutions in artificial intestinal fluid (AIF), the lipid droplets were characterised regarding size distribution. With these SNEDDS, drug release studies were performed in AIF with and without lipase. Results showed that the most hydrophobic complex can be formed with deoxycholate in an octreotide:anionic surfactant ratio of 1:5. Even 73.1 ± 8.1% of it could be quantified in the n-octanol phase. SNEDDS containing octreotide | olive oil | cremophor EL | propylene glycol (2|57|38|3) and octreotide | liquid paraffin | Brij 35 | propylene glycol | ethanol (2|66.5|25|5|1.5) showed after dilution in AIF, a mean droplet size of 232 ± 53 nm and 235 ± 50 nm, respectively. Drug release studies showed a sustained release of octreotide out of these formulations for at least 24 h, whereas > 80% of the drug was released within 2 h in the presence of lipase in the case of the triglyceride containing SNEEDS. In contrast the release profile from ester-free SNEDDS was not significantly altered (p < 0.05) due to the addition of lipase providing evidence for the stability of this formulation towards lipases. According to these results, SNEDDS could be identified as a useful tool for sustained oral peptide delivery taking an enzymatic degradation by intestinal lipases into considerations.

Controlled-release drug delivery system based on fluocinolone acetonide-cyclodextrin inclusion complex incorporated in multivesicular liposomes.

Multivesicular liposomes (MVLs) have been widely studied for encapsulation of hydrophilic drugs due to their structural properties and large aqueous inner cavities. In this study, to investigate MVLs and their potential application for incorporation of hydrophobic drugs, new drug delivery system for fluocinolone acetonide (FA), as a lipophilic model drug, was developed combining the advantages of cyclodextrin inclusion complexes (CD-IC) and multivesicular liposomes. FA was complexed with several CDs to form inclusion complex (FA-CD-IC) and then FA-CD-IC was incorporated into MVLs by reverse-phase evaporation method. Physicochemical characterization of drug-CD-IC, at a molar ratio of 1:1 (drug to CD) was studied using 1HNMR, FT-IR, DSC and UV spectroscopy. The influence of various types of CDs on the aqueous solubility of FA, encapsulation efficiency and release profile in MVLs was studied. The results revealed the formation of inclusion complexes between the drug and CDs. Both the CD's type and proportion played an important role in the physicochemical properties of the systems. The inclusion complex of the drug with hydroxypropyl-ß-cyclodextrin exhibited the most appropriate loading and sustained-release profile over prolonged periods. The results reveal the promising potential of MVLs as a stable drug delivery system to release the drug in a sustained manner for the treatment of ocular inflammatory disease.