Ling Chun Chen

Influence of micelle solubilization by tocopheryl polyethylene glycol succinate (TPGS) on solubility enhancement and percutaneous penetration of estradiol

The effect of micellar solubilization on the enhancement of the solubility and percutaneous penetration of estradiol by the surface-active agent, tocopheryl polyethylene glycol succinate (TPGS) was characterized in this study. Results show that the solubility of estradiol was improved in the presence of TPGS through micellar solubilization. The critical micelle concentration (CMC) of TPGS increased with increasing ethanol concentration in the medium. With the flux corrected to the saturated level (J(corrected)) of the free form of estradiol, an increase in the alcohol content of the medium resulted in an increase in J(corrected) for all levels of TPGS examined. For the same level of alcohol content, an increase in the TPGS concentration mostly led to a small extent of decrease in J(corrected). However, the extent of decrease was more obvious in media containing more than 60% alcohol. We also confirmed that only an insignificant amount of TPGS was transported across the skin (below the detection limit of 2 microg/ml). Permeabilities (P(eff)), which describe the overall effects (DK/H) on the stratum corneum (SC), decreased with increasing TPGS concentration for media containing 0, 40, 60, and 80% alcohol, whereas they increased then decreased with increasing TPGS concentration for media containing 10 and 20% alcohol. The enhancement ratios based on P(eff) assuming that the medium contained 0% TPGS and alcohol as unity did not increase accordingly with increases in TPGS concentration at the same level as alcohol. Likewise, the enhancement ratios for the same level of TPGS increased with low alcohol content, but then decreased with increasing alcohol content. We concluded that micellar solubilization by TPGS was able to improve the solubility of estradiol, but it only had an insignificant influence on the skin. Interfacial coverage of TPGS with increasing TPGS concentration and hindrance of the partitioning of estradiol by the increasing alcohol content might play a role in influencing the permeability of estradiol.

Penetration enhancement by menthol combined with a solubilization effect in a mixed solvent system.

The improvement in solubility of indomethacin due to the presence of menthol in various cosolvent systems consisting of water, alcohol and propylene glycol was examined by a mixture design in this study. A proper model to quantitatively describe the effect of menthol at different concentrations on the solubility of indomethacin was compared based on the statistical parameters provided by DESIGN-EXPERT. Then three cosolvent systems with the addition of menthol to solubilize indomethacin to extents of 1.0, 1.5 or 2.0% w/v were selected. The penetration of indomethacin through nude mouse skin from these three cosolvent systems with the addition of 0-12% menthol was investigated and followed by a discussion on the penetration mechanism. The results showed that menthol was able to improve drug solubility to different extents for different cosolvent systems. Optimally, a cosolvent system with an equal ratio of the three solvents, water, alcohol and propylene glycol, showed the highest extent of improvement in the solubility at all concentrations of menthol. The enhancement factors for indomethacin penetration due to menthol in different cosolvent systems were compared, based either on the permeation coefficient (Kp) or the separate overall effects on the skin (Flux). Both comparisons gave similar results. The influence of menthol was more significant compared to that of the cosolvent systems and the extent of this influence increased with an increase in the amount added, reaching a maximum at a specific amount of menthol for each different cosolvent system.

Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy

Doxorubicin (DOX) thermosensitive hydrogels (TSHs) incorporated with docetaxel (DOC)-loaded mixed micelles were developed to co-deliver these two drugs through a TSH system, DH700kMF-13.5/M-DocLF, to improve local cancer therapy and reduce side effects. First, Pluronics-based DOC-loaded mixed micelles were developed and optimized. The optimal formulation designated as M-DocLF was composed of 1mg/g docetaxel, 15mg/g Pluronic F127 (PF127), and 45mg/g Pluronic L121 (PL121). Rheological tests showed that DH700kMF-13.5/M-DocLF was an injectable flowing solution, which formed a nonflowing gel at body temperature. After intratumoral (IT) or peritumoral (PT) administration, DH700kMF-13.5/M-DocLF demonstrated efficient growth inhibition of CT-26 tumors in a Balb/c mice model. The tumor inhibitory rate after IT administration of DH700kMF-13.5/M-DocLF was 92.4%, followed by 85.8%, 75.6%, 62.9%, 50.6%, and 49.5% for DH700kMF-15, free DOX, F-13.5/M-DocLF, Tynen (DOC solution), and M-DocLF, respectively. Furthermore, PT administration of DH700kMF-13.5/M-DocLF resulted in similar efficacies. Pharmacokinetic and biodistribution studies showed that after subcutaneous (SC) and IT administration of the designated formulations, smaller amounts of DOX and DOC were absorbed from the local SC or tumor sites into systemic circulation, probably reducing their systemic toxicity. Tumor retention of DOX and DOC in biodistribution studies further revealed that co-delivery of these two drugs in DH700KMF-13.5/M-DocLF potentially enhanced the efficacy of tumor inhibition. In conclusion, our in situ injectable DOX and DOC TSH is a potential dual drug delivery system, which can enhance the efficacy of cancer chemotherapy with minimal side effects and reduced chemoresistance.

Simultaneous optimization of percutaneous delivery and adhesion for ketoprofen poultice.

Topical poultices of ketoprofen were prepared using deionized water, propylene glycol (X1), and glycerin (X2) as the vehicle in combination with hydrophilic matrix materials, including gelatin (X3) and sodium polyacrylate. A mixture design was utilized to evaluate the influence of these constituents (X1-X3) on the adhesion of the poultice and the percutaneous penetration of ketoprofen from poultices. The adhesion of the poultice was measured based on the L-Peel test method using a Tensile and Compression Testing Machine. Percutaneous delivery was conducted using nude mouse skin as the barrier. The poultice containing the highest weight fraction of gelatin demonstrated the highest value of peak stress, whereas the poultice containing 0% weight fraction of gelatin showed the smallest value among all formulations. This indicates that gelatin was the main factor determining the adhesion of the poultice. However, the interactive influence of propylene glycol with gelatin on the adhesion of the poultice cannot be ignored. On the contrary, the formulation having the maximal penetration rate was determined to be the vehicle with 0% weight fraction of gelatin and the highest percent weight fraction of glycerin. This indicates that the presence of glycerin in the poultice was able to increase the flux of ketoprofen to some extent. Quantification of individuals effect based on this mixture design resulted in a polynomial equation: Peak stress=0.033X1+0.016X2+0.12X3, flux=1.90X1+4.70X2-6.65X3. Finally, an optimized formulation with acceptable adhesion and a flux comparable to two commercial products was developed in this study.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic® P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60±5.02 nm, 0.589±0.198, 96.87%±9.04%, and 12.18%±1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17–7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration–time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core–shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability.

Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin.

Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.

Improving the Stability of Astaxanthin by Microencapsulation in Calcium Alginate Beads.

There has been considerable interest in the biological functions of astaxanthin and its potential applications in the nutraceutical, cosmetics, food, and feed industries in recent years. However, the unstable structure of astaxanthin considerably limits its application. Therefore, this study reports the encapsulation of astaxanthin in calcium alginate beads using the extrusion method to improve its stability. This study also evaluates the stability of the encapsulated astaxanthin under different storage conditions. The evaluation of astaxanthin stability under various environmental factors reveals that temperature is the most influential environmental factor in astaxanthin degradation. Stability analysis shows that, regardless of the formulation used, the content of astaxanthin encapsulated in alginate beads remains above 90% of the original amount after 21 days of storage at 25°C. These results suggest that the proposed technique is a promising way to enhance the stability of other sensitive compounds.

Development and characterization of docetaxel-loaded lecithin-stabilized micellar drug delivery system (LsbMDDs) for improving the therapeutic efficacy and reducing systemic toxicity

Graphical abstract Figure. No Caption available. Abstract In the present study, we attempted to develop a lecithin‐stabilized micellar drug delivery system (LsbMDDs) for loading docetaxel (DTX) to enhance its therapeutic efficacy and minimize systemic toxicity. A novel DTX‐loaded LsbMDDs was optimally prepared by a thin‐film hydration method and then hydrated with a lecithin nanosuspension while being subjected to ultrasonication. Physical characteristics of the optimized DTX‐loaded LsbMDDs formulations were examined and found to have a mean size of <200 nm, an encapsulation efficiency of >90%, and drug loading of >6% with stability at room temperature and at 4 °C being longer than 2 and 7 days, respectively. The in vitro release of DTX from the DTX‐loaded LsbMDDs was slower than that from the generic product of DTX (Tynen®). A cell viability assay demonstrated that the LsbMDDs showed better cytotoxicity than Tynen® against CT26 cancer cells. The in vivo antitumor efficacy of the DTX‐loaded LsbMDDs was observed to be better than that of Tynen® in a CT26 tumor‐bearing mice model. A high‐dose regimen of the DTX‐loaded LsbMDDs formulation showed greater inhibition of DU145 tumor growth than did Tynen®, but with less to similar systemic toxicity. An in vivo study also showed that a greater amount of drug was able to accumulate in the tumor site with the DTX‐loaded LsbMDDs, and its maximal tolerable doses for single and repeated injections were 2–2.5‐fold higher than those of Tynen®. In conclusion, the LsbMDDs could be a promising high drug‐loaded nanocarrier for delivering hydrophobic chemotherapeutic agents that can enhance the efficacy of chemotherapy and reduce systemic toxicity.

Physical and Pharmacokinetic Characterizations of trans -Resveratrol ( t -Rev) Encapsulated with Self-Assembling Lecithin-based Mixed Polymeric Micelles ( sa LMPMs)

This study involved physical and pharmacokinetic characterizations of trans-resveratrol (t-Rev)-loaded saLMPMs which attempted to improve t-Rev’s pharmacokinetic profiles and bioavailability resolving hurdles limiting its potential health benefits. The optimal formulation consisted of t-Rev, lecithin, and Pluronic® P123 at 5:2:20 (t-Rev-loaded PP123 saLMPMs) provided mean particle size <200 nm, encapsulation efficiency >90%, and drug loading >15%. Compared to t-Rev solubilized with HP-β-CD, t-Rev-loaded PP123 saLMPMs enhanced t-Rev’s stability in PBS at RT, 4 °C, and 37 °C and in FBS at 37 °C, and retarded the in vitro release. Intravenous administration of t-Rev-loaded PP123 saLMPMs was able to enhance 40% absolute bioavailability and a greater portion of t-Rev was found to preferably distribute into peripheral compartment potentially establishing a therapeutic level at the targeted site. With oral administration, t-Rev-loaded LMPMs increases 2.17-fold absolute bioavailability and furnished a 3-h period of time in which the plasma concentration maintained above the desirable concentration for chemoprevention and accomplished a higher value of the dose-normalized area under the curve for potentially establishing an effective level at the target site. Therefore, intravenous and oral pharmacokinetic characteristics of t-Rev encapsulated with PP123 saLMPMs indicate that t-Rev can be translated into a clinically useful therapeutic agent.

Wound-healing effect of micronized sacchachitin (mSC) nanogel on corneal epithelium

The extraction residue of the Ganoderma fruiting body, named sacchachitin, has been demonstrated to have the potential to enhance cutaneous wound healing by inducing cell proliferation. In this study, a nanogel formed from micronized sacchachitin (mSC) was investigated for the potential treatment of superficial chemical corneal burns. Reportedly, mSC has been produced successfully and its chemical properties confirmed, and physical and rheological properties characterized. An in vitro cell proliferation study has revealed that at the concentrations of 200, 300, and 400 μg/mL, mSC nanogel significantly increased Statens Seruminstitut rabbit corneal (SIRC) cell proliferation after 24 hours of incubation. In cell migration assay, migration of SIRC cell to wound closure was observed after 24 hours of incubation with the addition of 200 μg/mL mSC of nanogel. In an animal study, acceleration of corneal wound healing was probably due to the inhibition of proteolysis. In conclusion, the findings of this study substantiate the potential application of sacchachitin in the form of mSC nanogel for the treatment of superficial corneal injuries.