温度敏感原位凝胶在眼部给药系统中的研究进展

温度敏感原位凝胶可随温度变化发生凝胶反应,从而缓慢持久地释放药物,提高药物的生物利用度,是一种很有开发价值的新型药物传递系统.本文主要对温度敏感原位凝胶中聚合物的种类及应用,以及该剂型在眼部给药系统中的应用进行了综述.     

盐酸博安霉素注射用温度敏感原位凝胶的研究

本文以泊洛沙姆F127为主要基质材料,复合使用泊洛沙姆F68和高分子材料羟丙基甲基纤维素K4M,制备盐酸博安霉素注射用温度敏感原位凝胶。对凝胶的胶凝温度、流变学、质构特性、电镜结构和体外释放等性能进行了研究,并考察了该制剂在大鼠体内的药代动力学。结果表明,制备的盐酸博安霉素注射用温度敏感原位凝胶在常温下为流动的液体,在人体温度下能够发生相转变,成为具有一定胶凝强度的半固体,方便注射给药,胶凝后呈现三维网状空间结构,药物的扩散和凝胶材料的溶蚀为控制药物释放的主要因素。该制剂具有明显的缓释作用,在大鼠体内可以持续释放48 h以上。     

温度敏感型水凝胶

目的 综述以PNIPAm水凝胶为代表的温度敏感型水凝胶的性质及其在药学方面的应用.方法 针对目前存在的问题,阅读国内外相关文献资料,进行分析整理和归纳.结果 聚(N-异丙基丙烯酰胺)(PNIPAm)水凝胶具有一个较低临界溶解温度(LCST,33℃)或相转变温度(Ttr),具有温度敏感特性.PNIPAm水凝胶的这种特殊性能己被广泛应用在许多领域中,如药物的控制释放.结论 人们对于这类凝胶的敏感机制尚未取得共识,其在应用领域的研究尚有待于进一步的开发.     

地塞米松磷酸钠温度敏感原位凝胶的特性研究

本文以泊罗沙姆PluronicF127为温度敏感原位凝胶材料，考察了PluronicF127与PluronicF68不同浓度处方对地塞米松磷酸钠温度敏感原位凝胶的胶凝温度、相转变温度、凝胶强度、稳态黏度、溶蚀和药物释放行为等特性的影响。采用试管倒转法测定胶凝温度；旋转流变仪测定相转变温度、弹性模量、稳态黏度等流变学参数；无膜溶出法测定凝胶的溶蚀行为；HPLC测定地塞米松磷酸钠的释放度。结果表明，随着处方中F127浓度的增高，凝胶的胶凝温度和相转变温度降低，黏度和弹性模量增加，溶蚀速率和药物释放速率减慢；而处方中F68对凝胶特性的影响与F127相反。温度敏感原位凝胶在低温时为牛顿流体，黏度很小；随着温度升高，黏度增大；当增至相转变温度附近，表现出典型的假塑性流体特征；药物释放速率受控于凝胶溶蚀速率，二者遵循零级动力学方程。处方中含F127 22.5% / F68 2.5%的地塞米松磷酸钠温度敏感原位凝胶的性质与临床治疗要求基本吻合，有望在临床中获得应用。     

喷昔洛韦眼用温度敏感原位凝胶的制备及评价（英文）

目的研制以普朗尼克F127为主要基质的喷昔洛韦制剂,以提高其眼部生物利用度。方法通过将HPMC K4M或卡波姆934P与普朗尼克F127复合使用,制备了喷昔洛韦的温度敏感原位凝胶。以胶凝温度、流变学、药物释放特性、药代动力学及眼部刺激性等为指标进行筛选,得到最优化处方。结果使用HPMC K4M或者卡波姆934P均能降低凝胶的胶凝温度,略微增加其粘度,延缓体系中药物的释放速率;药物释放为非Fick扩散;所有处方均未表现出眼部刺激或对角膜的损伤;含卡波姆934P和普朗尼克F127的凝胶体系的眼部生物利用度最高。结论含普朗尼克F127的喷昔洛韦制剂能够以滴眼液的形式给药,而达到眼部温度时可形成凝胶;体内外评价结果表明,含有HPMC K4M或卡波姆934P以及低浓度普朗尼克F127（12%）的喷昔洛韦制剂,提高了药物在眼部的生物利用度,是一种很有前景的眼部给药系统。     

环丙沙星温度敏感原位凝胶的制备及质量控制

目的:制备环丙沙星温度敏感原位凝胶,并建立其质量控制方法。方法:以环丙沙星为主药,通过考察相变温度得出以16%泊洛沙姆407为适宜基质处方制备凝胶;采用紫外分光光度法测定其中环丙沙星的含量,并进行初步稳定性考察。结果:所制制剂为透明度高、流动性良好的凝胶剂;环丙沙星检测浓度的线性范围为1.92～9.60μg.mL-1,平均回收率为99.73%(RSD=1.80%);稳定性考察制剂外观无变化。结论:本制剂制备工艺简单可行,质量稳定可控。     

地塞米松磷酸钠温度敏感原位凝胶释药与溶蚀行为的影响因素考察

目的:制备泊洛沙姆温度敏感原位凝胶,考察地塞米松磷酸钠(DSP)在其中的释放行为以及影响释放的因素。方法:以PluronicF127和F68为材料,DSP为模型药物制备温度敏感原位凝胶并测定胶凝温度。采用无膜溶出法和HPLC法测定DSP的释放行为;考察释放介质的接触面积、体积、pH值及振荡频率对DSP释放的影响。测定凝胶的溶蚀行为及其对药物释放的影响。结果:胶凝温度随F127浓度增大而升高,释放介质的接触面积、体积、振荡频率对药物的释放速率有显著影响,释放介质的pH对药物释放速率无显著影响。DSP的释放和凝胶的溶蚀遵循零级动力学方程,释放量随溶蚀量增加而增加,二者间存在线性关系。结论:DSP温度敏感原位凝胶的缓释效果良好,凝胶溶蚀速率、凝胶与释放介质的接触面积是控制药物释放的主要因素。     

温度敏感型水凝胶

目的综述以PNIPAm水凝胶为代表的温度敏感型水凝胶的性质及其在药学方面的应用。方法针对目前存在的问题,阅读国内外相关文献资料,进行分析整理和归纳。结果聚(N-异丙基丙烯酰胺)(PNIPAm)水凝胶具有一个较低临界溶解温度(LCST,33℃)或相转变温度(Ttr),具有温度敏感特性。PNIPAm水凝胶的这种特殊性能己被广泛应用在许多领域中,如药物的控制释放。结论人们对于这类凝胶的敏感机制尚未取得共识,其在应用领域的研究尚有待于进一步的开发。     

pH敏感型原位凝胶的研究进展

pH敏感型原位凝胶随pH的变化而发生胶凝反应,缓慢持久地释放药物,可提高药物的生物利用度,是一种很有开发价值的新型药物传递系统。     

聚合物在温度敏感型原位凝胶中的应用

多种聚合物可用于原位凝胶系统,使其随温度的变化而胶凝,缓慢持久地释放药物,在临床上有着广阔的应用前景。聚合物的开发应用必将不断地促进温度敏感型原位凝胶的快速发展。     

Synthesis,physicochemical properties and ocular pharmacokinetics of thermosensitive in situ hydrogels for ganciclovir in cytomegalovirus retinitis treatment

Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design in situ thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly-(β-butyrolactone-co-lactic acid)-polyethylene glycol-poly (β-butyrolactone-co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring-opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA in situ hydrogels (15%, w/w) were then prepared with drug concentration at 2?mg·mL^?1 and the gelation temperatures, rheological properties, in vitro degradation and syringeability of in situ hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA in situ hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96?h, respectively, which was verified by a non-Fickian diffusion mechanism. In vivo ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA in situ hydrogel was higher (AUC was 61.80?μg·mL^?1·h (p?t_1/2 was 10.29?h in aqueous humor; AUC was 1008.66?μg·mL^?1·h (p?t_1/2 was 13.26?h (p?in situ hydrogel is a promising carrier of GCV for intravitreal injection.     

Development of a Thermosensitive In-Situ Gel Formulations of Vancomycin Hydrochloride: Design,Preparation, In Vitro and In Vivo Evaluation

The purpose of this study was to develop a thermosensitive in situ gel delivery system based on Poloxamer 407 and Poloxamer 188 for ocular administration of vancomycin to treat systemic diseases. The vancomycin thermosensitive in situ gel was characterized using differential scanning calorimetry, rheological and drug release analyses. Additionally, pharmacokinetic studies and irritation tests of the gel were conducted after ocular administration in rabbits. The gel maintained a flowing liquid state under non-physiological conditions (25°C) to facilitate administration, and it transformed into a semi-solid state under physiological conditions (dilution with tears, 34°C), which prolonged its retention time in the eye. The gel erosion and drug release tests showed an excellent linear relationship between the cumulative drug release rate and the cumulative gel erosion rate, indicating a zero-order kinetic process. The pharmacokinetic analyses showed that the peak concentration, area under the curve, and bioavailability of the vancomycin thermosensitive in situ gel were 1.44, 1.98 and 1.93 times greater, respectively, that the values of vancomycin eye drops. Therefore, thermosensitive in situ gel may serve as a drug delivery system that can overcome the limitations of existing formulations of small-molecule peptides.     

INTESTINAL ABSORPTION KINETICS OF AMIODARONE IN RAT SMALL INTESTINE

Amiodarone is a widely used antiarrhythmic agent with highly variable therapeutic effects. These seem to be related, at least in part, to the pharmacokinetics of the drug and particularly to some features of its gastrointestinal absorption process. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes, but its low aqueous solubility can act as the rate limiting step for absorption, making the process erratic and variable. In order to gain an insight into the intestinal absorption mechanism of the drug and detect possible non-linearities, a series of experiments using a classical rat gut in situ preparation were carried out with three amiodarone hydrochloride solutions (10, 75, and 200 μg mL⁻¹). A synthetic non-ionic surfactant, polysorbate 80, at supramicellar concentration (2 mM) was used as the drug solubilizer. Amiodarone was assayed in biological samples by HPLC using a rapid, sensitive technique that was validated. The amiodarone first-order absorption rate constants obtained in these conditions were similar. No significant differences between k_a values were found. Amiodarone absorption was clearly identified as a passive diffusion process. © 1997 John Wiley & Sons, Ltd.     

Diffusion studies of methotrexate in Carbopol and Poloxamer gels

The diffusion properties of methotrexate (MTX) in two hydrogels, Carbopol 934 (Carbopol) and Poloxamer 407 (PF-127), were compared with those in PEG 1500 and white petrolatum ointments in order to evaluate various factors governing the diffusion of MTX in different semisolid vehicles. A new membraneless method, which employed an MTX gel as the donor phase, was used for the measurement of the diffusivity of MTX in the vehicles. The flux of MTX in the hydrogels was at least 20-fold faster than those found in the ointments. The diffusion coefficients (D) of MTX were 3.58 (±0.31)×10⁻⁶ cm²/s in the 2% Carbopol gel and 1.03 (±0.01)×10⁻⁶ cm²/s in the 25% PF-127 gel at 34°C, despite similar bulk viscosities of the two gels. The activation energies for the diffusion of MTX in the Carbopol and PF-127 gels were 6.13 kcal/mol and 5.56 kcal/mol respectively, which were in the same order of magnitude as the diffusion of the small molecules in water, indicating that microviscosity rather than bulk viscosity of the gel was primarily responsible for the diffusion of MTX in the gels. D values of MTX in the PF-127 gel were significantly accelerated at higher temperatures, despite increased bulk viscosity of the gels due to the reverse thermal gelation property of PF-127. The diffusivity of MTX was the inverse function of polymer concentration, over the range of 20–30% of PF-127 and 1–3% of Carbopol at 34°C. Significant effects of pH and drug concentration on the diffusivity of MTX in the Carbopol gels were observed, while no such effects were found in the PF-127 gels.     

In-vivo anti-tumor activity of a novel poloxamer-based thermosensitive in situ gel for sustained delivery of norcantharidin

In order to develop a novel norcantharidin (NCTD) delivery system with slow drug release and specific targeting characteristics, we have developed a Poloxamer-based NCTD thermosensitive in situ gel. The evaluation of the characteristics of this system using both in vitro and in vivo methods was previously reported. However, its anti-tumor activity in vivo is still not confirmed. Thus, the potential anti-tumor activity and relative mechanism were investigated in a murine H22 hepatoma model. Tumor-bearing mice were treated with different dose of NCTD thermosensitive in situ gel (3.3?mg/kg, 6.6?mg/kg, and 9.9?mg/kg, respectively by intra-tumor injection once every three days, totaling 5 injections per group. Control groups included untreated or NCTD injection (2.2?mg/kg, qd) or blank in situ gel. The expression of vascular endothelial growth factor (VEGF) and CD44 in tumor tissue was examined by immunohistochemistry (IHC) staining. Treatment with middle or high dose of NCTD thermosensitive in situ gel significantly induced tumor regression, inhibited VEGF and CD44 expression and improved survival of tumor-bearing mice. The efficacy of NCTD thermosensitive in situ gel is higher than that of free NCTD injection. Therefore, NCTD thermosensitive in situ gel is a novel NCTD delivery approach for chemotherapeutic treatment of cancer.     

Controlled Release of Substituted Benzole and Naphthoic Acids Using Carbopol ® Gels: Measurement of Drug Concentration Profiles and Correlation to Release Rate Kinetics

Purpose. The objective of this study is to correlate drug release mechanism with measured drug concentration profiles in gel layers of Carbopol^® matrices containing mesalamine or benzoic acid. Methods. Release rate experiments with Carbopol^® matrices were performed using a rotating disk apparatus. Matrices were frozen and the gel layer in the matrices was sliced using a microtome in a cryostat. Drug concentration profiles were determined by direct measurement of the concentration of the drug in the gel slices. The pH of the slices was measured using microelectrodes, and water content was measured by Karl Fisher titration. Results. The concentration gradient in mesalamine matrices decreased over time and correlated with square root of time release rate kinetics. The concentration profiles of benzoic acid were unchanged over time and correlated with zero order release rate kinetics. Carbopol gel layers were highly hydrated (93–95% water). Gel layers in matrices with mesalamine had a more alkaline microenvironmental pH. This higher pH resulted in increased growth of the thickness of the gel layer and a reduction drug diffusivity in comparison to benzoic acid matrices. Conclusions. The release rate kinetics of mesalamine and benzoic acid correlated to the measured concentration profiles. The shape of the concentration profiles is determined by the rate of growth of the Carbopol^® gel layer and drug diffusivity.     

Dual sustained release delivery system for multiple route therapy of an antiviral drug

Abstract

Context: The first successful molecule against herpes infections was Acyclovir, which competes with new generations in the market, with its potential activity. The major physicochemical constraints and pharmacokinetics of Acyclovir such as low solubility, poor permeability, less half-life, high dose has initiated many researchers to develop diverse modified release dosage forms.

Objective: The objective of this work was to design polymeric nanoparticles of Acyclovir and then incorporate the drug-loaded nanoparticles within an in situ gelling system to provide dual sustained release effect, whereby the duration of action and bioavailability through different routes of administration could be improved.

Materials and methods: The formulation was designed through 3² factorial design, first developing the nanoparticles using Polycaprolactone and Pluronic F127 by Solvent evaporation process, followed by dispersion of the suspended nanoparticles into thermosensitive in situ gelling system of Pluronic F127 with Carbopol.

Results and discussion: The characterization of the nanoparticles and its sol-gel system performed through zeta sizer, SEM, XRD, TG-DSC, FTIR and rheology helped to optimize the formulation. The drug release could be sustained to 60% and 30% at eight hours, for the nanoparticles and their in situ gel systems, respectively, with non-Fickian diffusion mechanism of drug release. The test for % cell viability with NIH3T3 cell line revealed low level of toxicity for the nanoparticles.

Conclusion: The statistical significance obtained for the trail formulations experimentally proved its suitability for this dosage form design to achieve desired level of drug release.     

Thermosensitive hydrogel containing sertaconazole loaded nanostructured lipid carriers for potential treatment of fungal keratitis

This study was conducted to develop an in situ thermosensitive gel containing sertaconazole-loaded nanostructured lipid carriers (NLCs) for prolonged ocular drug delivery. To this end, sertaconazole-loaded NLCs (sertaconazole-NLCs) were prepared by emulsification solvent-diffusion method and the effects of different formulation variables were assessed using the fractional factorial design. Then, optimized sertaconazole-NLCs were incorporated into the pluronic F127 (PF127)/hydroxy propylmethylcellulose (HPMC) K4M hydrogel. The formulations were examined for pH, gelation temperature, rheological properties, in vitro permeation studies, and anti-fungal activity. The optimized sertaconazole-NLCs showed a mean particle size of 272.40?nm, encapsulation efficiency of 89.97%, zeta potential of 12.9?mV, and polydispersity index of 0.31. All the in situ formulations had acceptable pH, ranging from 5.89 to 6.28. The gelation temperature of the optimized formulation was 35.1?°C after dilution with simulated tear fluid (STF). Sertaconazole-NLCs showed a higher antifungal activity and permeation through the bovine cornea compared to the free drug and the in situ gel formulation. The cornea penetration of sertaconazole for the in situ gel of NLCs was also comparable to that for free drug. The obtained results indicated that the prepared nanocomposite system may have potential for treatment of fungal keratitis.     

Bleomycin A6-loaded anionic liposomes with in situ gel as a new antitumoral drug delivery system

The goal is to develop an in situ gel system comprising anionic liposomes (AL) containing bleomycin A6 (BLM A6) dispersed within the thermosensitive in situ gel for sustained release. The results indicated that the gelation temperature decreased due to AL within gel. Similarly, viscosity and mechanical parameters, such as gel strength for gel, could be enhanced by inducing lipid material with negative charge (phosphatidylglycerol) at 37?°C, which provided against corrosion at physiological condition. The in vitro release experiments performed with a dialysis method revealed that in situ gel with AL exhibited the longer drug-release period compared to that with or without nonionic liposomes. An in vivo fluorescence imaging study suggested that the gel with AL loading FITC-BLM A6 stayed in administration site at least for five days. A thermosensitive in situ gel with anionic liposome was a promising carrier for hydrophilic BLM A6, to be used in parenteral delivery system for anti-tumor treatment.     

Thermally reversible xyloglucan gels as vehicles for nasal drug delivery

The aim of this study was to investigate the potential application of thermosensitive gels formed by a xyloglucan polysaccharide derived from tamarind seed for nasal drug delivery. Xyloglucan that had been partially degraded by β-galactosidase to eliminate 45% of galactose residues formed gels at concentrations of 2.5% w/w at gelation temperatures decreasing over the range 27–28°C. The in vitro release of ondansetron hydrochloride from the enzyme-degraded xyloglucan gels followed higuchi kinetics over a period of 5?h at 34°C by anomalous transport mechanism. The ex vivo permeation of ondansetron hydrochloride from the gels was sustained. Histological examination of nasal mucosa following a single administration of the gels showed no evidence of mucosal damage. Finally, the bioavailability study in rabbits revealed that the absolute bioavailability of ondansetron hydrochloride was significantly increased from 28.64% in the case of the oral drug solution to 52.79% in the case of the nasal in situ gel. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for nasal delivery of drugs.