Enteric coated mucoadhesive micropellets in rotary agglomeration process for wet spheronization

In this work a generally applicable method for the preparation of mucoadhesive micropellets of 250 to 600µm diameter is presented using rotor processing without the use of electrolytes. The mucoadhesive micropellets were developed to combine the advantages of mucoadhesion and microparticles. It was possible to produce mucoadhesive micropellets based on different mucoadhesive polymers Na-CMC, Na-alginate and chitosan. These micropellets are characterized by a lower friability (6 to 17%) when compared to industrial produced cellulose pellets (Cellets®) (41.5%). They show great tapped density and can be manufactured at high yields. The most influencing variables of the process are the water content at the of the end spraying period, determined by the liquid binder amount, the spraying rate, the inlet air temperature, the airflow and the humidity of the inlet air and the addition of the liquid binder, determined by the spraying rate, the rotor speed and the type of rotor disc. In a subsequent step a fluidized bed coating process was developed. It was possible to manifest a stable process in the Hüttlin Mycrolab® in contrast to the Mini-Glatt® apparatus. To reach enteric resistance, a 70% coating for Na-CMC micropellets, an 85% for chitosan micropellets and a 140% for Na-alginate micropellets, based on the amount of the starting micropellets, was necessary. Comparative dissolution experiments of the mucoadhesive micropellets were performed using the paddle apparatus with and without a sieve inlay, the basket apparatus, the reciprocating cylinder and flow-through cell. The paddle apparatus and the modified flow-through cell method turned out to be successful methods for the dissolution of mucoadhesive micropellets. All dissolution profiles showed an initial burst release followed by a slow release due to diffusion control. Depending on the method, the dissolution profiles changed from immediate release to slow release. The dissolution rate in the paddle apparatus was mainly influenced by the agitation rate whereas the flow-through cell pattern was mainly influenced by the particle size. Also, the logP and the HLB values of different emulsifiers were correlated to transfer HLB values of excipients into logP values and logP values of API´s into HLB values. These experiments did not show promising results. Finally, it was shown that manufacture of mucoadhesive micropellets is successful resulting in product being characterized by enteric resistency combined with high yields and convincing morphology.

Einfluss von Hilfsstoffen auf die Bioverfügbarkeit von Substanzen der BCS Klasse III

In dieser Arbeit wurde der Effekt verschiedener Hilfsstoffe auf die Permeabilität von Substanzen der BCS Klasse III untersucht. Drei pharmazeutische Hilfsstoffe wurden hinsichtlich der Möglichkeit ihres Einsatzes als Permeationsverbesserer in Arzneistoffformulierungen untersucht. Außerdem wurde die Beteiligung von Gallensalzen an der Nahrungsmittel-Interaktion von Trospium untersucht.rnEs wurden Komplexe aus Trospium und λ-Carrageen hergestellt. Eine verbesserte Permeation, die höchstwahrscheinlich durch Mukoadhäsion zustande kam, war im Ussing-Kammer-Modell sehr gut reproduzierbar. In vivo war der Effekt nur bei einigen Tieren zu sehen und es kam zu hohen Standardabweichungen.rnTrospium bildet Ionenpaare mit Gallensalzen, welche zu einer besseren Permeabilität des Wirkstoffes führten. In Gegenwart von Nahrungsfetten blieb dieser Effekt aus. Eine Beteiligung der Interaktion von Trospium und Gallensalzen am Food-Effekt kann auf Basis dieser Ergebnisse als wahrscheinlich gelten.rnIm Caco-2-Modell konnte bereits eine Verbesserung der Permeabilität von Trospium durch Zusatz von Eudragit E gezeigt werden. Nun konnte gezeigt werden, dass durch den Hilfsstoff auch in vivo in Ratten eine verbesserte Permeation erreicht werden kann.rnDie Permeationsverbesserung von Aciclovir durch Zusatz von Chitosan-HCl sollte untersucht werden. Im Caco-2-Modell kam es zu einer signifikanten Permeationsverbesserung. Im Ussing-Kammer-Modell wurde die Permeation nicht verbessert. In Loop-Studien konnte nur bei hohen Hilfsstoff-Konzentrationen eine Tendenz zur Permeationsverbesserung erkannt werden.rn

Nanoparticle preparation process using novel microjet reactor technology for enhancing dissolution rates of poorly water soluble drugs

In this study a novel method MicroJet reactor technology was developed to enable the custom preparation of nanoparticles. rnDanazol/HPMCP HP50 and Gliclazide/Eudragit S100 nanoparticles were used as model systems for the investigation of effects of process parameters and microjet reactor setup on the nanoparticle properties during the microjet reactor construction. rnFollowing the feasibility study of the microjet reactor system, three different nanoparticle formulations were prepared using fenofibrate as model drug. Fenofibrate nanoparticles stabilized with poloxamer 407 (FN), fenofibrate nanoparticles in hydroxypropyl methyl cellulose phthalate (HPMCP) matrix (FHN) and fenofibrate nanoparticles in HPMCP and chitosan matrix (FHCN) were prepared under controlled precipitation using MicroJet reactor technology. Particle sizes of all the nanoparticle formulations were adjusted to 200-250 nm. rnThe changes in the experimental parameters altered the system thermodynamics resulting in the production of nanoparticles between 20-1000 nm (PDI<0.2) with high drug loading efficiencies (96.5% in 20:1 polymer:drug ratio).rnDrug releases from all nanoparticle formulations were fast and complete after 15 minutes both in FaSSIF and FeSSIF medium whereas in mucodhesiveness tests, only FHCN formulation was found to be mucoadhesive. Results of the Caco-2 studies revealed that % dose absorbed values were significantly higher (p<0.01) for FHCN in both cases where FaSSIF and FeSSIF were used as transport buffer.rn

Hydrodynamics and solid dosage form disintegration/dissolution : immediate release tablets and novel in situ polyelectrolyte gastroretentive drug delivery systems

Solid oral dosage form disintegration in the human stomach is a highly complex process dependent on physicochemical properties of the stomach contents as well as on physical variables such as hydrodynamics and mechanical stress. Understanding the role of hydrodynamics and forces in disintegration of oral solid dosage forms can help to improve in vitro disintegration testing and the predictive power of the in vitro test. The aim of this work was to obtain a deep understanding of the influence of changing hydrodynamic conditions on solid oral dosage form performance. Therefore, the hydrodynamic conditions and forces present in the compendial PhEur/USP disintegration test device were characterized using a computational fluid dynamics (CFD) approach. Furthermore, a modified device was developed and the hydrodynamic conditions present were simulated using CFD. This modified device was applied in two case studies comprising immediate release (IR) tablets and gastroretentive drug delivery systems (GRDDS). Due to the description of movement provided in the PhEur, the movement velocity of the basket-rack assembly follows a sinusoidal profile. Therefore, hydrodynamic conditions are changing continually throughout the movement cycle. CFD simulations revealed that the dosage form is exposed to a wide range of fluid velocities and shear forces during the test. The hydrodynamic conditions in the compendial device are highly variable and cannot be controlled. A new, modified disintegration test device based on computerized numerical control (CNC) technique was developed. The modified device can be moved in all three dimensions and radial movement is also possible. Simple and complex moving profiles can be developed and the influence of the hydrodynamic conditions on oral solid dosage form performance can be evaluated. Furthermore, a modified basket was designed that allows two-sided fluid flow. CFD simulations of the hydrodynamics and forces in the modified device revealed significant differences in the fluid flow field and forces when compared to the compendial device. Due to the CNC technique moving velocity and direction are arbitrary and hydrodynamics become controllable. The modified disintegration test device was utilized to examine the influence of moving velocity on disintegration times of IR tablets. Insights into the influence of moving speed, medium viscosity and basket design on disintegration times were obtained. An exponential relationship between moving velocity of the modified basket and disintegration times was established in simulated gastric fluid. The same relationship was found between the disintegration times and the CFD predicted average shear stress on the tablet surface. Furthermore, a GRDDS was developed based on the approach of an in situ polyelectrolyte complex (PEC). Different complexes composed of different grades of chitosan and carrageenan and different ratios of those were investigated for their swelling behavior, mechanical stability, and in vitro drug release. With an optimized formulation the influence of changing hydrodynamic conditions on the swelling behavior and the drug release profile was demonstrated using the modified disintegration test device. Both, swelling behavior and drug release, were largely dependent on the hydrodynamic conditions. Concluding, it has been shown within this thesis that the application of the modified disintegration test device allows for detailed insights into the influence of hydrodynamic conditions on solid oral dosage form disintegration and dissolution. By the application of appropriate test conditions, the predictive power of in vitro disintegration testing can be improved using the modified disintegration test device. Furthermore, CFD has proven a powerful tool to examine the hydrodynamics and forces in the compendial as well as in the modified disintegration test device. rn