Youness Karrout

Novel polymeric film coatings for colon targeting: Drug release from coated pellets

The aim of this study was to prepare and characterize novel types of polymer coated pellets allowing for the site-specific delivery of drugs to the colon. 5-Aminosalicylic acid (5-ASA)-loaded beads were prepared by extrusion-spheronization and coated with different Nutriose:ethylcellulose blends. In vitro drug release from these systems was measured under various conditions, including the exposure to fresh fecal samples from inflammatory bowel disease patients under anaerobic conditions. Nutriose is a starch derivative, which is preferentially degraded by enzymes secreted by the microflora in the colon of Crohns disease and ulcerative colitis patients. Interestingly, the release of 5-ASA (which is commonly used for the local treatment of inflammatory bowel diseases) could effectively be suppressed upon exposure to release media simulating the conditions in the upper GIT, irrespective of the degree of agitation and presence or absence of enzymes. But as soon as the pellets came into contact with fecal samples of inflammatory bowel disease patients, the release rate significantly increased and the drug was released in a time-controlled manner. Thus, this novel type of colon targeting system is adapted to the pathophysiology of the patient. Furthermore, culture media containing specific colonic bacteria are presented providing an interesting potential as substitutes for fresh fecal samples.

Application of terahertz pulsed imaging to analyse film coating characteristics of sustained-release coated pellets

Terahertz pulsed imaging (TPI) was employed to explore its suitability for detecting differences in the film coating thickness and drug layer uniformity of multilayered, sustained-release coated, standard size pellets (approximately 1mm in diameter). Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat(®) SR:Kollicoat(®) IR polymer blend for different times giving three groups of pellets (batches I, II and III), each with a different coating thickness according to weight gain. Ten pellets from each batch were mapped individually to evaluate the coating thickness and drug layer thickness between batches, between pellets within each batch, and across individual pellets (uniformity). From the terahertz waveform the terahertz electric field peak strength (TEFPS) was used to define a circular area (approximately 0.13 mm(2)) in the TPI maps, where no signal distortion was found due to pellet curvature in the measurement set-up used. The average coating thicknesses were 46 μm, 71 μm and 114 μm, for batches I, II and III respectively, whilst no drug layer thickness difference between batches was observed. No statistically significant differences in the average coating thickness and drug layer thickness within batches (between pellets) but high thickness variability across individual pellets was observed. These results were confirmed by scanning electron microscopy (SEM). The coating thickness results correlated with the subsequent drug release behaviour. The fastest drug release was obtained from batch I with the lowest coating thickness and the slowest from batch III with the highest coating thickness. In conclusion, TPI is suitable for detailed, non-destructive evaluation of film coating and drug layer thicknesses in multilayered standard size pellets.

Colon targeting with bacteria-sensitive films adapted to the disease state

The aim of this study was to identify novel polymeric films allowing for the site-specific delivery of drugs to the colon of patients suffering from inflammatory bowel diseases. Ethylcellulose was blended with different types of bacteria-sensitive starch derivatives. The water uptake and dry mass loss kinetics of the systems were monitored upon exposure to media simulating the contents of the stomach, small intestine and colon (including fresh fecal samples from Crohns Disease and Ulcerative Colitis patients). Importantly, ethylcellulose:Nutriose FB 06 and ethylcellulose:Peas starch N-735 films showed highly promising water uptake and dry mass loss kinetics in all the investigated media, indicating their potential to minimize premature drug release in the upper gastro-intestinal tract, and allowing for controlled release once the colon is reached. This can be attributed to the fact that the starch derivatives serve as substrates for the enzymes, which are secreted by the bacteria present in the colon of inflammatory bowel disease patients. Thus, the identified new polymeric films are adapted to the pathophysiological conditions in the gastro-intestinal tract in the disease state. Furthermore, Nutriose is known to provide pre-biotic effects, which can be of great benefit for these patients.

MALDI-TOF MS imaging of controlled release implants

MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) imaging is used to characterize novel lipid implants allowing for controlled drug delivery. Importantly, this innovative technique provides crucial information on the inner structure of the implants before and after exposure to the release medium and does not require the addition of marker substances. Implants were prepared by extrusion at room temperature. Thus, in contrast to hot-melt extruded systems, the risks of drug inactivation and solid state transformations of the lipid matrix former are reduced. Hydrogenated/hardened soybean oil and glyceryl tristearate were studied as lipids and propranolol hydrochloride and theophylline as drugs, exhibiting significantly different solubility in water. The implants were also characterized by optical microscopy, differential scanning calorimetry, water uptake and lipid erosion studies, mathematical modeling as well as in vitro drug release measurements. Importantly, broad spectra of drug release patterns with release periods ranging from a few days up to several months could easily be provided when varying the initial drug content and type of lipid, irrespective of the type of drug. The diameter of the implants can be as small as 1mm, facilitating injection. MALDI-TOF MS imaging revealed homogeneous macroscopic drug distributions within the systems, but steep drug concentration gradients in radial and axial direction at the lower micrometer level, indicating drug- and lipid-rich domains. As the implants do not significantly swell, local irritation upon administration due to mechanical stress can be expected to be limited. Good agreement between experimentally measured and theoretically calculated drug release kinetics revealed that diffusional mass transport plays a major role for the control of drug release from this type of advanced drug delivery systems.

In vivo efficacy of microbiota-sensitive coatings for colon targeting: a promising tool for IBD therapy.

The first proof of concept in vivo for a new type of microbiota-sensitive film coatings allowing for colon targeting is presented. The efficacy of these polysaccharide barriers to optimize drug release for the treatment of inflammation is demonstrated in an experimental colitis model with Wister rats. 5-Aminosalicylic acid (5-ASA) pellets were prepared by extrusion-spheronization and coated with Nutriose:ethylcellulose (EC) 1:4 or peas starch:ethylcellulose 1:2 blends. The pellets were mixed with standard chow, and the daily drug dose was 150mg/kg. For reasons of comparison, also commercially available Pentasa pellets and placebo pellets were studied. At day 3 after the beginning of the treatment, colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS). Animals were sacrificed on day 6. Macroscopic and histological evaluations of colitis were performed blindly. In addition, inflammatory markers were evaluated using ELISA and real-time PCR. Rats receiving TNBS and placebo pellets developed a severe colitis in the distal half of the colon. 5-ASA administered in the form of Pentasa pellets reduced macroscopic inflammation by only 5%. In contrast, the colon lesions were much less severe upon treatment with Nutriose:EC- and peas starch:EC-coated pellets: The macroscopic score was reduced by 25 and 24%, respectively. Decreases of 37 and 38% of the histological lesions confirmed the efficacy of these new colon targeting systems. Also, inflammatory markers (MPO, IL-1β mRNA, TNF mRNA) were significantly decreased in rats receiving Nutriose:EC- and peas starch:EC-coated pellets compared to Pentasa pellets. Furthermore, real-time PCR analysis indicated increased activation of the target receptor PPAR-γ and the HMGCS2 gene in rats upon administration of 5-ASA loaded Nutriose:EC- and peas starch:EC pellets compared to the commercial product. Also, HPLC-MS/MS analysis of plasma samples demonstrated that the level of the main metabolite of the drug (N-acetyl-5-ASA) was much lower upon administration of Nutriose:EC or peas starch:EC coated pellets compared to Pentasa pellets, indicating that undesired premature drug release in the upper gastrointestinal tract was more effectively hindered. In addition to the rat study, in vivo imaging of transgenic mice expressing the luciferase gene evidenced much more pronounced PPAR-γ activation upon 5-ASA administration in the form of Nutriose:EC-coated pellets versus Pentasa pellets. All these results clearly demonstrate the superiority of these microbiota-sensitive polysaccharide-based film coatings for colon targeting in vivo.

Enzymatically degraded Eurylon 6 HP-PG: ethylcellulose film coatings for colon targeting in inflammatory bowel disease patients.

Objectives  Film coatings based on blends of Eurylon 6 HP‐PG (a hydroxypropylated and pregelatinized high amylose starch) and ethylcellulose were to be evaluated as promising coating materials for site‐specific drug delivery to the colon of patients suffering from inflammatory bowel diseases.

Characterization of ethylcellulose: starch-based film coatings for colon targeting

Background: The site-specific delivery of drugs to the colon can be highly advantageous for various applications, including the local treatment of inflammatory bowel diseases. The aim of this study was to provide efficient tools that can be used to easily adjust the key properties of novel polymeric film coatings allowing for colon targeting. Methods: Free films based on blends of ethylcellulose and different types of starch derivatives (partially being pregelatinized, acetylated, and/or hydroxypropylated) were prepared and characterized. Results: The key properties of the polymeric systems can effectively be adjusted by varying the polymer blend ratio and type of starch derivative. This includes the water uptake and dry mass loss kinetics as well as the mechanical properties of the films before and upon exposure to aqueous media simulating the contents of the upper GIT. Conclusion: Broad ranges of film coating properties can easily be provided, being adapted to the needs of the respective drug treatment.

Limited drug solubility can be decisive even for freely soluble drugs in highly swollen matrix tablets

The aim of this study was to elucidate the importance of potential limited solubility effects for the control of drug release from hydrophilic matrix tablets loaded with a freely water-soluble drug. It is often assumed that the considerable amounts of water penetrating into this type of advanced drug delivery systems are sufficient to rapidly dissolve the entire drug loading, and that limited drug solubility is not playing a role for the control of drug release. Here, we show that this assumption can be erroneous. HPMC/lactose matrix tablets were loaded with 5 to 60% diprophylline (e.g. solubility in 0.1M HCl at 37°C: 235mg/mL), and drug release was measured at low and neutral pH, respectively. A mechanistically realistic mathematical theory was applied, considering drug diffusion in axial and radial direction in the cylindrical matrices and the potential co-existence of dissolved and non-dissolved drug. Importantly, only dissolved drug is available for diffusion. It is demonstrated that during major parts of the release periods, non-dissolved drug excess exists within tablets containing 30% or more diprophylline, despite of the substantial water contents of the systems. This leads to partially almost linear drug concentration distance profiles within the tablets, and reveals a major contribution of limited drug solubility effects to the control of drug release, even in the case of freely water-soluble diprophylline. It can be expected that also in other types of drug delivery systems, e.g. microparticles and implants (containing much less water), limited drug solubility effects play a much more important role than currently recognized.

When drugs plasticize film coatings: Unusual formulation effects observed with metoprolol and Eudragit RS

Metoprolol tartrate and metoprolol free base loaded pellet starter cores were coated with Eudragit RS, plasticized with 25% triethyl citrate (TEC). The initial drug loading and coating level were varied from 10 to 40 and 0 to 20%, respectively. Drug release was measured in 0.1 N HCl and phosphate buffer pH 7.4. The water uptake and swelling kinetics, mechanical properties and TEC leaching of/from coated pellets and/or thin, free films of identical composition as the film coatings were monitored. The following unusual tendencies were observed: (i) the relative drug release rate from coated pellets increased with increasing initial drug content, and (ii) drug release from pellets was much faster for metoprolol free base compared to metoprolol tartrate, despite its much lower solubility (factor >70). These phenomena could be explained by plasticizing effects of the drug for the polymeric film coatings. In particular: 1) Metoprolol free base is a much more potent plasticizer for Eudragit RS than the tartrate, leading to higher film permeability and overcompensating the pronounced differences in drug solubility. Also, Raman imaging revealed that substantial amounts of the free base migrated into the film coatings, whereas this was not the case for the tartrate. 2) The plasticizing effects of the drug for the film coating overcompensated potential increasing limited solubility effects when increasing the initial drug loading from 10 to 40%. In summary, this study clearly demonstrates how important the plasticization of polymeric controlled release film coatings by drugs can be, leading to unexpected formulation effects.