Electrodynamic investigations of ion transport and structural properties in drug-containing gels: dielectric spectroscopy and transient current measurements on catanionic carbopol systems.

The aim of this study is to show the potential of using electrodynamic methods as characterization tools in the controlled drug release process, on complex drug release systems. The two formulations under study were a Carbopol gel containing diphenhydramine and an identical gel also containing the surfactant sodium dodecyl sulfate which forms catanionic vesicles with the diphenhydramine. The average diffusion coefficients were calculated from both the dielectric spectroscopy and the transient current measurements. Comparing the herein-obtained diffusion coefficients with those obtained in another study using a traditional USP technique for the same system, the values are virtually the same. The two electrodynamic methods proved to be potentially valuable tools for obtaining information about the concentration and the motion of the drug molecules inside the gel. The transient current measurements are particularly interesting in this case, as the method gives information not only on an average level, but also of the different charged moieties separately. Interestingly, it seems that the methods also are applicable for obtaining information about the mesh size in the gel.

Controlled drug release from gels using surfactant aggregates: I. Effect of lipophilic interactions for a series of uncharged substances.

Gels are often used for the delivery of drugs because they have rheological properties that will give a long residence time. Most pharmaceutical gels consist of approximately 99% water and a polymer matrix that will not hinder the release of drugs with a small molecular weight. To fully take advantage of the residence time, it is necessary to have a sustained drug release. In this paper it is suggested that surfactant micelles can be used to control the release from gels. The in vitro release under physiological conditions of five parabens from four different poly(acrylic acid) gels (Carbopol 934, 940, 1342) and one gellan gum (Gelrite) gel was measured using a USP dissolution bath modified for gels, and the diffusion coefficients were calculated. The diffusion coefficient of uncharged parabens was generally lower in gels with lipophilic modifications, such as C1342, and the greatest effect was seen for butylparaben, with a diffusion that was 25% lower than that in C934 (lacking lipophilic modification). Addition of surfactant micelles to gels delayed the release of all the uncharged drugs in all types of gels studied. The slowest release was seen for butylparaben in a lipophilically modified gel with micelles present. The diffusion coefficient in such a system was almost 30 times smaller than that in C934 without micelles.

Controlled drug release from gels using surfactant aggregates. II. Vesicles formed from mixtures of amphiphilic drugs and oppositely charged surfactants.

PURPOSE: The aim of this study was to control the release of charged drugs from gels by adding surfactants that can interact with the drug and polymer matrix. METHODS: The in vitro release from gels was measured by using 6-mL gel holders immersed in 250 mL of simulated tear fluid and detecting the ultraviolet absorbance on-line. Gels were characterized by using a controlled rate rheometer, and surfactant aggregates were characterized by using cryo-transmission electron microscopy. RESULTS: The diffusion coefficient of alprenolol was 2.8 x 10(-6) cm2/s in a lipophilically modified poly(acrylic acid) gel without surfactants present and 0.14 x 10(-6) cm2/s when formulated with 1% sodium dodecyl sulfate. For fluvastatin, the diffusion coefficient changed from 3.0 x 10(-6) cm2/s to 0.07 x 10(-6) cm2/s in the presence of 0.2% benzyldimethyldodecyl-ammonium bromide. Alprenolol, betaxolol, metoprolol, diphenhydramine, and fluvastatin formed vesicles with oppositely charged surfactants in physiologic salt conditions. CONCLUSIONS: In this article we show that it is feasible to control the release of charged drugs from gels by using surfactants. Vesicles are generally formed when surface active drugs are mixed with oppositely charged surfactants in physiologic conditions. The strongest effects on the release rate are seen for lipophilically modified polymer gels in which the drug and the oppositely charged surfactant form vesicles, but systems with micelles also give a slower release.

Interpretation of mucoadhesive properties of polymer gel preparations using a tensile strength method.

We have developed a new tensile strength method for assessing mucoadhesive properties of polymer gels utilising freshly excised porcine nasal mucosa and a texture analyser. In conjunction with this, we propose a method for interpreting the mucoadhesive properties that is based on reasoning about the locus of the failure of a mucoadhesive joint. This involves measuring the cohesiveness of the gel and the mucus layer, respectively, and comparing these results with those obtained from a mucoadhesion measurement. Linear polymers (sodium carboxymethylcellulose, poly(acrylic acid) and sodium hyaluronate) and a cross-linked polymer (poly(acrylic acid)) were used as model polymers in this study. It was shown that the withdrawal speed of the probe should be low, about 0.1 mm s(-1), and that a contact time of 2 min was sufficient. In the mucoadhesion measurements there was no dependence of the results on the contact time in the interval 2-20 min. The tensile work appeared to be more applicable than the fracture strength for interpreting mucoadhesive properties. Furthermore, it was concluded that the interpretation procedure offers a good basis by which to assess whether the measured tensile work reflects a cohesive failure of the gel or a true interaction of the gel with the mucus layer.

Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method.

A rheological method to measure mucoadhesion was evaluated for two ion-sensitive polymers, Carbopol 934 and Gelrite((R)) (deacetylated gellan gum), in a simulated physiological environment using two commercially available mucins. The method simulates the interpenetration layer in the mucoadhesion process. The elastic modulus for a polymer/mucin mixture is compared with the elastic modulus for the polymer alone, and an increase in the elastic modulus for the mixture compared to the polymer is interpreted as a positive interaction caused by mucoadhesion. In this study the influence of polymer concentration, type of mucin and experimental rheological factors, such as gap width, were examined. The choice of polymer concentration was crucial, especially with the porcine gastric mucin. We found that one is more likely to obtain positive interactions with weak gels. It was also shown that the choice of mucin has a large influence on the results obtained. Carbopol 934 interacted more strongly with the bovine submaxillary gland mucin than with the porcine gastric mucin, whereas the gel structure of Gelrite((R)) was destroyed when mixed with the bovine mucin. Furthermore, it was concluded that with hydrogels consisting of gel particles (such as Carbopol 934), rheological measurements can give highly varying results, depending on, for example, the concentration and ion-sensitivity of the polymer, the quantity of ions present, as well as the gap width of the measuring system.

Rheological studies of the gelation of deacetylated gellan gum (Gelrite) in physiological conditions.

Gels have been successfully used to increase the mucosal contact time and hence the bioavailability of nasal and ophthalmic formulations. The use of in situ gelling polymers requires a rapid sol-gel transition that produces a strong gel for an optimal contact time. In this study, the rheological behaviour of deacetylated gellan gum (Gelrite) was analysed in order to better understand the reasons for the good performance in humans. Thermal scans were used to study gel formation and other changes in the structure of the samples when the macromolecular and ionic contents were altered. The effect the different ions in tear fluid (Na+, K+, Ca2+) had on the gel strength and the consequences of dilution due to the ocular protective mechanisms were examined. Na+ was found to be the most important gel-promoting ion in vivo. It was also found that gels are formed in tear fluid even when the concentration of Gelrite) is only 0.1%. Samples with concentrations of Gelrite of 0.5-1% do not require more ions than 10-25% of those in tear fluid to form gels. These two findings can partly explain the good performance of Gelrite in vivo. Gels with a high elastic modulus can thus be formed even though dilution of instilled drops takes place.

Rheological evaluation of poloxamer as an in situ gel for ophthalmic use.

The contact time of a vehicle on the cornea is of utmost importance for ocular drug delivery. In the present study rheological measurements were performed to study the gel and the sol-gel transition of an in situ gel, Poloxamer 407. The rheological measurements and a small in vivo study of ocular residence times in humans were used to evaluate poloxamer as an ocular vehicle. An increasing concentration of poloxamer resulted in a slightly increasing elasticity of the gels and a decreasing sol-gel transition temperature. The contact time increased with increasing concentration of poloxamer which could be explained and correlated with the rheology of poloxamer solutions/gels mixed with simulated tear fluid. The maximum contact time for the preparations studied was about 1 h. The poloxamer system did not seem to be promising as an ophthalmic in situ gel due to the strong concentration dependence of the sol-gel transition temperature combined with the dilution that occurs in the eye.

Rheological evaluation of Gelrite in situ gels for ophthalmic use.

One of the reasons for the relatively low bioavailability of conventional eye drops is their short precorneal contact times. In situ gels are promising ocular drug delivery systems since they are conveniently dropped into the eye as a liquid whereafter they undergo a transition into a gel. Due to their elastic properties hydrogels resist ocular drainage leading to longer contact times. In this paper the rheology of Gelrite in situ gels was studied. A complementary in vivo study for determining precorneal contact times in humans and in rabbits was performed. The elastic moduli of the gels increased with increasing concentration of electrolytes. At physiological concentration of the electrolytes, the elasticity of the gels was independent of Gelrite concentration. The human contact times increased up to 20 h with decreasing osmolality of the formulations. The results indicate that a high rate of the sol/gel transition results in long contact times.

Rapid transport of macromolecules in polysaccharide systems by means of dissipative structures.

A gravitationally stable boundary between two polymer solutions in a ternary system can develop into an interphase of structured convectional flow. The transport over this interphase is by counter-current distribution and as a result high-molecular weight material moves by bulk-flow and much more rapidly than low-molecular weight material, which is transported essentially by ordinary diffusion.