Characterization of thermosensitive chitosan-based hydrogels by rheology and electron paramagnetic resonance spectroscopy.

Chitosan, an amino-polysaccharide, has been proposed as a promising biopolymer for tissue repair and drug delivery. Chitosan solutions containing glycerol-2-phosphate (beta-GP) have been described as injectable in situ gelling thermosensitive formulations, which undergo sol-gel transition at physiological pH and temperatures. This feature makes them suitable for the parenteral administration of drugs, especially for peptides and proteins. The aim of the present study was to get a deeper insight into the macro- and microstructure of chitosan/beta-GP systems. In addition to oscillating rheology, electron paramagnetic resonance (EPR) spectroscopy was applied to examine the microviscosity and pH inside the gels depending on the beta-GP concentration and to follow the loading and release of spin-labelled Insulin. All chitosan/beta-GP solutions showed a physiological pH ranging from 6.6 to 6.8 that did not change during gelation, irrespective of the proportion of beta-GP. The dynamics of the spin-labelled Insulin and its microviscosity inside the gels and during release were monitored by EPR spectroscopy. The results indicate that the Insulin was incorporated into the aqueous environment of the gel and was released in its native form. The in vitro drug release from the gels was governed by diffusion of drug from the gel matrix. A sustained release of Insulin was observed over a period of 2 weeks. Increasing the proportion of beta-GP increased the amount of released Insulin and the velocity thereof.     

温度敏感原位凝胶中药物的扩散行为温度敏感原位凝胶中药物的扩散行为

环境敏感凝胶对外界物理或化学条件的微小变化发生响应的性质在药物控制释放领域得到广泛应用.原位凝胶(in situ gel)是指高分子材料的溶液因温度[1,2]、离子强度[3]或pH[4]的改变而在用药部位发生相转变,形成的半固体制剂.由于完美地融合了液体与凝胶制剂的优点,该药物传递系统近年来已逐步发展成为环境敏感凝胶最受瞩目的分支.     

A new ultrasonic method for the measurement of the diffusion coefficient of drugs within hydrogel matrices

A new method for the determination of the diffusion coefficient within a solid matrix has been developed. The method is based on the simultaneous, automatic measurement of the ultrasonic velocity at two fixed positions within the solid matrix as a function of time. Application of the method to the diffusion of sodium chloride through dilute gelatin gels gave a diffusion coefficient in reasonable agreement with the literature value for the diffusion in pure water. Diffusion coefficients of 4.3 and 2.8 × 10 ^?6 cm² s^?1 were determined for the diffusion of the hydrochlorides of ephedrine and pethidine, respectively, through polyacrylamide hydrogels.     

Diffusion from gelatin-glycerin-water gels

The effect of gelatin, glycerin and methylene blue concentration on the diffusion of a dye from gelatin-glycerin-water gels has been examined. The rate of diffusion depended on the pore size of the gel and on the viscosity of the interspace fluid. Except at very low concentrations of methylene blue, an aggregation factor must be added to those factors suggested by Friedman & Kraemer (1930) as controlling the rate of diffusion from gels.     

Microviscosity of hydroxypropylcellulose gels as a basis for prediction of drug diffusion rates

This study investigated the influence of the rheological properties of hydroxypropylcellulose (HPC) gels on the in vitro release of theophylline included in the gel at 0.2 g/l. Experiments were performed with six HPC varieties (mean molecular weight between 5x105 and 1.2x106, nominal viscosity between 100 and 4000 mPa.s) at concentrations of 0-2% (w/w). Theophylline diffusion coefficients at 37 degrees C ranged from 3.5x10-7 to 1.1x10-3 cm2/min, and were in all cases markedly higher than those predicted on the basis of gel macroviscosity as determined by capillary viscometry. In general, the theophylline diffusion coefficient declined exponentially with HPC concentration; in the case of the lowest-molecular-weight HPC, however, the diffusion coefficient remained constant to HPC concentrations of up to 0.8%, probably because of the high entanglement concentration of the HPC. Gel microviscosities as determined by dynamic light scattering (DLS) with latex microspheres (162 nm diameter) were considerably lower than the macroviscosities determined by capillary viscometry, and similar to microviscosities estimated on the basis of theophylline diffusion. Nevertheless, macroviscosity was correlated with microviscosity, suggesting that it is of value for approximate estimates of rates of diffusion of theophylline from HPC gels.     

Use of ATR-FTIR Spectroscopy to Study the Diffusion of Ethanol Through Glycerogelatin Films

The use of ATR-FTIR spectroscopy to study the permeability of a glycerogelatin film is described. Measurement of the diffusion coefficient of ethyl alcohol-d in the film showed excellent reproducibility. Comparison of results from this technique with those previously obtained using an air-flow receptor phase diffusion cell show good agreement in terms of lag time assessed diffusion coefficients. ATR-FTIR spectroscopy revealed time-dependent changes in the composition of the glycerogelatin film during the diffusional process. It was also demonstrated that the concurrent assessment of both diffusant penetration and film composition is feasible.     

The influence of viscosity on the migration of chloramphenicol and 4-hydroxybenzoic acid through glycerogelatin gels

Migration of chloramphenicol and 4-hydroxybenzoic acid from solutions in 1-octanol into Glycerol Suppository Base, BP and soft gelatin capsule shells is reported. Rates of migration through the gels, quantified in terms of diffusion coefficients, are given. An electron spin resonance probing technique was used to determine the microscopic viscosity. The latter, rather than the bulk viscosity, was shown to be the major rheological influence on the rate of diffusion.     

Studies on dressings for dental surgery use. Part 1: Effect of plasticizers on gelatin gel etching rate

For quantitative evaluation of the absorption rate of dental dressings made of gelatin, a biopharmaceutical model of etching of gelatin gels in vitro has been elaborated. For the optimum etching conditions of gelatin gel columns 900 BAEE units per ml trypsin solution was used at a temperature of 25 degrees C. It has been found, that addition of glycerol and propylene glycol insignificantly reduces the etching rate of gelatin gels, whereas the PEG 400, PEG 1500 and PVAL increase resistance of the gels against the etching action of trypsin. In the model provided well repeatable results the coefficient of variation of the average gel etching rate remained within the range of 0.45-0.57%.     

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.     

The effect of composition upon the physical and chemical properties of biodegradable gelatin polymer matrixes

The aim of the research was to obtain porous, elastic gel matrix with a long decomposition time as a carrier of therapeutic substance. The pigskin gelatin of various degrees of gelation and glycerol was used in the experiment. The studies showed that such biopolymer as gelatin is enable to prepare the matrix which can remain in organism for a long time and a porous structure of the sponge allows to increase absorbing capacity of exudate.     

酮咯酸氨丁三醇凝胶剂体外经皮渗透研究

目的：考察凝胶剂作为酮咯酸氨丁三醇透皮给药载体的可行性。方法：制备卡波姆940药物凝胶，采用Franz扩散池用离体大鼠皮肤进行体外经皮渗透实验，以HPLC法测定渗透介质中药物含量并求算累积渗透量及稳态透皮速率。结果：以1．0％卡波姆940为凝胶基质，以硼砂溶液调节凝胶的pHN6．0时所制备的凝胶为最佳凝胶基质。3％的月桂氮革酮及5％的丙二醇均可以显著提高凝胶中药物的经皮渗透，且两者联用存在协同作用。结论：本实验的凝胶基质可为生产提供参考依据。     

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.     

Modeling of Caffeine Release from Crosslinked Water-Swellable Gelatin and Gelatin-Maltodextrin Hydrogels

Research from this group has recently led to the development of a genipin-crosslinked gelatin gel that may be used as a controlled release matrix for bioactive compounds. This study presents a model that simulates the release of entrapped caffeine from the hydrogel and the ingress of water into these gels. Fick's second law of diffusion is used to describe the water penetration and bioactive release in the system. To validate the model, caffeine release experiments from the gel were carried out. The predicted bioactive release profiles are in very good agreement with experimental data at different gel compositions. The model may also be used for a wide range of bioactive molecules and hydrogels with different cylindrical dimensions.     

Modeling of caffeine release from crosslinked water-swellable gelatin and gelatin-maltodextrin hydrogels

Research from this group has recently led to the development of a genipin-crosslinked gelatin gel that may be used as a controlled release matrix for bioactive compounds. This study presents a model that simulates the release of entrapped caffeine from the hydrogel and the ingress of water into these gels. Fick's second law of diffusion is used to describe the water penetration and bioactive release in the system. To validate the model, caffeine release experiments from the gel were carried out. The predicted bioactive release profiles are in very good agreement with experimental data at different gel compositions. The model may also be used for a wide range of bioactive molecules and hydrogels with different cylindrical dimensions.     

Multivariate parameter evaluation of pharmaceutically important cellulose ethers.

A set of nonionic cellulose ethers with varying hydrophobicity and molecular weight has been investigated by principal component analysis (PCA). Several experimental variables such as dynamic surface tension, diffusion coefficient, microviscosity as monitored by a fluorescence probe technique, and intrinsic viscosity are included in the analysis. The experimental variables and observations (polymer fractions) are analyzed in models with good predictive capacities. The apparent equilibrium surface tension correlates to the cloud point and to the critical aggregation concentration in the presence of surfactant. The microviscosity is shown to be a predictive parameter for the degree of hydrophobic substitution. The irreversible process of dynamic surface tension is dependent on the diffusion coefficient but to an even larger degree on the polymer concentration, which is well illustrated by the PCA models.     

In vitro release of lidocaine from pluronic F-127 gels

The release of lidocaine from aqueous, crystal clear and colorless gels of Pluronic F-127 (a polyoxyethylene-polyoxypropylene surface-active block polymer) has been studied in an in vitro release model which did not utilize a membrane. Pluronic F-127 forms micelles in aqueous systems and the gels are believed to be viscous isotropic liquid crystals. Due to their reverse thermal gelation behavior, good solubilization capacity, optical properties and low toxicity, they appear to have potential application as topical drug delivery systems. It has been found that the rate of lidocaine release was inversely proportional to its concentration, the concentration of Pluronic F-127 and electrolyte concentration (sodium chloride). Release of lidocaine was maximal at pH values close to its pK_a; however, release of the more water-soluble benzocaine (included for comparison purposes) was relatively pH-independent over the pH range studied. Since the apparent diffusion coefficient of lidocaine increased with increasing temperature, in spite of increasing macro-viscosity of the gel, it is apparent that drug is released by diffusion through the extramicellar aqueous channels of the gel matrix. Hence, the rate of drug release was determined by the micro-viscosity of the extramicellar fluid, the dimensions of the aqueous channels, and the equilibrium relationship of drug between the micelles and the external aqueous phase.     

Radiation-induced changes in the properties of gelatin

The impact of high energetic rays between 10 and 100 kGy on gels and solutions of gelatin is studied. Physical and biopharmaceutical properties are changing dependent on the rayage and the content of glycerol and water. The possibilities of influencing melting behaviour, viscosity, rigidity, temperature of gel formation, imbibition behaviour and dissolution in foillike preparations are determined. Glycerol is able to compensate the radioinduced changes of the structure of gelatin up to a dose of 50 kGy. Its use as a radioprotective material is being discussed.     

Influence of gamma radiation on the gel rigidity index and binding capability of gelatin

Changes in the rigidity indices of gelatin gel before and after gamma irradiation were characterized by dynamic mechanical testing, and the significance of these changes on the strength of granules was evaluated. Results illustrate the difficulty of obtaining reproducible values for gels containing less than 20% gelatin. However, rigidity indices for gels with a gelatin content of 20% and higher are consistent and may provide a useful controlling factor for preparation of gelatins of more precise specifications. The data indicate that rigidity degradation kinetics of several concentrations of gelatin gel at different radiation doses are complex, showing both increasing and decreasing rates. These findings strongly suggest that doses of less than 2.0 Mrad of gamma radiation should be used in order to obtain gelatins of acceptable quality for pharmaceutical applications. The crushing strength of granules of lactose powder granulated with irradiated gelatin reveals that the binding capability of such gelatin is significantly reduced. The results obtained for various size fractions and granule hardnesses containing different binder concentrations also suggest that particle size influences the granule strength to a lesser extent than does binder concentration and its consistency.     

Effect of water-soluble carriers on morphine sulfate release from a silicone polymer.

The influence of gelatin, sodium lauryl sulfate, lactose, and sodium alginate on morphine sulfate diffusion from cylindrical silicone polymer pellets was examined in isotonic pH 7.4 phosphate buffer. These water-soluble carriers caused the pellets to swell in aqueous media. Sodium alginate exerted the greatest influence on drug release. The morphine sulfate diffusion rate from the cylindrical pellets increased as the matrix alginate content increased up to 20%. Water-soluble carrier incorporation into silicone polymeric matrixes permits controlled release of water-soluble drugs that otherwise would be released extremely slowly from the polymer. Drug diffusion from the silicone matrix containing sodium alginate followed second-order kinetics. The release mechanism probably involves the creation of pores or pathways through the matrix secondary to the swelling.     

温敏型原位凝胶的热力学及流变学性质研究

目的:以磷酸川芎嗪为模型药物,探讨运用泊洛沙姆P407(P407)制备鼻用温敏型原位凝胶的可行性。方法:采用搅拌转子法测定不同处方磷酸川芎嗪原位凝胶的胶凝温度(胶凝温度:T);在不同温度下,以旋转式黏度计测定加入不同浓度辅料后P407溶液的黏度,以考察黏度随温度的变化规律。结果:P407溶液浓度越高,T越低;辅料的加入可以使P407溶液T升高,而处方药物和等渗调节剂(0.9%NaCl)使P407溶液T降低。当温度升高时,P407黏度增大,而辅料的加入会使P407黏度突变点的温度升高,黏度变小。结论:通过调节P407溶液的浓度或加入一定量辅料的方法,可以使TMPP原位凝胶在鼻腔温度(33℃左右)下胶凝,从而达到增大生物利用度和减少给药流失的要求。