膜修复材料在脊髓损伤修复中的研究进展

神经元膜的完整性对其完成特定的生理功能具有重要意义,而脊髓损伤（SCI）会使神经元膜遭到破坏.目前,治疗SCI的一种新思路是在SCI后早期修复受损的细胞膜.就近年来用膜修复材料治疗SCI的进展进行综述,主要包括聚乙二醇（PEG）、泊洛沙姆188（P188）、壳聚糖及一些纳米材料的研究进展;同时指出了目前研究中存在的问题,并对其发展趋势进行了展望.     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

Evaluation of selected micronized poloxamers as tablet lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68^®) and micronized poloxamer 407 (Lμ trol micro 127^®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

In vitro and in vivo characteristics of a thermogelling and bioadhesive delivery system intended for rectal administration of quinine in children

The aim of this work was to improve the rectal bioavailability of quinine hydrochloride by designing thermosensitive and mucoadhesive gels intended for rectal delivery. The rheological and mucoadhesive properties of poloxamer 407 solutions have been modulated by addition of hydroxypropylmethycellulose (HPMC) and propanediol-1,2. In vitro release and rectal absorption of quinine have been highlighted by a dialysis dissolution testing method and by the determination of bioavailability of the different formulations in rabbits. Increasing the proportions of HPMC and poloxamer in the formulations resulted in a prolonged release of quinine. Indeed, compared to the DT 50% of a rectal solution and a simple HPMC gel (27 and 65 min, respectively) the DT 50% of thermosensitive ternary systems was increased and ranged between 80 and 138 min, depending on the system composition. The release rate depended strongly on the elasticity of the gels after thermogelation. The absolute rectal bioavailability of quinine determined in rabbits was significantly improved with these thermosensitive and adhesive systems. It increased from 62% for the rectal solution to 98% for a ternary system 16/0.5/30 (poloxamer (16%)/HPMC (0.5%)/propanediol-1,2 (30%)). As a result of combined bioadhesion and prolonged release of quinine in vivo, higher average values of MRT and t_max (9.1 ± 0.2 h and 30 min, respectively) were obtained compared to the rectal solution (6.9 ± 0.9 h and 15 min, respectively). Moreover, these formulations presented a very good rectal tolerance.

Modulation by HPMC of the viscoelastic and mucoadhesive properties of poloxamer 407 thermogelling solutions allowed a prolonged release of quinine hydrochloride and an improvement of bioavailability in rabbit.     

甲硝唑阴道用原位凝胶的处方设计及体外质量评价

目的:研制甲硝唑阴道用原位凝胶,并考察其体外质量.方法:以卡波姆及泊洛沙姆为混合凝胶基质,筛选其最佳配比,制备甲硝唑阴道用原位凝胶.对其体外流变性、黏附性进行考察,并与上市甲硝唑阴道用凝胶做对照,考察其阴道滞留性.结果:原位凝胶的最佳基质配比为泊洛沙姆407的质量分数为17.5%,卡波姆971P的质量分数为1.5%.黏附力测定结果表明其具有较大的温度敏感性.与上市产品相比,原位凝胶可显著增加阴道滞留性.结论:该原位凝胶具有显著的温度敏感性,本品值得进一步研发.     

以泊洛沙姆188为助乳化剂制备双氯芬酸钠亚微乳的研究

目的:考察泊洛沙姆188为助乳化剂对乳剂制剂学性质的影响。方法:以双氯芬酸钠为模型药物,泊洛沙姆188为助乳化剂,采用高压均质-初乳pH调节法制备乳剂并测定其包封率、粒径及ξ-电位等指标。结果:与未添加泊洛沙姆188的制剂比较,添加后的制剂包封率、ξ-电位下降,粒径升高。结论:助乳化剂泊洛沙姆188的添加不一定使含药乳剂的制剂学性质提高。     

Pluronic gels for nasal delivery of Vitamin B12. Part I: preformulation study

Thermoreversible nasal gels of Vitamin B₁₂ using pluronic PF 127 were aimed to improve absorption and patient compliance. In the present research work, effects of Vitamin B₁₂ and gel additives, viz. PF concentration, osmolarity, polyethylene glycol (PEG 15000) on thermodynamic properties of phase transitions at gelation (T₁) and gel melting (T₂) is reported. Aqueous PF 127 gels prepared by cold method containing pluronic (20–24%, w/w), vitamin, sorbitol, PEG, and benzalkonium chloride. T₁ decreases and T₂ increases with vitamin and PF concentration. Gelation range narrows with sorbitol and PEG. Suppression of T₂ is significantly higher than T₁ with both the additives. The linearity was observed only for semilogarithmic plot of PF concentration and 1/T₂ for sorbitol and PEG, which reveals significant interaction of both at gel melting. Enthalpy of both transitions remains unchanged with vitamin indicating no interaction with polymer. Benzalkonium chloride decreased gelation onset temperature. Thermodynamic properties of PF 127 gels are significantly altered with polymer concentration and water-soluble formulation additives.     

Fluorescence spectroscopy studies on micellization of poloxamer 407 solution

It has been reported that at low temperature region, poloxamers existed as a monomer. Upon warming, an equilibrium between unimers and micelles was established, and finally micelle aggregates were formed at higher temperature. In this study, the fluorescence spectroscopy was used to study the micelle formation of the poloxamer 407 in aqueous solution. The excitation and emission spectra of pyrene, a fluorescence probe, were measured as a function of the concentration of poloxamer 407 and temperature. A blue shift in the emission spectrum and a red shift in the excitation spectrum were observed as pyrene transferred from an aqueous to a hydrophobic micellar environment. From the I1/I3 and I339/I333 results, critical micelle concentration (cmc) and critical micelle temperature (cmt) were determined. Also, from the fluorescence spectra of the probe molecules such as 8-anilino-1-naphthalene sulfonic acid and 1-pyrenecarboxaldehyde, the blue shift of the lambdamax was observed. These results suggest a decrease in the polarity of the microenvironment around probe because of micelle formation. The poloxamer 407 above cmc strongly complexed with hydrophobic fluorescent probes and the binding constant of complex increased with increasing the hydrophobicity of the probe.     

Release of flurbiprofen from poloxamer 407 gel

Release rates of flurbiprofen from transdemal gels made of poloxamer 407 were evaluated using a membraneless diffusion cell in order to study the effects of formulation variables on flurbiprofen release such as poloxamer 407 (17.5–25%), drug (0.1–1.0%), ethanol (10–20%), PG or PEG 300 (5–15%) concentrations and gel pH (3–7). Isopropyl myristate was employed as a receptor medium for the drug released from the gel. The diffusion coefficient of flurbiprofen decreased linearly as the amount of poloxamer 407 and the drug in the gel increased. The release rate of flurbiprofen was gel pH-dependent and the diffusion coefficient of the drug in the gel increased as the pH of the gel increased. The addition of more ethanol in the gel increased the drug release, resulting from the increase of the thermodynamic activity of the drug in the aqueous phase of the gel. However, the concentration effects of PG and PEG 300 on the release rate of flurbiprofen were negligible over the concentration range used.     

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation,characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH₂) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH₂-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH₂ is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH₂ and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.