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Release of a Poorly Soluble Drug from Hydrophobically Modified Poly (Acrylic Acid) in Simulated Intestinal Fluids.

Knöös P, Svensson AV, Ulvenlund S, Wahlgren M - PLoS ONE (2015)

Bottom Line: Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery.Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media.However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Division of Physical Chemistry, Lund University, Lund, Sweden.

ABSTRACT
A large part of new pharmaceutical substances are characterized by a poor solubility and high hydrophobicity, which might lead to a difference in drug adsorption between fasted and fed patients. We have previously evaluated the release of hydrophobic drugs from tablets based on Pemulen TR2 and showed that the release can be manipulated by adding surfactants. Here we further evaluate the possibility to use Pemulen TR2 in controlled release tablet formulations containing a poorly soluble substance, griseofulvin. The release is evaluated in simulated intestinal media that model the fasted state (FaSSIF medium) or fed state (FeSSIF). The rheology of polymer gels is studied in separate experiments, in order to gain more information on possible interactions. The release of griseofulvin in tablets without surfactant varied greatly and the slowest release were observed in FeSSIF. Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery. Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media. The study shows that Pemulen TR2 is a candidate for controlled release formulations in which addition of surfactant provides a way to eliminate food effects on the release profile. However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated.

No MeSH data available.


The elastic modulus (G’) at 0.2 Hz as a function of the NaTC concentration of for 1 wt% Pemulen TR1 (filled square), TR2 (open squares) and Carbopol 981 (filled circles).The data points represent the mean values of three samples and error bars show the standard deviation (n = 3).
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pone.0140709.g003: The elastic modulus (G’) at 0.2 Hz as a function of the NaTC concentration of for 1 wt% Pemulen TR1 (filled square), TR2 (open squares) and Carbopol 981 (filled circles).The data points represent the mean values of three samples and error bars show the standard deviation (n = 3).

Mentions: In order to investigate possible effects of surfactants on the rheology of the polymer in the intestinal fluid, simplified media containing NaTC and lecithin were investigated. Furthermore, SDS was used as reference surfactant, also allowing comparisons with previous results [7, 27]. Figs 2 and 3 show the elastic modulus, G’ (at 0.2 Hz), as a function of the concentration of SDS or NaTC for Pemulen TR1, Pemulen TR2 and Carbopol 981. The G’ value without additives (i.e. at a surfactant concentration cs = 0), will henceforth be referred to as G’0. The behaviour on increasing surfactant concentration is similar to that already seen for similar materials (Pemulen TR2 and Carbopol 934) with addition of non-ionic surfactants [28]. For HMPAA (Pemulen TR1 and TR2) solutions, both NaTC and SDS gave rise to a maximum in G’, albeit at slightly different concentrations for the two polymers, due to their different degrees of hydrophobic modification. Carbopol, on the other hand, was nearly unaffected by the addition of the surfactants. For SDS, the G’ maximum appeared at concentrations close to the CMC. It is well known that upon addition of surfactant to a HM-polymer solution, the surfactant associates with the hydrophobes of the polymer and forms mixed aggregates [27, 29]. At low concentrations, the interactions between surfactant molecules and hydrophobes from different strands strengthen the gel network and the viscosity increases. However, further increase of the concentration of surfactant eventually leads to solubilisation of the hydrophobes in surfactant micelles, so that the hydrophobic crosslinking of polymer chains is lost. In this regime, G’ decreases to a value below G’0. No G’ maximum was observed for Carbopol 981 on addition of surfactant, consistent with the lack of hydrophobes in this polymer.


Release of a Poorly Soluble Drug from Hydrophobically Modified Poly (Acrylic Acid) in Simulated Intestinal Fluids.

Knöös P, Svensson AV, Ulvenlund S, Wahlgren M - PLoS ONE (2015)

The elastic modulus (G’) at 0.2 Hz as a function of the NaTC concentration of for 1 wt% Pemulen TR1 (filled square), TR2 (open squares) and Carbopol 981 (filled circles).The data points represent the mean values of three samples and error bars show the standard deviation (n = 3).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608824&req=5

pone.0140709.g003: The elastic modulus (G’) at 0.2 Hz as a function of the NaTC concentration of for 1 wt% Pemulen TR1 (filled square), TR2 (open squares) and Carbopol 981 (filled circles).The data points represent the mean values of three samples and error bars show the standard deviation (n = 3).
Mentions: In order to investigate possible effects of surfactants on the rheology of the polymer in the intestinal fluid, simplified media containing NaTC and lecithin were investigated. Furthermore, SDS was used as reference surfactant, also allowing comparisons with previous results [7, 27]. Figs 2 and 3 show the elastic modulus, G’ (at 0.2 Hz), as a function of the concentration of SDS or NaTC for Pemulen TR1, Pemulen TR2 and Carbopol 981. The G’ value without additives (i.e. at a surfactant concentration cs = 0), will henceforth be referred to as G’0. The behaviour on increasing surfactant concentration is similar to that already seen for similar materials (Pemulen TR2 and Carbopol 934) with addition of non-ionic surfactants [28]. For HMPAA (Pemulen TR1 and TR2) solutions, both NaTC and SDS gave rise to a maximum in G’, albeit at slightly different concentrations for the two polymers, due to their different degrees of hydrophobic modification. Carbopol, on the other hand, was nearly unaffected by the addition of the surfactants. For SDS, the G’ maximum appeared at concentrations close to the CMC. It is well known that upon addition of surfactant to a HM-polymer solution, the surfactant associates with the hydrophobes of the polymer and forms mixed aggregates [27, 29]. At low concentrations, the interactions between surfactant molecules and hydrophobes from different strands strengthen the gel network and the viscosity increases. However, further increase of the concentration of surfactant eventually leads to solubilisation of the hydrophobes in surfactant micelles, so that the hydrophobic crosslinking of polymer chains is lost. In this regime, G’ decreases to a value below G’0. No G’ maximum was observed for Carbopol 981 on addition of surfactant, consistent with the lack of hydrophobes in this polymer.

Bottom Line: Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery.Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media.However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Division of Physical Chemistry, Lund University, Lund, Sweden.

ABSTRACT
A large part of new pharmaceutical substances are characterized by a poor solubility and high hydrophobicity, which might lead to a difference in drug adsorption between fasted and fed patients. We have previously evaluated the release of hydrophobic drugs from tablets based on Pemulen TR2 and showed that the release can be manipulated by adding surfactants. Here we further evaluate the possibility to use Pemulen TR2 in controlled release tablet formulations containing a poorly soluble substance, griseofulvin. The release is evaluated in simulated intestinal media that model the fasted state (FaSSIF medium) or fed state (FeSSIF). The rheology of polymer gels is studied in separate experiments, in order to gain more information on possible interactions. The release of griseofulvin in tablets without surfactant varied greatly and the slowest release were observed in FeSSIF. Addition of SDS to the tablets eliminated the differences and all tablets showed a slow linear release, which is of obvious relevance for robust drug delivery. Comparing the data from the release studies and the rheology experiment showed that the effects on the release from the different media could to a large extent be rationalised as a consequence of the interactions between the polymer and the surfactants in the media. The study shows that Pemulen TR2 is a candidate for controlled release formulations in which addition of surfactant provides a way to eliminate food effects on the release profile. However, the formulation used needs to be designed to give a faster release rate than the tablets currently investigated.

No MeSH data available.