Synthesis and characterization of amphiphilic star-shaped copolymers based on ß-cyclodextrin for micelles drug delivery.

PURPOSE: A series of ß-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated. METHODS: A series of amphiphilic copolymers based on ß-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-ß-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of ß-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated. RESULTS: Around 60 types of ß-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80 × 10-4 to 5.24 × 10-2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded ß-CD-P4 micelles prepared with optimal formulation were about 65 nm, 21.44 ± 0.14%, and 49.05 ± 0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72 h of VP-loaded ß-CD-P4 micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded ß-CD-P4 micelles was 8.98 times higher than that of VP injection. CONCLUSION: The VP-loaded ß-CD-P4 micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the ß-CD-P4 copolymers are an excellent candidate for micelles drug delivery.

mPEG-PLA/TPGS mixed micelles via intranasal administration improved the bioavailability of lamotrigine in the hippocampus.

PURPOSE: This study aimed to develop a novel methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelle drug delivery system to improve lamotrigine (LTG) distribution in the hippocampus. METHODS: LTG-loaded mPEG-PLA/TPGS mixed micelles and LTG-loaded mPEG-PLA micelles were formulated, and their characteristics, particle size, surface morphology, and release behavior in vitro were researched. Then, a microdialysis sampling technique coupled with two validated chromatographic systems was developed for the continuous measurement of the protein-unbound form of LTG in the rat plasma and hippocampus after administering two kinds of micelles and LTG solution intranasally. RESULTS: The drug loading and mean size of LTG-loaded micelles and LTG-loaded mixed micelles prepared with optimal formulation were 36.44%±0.14%, 39.28%±0.26%, 122.9, and 183.5 nm, respectively, with a core-shell structure. The cumulative release rate in vivo of LTG-loaded mixed micelles was 84.21% at 24 hours and showed more sustained release while that of LTG-loaded micelles was 80.61% at 6 hours. The Tmax and area under concentration-time curve from zero to time of last quantifiable concentration of LTG solution, LTG-loaded micelles, and LTG-loaded mixed micelles were 55, 35, and 15 minutes and about 5,384, 16,500, and 25,245 (min⋅µg)/L in the hippocampus, respectively. CONCLUSION: The results revealed that LTG-loaded mPEG-PLA/TPGS mixed micelles enhanced the absorption of LTG at the nasal cavity and reduced the efflux of LTG in the brain, suggesting that the function of TPGS inhibited P-glycoprotein and LTG-loaded mPEG-PLA/TPGS mixed micelles had the potential to overcome refractory epilepsy.

Methodological assessment of the reduction of the content of impurities in nimodipine emulsion via the use of 21 amino acid protection.

PURPOSE: The present study examined the factors affecting the content of impurities of nimodipine (NMP) emulsion and the associated methods of compound protection. METHODS: Destructive testing of NMP emulsion and its active pharmaceutical ingredient (API) were conducted, and ultracentrifugation was used to study the content of impurities in two phases. The impurity of NMP was measured under different potential of hydrogen (pH) conditions, antioxidants and pH-adjusting agents. RESULTS: Following destruction, the degradation of NMP notably occurred in the basic environment. The consumption of the pH-adjusting agent NaOH was proportional to the production of impurities since the inorganic base and/or acid promoted the degradation of NMP. The organic antioxidants, notably amino acids with an appropriate length of intermediate chain and electron-donating side group, exhibited improved antioxidant effects compared with inorganic antioxidants. The minimal amount of impurities was produced following addition of 0.04% lysine and 0.06% leucine in the aqueous phase and adjustment of the pH to a range of 7.5-8.0 in the presence of acetic acid solution. CONCLUSION: NMP was more prone to degradation in an oxidative environment, in an aqueous phase and/or in the presence of inorganic pH-adjusting agents and antioxidants. The appropriate antioxidant and pH-adjusting agent should be selected according to the chemical structure, while destructive testing of the drug is considered to play the optimal protective effect.

[Relation between drug release and the drug status within curcumin-loaded microsphere].

To study the relation between drug release and the drug status within curcumin-loaded microsphere, SPG (shirasu porous glass) membrane emulsification was used to prepare the curcumin-PLGA (polylactic-co-glycolic acid) microspheres with three levels of drug loading respectively, and the in vitro release was studied with high-performance liquid chromatography (HPLC). The morphology of microspheres was observed with scanning electron microscopy (SEM), and the drug status was studied with X-ray diffraction (XRD), differential scanning calorimetry (DSC) and infrared analysis (IR). The drug loading of microspheres was (5.85 ± 0.21)%, (11.71 ± 0.39)%, (15.41 ± 0.40)%, respectively. No chemical connection was found between curcumin and PLGA. According to the results of XRD, curcumin dispersed in PLGA as amorphous form within the microspheres of the lowest drug loading, while (2.12 ± 0.64)% and (5.66 ± 0.07)% curcumin crystals was detected in the other two kinds of microspheres, respectively, indicating that the drug status was different within three kinds of microspheres. In the data analysis, we found that PLGA had a limited capacity of dissolving curcumin. When the drug loading exceeded the limit, the excess curcumin would exist in the form of crystals in microspheres independently. Meanwhile, this factor contributes to the difference in drug release behavior of the three groups of microspheres.

[Based on in vivo fluorescence imaging technology, to extablish a fluorescence modification method for amphipathic block polymers].

Rhodamine B (Rh B) was used to decorate an amphipathic block polymers (ß-CD-[P(AA- co-MMA)-b-PVP](4)) in this study. First, after activated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, rhodamine B was marked with hydroxyethyl methacrylate (HEMA) through ester exchange reaction. Second, the labeled amphipathic block polymers (ß-CD-[P(AA-(HEMA-RhB)-MMA)-b-PVP](4)) were synthesized after polymerization reaction of double bones between Rh B-HEMA and other reactants. Finally, the structure of product was measured by FT-IR spectra and fluorospectro photometer (FLUORO). The critical micelle concentration of Rh B-labeled and unlabeled amphipathic block polymers were 4.96×10(-3), 5.09×10(-3)mg·L(-1), respectively, indicating no change of their micellization behavior. In vivo tissue distribution and whole- body fluorescent imaging were studied by vinpocetine (VP)-loaded polymeric micelles which were prepared through a solvent evaporation method. Compared to the result of in vivo tissue distribution and whole-body fluorescence imaging, a similar bio-distribution behavior of VP-loaded polymeric micelles was found. Those proved the successful fluorescence modification with a labeling yield of 4.13%. With in vivo fluorescence imaging technology, we established a fluorescence method for modification of amphipathic block polymers.