Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion

Albers, Jessica; Alles, Rainer; Matthée, Karin; Knop, Klaus; Nahrup, Julia Schulze; Kleinebudde, Peter

doi:10.1016/j.ejpb.2008.10.002

Cited by 93 publications

(50 citation statements)

References 25 publications

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“…Examples include the use of co-solvents (1), cyclodextrin (6), a self-microemulsifying drug delivery system (7), salt formation combined with precipitation inhibitors (8), reduction in particle size (9,10) and formation of amorphous nanoparticles (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Beta-casein nanocarriers of celecoxib for improved oral bioavailability

Perlstein¹,

Bavli²,

Turovsky

et al. 2014

European Journal of Nanomedicine

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Beta-casein (bCN) micelles were developed as a platform for improved oral bioavailability (BA) of poorly water-soluble drugs. Here we demonstrate a proof-ofconcept using the NSAID celecoxib (Cx) loaded into bCN micelles (Cx/bCN). In a crossover pharmacokinetic (PK) study in pigs (n = 4), dosed intraduodenally with either the commercial Cx formulation Celebra ® or Cx/bCN, the C max obtained after administration of Cx/bCN was 2.3-fold higher and the T max was 1.57-fold faster, leading to a 1.76-fold increase in the BA of Cx, compared to the Celebra ® formulation. It is suggested that this BA enhancement was caused by improvement of Cx solubility in intestinal fluids by bCN micelles, which maintained their Cx cargo in an amorphous state.

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Section: Introductionmentioning

confidence: 99%

Beta-casein nanocarriers of celecoxib for improved oral bioavailability

Perlstein¹,

Bavli²,

Turovsky

et al. 2014

European Journal of Nanomedicine

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“…Albers et al described that for a given binary formulation consisting of a polymer and an API, melt extrusion conditions were decisive for recrystallization tendency. 19 In case of opaque solid dispersions, a tendency of drug recrystallization in contact with aqueous medium was reported. In clear solid solutions, a release of drug in a polymer-controlled manner was seen.…”

Section: Discussionmentioning

confidence: 99%

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility

Frank¹,

Westedt²,

Rosenblatt³

et al. 2012

IJN

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Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 µg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).

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“…Thus, solid nanoemulsion has an advantage in maintaining high solubilization capacity, which ensures higher dissolution rates in comparison with the crude powder and the commercial product. 39,40 Pharmacokinetics Figure 6 shows the change in mean plasma levels of silymarin in rats following oral administration of the commercial product and nanoparticles at a dose of 10 mg/kg. The total plasma titers of drugs in nanoparticles were higher compared with those of the commercial product.…”

Section: Dissolutionmentioning

confidence: 99%