Self-nanoemulsifying drug delivery system of persimmon leaf extract: Optimization and bioavailability studies

In current study, a self-nanoemulsifying drug delivery system (SNEDDS) of persimmon (Diospyros kaki) leaf extract (PLE) was developed and characterized to compare its in vitro dissolution and relative bioavailability with commercially available tablets (Naoxinqing tablets). Pseudo-ternary phase diagrams were constructed by phase diagram by micro plate dilution (PDMPD) method, of which the evaluation method was improved to use Multiskan Ascent for identifying turbidity. The formulation of PLE-loaded SNEDDS was optimized by an extreme vertices experimental design. The optimized nanoemulsion formulation, loading with 44.48 mg/g PLE total flavonoids, consisted of Cremophor EL, Transcutol P, Labrafil M 1944 CS (56:34:10, w/w), and it remained stable after storing at 40 °C, 25 °C, 4 °C for at least 6 months. When diluted with water, the SNEDDS droplet size was 34.85 nm and the zeta potential was −6.18 mV. Compared with the commercial tablets, the AUC of both quercetin and kaempferol, which are representative active flavonoids of PLE, was increased by 1.5-fold and 1.6-fold respectively following oral administration of PLE-loaded SNEDDS in fasting beagle dogs. These results indicate that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of PLE.     

Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: Formulation and bioavailability studies

The aim of the present study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of Zedoary turmeric oil (ZTO), an essential oil extracted from the dry rhizome of Curcuma zedoaria. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification regions. ZTO could serve as a partial oil phase with the aid of the second oil phase to enhance drug loading. Increasing the surfactant concentration reduced the droplet size but increased the emulsification time, while the reverse effect was observed by increasing the co-surfactant concentration. Based on the emulsification time, droplet size and zeta potential after dispersion into aqueous phase, an optimized formulation consisting of ZTO, ethyl oleate, Tween 80, transcutol P (30.8:7.7:40.5:21, w/w) and loaded with 30% drug was prepared. Upon mixing with water, the formulation was rapidly dispersed into fine droplets with a mean size of 68.3 ± 1.6 nm and ξ-potential of ?41.2 ± 1.3 mV. The active components remained stable in the optimized SNEDDS stored at 25 °C for at least 12 months. Following oral administration of ZTO-SNEDDS in rats, both AUC and C_max of germacrone (GM), a representative bioactive marker of ZTO, increased by 1.7-fold and 2.5-fold respectively compared with the unformulated ZTO.     

A polymeric micellar carrier for the solubilization of biphenyl dimethyl dicarboxylate

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1 K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialy-sis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1 K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (>5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.     

Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: Preparation and evaluation

Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.     

Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15

Biphenyl dimethyl dicarboxylate (DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for chronic hepatitis. Amantadine is an antiviral agent, which is utilized primarily in the treatment of influenza, but also, occasionally in the treatment of hepatitis C. In a previous study, we reported that DDB, coupled with amantadine, would exert an anti-HBV effect, via the induction of interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not DDB and/or amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that DDB stimulates Jak/Stat signaling, and induces the expression of interferon alpha (IFN-alpha) stimulated genes, most notably 6-16 and ISG12. In addition, the antiviral effectors induced by IFN-alpha, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration (250 microg/mL), to a degree commensurate with the degree of induction associated with the IFN-alpha treated group. Finally, we determined that the replication of pregenomic RNA and HBeAg was inhibited by DDB treatment, and this inhibition was maximized when coupled with the administration of amantadine (25 microg/mL). In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited IFN-alpha signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.     

A novel solid dispersion system for natural product-loaded medicine: silymarin-loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity

Abstract

A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl₄-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin.     

Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability

The objective of this study was to prepare a solid supersaturatable self-emulsifying drug delivery system (S-sSEDDS) using docetaxel (DTX). Different from conventional self-emulsifying drug delivery systems (SEDDSs), a solid supersaturatable self-emulsifying drug delivery system of docetaxel (DTX-S-sSEDDS) was prepared by spray drying, using lactose as the solid carrier and hydroxypropyl methylcellulose (HPMC) as the supersaturation promoter. Physicochemical properties and in vitro dissolution was observed while taking into account factors such as formulations, supersaturated promoters, solid carriers, and preparation methods. The bioavailability of the DTX-S-sSEDDS(1) compared with other formulations of DTX was evaluated in rats. The results showed that the presence of HPMC effectively sustained the supersaturated state by retarding the precipitation kinetics. Although the total amount of emulsifying excipients in the DTX-S-sSEDDS(1) was only 3/5 as much as that of the conventional SEDDS (DTX-SEDDS(2)), the percent of the accumulated dissolved DTX-S-sSEDDS(1) at 2 h reached 90.96%, which was higher than that of the DTX-SEDDS(2) (76.26%) and approximately 29.8 times as much as that of the DTX crude powder. The in vivo studies indicated that the area under the concentration-time curve (AUC(0-∞)) of the DTX-S-sSEDDS(1) increased by nearly 8.77-fold, 1.45-fold more than those of the DTX powder and the conventional SEDDS without the presence of HPMC (DTX-SEDDS(1)) at a dose of 10 mg/kg. In conclusion, the S-sSEDDS provides an effective approach for improving the dissolution and bioavailability of docetaxel with a low level of emulsifying excipients and provides a reference for good stabilization and the safety of SEDDSs.     

Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.     

Effect of biphenyl dimethyl dicarboxylate on the humoral immunosuppression by ketoconazole in mice

The present study was undertaken to investigate the effect of biphenyl dimethyl dicarboxylate (PMC) on the humoral immunosuppression by ketoconazole (KCZ) in ICR mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14 consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered at 160 mg/kg/day 2 hrs after the administration of PMC. Mice were immunized and challenged with sheep red blood cells (SRBC). The results of the present study are summarized as follows; a gain of body weight and relative weights of spleen and liver were significantly increased by combination of PMC and KCZ, as compared with those in mice treated with KCZ alone. Splenic plaque forming cells (PFC) and hemagglutination (HA) titers to SRBC were greatly enhanced by the combination of PMC and KCZ, compared with treatment of KCZ alone. The elevation of serum glutamicpyruvic transaminase (S-GPT) and total protein levels caused by KCZ were reduced to normal level by the combination of PMC and KCZ. In addition, lower serum albumin and A/G ratio were also increased to normal level. These findings indicate that PMC has a protective effect against KCZ-induced humoral immunosuppression.     

Self-nanoemulsifying drug delivery systems of tamoxifen citrate: Design and optimization

Tamoxifen citrate is an antiestrogen for peroral breast cancer treatment. The drug delivery encounters problems of poor water solubility and vulnerability to enzymatic degradation in both intestine and liver. In the current study, tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent such obstacles. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were then constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%) was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 °C. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, our results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.     

Lacidipine self-nanoemulsifying drug delivery system for the enhancement of oral bioavailability

Low bioavailability of Lacidipine (LD), an calcium channel blocker pose many challenges in the treatment of hypertension. The objective of this study was to formulate and characterize LD self-nanoemulsifying drug delivery systems (SNEDDS) to improve oral bioavailability of the drug. Formulations were evaluated for globule size, surface morphology, emulsification time, cloud point, drug content, in vitro dissolution, ex vivo permeation, stability and oral bioavailability studies. Captex 810D, TPGS, Tween-60, Transcutol P and PEG 400 was selected based on the solubility study results. The optimized SNEDDS readily gets nanoemulsified at 37 °C with droplet size of 41 nm when mixed with 200 times of its water. Transmission electron microscope photographs confirmed the spherical shape of the globules. In vitro dissolution of SNEDDS showed more than 80 % of drug release within 15 min. The ex vivo permeation of LD from SNEDDS is 4.8- and 9-fold higher compared to pure drug in the absence and presence of verapamil respectively. The stability study of the SNEDDS confirmed no environmental effect on the physical nature and drug content. Oral bioavailability of SNEDDS is 2.5 times higher than marketed tablet. The results suggest that, the SNEDDS formulation can be used as a possible alternative for the traditional oral formulations of LD to improve its oral bioavailability.     

Optimized self-microemulsifying drug delivery systems (SMEDDS) for enhanced oral bioavailability of astilbin

The main purpose of this research work was to design an optimized self micro-emulsifying drug delivery system (SMEDDS) to enhance the bioavailability of the poor water soluble drug, astilbin. The solubility of astilbin was evaluated in various vehicles. Pseudoternary phase diagrams were used to select the components and their ranges by evaluating the micro-emulsification area. Central composite design was applied to optimize the properties of the formulation, including particle size, polydispersity index, drug loading capacity and effective intestinal permeability. The optimized SMEDDS characteristics were investigated including the study of factors influencing particle size and showed the stability of microemulsion when varying the pH and volume of diluents. In vitro drug release profile study was performed using the reverse dialysis method where 95% of the drug was released after 4 h. The developed astilbin SMEDDS was subjected to bioavailability studies in beagle dogs by LC-MS and showed a significant enhancement of bioavailability, indicating the possibility of using SMEDDS as possible drug carrier for astilbin.     

Effect of biphenyl dimethyl dicarboxylate on the cellular and nonspecific immunosuppressions by ketoconazole in mice

The effect of biphenyl dimethyl dicarboxylate (PMC) on the cellular and nonspecific immunosuppressions by ketoconazole (KCZ) was investigated in ICR mice. PMC at a dose of 6 mg/kg was administered orally to mice daily for 14 consecutive days. KCZ was suspended in RPMI 1640 medium and orally administered at 160 mg/kg/day 2 hrs after the administration of PMC. Immune responses of the delayed-type hypersensitivity (DTH) reaction to sheep red blood cells (SRBC), phagocytic activity and natural killer (NK) cell activity were evaluated. DTH reaction to SRBC was enhanced to normal level by the combination of PMC and KCZ, compared with treatment of KCZ alone. In the combination of PMC and KCZ, as compared with the treatment of KCZ alone, there were also significant increases in activities of natural killer (NK) cells and phagocytes along with circulating leukocytes. These findings indicate that PMC shows a significant restoration from the immunotoxic status induced by KCZ.     

Effect of biphenyl dimethyl dicarboxylate on the cellular and nonspecific immunotoxicity by ethanol in mice

Biphenyl dimethyl dicarboxylate (PMC) has been reported to protect against chronic ethanol toxicity. The present study was conducted to evaluate whether PMC might be accompanied by a reduction of ethanol-induced cellular immunotoxicity. PMC at a dose of 6 mg/kg was orally administered to ICR mice daily for 28 consecutive days, and normal mice were given vehicle. Mice treated with ethanol were given free access to 20% w/v ethanol instead of water. Mice were immunized and challenged with sheep red blood cells (SRBC). Delayed-type hypersensitivity (DTH) reaction to SRBC was increased to normal levels by the combination of PMC and ethanol, compared with the treatment of ethanol alone. Splenic CD4+ cells were also greatly enhanced by PMC treatment as compared with the treatment of ethanol alone. In the case of CD8+ cells, however, a slight reduction was observed by the PMC or ethanol treatment. The natural killer (NK) cell and phagocytic activity used for evaluation of nonspecific immunocompetence were significantly augmented in PMC plus ethanol-treated mice when compared with the treatment of ethanol alone. The number of peripheral leukocytes was significantly decreased by the treatment of ethanol alone, then also restored to normal levels by PMC treatment. These findings indicate that cellular immunotoxicity caused by ethanol consumption is significantly restored or prevented by PMC treatment.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein

The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C_max and AUC for S-SNEDDS. The enhancement of C_max for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.     

Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of protein drugs: III. In vivo oral absorption study

To use self-nanoemulsifying drug delivery system (SNEDDS) to deliver hydrophilic proteins orally. beta-Lactamase (BLM), a 29kDa protein was used as a model protein, and formulated into the oil phase of a SNEDDS through solid dispersion technique. The oral absorption of BLM in rats when delivered by such a SNEDDS was investigated. Oral delivery of 4500mU/kg of BLM in SNEDDS nanoemulsion resulted in the relative bioavailability of 6.34%, C(max) of 1.9mU/ml and mean residence time of 12.12h which was 1.5-, 2.7- and 1.3-fold higher than that by free solution, respectively. Delivery of BLM in the aqueous phase of the nanoemulsion resulted in a PK profile similar to that by the free solution. BLM when loaded in oil phase of SNEDDS, can significantly enhance the oral bioavailability of BLM. SNEDDS has a great potential for oral protein delivery.     

Solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability of poorly water-soluble tacrolimus: physicochemical characterisation and pharmacokinetics

Abstract

To develop a novel self-nanoemulsifying drug delivery system (solid SNEDDS) with better oral bioavailability of tacrolimus, the solid SNEDDS was obtained by spray-drying the solutions containing the liquid SNEDDS and colloidal silica. Its reconstitution properties were determined and correlated to solid state characterisation of the powder. Moreover, the dissolution and pharmacokinetics in rats was done in comparison to the commercial product. Among the liquid SNEDDS formulations tested, the liquid SNEDDS comprised of Capryol PGMC, Transcutol HP and Labrasol (10:15:75, v/v/v) presented the highest dissolution rate. In the solid SNEDDS, this liquid SNEDDS was absorbed in the pores and attached onto the surface of the colloidal silica. Drug was present in the amorphous state in it. The solid SNEDDS with 5% w/v tacrolimus produced the nanoemulsions and improved the oral bioavailability of tacrolimus in rats. Therefore, this solid SNEDDS would be a potential candidate for enhancing the oral bioavailability of tacrolimus.     

Nasal administration of a cognition enhancer provides improved bioavailability but not enhanced brain delivery

Compound 1 [3,3-bis(4-pyridylmethyl)-1-phenylindolin-2-one] is an experimental cognition-enhancing drug now being developed for cognitive disorders. Oral bioavailability of 1 in rats was less than 10% of the dose. Nasal dosing improved bioavailability to greater than 50%. Brain levels of total radioactivity were measured after iv and nasal doses of radiolabeled 1. The ratio of AUCbrain:AUCplasma was the same by both routes, so nasal dosing did not enhance brain delivery. This is in contrast to other reports of large molecular weight substances and metals gaining direct access to the brain through the nasal epithelium.     

Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of protein drugs: I. Formulation development

The global aim of this research project was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for non-invasive delivery of protein drugs. The specific aim of this study was to develop SNEDDS formulations. An experimental design was adopted to develop SNEDDS. Fluorescent labeled beta-lactamase (FITC-BLM), a model protein, was loaded into SNEDDS through solid dispersion technique. The experimental design provided 720 compositions of different oil, surfactant, and co-surfactant at various ratios, of which 33 SNEDDS prototypes were obtained. Solid dispersion of FITC-BLM in SoyPC prepared was able to dissolve in 16 SNEDDS prototypes (approximately 2200mU BLM in 1g SNEDDS). SNEDDS NE-12-7 (composition: Lauroglycol FCC, Cremophor EL and Transcutol; ratio: 5:4:3) formed O/W nanoemulsion with mean droplet size in the range of 22-50nm when diluted with various pH media and different dilution factor with PBS (pH 7.4). The phase diagram of NE-12-7 indicated a broad region of nanoemulsion. BLM-loaded SNEDDS (NE-12-7) stored at 4 degrees C for 12 weeks indicated 10% loss of BLM activity. A SNEDDS was developed to load FITC-BLM into the oil phase which can spontaneously form O/W nanoemulsion upon the addition of water.