In situ gel forming systems of poloxamer 407 and hydroxypropyl cellulose or hydroxypropyl methyl cellulose mixtures for controlled delivery of vancomycin

Poloxamers are a family of triblock copolymers consisting of two hydrophilic blocks of polyoxyethylene separated by a hydrophobic block of polyoxypropylene, which form micelles at low concentrations and form clear thermally reversible gels at high concentrations. The objective of this study was to develop an in situ gel forming drug delivery system for vancomycin using the minimum possible ratio of poloxamer 407 (P407). Decreasing the concentration of poloxamer could reduce the risk of hypertriglyceridemia induction. Different additives were added to the poloxamer formulations. It was observed that among different additives, hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC) can decrease poloxamer concentration required to form in situ gelation from 18 to 10%. The dynamic viscoelastic properties of the samples were determined. Both the storage modulus and the loss modulus of the samples increased abruptly as the temperature passed a certain point. The gelling temperature was in the order of P407 : HPC (10 : 10 w/w) < P407 : HPMC (10 : 10 w/w) < P407 : HPMC (15 : 5 w/w) < P407 : HPC (15 : 5 w/w). Drug release rate could be controlled by changing the type and ratio of additives as well as the amount of drug loaded. It can be concluded that combining P407 and cellulose derivatives could be a promising strategy for preparation of thermally reversible in situ gel forming delivery systems with low poloxamer concentration. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Solute and solvent effects on the thermorheological properties of poly(oxyethylene)–poly(oxypropylene) block copolymers: Implications for pharmaceutical dosage form design

Despite their widespread use as platforms for topical drug delivery systems, there is a relative lack of information concerning the thermorheological and viscoelastic properties of poloxamer systems and the effects of formulation components on these properties. To address this deficit, we examined the effects of the poloxamer concentration (25 and 35% w/w), molecular weight blend (poloxamer 407 and poloxamer 188), cosolvents (ethanol, propylene glycol, and glycerol), and presence of inorganic and organic electrolytes (sodium chloride and tetracaine hydrochloride, respectively) on these properties. The rheological properties were examined with a rheometer (4‐cm‐diameter, stainless steel, parallel‐plate geometry) in either thermal sweep (0.5 Hz) or frequency sweep (0.01–1.0 Hz and 37°C) modes. Increasing the poloxamer concentration increased the elasticity [i.e., increased the storage modulus (G′) and reduced the loss tangent (tan δ)] and reduced the sol–gel transition temperature (T_m) of all the formulations. Decreasing the ratio (407:188) increased T_m and reduced the elasticity of all the formulations. Increasing the concentration of ethanol, propylene glycol, or glycerol in the solvent reduced T_m. The presence of ethanol reduced G′ and increased tan δ in a concentration‐dependent fashion, whereas the viscoelastic properties of the poloxamers were more tolerant of glycerol (in particular) and propylene glycol. The elasticity of the formulations containing up to 10% glycerol and 5% propylene glycol was increased with respect to their aqueous counterparts. The presence of sodium chloride reduced T_m and, at lower concentrations (1 and 3%), increased G′ and reduced tan δ for aqueous poloxamer systems. Conversely, the addition of a model therapeutic agent, tetracaine hydrochloride (5 and 7% w/w), significantly increased T_m and altered the viscoelastic character of the poloxamer system, notably reducing G′ and increasing the loss modulus and tan δ. Alterations in the viscoelastic and thermorheological properties of aqueous poloxamer systems will have implications for their clinical performance. This study, therefore, has highlighted the need for the rational selection of components in the formulation of poloxamer systems as platforms for topical drug delivery. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1016–1026, 2003     

Novel polyurethane‐based thermosensitive hydrogels as drug release and tissue engineering platforms: design and in vitro characterization

Poloxamer P407 (P407) is a Food and Drug Administration approved triblock copolymer; its hydrogels show fast dissolution in aqueous environment and weak mechanical strength, limiting their in vivo application. In this work, an amphiphilic poly(ether urethane) (NHP407) was synthesized from P407, an aliphatic diisocyanate (1,6‐hexanediisocyanate) and an amino acid derived diol (N‐Boc serinol). NHP407 solutions in water‐based media were able to form biocompatible injectable thermosensitive hydrogels with a lower critical gelation temperature behavior, having lower critical gelation concentration (6% w/v versus 18% w/v), superior gel strength (G′ at 37 °C about 40 000 Pa versus 10 000 Pa), faster gelation kinetics (<5 min versus 15–30 min) and higher stability in physiological conditions (28 days versus 5 days) compared to P407 hydrogels. Gel strength and PBS absorption at 37 °C increased whereas dissolution rate (in phosphate‐buffered saline (PBS) at 37 °C) and permeability to nutrients (studied using fluorescein isothiocyanate–dextran model molecule) decreased as a function of NHP407 hydrogel concentration from 10% to 20% w/v. By varying the concentration, NHP407 hydrogels were thus prepared with different properties which could suit specific applications, such as in situ drug/cell delivery or bioprinting of scaffolds. Moreover, deprotected amino groups in NHP407 could be exploited for the grafting of bioactive molecules obtaining biomimetic hydrogels. © 2016 Society of Chemical Industry     

酸枣仁多组分鼻用温敏凝胶的制备、评价及其联合释放研究

以泊洛沙姆P407和泊洛沙姆P188为凝胶材料,甘油或聚乙二醇为保湿剂,制备了复方添加酸枣仁中主要有效成分酸枣仁皂苷a、酸枣仁皂苷b、斯皮诺素的复方多组分鼻用温敏凝胶。以无膜溶出法进行了凝胶体外释放评价,以渗透膜法考察了其活性成分的联合释放规律,通过f2检验法证实凝胶活性成为的体外释放行为具有协同性。     

Kinetics of sol-to-gel transition for poloxamer polyols

Kinetics of gelation for aqueous solutions of poloxamers 407 and 288 were determined using pulse shearometry. The principle of this method for determining the shear modulus of a semisolid was based on generation of a torsional force that is transmitted through the poloxamer sample at discrete time intervals. Three distinct linear phases were observed for the log dynamic shear modulus (G′) vs. time profiles as poloxamer 407 and 288 solutions of varying concentrations were allowed to passively warm at room temperature to a temperature exceeding the sol-to-gel transition temperature, T_m. The beginning of the second exponential phase coincided with the onset of the gelation process as determined by visual observation. Although gelation appeared visually to be complete at the beginning of the third exponential phase of the log G′ vs. time profiles, this last exponential phase may indicate the rate of formation of the polymer network. A comparison of poloxamer 407 [30% (w/w); T_m = 10.9°C] and poloxamer 288 [37% (w/w); T_m = 11.1°C] would suggest that the concentration of poloxamer required to achieve approximately the same gelation temperature for poloxamers having a similar ratio of poly(oxypropylene):poly(oxyethylene) units decreases with increasing molecular weight of the poly(oxypropylene) hydrophobe contained in the copolymer. Results of these preliminary studies suggest that the gelation process was significantly (p < .05) more rapid for poloxamer 407 at a 30% (w/w) concentration compared to a 30% (w/w) solution of poloxamer 288 when the poloxamer solutions were allowed to passively warm at room temperature. In addition, it appears that the rate of gelation for the poloxamer solutions studied was dependent on the rate of heat transfer through the polymer solution.     

促孕原位凝胶灌注液的制备及其体外释放度

以泊洛沙姆407 (P407)和188 (P188)为载体材料,采用冷溶法将促孕灌注液制成原位凝胶,考察了P407和P188浓度、羟丙基甲基纤维素浓度(HPMC)、海藻酸钠浓度及促孕灌注液对胶凝温度的影响,研究了体外溶蚀、体外释药特性. 结果表明,P407浓度为18%(w)、P188浓度为7.5%(w)、HPMC浓度为0.3%(w)时,凝胶平均胶凝温度为27.9℃, 6 h内平均体外累积溶蚀度和药物累积释放度分别为92.11%和95.42%,凝胶中的药物成分主要通过溶蚀方式释放,药物释放符合零级释药方程.     

Chitosan/alginate nanoparticles stabilized by poloxamer for the controlled release of 5‐fluorouracil

In this study, stable 5‐fluorouracil (5‐FU)‐loaded chitosan (CS)/alginate (Alg) nanoparticles (NPs) were prepared with poloxamer as a surfactant. The effects of the Alg concentration, CS/Alg weight ratio, and poloxamer concentration on the properties of the 5‐FU‐loaded CS/Alg NPs were studied. The results of dynamic light scattering and transmission electron microscopy indicated that stable 5‐FU‐loaded CS/Alg NPs of around 200 nm with low‐size polydispersities were achieved. Furthermore, the in vitro release of the 5‐FU‐loaded CS/Alg NPs was investigated in phosphate buffer solution at pH 7.4. The results show that the encapsulation efficiency of 5‐FU depended on the drug feeding amount (DFA), poloxamer concentration, Alg concentration, and CS concentration. However, the in vitro release rate of the 5‐FU‐loaded CS/Alg NPs was only related to the DFA, Alg concentration, and CS concentration and was independent of the poloxamer concentration. The time of 5‐FU release from the CS/Alg NPs could becontrolled to be sustained for more than 12 h. According to this study, CS/Alg NPs stabilized by poloxamer could serve as a suitable candidate for the controlled release of 5‐FU. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

In situ thermal polymerization of an ionic liquid monomer for quasi‐solid‐state dye‐sensitized solar cells

In situ thermal polymerization of a model ionic liquid monomer and ionic liquids mixture to form gel electrolytes is developed for quasi‐solid‐state dye‐sensitized solar cells (Q‐DSSCs). The chemical structures and thermal property of the monomers and polymer are investigated in detail. The effect of iodine concentration on the conductivity and triiodide diffusion of the gel electrolytes is also investigated in detail. The conductivity and triiodide diffusion of the gel electrolytes increase with the increasing I₂ concentration, while excessive I₂ contents will decrease the electrical performances. Based on the in situ thermal polymeric gel electrolytes for Q‐DSSCs, highest power conversion efficiency of 5.01% has been obtained. The superior long‐term stability of fabricated DSSCs indicates that the cells based on in situ thermal polymeric gel electrolytes can overcome the drawbacks of the volatile liquid electrolyte. These results offer us a feasible method to explore new gel electrolytes for high‐performance Q‐DSSCs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42802.     

Preparation and properties of poly(benzyl glutamate)–poloxamer–poly(benzyl glutamate) and poly(glutamic acid)–poloxamer–poly(glutamic acid) triblock polymers

The novel block copolymer poly(benzyl glutamate) (PBLG)–polomamer–PBLG were synthesized from glutamic acid and poloxamer in six steps with three different molecular weights, and another new block copolymer, poly(glutamic acid) (PGA)–poloxamer–PGA, was obtained by the benzyl deprotection of PBLG–poloxamer–PBLG. The obtained compounds were characterized by IR spectroscopy, gel permeation chromatography, and ¹H‐NMR. The in vitro biological degradation and water absorption of PBLG showed that a greater proportion of PBLG in the copolymer led to a slower degradation and weaker water absorption, so the speed of degradation and water absorption could be adjusted through adjustment of the ratio of poloxamer. Both PBLG–poloxamer–PBLG and PGA–poloxamer–PGA exhibited lower cytotoxicity and good biocompatibility in the methyl thiazolyl tetrazolium (MTT) assay. The results show that both block polymers are promising as drug‐carrier materials. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

A Novel Carbon Dots/Thermo-Sensitive In Situ Gel for a Composite Ocular Drug Delivery System: Characterization,Ex-Vivo Imaging,and In Vivo Evaluation

We developed a potential composite ocular drug delivery system for the topical administration of diclofenac sodium (DS). The novel carbon dot CD_C-HP was synthesized by the pyrolysis of hyaluronic acid and carboxymethyl chitosan through a one-step hydrothermal method and then embedded in a thermosensitive in situ gel of poloxamer 407 and poloxamer 188 through swelling loading. The physicochemical characteristics of these carbon dots were investigated. The results of the in vitro release test showed that this composite ocular drug delivery system (DS-CD_C-HP-Gel) exhibited sustained release for 12 h. The study of the ex vivo fluorescence distribution in ocular tissues showed that it could be used for bioimaging and tracing in ocular tissues and prolong precorneal retention. Elimination profiles in tears corresponded to the study of ex vivo fluorescence imaging. The area under the curve of DS in the aqueous humor in the DS-CD_C-HP-Gel group was 3.45-fold that in the DS eye drops group, indicating a longer precorneal retention time. DS-CD_C-HP with a positive charge and combined with a thermosensitive in situ gel might strengthen adherence to the corneal surface and prolong the ocular surface retention time to improve the bioavailability. This composite ocular delivery system possesses potential applications in ocular imaging and drug delivery.     

Thermosensitive PCL‐PEG‐PCL hydrogels: Synthesis,characterization, and delivery of proteins

In this work, a biodegradable and injectable in situ gel‐forming controlled drug delivery system based on thermosensitive poly(ε‐caprolactone)‐poly(ethylene glycol)‐poly(ε‐caprolactone) (PCL‐PEG‐PCL) hydrogels was studied. A series of PCL‐PEG‐PCL triblock copolymers were synthesized and characterized by ¹H‐NMR and gel permeation chromatography (GPC). Thermosensitivity of the PCL‐PEG‐PCL triblock copolymers was tested using the tube inversion method. The in vitro release behaviors of two model proteins, including bovine serum albumin (BSA) and horseradish peroxidase (HRP), from PCL‐PEG‐PCL hydrogels were studied in detail. The in vivo gel formation and degradation of the PCL‐PEG‐PCL triblock copolymers were also investigated in this study. The results showed that aqueous solutions of the synthesized PCL‐PEG‐PCL copolymers can form in situ gel rapidly after injection under physiological conditions. The PCL‐PEG‐PCL hydrogels showed the ability to control the release of incorporated BSA and HRP. The released HRP was confirmed to conserve its biological activity by specific enzymatic activity assay. The in vivo gel formation and degradation studies indicated that PCL‐PEG‐PCL copolymers hydrogels can sustain at least 45 days by subcutaneous injection. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PCL‐PEG‐PCL copolymers hydrogels show promise as an in situ gel‐forming controlled drug delivery system for therapeutic proteins. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Controlled Release from Crosslinked Poloxamer Hydrogels

Chemically modified derivatives of the copolymeric poloxamer surfactants have been polymerised to form crosslinked, swelling hydrogels. Mixtures of derivatives of poloxamers 188 and 181 form gels which show increased swelling with increased content of the more hydrophilic poloxamer 188. The rate of release of benzoic and p-hydroxybenzoic acids also increases with increasing content of poloxamer 188. Release rate data have been analysed in terms of the swelling controlled release model for these hydrogels.     

Effects of additives on phase transitions of Poloxamer 407/Poloxamer 188 mixture and release property of monoolein cubic phase containing the poloxamers

The gelling temperature of Poloxamer 407/Poloxamer 188 (16%/10%) mixture solution increased with increasing amount of surfactants. Among surfactants tested, the order of effectiveness in increasing the gelling temperature was sodium dodecyl sulfate (SDS) > tween 20 > cetyltrimethylammonium chloride (CTAC). The gelling temperature increased with the increasing concentration of cyclodextrin (CD). The order of effectiveness in increasing the gelling temperature was gamma CD > beta CD > alpha CD. The gelling temperature increased with increasing concentration of alcohols (ethanol and propylene glycol (PG)). On the contrary, dimethyl sulfoxide (DMSO) decreased the gelling temperature of P407/P188 (16%/10%) mixture solution. On the other hand, the gelling temperature decreased upon addition of NaCl but it increased by addition of MgCl₂. With P407/P188-loaded monoolein cubic phase, the degrees of release in 40 hr were about 52% at 25 °C and 37.5% at 47 °C. The suppressed release at 47 °C is possibly because P407/P188 in the water channel of cubic phase is in gel state at the temperature.     

Tyrosinase‐mediated in situ forming hydrogels from biodegradable chondroitin sulfate–tyramine conjugates

Tyrosinase‐mediated crosslinking of chondroitin sulfate–tyramine (CS‐TA) conjugates was successfully applied in the preparation of biodegradable in situ forming hydrogels under physiological conditions. Depending on the polymer concentration, the degree of substitution of TA residue and the tyrosinase concentration, the gelation times ranged from 2.3 to 129 min. Studies on the gel contents of CS‐TA hydrogels showed that their degrees of crosslinking could be controlled by varying the tyrosinase concentrations. CS‐TA hydrogels could be completely degraded by the chondroitinase ABC within a time range from 6 days to 11 weeks. CS‐TA hydrogels possessed highly elastic properties and their storage moduli varied from 120 to 1300 Pa, as determined by rheological analysis. Scanning electron microscopy observation confirmed that CS‐TA hydrogels contained a well‐interconnected pore structure. A live–dead assay demonstrated that NIH 3T3 fibroblasts incorporated in CS‐TA hydrogels retained their viability. In addition, in vitro release of methylene blue (a photodynamic therapy drug) from CS‐TA hydrogels could be effectively sustained by the drug encapsulation in the hydrogels. This study indicates that tyrosinase‐mediated in situ forming CS‐TA hydrogels are promising for biomedical applications including drug release and tissue engineering. © 2012 Society of Chemical Industry     

Thermoplastic hydrogel based on pentablock copolymer consisting of poly(γ‐benzyl L‐glutamate) and poloxamer

A thermoplastic hydrogel based on a pentablock copolymer composed of poly(γ‐benzyl L ‐glutamate) (PBLG) and poloxamer was synthesized by polymerization of BLG N‐carboxyanhydride, which was initiated by diamine‐terminated groups located at the ends of poly(ethylene oxide) (PEO) chains of the poloxamer, to attain a new pH‐ and temperature‐sensitive hydrogel for drug delivery systems. Circular dichroism measurements in solution and IR measurements in the solid state revealed that the polypeptide block existed in the α‐helical conformation, as in the PBLG homopolymer. The intensity of the wide‐angle X‐ray diffraction patterns of the polymers depended on the poloxamer content in the copolymer and showed basically similar reflections to the PBLG homopolymer. The melting temperature (T_m) of the poloxamer in the copolymer was reduced with an increase of the PBLG block in comparison with the T_m of the poloxamer, which is indicative of a thermoplastic property. The water contents of the copolymers were dependent on the poloxamer content in the copolymers, for example, those for the GPG‐2 (48.7 mol % poloxamer) and GPG‐1 (57.5 mol % poloxamer) copolymers were 31 and 41 wt %, respectively, indicating characteristics of a polymeric hydrogel. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 2649–2656, 2003     

Balance of mechanical and electrical performance in polyimide/nano titanium dioxide prepared by an in‐sol method

Hybrid polyimide (PI)/titanium dioxide (TiO₂) films were prepared by in situ polymerization and sol–gel and in‐sol methods (where in‐sol method indicates that in situ polymerization and the sol–gel method were used in the same samples). The mechanical and electrical properties were found to be sensitive to the processing methods and the dispersion of nano titanium dioxide (nano‐TiO₂) in the PI matrix. For the PI/TiO₂ films prepared by the in situ polymerization method, their tensile strength increased with increasing TiO_{2‐in situ} (“TiO_{2‐in situ}” is “the TiO₂ nano‐particles prepared by in situ polymerization method”) concentration. However, the optimal corona lifetime of the PI/TiO₂ films was 15 min at 20 kHz and 2 kV because of poor dispersion. For the PI/TiO₂ films prepared by the sol–gel method, the corona lifetime reached 113 min because of superior dispersion and a tensile strength of about 19.63 MPa. A balance of mechanical and electrical performances was achieved with the in‐sol method. The corona‐resistant life of the PI/TiO₂ films was 43 min, which was about six times longer than that of the neat PI. Their tensile strength was 83.5 MPa; these films showed no decrease in this value compared with the pure PI films. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44666.     

Preparation of a novel poloxamer hydrogel

Poloxamer hydrogels were prepared by photopolymerization from poloxamer macromer, which was synthesized by reaction of poloxamer 407 with acryloyl chloride. The synthesis of poloxamer macromer was confirmed using NMR and FTIR spectrometry. The gelation behavior and crystalline structure of poloxamer macromer was similar to those of poloxamer 407 itself; however, the amorphous scattering of poloxamer macromer was higher than that of poloxamer itself. Differential scanning calorimetric analysis showed that the melting temperature and enthalpy of poloxamer hydrogel were also lower than those of poloxamer itself. The compressive modulus of poloxamer hydrogels were similar (92.6–101.7 kPa), regardless of the concentration of poloxamer macromer. Equilibrium water uptake of poloxamer hydrogels decreased with an increase of concentration of poloxamer macromer. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 2670–2676, 2003     

星点设计-效应面法优化盐酸川芎嗪眼用温度敏感型原位凝胶的处方

探讨星点设计-效应面法优化盐酸川芎嗪眼用温度敏感型原位凝胶的处方。采用泊洛沙姆407和泊洛沙姆188为温敏材料,以模拟泪液稀释前后的溶液-凝胶相转变温度为考察指标,采用星点设计-效应面法对处方进行优化并进行验证。经过优化的处方组成为22.5%泊洛沙姆407和5%泊洛沙姆188;优化处方制备的凝胶在26.9℃为自由流动的液体,经模拟泪液稀释后在32.5℃转变为凝胶。星点设计-效应面法适用于盐酸川芎嗪眼用温度敏感型原位凝胶的处方优化,所建立的模型预测性良好,该眼用温敏凝胶符合眼部应用要求。     

Effect of the SA content of a novel thermo‐sensitive P(NIPAM‐co‐SA) copolymer on denatured lysozyme refolding in vitro

A novel hydrogel of P(NIPAM‐co‐SA) copolymer was synthesized by inverse suspension polymerization by adding sodium acrylate (SA) to improve the phase transition properties of poly(N‐isopropylacrylamide) (PNIPAM). The morphologies, size distribution and thermosensitive characteristics of gel particles were studied and the maximal swelling ratio and LCST (Lower Critical Solution Temperature) of gel particles increased obviously with the addition of SA comonomer. When the protein concentration was 250 μg/mL, the optimized refolding conditions of denatured lysozyme with P(NIPAM‐co‐SA) hydrogel were that operating at the temperature of 35°C and a urea concentration of 2M, in which the mass ratio of P(NIPAM‐co‐SA) hydrogel with 4% SA copolymerized to lysozyme was 10 : 1. Under the optimized conditions, the activity recovery of lysozyme increased to 76.5% assisted by P(NIPAM‐co‐SA) gel particles compared with 55.6% by simple dilution. When refolding finished, the gel particles could be removed and recovered easily and the activity recovery of lysozyme was still as high as 61.5% after reused for 5 batches. With the addition of different amounts of SA comonomer, the hydrophobicity of the copolymer could be varied. Then the copolymerized hydrogel inhibits protein molecules aggregation more effectively through the moderate hydrophobic interactions between copolymers and protein molecules in the course of lysozyme refolding compared with the presence of PNIPAM polymer. All results above demonstrate that the P(NIPAM‐co‐SA) is a cost effective additive with tunable hydrophobicity for application in the refolding of recombinant proteins expressed as inclusion bodies in vitro. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Preparation and properties of crosslinked chitosan thermosensitive hydrogel for injectable drug delivery systems

The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol–gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH‐dependent solutions into thermosensitive pH‐dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent “pores” and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three‐dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 1892–1898, 2006