Novel solid self-emulsifying drug delivery system of coenzyme Q10 with improved photochemical and pharmacokinetic behaviors.

The present study was undertaken to develop a solid self-emulsifying drug delivery system of coenzyme Q(10) (CoQ(10)/s-SEDDS) with high photostability and oral bioavailability. The CoQ(10)/s-SEDDS was prepared by spray-drying an emulsion preconcentrate containing CoQ(10), medium-chain triglyceride, sucrose ester of fatty acid, and hydroxypropyl cellulose, and its physicochemical, photochemical, and pharmacokinetic properties were evaluated. The CoQ(10)/s-SEDDS powder with a diameter of ca. 15 µm was obtained by spray-drying, in which the CoQ(10) was mostly amorphized. The CoQ(10)/s-SEDDS exhibited immediate self-emulsification when introduced to aqueous media under gentle agitation, forming uniform fine droplets with a mean diameter of ca. 280 nm. There was marked generation of reactive oxygen species, in particular superoxide, from CoQ(10) exposed to simulated sunlight (250W/m(2)), suggesting potent photoreactivity. Nano-emulsified solution of CoQ(10) under light exposure underwent photodegradation with 22-fold higher degradation kinetics than crystalline CoQ(10), although the CoQ(10)/s-SEDDS was less photoreactive. After the oral administration of CoQ(10)/s-SEDDS (100 mg-CoQ(10)/kg) in rats, enhanced exposure of CoQ(10) was observed with increases in both C(max) and AUC of ca. 5-fold in comparison with those of orally administered crystalline CoQ(10). From the improved physicochemical and pharmacokinetic data, the s-SEDDS approach upon spray-drying might be a suitable dosage option for enhancing nutraceutical and pharmaceutical values of CoQ(10).

In vitro and in vivo characterization of new formulations of St. John's Wort extract with improved pharmacokinetics and anti-nociceptive effect.

The main purpose of the present study was to develop a novel formulation of St. John's Wort (SJW) extract with the aim of improving its pharmacokinetics and anti-nociceptive effect. Several formulations of SJW were prepared, including cyclodextrin inclusion (SJW-CD), solid dispersion (SJW-SD), dry-emulsion (SJW-DE), and nano-emulsion (SJW-NE). Physicochemical properties of SJW formulations were characterized with a focus on the morphology, dissolution behavior, colloidal properties, and dispersion stability in water. Although all the SJW formulations and SJW extract itself exhibited fine dissolution behavior in water, SJW extract and most formulations tended to cream, aggregate, or flocculate after dispersion in distilled water. In contrast, there were no significant changes in appearance and particle size of the SJW-NE for at least a few weeks, suggesting that SJW-NE was the most stable form as a carrier of SJW in the present study. After oral administration of the SJW-NE formulation (5.2 mg hyperforin/kg) in mice, higher hyperforin exposure in plasma (1188 ± 41 nM·h) and the brain (52.9 ± 1.6 pmol/g tissue·h) was observed with 2.8- and 1.3-fold increases of the area under the concentration curve from 0 to 6 hours (AUC(0-6)) compared to those of the SJW extract (417 ± 41 nM·h in plasma and 41.6 ± 1.5 pmol/g tissue·h in the brain). In the formalin test for scoring properties of the first and second phases of the pain response in mice, single oral administration of SJW-NE significantly reduced the nociceptive response compared with SJW extract. From these findings, the NE approach might be efficacious in improving the oral bioavailability and anti-nociceptive effect of SJW extract.

Physicochemical and pharmacological characterization of alpha-tocopherol-loaded nano-emulsion system.

The main purpose of the present study is to develop a novel nano-emulsion (NE) formulation of alpha-tocopherol (alpha-TC) with enhanced oral bioavailability and pharmacological effects. Three NE formulations of alpha-TC at different loading amounts (10%, 30% and 50%) were prepared by a mechanochemical method. Physicochemical properties of NE formulations were characterized with a focus on the morphology by transmission electron microscopy (TEM), droplet size distribution and zeta-potential by dynamic light scattering (DLS), and long-term stability. According to the TEM images and DLS data, mean diameters of NE droplets ranged from 80 to 400nm, in proportion to the amount of loaded alpha-TC. Although all NE formulations of alpha-TC were found to be negatively charged with the zeta-potential of ca -40mV, NE formulations at alpha-TC content of 30% or higher exhibited severe aggregation of droplets in NE formulations during long-term storage. After oral administration of 10% alpha-TC-loaded NE formulation (30mg alpha-TC/kg) in rats, higher alpha-TC exposure was observed with a 2.6-fold increase of bioavailability as compared to the control mixture of oil and alpha-TC. In streptozotocin-induced diabetic rats, oral administration of the alpha-TC-loaded NE formulation (30mg alpha-TC/kg) exhibited a significant reduction of lipoperoxidant in several organs, especially the liver; however, the control mixture was less effective. With these findings, the NE approach might be efficacious to improve the oral bioavailability and anti-oxidative activities of alpha-TC.

Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability.

Considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders, however, the therapeutic potential of curcumin could often be limited by its poor solubility, bioavailability, and photostability. To overcome these drawbacks, efficacious formulations of curcumin, including nanocrystal solid dispersion (CSD-Cur), amorphous solid dispersion (ASD-Cur), and nanoemulsion (NE-Cur), were designed with the aim of improving physicochemical and pharmacokinetic properties. Physicochemical properties of the prepared formulations were characterized by scanning/transmission electron microscope for morphological analysis, laser diffraction, and dynamic light scattering for particle size analysis, and polarized light microscope, powder X-ray diffraction and differential scanning calorimetry for crystallinity assessment. In dissolution tests, all curcumin formulations exhibited marked improvement in the dissolution behavior when compared with crystalline curcumin. Significant improvement in pharmacokinetic behavior was observed in the newly developed formulations, as evidenced by 12- (ASD-Cur), 16- (CSD-Cur), and 9-fold (NE-Cur) increase of oral bioavailability. Upon photochemical characterization, curcumin was found to be photoreactive and photodegradable in the solution state, possibly via type 2 photochemical reaction, whereas high photochemical stability was seen in the solid formulations, especially CSD-Cur. On the basis of these observations, taken together with dissolution and pharmacokinetic behaviors, CSD strategy would be efficacious to enhance bioavailability of curcumin with high photochemical stability.

Liposomal formulations of glucagon-like peptide-1: improved bioavailability and anti-diabetic effect.

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is recognized to be potent drug candidate for treatment of diabetes, however its clinical application has been highly limited, because of rapid enzymatic degradation by dipeptidyl-peptidase IV. To protect GLP-1 from enzymatic degradation and improve pharmacological effects, liposomal formulations of GLP-1 were prepared using three types of lyophilized empty liposomes such as anionic, neutral and cationic liposomes. Electron microscopic and dynamic light scattering experiments indicated the uniform size distribution of GLP-1-loaded liposomes with mean diameter of 130-210 nm, and inclusion of GLP-1 did not affect the dispersibility and morphology of each liposome. Of all liposomal formulations tested, anionic liposomal formulation exhibited the highest encapsulation efficiency of GLP-1 (ca. 80%). In intraperitoneal glucose tolerance testing in rats, marked improvement of hypoglycemic effects were observed in anionic liposomal formulation of GLP-1 (100 nmol/kg) with 1.7-fold higher increase of insulin secretion, as compared to GLP-1 solution. In pharmacokinetic studies, intravenous administration of anionic liposomal formulation of GLP-1 (100 nmol/kg) resulted in 3.6-fold higher elevation of serum GLP-1 level as compared to GLP-1 injection. Upon these findings, anionic liposomal formulation of GLP-1 would provide the improved pharmacokinetics and insulinotropic action, possibly leading to efficacious anti-diabetic medication.

Physicochemical and pharmacokinetic characterization of water-soluble Coenzyme Q(10) formulations.

Coenzyme Q(10) (CoQ(10)) has been used as a drug for chronic heart failure. Furthermore, various biological effects of CoQ(10) have also been applied for food supplements and cosmetics. However, CoQ(10) was found to be poorly soluble in water, so that its bioavailability was low and variable depending on food intake. In the present investigation, a novel liquid (nano-emulsion, NE) and water-soluble powder formulations, including cyclodextrin-Q10 complex (CoQ(10)-CD) and dry-emulsion (DE), were prepared. The physicochemical properties of each formulation were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), powder X-ray diffractometry (PXRD), and differential scanning calorimetry (DSC). In all powder formulations prepared, CoQ(10) existed mainly as an amorphous form as determined by PXRD and DSC, and each powder formulation exhibited high solubility and dispersibility in water resulting in the formation of a nano-sized emulsion (NE; 60nm) and micron sized particles (DEs and CoQ(10)-CD; 0.77-2.4microm). The pharmacokinetic study of each dosage form, in comparison to a CoQ(10) crystal suspension, was also carried out in rats after a single oral dose. Although similar kinetic values were seen with T(max) of 1.5 and 1.7h, respectively, for NE and crystalline CoQ(10), NE exhibited ca 1.7-fold higher AUC and C(max) than the crystalline CoQ(10).

Antinociceptive effects of St. John's wort, Harpagophytum procumbens extract and Grape seed proanthocyanidins extract in mice.

Hypericum perforatum extract (St. John's wort, SJW), Harpagophytum procumbens extract (HPE) and Grape seed proanthocyanidin extract (GSPE) have a broad spectrum of biological activities including antidepressant, anti-inflammatory or anti-oxidant effects. The aim of this study was to clarify antinociceptive properties of SJW, HPE and GSPE in mice with mechanisms that might potentially underlie these activities. Also, the effects of these herbal extracts on the antinociception and plasma and brain concentrations of morphine were examined. Oral pretreatment with SJW (100-1000 mg/kg) and HPE (30-300 mg/kg) attenuated significantly times of licking/biting both first and second phases of formalin injection in mice in the dose-dependent manner, and GSPE (10-300 mg/kg) suppressed second phase. Naloxone (5 mg/kg, s.c.) significantly attenuated antinociceptive effect of HPE but not SJW and GSPE. Formalin injection resulted in significant increase in the content of nitrites/nitrates (NO(x)) in mouse spinal cord. The rise of spinal NO(x) content by formalin was significantly attenuated by HPE and SJW. The pretreatment with SJW significantly potentiated an antinociceptive effect of morphine (0.3 mg/kg, s.c.), although concentrations of morphine in plasma and brain were not significantly changed by these herbal extracts. In conclusion, the present study has shown that SJW, HPE and GSPE exert significant antinociceptive effects in the formalin test of mice. In addition, opioidergic system seems to be involved in the antinociceptive effect of HPE but not SJW and GSPE. Furthermore, SJW potentiates morphine-induced antinociception possibly by pharmacodynamic interaction.