Susanne Muschert

Effects of film coating thickness and drug layer uniformity on in vitro drug release from sustained-release coated pellets: A case study using terahertz pulsed imaging

Film coating thickness and terahertz electric field peak strength (TEFPS) were determined using terahertz pulsed imaging (TPI) and employed for the analysis of sustained-release coated pellets (theophylline layered sugar cores coated with Kollicoat SR:Kollicoat IR polymer blends). The effects of coating thickness, drug layer uniformity and optional curing were investigated using eight batches of pellets. Ten pellets from each batch were imaged with TPI to analyse the coating morphology (depicted in TEFPS) and thickness prior to release measurements. The results showed TEFPS values of 15.8% and 14.5% for pellets with a smooth drug layer coated at 8.2 and 12.5% (w/w) polymer weight-gain, respectively. Whereas 6.7% was derived for pellets with a coarse drug layer coated at both weight-gains. Although there were major differences in TEFPS, the resulting drug release kinetics were very similar. It was also shown that a 36 microm coating thickness difference was not drug release rate determining. These results suggested that drug release for the pellets studied was not predominately governed by drug diffusion through the polymeric film coating but probably to a large extent limited by drug solubility. TPI proved to be highly suitable to detect non-homogeneities in the drug layer and polymeric film coating.

Drug release mechanisms from ethylcellulose: PVA-PEG graft copolymer-coated pellets.

The aim of this study was to better understand the underlying drug release mechanisms from aqueous ethylcellulose-coated pellets containing different types of drugs and starter cores. Theophylline, paracetamol, metoprolol succinate, diltiazem HCl and metoprolol tartrate were used as model drugs exhibiting significantly different solubilities (e.g. 14, 19, 284, 662 and 800 mg/mL at 37 degrees C in 0.1N HCl). The pellet core consisted of a drug matrix, drug-layered sugar bead or drug-layered microcrystalline cellulose (MCC) bead, generating different osmotic driving forces upon contact with aqueous media. Importantly, the addition of small amounts of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer (PVA-PEG graft copolymer) to the ethylcellulose coatings allowed for controlled drug release within 8-12h, irrespective of the type of drug and composition of the pellet core. Drug release was found to be controlled by diffusion through the intact polymeric membranes, irrespective of the drug solubility and type of core formulation. The ethylcellulose coating was dominant for the control of drug release, minimizing potential effects of the type of pellet core and nature of the surrounding bulk fluid, e.g. osmolality. Thus, this type of controlled drug delivery system can be used for very different drugs and is robust.

Improved long term stability of aqueous ethylcellulose film coatings: importance of the type of drug and starter core.

Instability during long term storage due to further gradual coalescence of the film remains one of the major challenges when using aqueous polymer dispersions for controlled release coatings. It has recently been shown that the addition of small amounts of poly(vinyl acetate)-poly(ethylene glycol)-graft-copolymer (PVA-PEG-graft-copolymer) to aqueous ethylcellulose dispersion provides long term stable drug release patterns even upon open storage under stress conditions in the case of theophylline matrix cores. However, the transferability of this approach to other types of drugs and starter cores exhibiting different osmotic activity is yet unknown. The aim of this study was to evaluate whether this novel approach is also applicable to freely water-soluble drugs and osmotically active sugar starter cores. Importantly, long term stable drug release profiles from coated diltiazem HCl-layered sugar cores could be achieved even upon open storage for 1 year under stress conditions (40 degrees C and 75% relative humidity). However, to provide desired drug release profiles the amount of added PVA-PEG-graft-copolymer must be adjusted. A minimal critical content of 10% (w/w) of this hydrophilic additive was identified, under which further polymer particle coalescence upon long term storage under stress conditions cannot be excluded. Potentially too rapid drug release can effectively be slowed down by increasing the coating level. Thus, adapting the polymer blend ratio and coating thickness desired and long term stable drug release profiles (even under stress conditions and open storage) can be provided for very different types of drugs and starter cores by the addition of small amounts of PVA-PEG-graft-copolymer to aqueous ethylcellulose dispersion.

Simulated food effects on drug release from ethylcellulose: PVA-PEG graft copolymer-coated pellets.

Background: Food effects might substantially alter drug release from oral controlled release dosage forms in vivo. Methods: The robustness of a novel type of controlled release film coating was investigated using various types of release media and two types of release apparatii. Results: Importantly, none of the investigated conditions had a noteworthy impact on the release of freely water-soluble diltiazem HCl or slightly water-soluble theophylline from pellets coated with ethylcellulose containing small amounts of PVA–PEG graft copolymer. In particular, the presence of significant amounts of fats, carbohydrates, surfactants, bile salts, and calcium ions in the release medium did not alter drug release. Furthermore, changes in the pH and differences in the mechanical stress the dosage forms were exposed to did not affect drug release from the pellets. Conclusion: The investigated film coatings allowing for oral controlled drug delivery are highly robust in vitro and likely to be poorly sensitive to classical food effects in vivo.

Accelerated ketoprofen release from spray-dried polymeric particles: importance of phase transitions and excipient distribution.

Abstract HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1 M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug:polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems.