Development of indomethacin Carbopol ETD 2001 gels and the influence of storage time and temperature on their stability

We investigated the development of a topical indomethacin gel formulation of suitable consistency using Carbopol ETD 2001 as the gelling agent. Topical gel formulations containing 1% w/w indomethacin (IND), 1% w/w Carbopol ETD 2001 (C2001), 1% of trethanolamine (TEA), 30% hexylene glycol (HG) and 10% polyethylene glycol (PEG 300) were prepared with excipients Tween 80, PVP 25, both Tween 80 and PVP 25 or neither agent. These four gel formulations were tested after a period of 1 and 4 weeks at storage temperature of 6 degrees C, 20 +/- 2 degrees C and 45 degrees C. Physical evaluation of the stability of these gels was carried out by microscopic and rheological tests, measurement of pH and by visual inspection. Rheological properties were studied using the cone and plate method at shear rates of 600 to 6000 1/s. Viscosities corresponding to shear rates were also calculated. Our results indicated that C2001 could be used as a gelling agent for IND in topical preparations. IND-C2001 gels were clear and exhibited an acceptable appearance; gel behaviour was non-Newtonian and pseudoplastic. The addition of either Tween 80 or PVP 25 to the base gel formulation significantly increased the shear stresses and viscosity of the gels. These novel formulations exhibited good physical stability throughout the 4-week examination periods as inferred from pH measurements and microscopic examination. Additionally, the non-Newtonian pseudoplastic behaviour of the gels was maintained throughout storage, with only a minimal decrease in gel viscosity after 4 weeks. Differences in consistencies of the four formulations, although initially apparent, were no longer evident after 4 weeks of storage for all temperature conditions examined. Gels stored at high temperature (45 degrees C) developed a dark yellow color and decreased in viscosity compared to other storage temperature.     

The rheological properties of carbopol gels II. Oscillatory properties of carbopol gels

Viscoelastic properties of aqueous Carbopol gels were examined at frequencies of 7.91 × 10^?3 to 25 Hz using a Weissenberg rheogoniometer. Neutralized gels changed little from 10 to 50dgC and were similar to unneutralized gels. Data confirmed the dominant elastic nature of Carbopol gels (phase lags of 2–14°) and the relative small change of the storage modulus with frequency indicated that the polymer was strongly entangled and the gels were examined in their plateau region of viscoelastic behaviour. Some correlation of oscillatory data with continuous shear properties was observed.Oscillatory data obtained at different temperatures were combined with creep data using the method of reduced variables; satisfactory composite curves over a slightly increased frequency range were obtained. When creep data were transformed into dynamic data and combined with experimental oscillatory results, using exact viscoelastic relationships, curves were obtained which described the behaviour of Carbopol gels over seven frequency decades. From this behaviour it was suggested that Carbopols were high molecular weight amorphous polymers with long side chains. The practical aspects of the transformation procedure were discussed and it was shown that neither small strain technique alone covered the entire frequency or time range necessary for an exhaustive study of Carbopol gels.     

Influence of methyl-beta-cyclodextrin and liposomes on rheological properties of Carbopol 974P NF gels

The influence of positively-charged and sterically stabilized liposomes and/or methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels was investigated. All formulations have displayed a shear-thinning behavior of Carbopol gels, and the rate stress as a function of the shear rate was fitted using the Cross equation. An important loss of viscosity was observed when 1.5% Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was dissolved in buffer at 5% there was no additional effect on gel viscosity reduction. The incorporation of positively-charged and sterically stabilized liposomes at 2 mM of lipid concentration had no incidence on rheological properties of the Carbopol gels, whereas gel viscosity was significantly increased in the presence of positively-charged liposomes at 10 mM of lipid concentration. Finally, the viscosity of hydrogels containing both liposomes and methyl-beta-cyclodextrin tended to be close to control gels, remaining high and relevant for a topical delivery.     

Pluronic F-127 gels as a vehicle for topical formulations of indomethacin and rheological behaviour of these formulations

Topical gel formulations containing a non-steroidal anti-inflammatory drug, indomethacin (IND), were prepared using 20% w/w Lutrol PF-127 as a gel-forming agent, and 16, 20 and 24% w/w Hexylene glycol (HG) or polyethylene glycol 300 (PEG) as solvents. 1% w/w Tween 80 and 1% w/w PVP 25 were added as excipients. The effects of the amounts of solvent and excipients on the physical characteristics of IND gel such as consistency, appearance, crystallization, pH and viscosity were studied. The results indicated that 1% w/w IND is able to form a structural gel. The viscosity values were calculated from the rheograms which were determined by a Haake Rotovisco sensor at a shear rate of 10,000 l/s. Viscosities corresponding to shear rates of 1000, 3000, 6000 and 9000 l/s were also calculated. Yield points were approximated from the rheograms. Although all IND gels maintained their pseudoplastic flow behaviour, their viscosities decreased markedly with increasing shear rates. Furthermore, increasing the amount of HG or PEG gave a more viscous gel except for the 24 w/w% HG gels which turned a jelly with or without either Tween or PVP. The difference in viscosities was explained by the changes in the gel compositions. 20% of PEG-1% PVP ranked first in viscosity followed by 16% PEG-1% PVP, 16% PEG-1% Tween, 24% PEG, 20% PEG-1% Tween and 16% HG-1% PVP. The results indicate that the excipients influence the physical characteristics of the gels. The optimum concentration for gels manifesting as strength of gel was 20% PEG in combination with 1% PVP which had the highest viscosity and yield value at a low shear rate.     

Rheological properties of poloxamer vehicles

The rheological behavior of poloxamer vehicles as a function of composition and temperature was evaluated using continuous shear methods. For poloxamer vehicles in the sol state (low concentration and temperature) a linear relationship was observed between shear rate and shear stress. For some of the vehicles, as concentration or temperature was increased, the systems underwent a sol-gel transition and their theological behavior became non-Newtonian.The addition of sodium chloride or polyhydroxy compounds such as glycerin or propylene glycol to the vehicles produced an increase in their apparent viscosities. At low temperature (5°C) apparent viscosities were exponentially related to concentration. As temperature was increased to 15°C, positive deviations from the expected viscosities were observed at the higher polymer concentrations.     

Anhydrous Carbopol polymer gels for the topical delivery of oxygen/water sensitive compounds

PURPOSE: The purpose of this study was the development and evaluation of an anhydrous glycerin-based Carbopol gel in order to study the stability of the oxygen/water-sensitive agent epigallocatechin gallate (EGCG). METHODS: Various Carbopol polymers were investigated rheologically at concentrations of 0.25-1% using a Brookfield viscometer in order to evaluate their ability to form anhydrous glycerin-based formulations. The addition of Transcutol P was evaluated in order to create a gel that can be utilized for the incorporation of more lipophilic compounds. The suitability of standard neutralizers and their useful concentrations were determined to develop guidelines for formulation optimization. An accelerated stability study was performed at 50 degrees C to evaluate the degradation of EGCG in an anhydrous glycerin gel. RESULTS: It was found that Carbopol 974 is the most efficient thickener for anhydrous glycerin formulations. In contrast to aqueous gels, anhydrous gels are formed without the addition of neutralizers. The rank-order viscosity of the nonneutralized gels studied was 974 > 971 > 981 > Pemulen TR-2 approximately 980. The addition of neutralizers resulted in a further increase in gel viscosity, with a maximum being reached at a concentration of approximately 0.5% w/w. The incorporation of Transcutol P resulted in a concentration-dependent loss of gel viscosity. The stability data showed that no degradation of EGCG had occurred. CONCLUSION: It was shown that anhydrous glycerin-based Carbopol gels can be prepared without the need for neutralization. Such vehicles are promising for the incorporation of oxygen/water-sensitive drugs.     

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.     

琼胶流变学性质和胶凝性质的研究

目的研究琼胶的静态流变性质和动态流变性质。方法采用MCR101型流变仪测定流变学性质;质构仪测定胶凝性质。结果与结论琼胶溶液是一种剪切变稀的假塑性流体,其表观粘度随质量分数的增加逐渐增加;温度对琼胶溶液粘度的影响符合Arrhenius模型,琼胶溶液在不同的温度下触变性不同;电解质及蔗糖均会导致溶液的粘度降低。琼胶溶液表现出弱凝胶的特性。琼胶溶液形成的凝胶是一种热可逆的冷致凝胶,其胶凝点远低于熔化点,温差为55℃;凝胶强度在一定的时间区域内,随时间的延长逐渐增大;电解质使琼胶的凝胶强度显著降低,少量蔗糖使琼胶的凝胶强度升高。     

A comparative rheological study on carbopol viscous solutions and, the evaluation of their suitability as the ophthalmic vehicles and artificial tears.

The rheological behaviours of different types of Carbopol (Carbopol 940, 934, 941 and 910) were investigated in the present work. Viscous solutions of these polymers were prepared in the range of concentration between 0.01-0.25% (w/w). 10% aqueous solution of sodium hydroxide was used for the neutralization procedure. Mannitol, sorbitol, sodium chloride and borate were tested to make the isotonic solutions. The viscosities of the solutions decreased dramatically with sodium chloride and sodium borate. Mannitol had no effect on the pH values of the solutions while sorbitol has showed a small effect. The solution prepared were sterilized by autoclaving and stored at 4 degrees C for 3 months. The pH value, viscosity and osmolality measurements were made after neutralization and sterilization, at the end of 1 and 2 weeks, 1, 2 and 3 months of storage. It could be concluded that four types of Carbopol are suitable for ophthalmic use. The aqueous vehicles of Carbopol 940 had an excellent appearance and clarity when compared with the other types of polymer.     

Optimisation of polyherbal gels for vaginal drug delivery by Box-Behnken statistical design.

The present research work aimed at development and optimisation of mucoadhesive polyherbal gels (MPG) for vaginal drug delivery. As the rheological and mucoadhesive properties of the gels correlate well to each other the prepared MPGs were optimised for maximum mucoadhesion using a relationship between the storage modulus (G') and Gel Index (GI), by employing a 3-factor, 3-level Box-Behnken statistical design. Independent variables studied were the polymer concentration (X(1)), honey concentration (X(2)) and aerosil concentration (X(3)). Aerosil has been investigated for the first time to improve the consistency of gels. The dependent variables studied were the elastic modulus, G'(Y(1)), gel index (Y(2)), and maximum detachment force (Y(3)) with applied constraints of 500相似文献   

乙酸异丁酸蔗糖酯原位凝胶流变学性质的研究

原位凝胶易于注射,注射后在体内发生相变,迅速转变为药物贮库的传递系统。原位凝胶中一种较好的小分子基质为乙酸异丁酸蔗糖酯(sucroseacetate isobutyrate,SAIB)[1,2],具有良好的生物相容性,在体内可被酶降解并逐渐代谢[3~5],其黏度超过100 Pa·s。与聚合物不同,当浓度高达85%     

Rheological Characterization of Topical Carbomer Gels Neutralized to Different pH

PURPOSE: The primary objective of this study is to perform detailed and extensive rheological characterization of rheology of carbomer (Carbopol) microgels formulated using a solvent system typically used in topical gel formulations. Solvents like glycerin and propylene glycol can alter rheology and drug delivery characteristics of topical gels owing to their different viscosities and due to the change in solvent-polymer and solvent-solvent interactions. METHODS: Aqueous gels with different pH were prepared by dissolving cross-linked Carbopol polymers in a co-solvent system comprising water, propylene glycol, and glycerol and subsequently neutralizing the carboxylic groups of the polymers with triethanolamine (TEA). Oscillatory, steady, and transient shear measurements were performed to measure viscoelastic properties, temperature dependency, yield strength, and thixotropy of carbomer pharmaceutical gels. RESULTS: The topical pharmaceutical gels exhibit remarkable temperature stability. Flow curves obtained at different temperatures indicate Carbopol microgels show much more pseudoplastic behavior (lower power law index) compared to Carbopol gels dissolved only in water. Substantial yield strength is required to break the microgel network of the topical gels. The gel samples exhibit modest thixotropy at higher deformation rates. CONCLUSIONS: The theological behavior of the Carbopol microgels do not change appreciably in the pH range 5.0-8.0, and the gels can be used as effective dermatological base for topical applications.     

Influence of storage time and temperature on the stability of indomethacin Pluronic F-127 gels

The stability of 20 topical gel formulations containing drug, 1% w/w indomethacin (IND), and 20% w/w Pluronic (PF-127) as a gel-forming agent, hexylene glycol (HG) and polyethylene glycol 300 (PEG) in different amounts (16, 20 and 24% w/w) as solvents and 1% w/w polyvinyl pyrrolidone (PVP, K-25) and Tween as excipients was determined by appearance and consistency of the gels, microscopy, pH and rheological measurements after 1 and 4 weeks storage, at 6 degrees C, 20 +/- 2 degrees C and 45 degrees C. Viscosity values were determined from rheograms by a Haake Rotovisco sensor at shear rates of 1000 to 10,000 l/s. The relationship between effectors (temperature and storage time) and response (viscosity) was determined using multiple regression analysis. All formulations were stable at room temperature (20 +/- 2 degrees C). The consistency of the gels containing HG and PEG decreased during storage at 6 degrees C. Storing the gels at 6 degrees C resulted in the precipitation of IND, but when PVP was incorporated into the IND-PF-127 gels, the stability of the gels was improved. All IND gels sustained their pseudoplastic flow behaviour. The viscosity decreased as storage time increased. A statistically significant model was obtained, showing that the effect of storage temperatures on the viscosity was much less than the effect of storage time.     

In vitro percutaneous penetration of acyclovir from solvent systems and Carbopol 971-P hydrogels: influence of propylene glycol

The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increases; this effect could be attributed to the increase of the viscosity in the diffusional pathway. When gels are used skin permeation values of ACV were smaller than those of the solvent systems. This could be attributed to the network structure created by the polymer that increases the length of the diffusional pathway. The maximum ER (= 6.8) was for Carbopol gel containing 50% PG. Therefore, these gels can be considered candidates for further research to confirm their usefulness as delivery systems for ACV topical formulations.     

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。     

Rheological evaluation of the influence of sterilisation on ocular gels using an experimental design

Different rheological characterisation methods are employed to investigate the influence of the sterilisation method (autoclaving), the polymer concentration (0.50, 0.75 and 1.00%) and the dispersing medium (i.e. isotonic phosphate buffer and mannitol solution) on Carbopol 974 P NF dispersions, used as ocular gels. The evaluation of the different polyacrylic acid-based dispersions was performed using flow and oscillatory shear measurements, and herewith an experimental design was set up. The rheological data show that the choice of the dispersing medium has a significant influence on the rheological behaviour of the ocular gels prepared. The dispersions in mannitol exhibit higher elastic properties than those made in the phosphate buffer solution (PBS). Sterilisation increases only the elastic properties of the 0.50% (w/w) Carbopol 974 P NF/PBS dispersion but has no influence on the other dispersions prepared.     

Viscoelastic Properties of Carbopol 940 Gels and Their Relationships to Piroxicam Diffusion Coefficients in Gel Bases

Purpose This study was conducted to determine the effect of formula compositions on viscoelastic properties of piroxicam gels using Carbopol 940 as a gelling agent and to determine the relationships between viscoelastic properties of Carbopol 940 gel bases and diffusion coefficients of piroxicam in gel bases. Methods Piroxicam gels (1.0% w/w) were prepared by using Carbopol 940 as a gelling agent and varying Carbopol 940 concentrations, glycerin, and sodium chloride contents. The in vitro release of piroxicam from gel bases to the receiving media, isotonic phosphate buffer solution (pH 7.4), were carried out using Franz-modified cell. The piroxicam diffusion coefficients were obtained by Higuchi's equation. Rheological property measurements of gel samples were performed via a cone and plate fluid rheometer. Relationships between viscoelastic properties of gel samples and piroxicam diffusion in gel bases were analyzed by Pearson's test at a p value of less than 0.05. Results All piroxicam gels exhibited predominantly elastic solid behavior whose magnitude depended on Carbopol 940 concentration. Preparations containing good solvent exhibited more elastic solid characters. In contrast, the piroxicam gels containing higher sodium chloride contents possessed more viscous fluid behavior. Analyzed by Pearson's test at a p value of less than 0.05, piroxicam diffusion coefficients were directly proportional to loss tangent, but were inversely proportional to storage modulus, loss modulus, complex modulus, and viscosity. Conclusions There is a potential for predicting drug diffusion coefficients from their correlations to rheological parameters. This could be beneficial to the formulation design of transdermal drug delivery systems including mucoadhesive drug delivery systems.     

Viscosity and temperature relationship in ethanol/water mixtures gelified with Carbopol Ultrez 10

The rheological characterization of Carbopol Ultrez 10 ethanolic (15%) gels is complemented by studying flow behavior as a function of temperature (20-50 degrees C) at different pH (4.0-7.0) and polymer concentrations (0.1-0.5%). Flow curves were adjusted to the Ostwald model, showing a fall in viscosity, together with an enhancement in flow index with increasing temperature. Calculated flow activation energies at constant shear rate (Egamma) were found to be related to the final pH of hydroalcoholic gels. Nevertheless, at the polymer concentration range evaluated, no significant correlations were obtained between activation energy and concentration. In general, the Carbopol Ultrez 10 gels exhibit little viscosity change under the temperature variations of normal use and storage, which minimizes possible unacceptable changes in the product's characteristics.     

Gamma-irradiation of lyophilised wound healing wafers

Lyophilised wafers are being developed as drug delivery systems that can be applied directly to the surface of suppurating wounds. They are produced by the freeze-drying of polymer solutions and gels. This study investigates the possibility of sterilising these glassy, solid dosage forms with gamma-irradiation and determining the rheological properties of rehydrated wafers post-irradiation. One series of wafers was formulated using sodium alginate (SA) modified with increasing amounts of methylcellulose (MC), the other being composed of xanthan gum (XG) and MC. Batches were divided into three lots, two of which were exposed to 25 and 40 kGrays (kGy) of Cobalt-60 gamma-irradiation, respectively, the third being retained as a non-irradiated control. Apparent viscosities of solutions/gels resulting from the volumetric addition of distilled water to individual wafers were determined using continuous shear, flow-rheometry. Flow behaviour on proprietary suppurating surfaces was also determined. Large reductions in viscosity were apparent for irradiated SA samples while those of XG appeared to be largely unaffected. In addition, an increase in the yield stress of xanthan formulations was observed. Xanthan wafers appeared to withstand large doses of irradiation with no detrimental effect on the rheology of reconstituted gels. This offers the possibility of manufacturing sterilisable delivery systems for wounds.     

Rheological, mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents

Carbopol is one of the most common thickening agent for water phases. It is used after neutralisation and its rheological properties in the aqueous medium are well known. The aim of this work was to investigate the gelation properties of Carbopol 971 e 974 polymeric systems in water-miscible cosolvents such as glycerine and PEG 400. Since in these cosolvents, carboxypolymethylene precipitates after neutralisation with a base, then the attention was pointed out of the gelation properties of the different systems at increasing temperature, in order to obtain Carbopols gels avoiding neutralisation and, at the same time, making possible the dissolution in these gels of insoluble or poorly soluble water drugs. Rheological properties of PEG 400 and glycerine samples were compared with similar systems in water by performing oscillatory analyses and measuring the main rheological parameters, G', G" and delta. The results obtained showed that Carbopol 971 and 974 in PEG 400 gave rise after heating to gels that show a satisfactory rheological behaviour. The elastic modulus is greater than the viscous one showing a remarkable elastic character of these samples and the performed frequency sweeps show a typical spectrum of a "gel-like" structure. Being Carbopols well-known mucoadhesive polymers, gels adhesive properties were studied using the ex vivo method. Then, the possible cutaneous irritation were also tested using the in vivo method (Draize test). No signs of cutaneous irritation and good mucoadhesive properties were obtained for the PEG 400 and water gels of Carbopol 974 prepared by heating. After rheological and mucoadhesive properties were set, paracetamol as a model drug was then inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of PEG 400-Carbopol 971 samples. These studies showed PEG 400-Carbopol systems as a first-rate alternative to traditional water gels.