Sustained release of lidocaine from Poloxamer 407 gels

In this work, we show that alteration of P407 gel content can affect drug release rates. The inorganic salts and PEG 400 commonly included in the formulation of P407 gels can also change the rate at which a drug is released. Lidocaine was selected as a model drug because, although widely used in the treatment of pain, its use is limited by short duration of its effects. The use of P407 gels prolongs the residence time of the lidocaine at the injection site, sustains drug release and increases therapeutic efficacy. Release studies were performed in a diffusion system. During release, data followed the Higuchi square root law time kinetic (r>0.98). Increased polymer concentration in the gel increases viscosity and reduces lidocaine release rates and diffusion coefficients via extended gel dissolution time and prolonged drug diffusion through the gel matrix. Lidocaine release rates and diffusion coefficients increased in gels composed of NaCl or PEG 400 aqueous solution. Because these additives are hydrophilic, they reduce gel dissolution time, thereby accelerating drug diffusion. Poloxamer is biocompatible and the results support the possibility of using Poloxamer gel as a sustained release injectable formulation.     

布洛芬眼用在体凝胶的制备及体外特性研究

目的制备布洛芬眼用在体凝胶,并考察其体外特性,为其临床应用奠定基础。方法以泊洛沙姆407为基质制备布洛芬温度敏感在体凝胶,应用动态流变实验测定温敏凝胶相变过程的流变学性质,并采用无膜溶出模型考察其体外溶蚀及释药情况。结果泊洛沙姆407凝胶经人工泪液稀释后相变温度提高7℃左右。布洛芬在体凝胶稀释后相变温度为32℃,其相转变表现为模量和动态黏度呈指数增长,体外释药呈现良好的零级释放特征。结论布洛芬在体凝胶兼具液体剂型和凝胶剂型的优点,是一种具有良好应用前景的新型眼用制剂。     

利巴韦林鼻用温敏凝胶热力学和流变学性质研究

考察了不同浓度泊洛沙姆407、PEG6000和泊洛沙姆188及处方量利巴韦林对鼻用温敏凝胶的热力学[胶凝温度（T1）、胶融温度（T2）]和流变学性质（黏度）的影响。结果表明，凝胶的T1和黏度均与泊洛沙姆407浓度呈负相关，而T2则与其呈正相关；利巴韦林和相应辅料对凝胶的T1、T2和黏度都有不同程度的影响。     

Effect of Mechanical Properties on the Release of Meloxicam from Poloxamer Gel Bases

Thermoreversible gel of meloxicam, efficient for the treatment of joint diseases, was aimed to prepare for night application available for chronotherapy in this study. Poloxamer 407 and 188 polymers were used at 20-30% w/w as a vehicle in combination with different additives (polyvinylmethylether maleic anhydride copolymer, hydroxypropyl methylcellulose, polyethylene glycol 400, dimethyl sulfoxide, sodium chloride). Characterisation of prepared gels was evaluated by viscosity and texture analysis, and the effect of formulation variables on the gel formulations were evaluated by in vitro drug release and erosion studies. Between the investigated gel bases, Poloxamer 407-hydroxypropyl methylcellulose gel was found to be ideal due to its gel strength (1.560±0.0135 N), viscosity (312.3±2.06 cP) and release characteristics. These promising results could be encouraging for further studies to make it an alternative to commercial dosage forms.     

A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics

Abstract Poloxamer 407 copolymer (ethylene oxide and propylene oxide blocks) shows thermoreversible properties, which is of the utmost interest in optimising drug formulation (fluid state at room temperature facilitating administration and gel state above sol–gel transition temperature at body temperature promoting prolonged release of pharmacological agents). Pharmaceutical evaluation consists in determining the rheological behaviour (flow curve or oscillatory studies), sol–gel transition temperature, in vitro drug release using either synthetic or physiological membrane and (bio)adhesion characteristics. Poloxamer 407 formulations led to enhanced solubilisation of poorly water-soluble drugs and prolonged release profile for many galenic applications (e.g., oral, rectal, topical, ophthalmic, nasal and injectable preparations) but did not clearly show any relevant advantages when used alone. Combination with other excipients like Poloxamer 188 or mucoadhesive polymers promotes Poloxamer 407 action by optimising sol–gel transition temperature or increasing bioadhesive properties. Inclusion of liposomes or micro(nano)particles in Poloxamer 407 formulations offers interesting prospects, as well. Besides these promising data, Poloxamer 407 has been held responsible for lipidic profile alteration and possible renal toxicity, which compromises its development for parenteral applications. In addition, new findings have demonstrated immuno-modulation and cytotoxicity-promoting properties of Poloxamer 407 revealing significant pharmacological interest and, hence, human trials are in progress to specify these potential applications.     

Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes

The purpose of this study is to develop a thermoresponsive sustained release delivery system combining phytantriol cubosomes and poloxamer 407 (P407). P407 undergoes thermoreversible gelation, where it exists as a free-flowing liquid at low temperature and gels upon heating. However, this polymer has the major draw back of fast erosion in aqueous environments which needs to be addressed. Three different concentrations of P407 (12%, 15% and 17% (w/v)) were formulated with various additives (methyl cellulose (MC), dextran, carrageenan and Pluronic-R (25R4)). The rheological characteristics and in vitro stability were investigated. The sol-gel transition temperature of P407 was lowered in the presence of the phytantriol cubosomes. The addition of MC and dextran did not affect the sol-gel transition temperature whereas 25R4 increased the gelation temperature. No transition was observed for the carrageenan formulations. The presence of 25R4 allowed the development of formulations that were free flowing liquid at working temperature (22 °C), gelled at body temperature (37 °C) and had improved stability in an aqueous environment. Both rheological and in vitro stability studies suggested that cubosome-loaded 17% (w/v) P407 with 25R4 in 1:1 molar ratio may have a potential as sustained release delivery system.     

Design and evaluation of thermoreversible in situ gelling system of forskolin for the treatment of glaucoma

The contact time of a vehicle on the cornea is of utmost importance for ophthalmic drug delivery. The poor bioavailability and therefore poor therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of a drug may be overcome by the use of the in situ gel forming systems, which upon instillation as drops into the eye, undergo a sol-gel transition in the cul-de-sac. The purpose of this work was to develop an ophthalmic delivery system of the forskolin, based on the concept of temperature activated in situ gelation. Poloxamer 407 (Pluronic F-127) is a block copolymer made of poly (oxy ethylene) and poly (oxy propylene). The sol-gel transition is induced by an increase in temperature; however, it depends on the concentration of the polymer and presence of other additives. The developed formulations were therapeutically efficacious (on albino New Zealand rabbit model); reducing intra ocular pressure (IOP) for 12 hours and showed sol-gel phase transition (gelling) temperature of 22°C and sustained drug release 72%?±?0.056% in vitro behavior over a period of 4?h.     

Approche du mécanisme de gélification des sols d'agarose I. Evolution des caractéristiques rhéologiques des sols

Thermal rheological studies describe the flow properties of A37 agarose sols. Their behavior displays plastic flow as shear strain increases. Rheological characteristtcs, viscosity, apparent viscosity and yield value are measured. Their variations with decreasing temperature pathway followed structural changes within the gelling process. A thixotropic flow occurred at the sol-gel transition point. The concentration of polymer in the gel is related to the absolute temperature of gelification in order to evaluate the heat of crosslinking. The high value corroborates the assumption of the crystalline nature of agarose gels.     

Influence of lecithin on some physical chemical properties of poloxamer gels: rheological, microscopic and in vitro permeation studies

Thermoreversible gels may be used in delivery systems which require a sol-gel transition at body temperature. The influence of the addition of lecithin, a permeation enhancer, on the rheological and in vitro permeation properties of poloxamer 407 gels was investigated. Light microscopy and rheological parameters were used to characterize the microscopic structure of the formulations which showed non Newtonian behaviour, pseudoplastic flow with a yield value. Increased concentrations of lecithin increased the thixotropy, yield value, apparent viscosity, and the gelation temperature of the gels. Light microscopy showed the formation of micellar structures by the addition of lecithin, which may account for changes in rheological properties. In vitro permeation of a model drug, triamcinolone acetonide, was decreased when the lecithin concentration was increased. The presence of lecithin in the poloxamer gel improved the characteristics for topical drug delivery.     

Formulation, characterization, and in vitro evaluation of bioadhesive gels containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16-18% w/w) either alone or in combination with HPMC K 15 M and Gantrez S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 x 10(-4) cm/s and 3.94 x 10(-5) cm/s, respectively, and differed significantly ( p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

马来酸噻吗洛尔眼用温敏凝胶的处方筛选与体外释放评价

目的:筛选马来酸噻吗洛尔眼用温敏型凝胶优化处方,并对其体外释放进行评价。方法:选用泊洛沙姆P407、P188为载体材料制备眼用温敏凝胶,测定不同处方的凝胶前体溶液分别在未经处理和经人工泪液稀释条件下,从溶液态转变为凝胶态的胶凝温度,通过星点设计-效应面法筛选优化处方,并考察胶凝时间和释放行为。结果:根据温敏凝胶保存和使用的温度要求,筛选出优化处方为P407:P188(24.25%:1.56%)。前体溶液能够在34℃人工泪液中迅速形成凝胶,并在体外缓慢释放6 h以上。结论:经过筛选并制备出的噻吗洛尔温敏型凝胶具有良好的载药能力、稳定性及释放性能,满足眼用制剂质量要求和实际应用要求。     

Intratumoral administration of paclitaxel in an in situ gelling poloxamer 407 formulation

In order to examine the efficacy of paclitaxel (Taxol, Bristol-Myers Squibb) after administration locally at the tumor site, we have developed a thermo-reversible gelling formulation in poloxamer 407 (Pluronic F-127) solution. Paclitaxel was incorporated in poloxamer 407 [20% (w/w)] at 0.5- and 1.0-mg/mL concentrations. The in vitro release studies were carried out in phosphate-buffered saline (pH 7.4) at 37 degrees C. Control and paclitaxel-poloxamer 407 formulations were administered intratumorally at a dose of 20 mg/kg in B16F1 melanoma-bearing mice. The change in tumor volume as a function of time and the survival of treated animals were used as measures of efficacy. Poloxamer 407 solution undergoes a reversible sol-gel transition when the temperature is raised to above 21 degrees C. In vitro paclitaxel release from poloxamer 407 gels was very slow (only 6.1% after 6 hr) probably due to the poor aqueous solubility of the drug. Significant enhancement in the anti-tumor efficacy was noted following intratumoral administration of paclitaxel-poloxamer 407 formulation. The initial tumor growth rate was delayed by 67% and the tumor volume doubling time was increased by 72% relative to saline control. In addition, more than 91% of the tumor-bearing animals that received paclitaxel in poloxamer 407 gel survived on day 15 post-administration as compared to 58% in the control group. The results of this study show significant benefit of paclitaxel for solid tumor when administered locally in an in situ gelling poloxamer 407 formulation.     

Formulation,Characterization, and In Vitro Evaluation of Bioadhesive Gels Containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez® S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16–18% w/w) either alone or in combination with HPMC K 15 M and Gantrez® S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez® S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 × 10^?4 cm/s and 3.94 × 10^?5 cm/s, respectively, and differed significantly (p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

Effect of sodium chloride on the release,absorption and safety of diclofenac sodium delivered by poloxamer gel

Poloxamer solutions prepared with poloxamers and sodium chloride were previously reported to undergo a phase transition to bioadhesive gels at body temperature. For the development of a thermosensitive diclofenac sodium-loaded poloxamer gel, here we investigated the effect of sodium chloride on the release, safety and rectal absorption in rats of diclofenac sodium delivered by the poloxamer gels. P 188 delayed the release rates of diclofenac sodium from poloxamer gels. However, sodium chloride showed no significant effect on the release rates of diclofenac sodium from poloxamer gels. Release mechanism analysis showed the release of diclofenac sodium was proportional to the time. The initial plasma concentrations of diclofenac sodium in the rectal formulation [diclofenac sodium/poloxamer 407 (P 407)/poloxamer 188 (P 188)/sodium chloride (2.5/15/17/0.8%)] were significantly higher compared with those in semi-solid suppository. Furthermore, it gave significantly faster Tmax of diclofenac sodium than did semi-solid suppository, indicating that the diclofenac sodium from poloxamer gel could be absorbed faster than that from semi-solid one in rats. It did not cause any morphological damage to the rectal tissues. These results suggested that poloxamer gel with sodium chloride could be a more effective and safe rectal delivery system of diclofenac sodium.     

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.     

盐酸川芎嗪眼用原位温敏凝胶的制备及体外释药特性研究

目的：制备盐酸川芎嗪眼用原位温敏凝胶并对其体外释药特性进行考察。方法采用泊洛沙姆407和泊洛沙姆188为温敏基质制备眼用温敏凝胶,采用无膜溶出模型,研究药物在某一时间的累积释放百分率与时间的变化,对曲线进行拟合分析,研究川芎嗪的体外释放特性。结果所制得凝胶为均匀稍带黏性的澄清溶液,该制剂的体外释放行为遵循零级动力学方程（r ＝0．9887）,由 Ritger －Peppas 方程拟合的 n 值为0．7533。结论盐酸川芎嗪眼用温敏凝胶体外释药是由药物扩散和凝胶溶蚀双重机制控制。     

Thermorheologic Properties of Aqueous Solutions and Gels of Tetronic 1508

The rheologic properties of aqueous solutions and gels of Tetronic 1508 were investigated as a function of polymer concentration and temperature utilizing rotational viscometry. Below the sol–gel transition temperature the polymer solutions were low in viscosity and exhibited Newtonian rheologic behavior even at concentrations of 20 and 25% (w/w). Upon sol–gel transition, the more concentrated polymer solutions underwent a dramatic four- to five-orders of magnitude increase in viscosity, resulting in the formation of a rigid gel structure. Above the sol-gel transition temperature, the gels displayed pseudoplastic and plastic rheologic properties and the viscosity of the gels remained at a relatively constant value over a wide temperature range. Eventually, the thermal energy of the system exceeded the bonding forces within the gel structure, resulting in a gel–sol transition which was marked by a dramatic decrease in the viscosity of the system. Above the gel–sol transition temperature, the system reverted to a Newtonian fluid with viscosities very similar to those found for the Tetronic 1508 solutions at temperatures below the sol–gel transition temperature. The thermodynamic implications of the gel–sol transition are discussed.     

The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle

Topical 5% alpha lipoic acid (ALA) has shown efficacy in treatment of photo-damaged skin. The aim of this work was to evaluate the potential of poloxamer (P407) gel as a vehicle for the novel lipid base particulate system (cubosome dispersions) of ALA. Cubosome dispersions were formulated by two different approaches, emulsification of glyceryl monoolein (GMO) and poloxamer (P407) in water followed by ultrasonication, and the dilution method using a hydrotrope. Three different concentrations of GMO were used to formulate the cubosome dispersions using the first method, 5% (D1), 10% (D2) and 15% w/w (D3). In the second technique an isotropic liquid was produced by combining GMO with ethanol, and this isotropic liquid was then diluted with a P407 solution (D4). The dispersions were characterized by zeta potential, light scattering techniques, optical and transmission electron microscopy, encapsulation efficiency and in vitro drug release. Results showed that D4 was not a uniform dispersion and that D1, D2 and D3 were uniform dispersions, in which by increasing the GMO content in the dispersion, the size of the cubosomes decreased, zeta potential became more negative, encapsulation efficiency increased up to 86.48% and the drug release rate was slower. P407 gels were prepared using the cold method. Two concentrations of P407 gel were fabricated, 20 and 30% w/w. P407 gels were loaded with either ALA or dispersions containing ALA cubosomes. P407 gels were characterized by critical gelation temperature, rheological measurements and in vitro drug release studies. Results suggested that by increasing P407 concentration, the gelation temperature decreases and viscosity increases. Drug release in both cases was found to follow the Higuchi square root model. Gel loaded with ALA cubosomes provided a significantly lower release rate than the gel loaded with the un-encapsulated ALA. A double blinded placebo controlled clinical study was conducted, aiming to evaluate the efficacy as an anti-wrinkle agent and volunteer’s satisfaction upon application of topical 30% P407 gel loaded with ALA cubosomes. Results indicated reduction in facial lines, almost complete resolution of fine lines in the periorbital region and upper lip area and overall improvement in skin color and texture in most volunteers. There were no instances of irritation, peeling or other apparent adverse side effects.     

Influence of magnesium aluminium silicate on rheological, release and permeation characteristics of diclofenac sodium aqueous gels in-vitro

The effect of magnesium aluminium silicate (MAS) on rheological, release and permeation characteristics of diclofenac sodium (DS) aqueous gels was investigated. DS aqueous gels were prepared using various gelling agents, such as 15% w/w poloxamer 407 (PM407), 1% w/w hydroxypropylmethylcellulose (HPMC), and 1% w/w high and low viscosity grades of sodium alginate (HV-SA and LV-SA, respectively). Different amounts of MAS (0.5, 1.0 and 1.5% w/w) were incorporated into the DS gels. Incorporation of MAS into the DS gels prepared using SA or PM407 caused a statistical increase in viscosity (P<0.05) and a shift from Newtonian flow to pseudoplastic flow with thixotropic property. The DS release rates of these composite gels were significantly decreased (P<0.05) when compared with the control gels. This was due to an interaction between MAS and PM407 or SA, and adsorption of DS onto MAS particles. Moreover, a longer lag time and no change in DS permeation flux were found when MAS was added to the gels. The findings suggest that the rheological characteristics of gels prepared using PM407 or SA could be improved by incorporating MAS. However, the use of MAS could retard the DS release and extend the lag time of DS permeation.     

Thermosensitive Micelles–Hydrogel Hybrid System Based on Poloxamer 407 for Localized Delivery of Paclitaxel

A thermosensitive micelles–hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through in-tratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol®, PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2707–2717, 2013