Nanoemulsion Loaded with Clotrimazole Based on Rapeseed Oil for Potential Vaginal Application-Development, Initial Assessment, and Pilot Release Studies.

Vaginal candidiasis (VC) is an emerging global hardly treated health issue affecting millions of women worldwide. In this study, the nanoemulsion consisting of clotrimazole (CLT), rapeseed oil, Pluronic F-68, Span 80, PEG 200, and lactic acid was prepared using high-speed and high-pressure homogenization. Yielded formulations were characterized by an average droplet size of 52-56 nm, homogenous size distribution by volume, and a polydispersity index (PDI) < 0.2. The osmolality of nanoemulsions (NEs) fulfilled the recommendations of the WHO advisory note. NEs were stable throughout 28 weeks of storage. The stationary and dynamic (USP apparatus IV) pilot study of the changes of free CLT over time for NEs, as well as market cream and CLT suspension as references, were conducted. Test results of the changes in the amount of free CLT released from the encapsulated form were not coherent; in the stationary method, NEs yielded up to 27% of the released CLT dose within 5 h, while in the USP apparatus IV method, NEs released up to 10% of the CLT dose. NEs are promising carriers for vaginal drug delivery in the treatment of VC; however, further development of the final dosage form and harmonized release or dissolution testing protocols are needed.

Drug-Release Mechanisms Elucidated by Imaging Techniques: Visualizing the Invisible!

Imaging techniques such as Raman spectroscopy, electron microscopy, laser scanning confocal microscopy, atomic force microscopy, tomography, magnetic resonance imaging, and terahertz are powerful tools to elucidate drug-release mechanisms from different types of delivery devices [...].

Towards a Better Understanding of Verapamil Release from Kollicoat SR:IR Coated Pellets Using Non-Invasive Analytical Tools.

The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline cellulose) were prepared by extrusion/spheronization and coated with 5% Kollicoat SR:IR 95:5 or 10% Kollicoat SR:IR 90:10. Drug release was measured from ensembles of pellets as well as from single pellets upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The swelling of single pellets was observed by optical microscopy, while dynamic changes in the pH in the pellet cores were monitored by fluorescence spectroscopy. Also, mathematical modeling using a mechanistically realistic theory as well as SEM and Raman imaging were applied to elucidate whether drug release mainly occurs by diffusion through the intact film coatings or whether crack formation in the film coatings plays a role. Interestingly, fluorescence spectroscopy revealed that the pH within the pellet cores substantially differed upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4, resulting in significant differences in drug solubility (verapamil being a weak base) and faster drug release at lower pH: from ensembles of pellets and single pellets. The monitoring of drug release from and the swelling of single pellets indicated that crack formation in the film coatings likely plays a major role, irrespective of the Kollicoat SR:IR ratio/coating level. This was confirmed by mathematical modeling, SEM and Raman imaging. Importantly, the latter technique allowed also for non-invasive measurements, reducing the risk of artifact creation associated with sample cutting with a scalpel.

Formulation and Coating of Alginate and Alginate-Hydroxypropylcellulose Pellets Containing Ranolazine.

The formulation and the coating composition of biopolymeric pellets containing ranolazine were studied to improve their technological and biopharmaceutical properties. Eudragit L100 (EU L100) and Eudragit L30 D-55-coated alginate and alginate-hydroxypropylcellulose (HPC) pellets were prepared by ionotropic gelation using 3 concentrations of HPC (0.50%, 0.65%, and 1.00% wt/wt) and applying different percentages (5%, 10%, 20%, and 30% wt/wt) of coating material. The uncoated pellets were regular in shape and had mean diameter between 1490 and 1570 µm. The rate and the entity of the swelling process were affected by the polymeric composition: increasing the HPC concentration, the structure of the pellets became more compact and slowed down the penetration of fluids. Coated alginate-HPC formulations were able to control the drug release at neutral pH: a higher quantity of HPC in the system determined a slower release of the drug. The nature of the coating polymer and the coating level applied affected the drug release in acidic environment: EU L100 gave better performance than Eudragit L30 D-55 and the best coating level was 20%. The pellets containing 0.65% of HPC and coated with 20% EU L100 represented the best formulation, able to limit the drug release in acidic environment and to control it at pH 6.8.

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

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.

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.

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.