Mucoadhesive microparticles for local treatment of gastrointestinal diseases.
Mucoadhesive microparticles formulated in a capsule and delivered to the gastrointestinal tract might be useful for local drug delivery. However, swelling and agglomeration of hydrophilic polymers in the gastrointestinal milieu can have a negative influence on particle retention of mucoadhesive microparticles. In this work, we investigated the impact of dry-coating with nano-sized hydrophilic fumed silica on dispersibility and particle retention of mucoadhesive microparticles. As a model for local treatment of gastrointestinal diseases, antibiotic therapy of Clostridium difficile infections with metronidazole was selected. For particle preparation, we used a two-step fluidized-bed method based on drug loading of porous microcarriers and subsequent outer coating with the mucoadhesive polymer chitosan. The prepared microparticles were analysed for drug content, and further characterized by thermal analysis, X-ray diffraction, and scanning electron microscopy. The optimal molecular weight and content of chitosan were selected by measuring particle retention on porcine colonic mucosa under dynamic flow conditions. Mucoadhesive microparticles coated with 5% (weight of chitosan coating/total weight of particles) of low molecular weight chitosan showed good in vitro particle retention, and were used for the investigation of dispersibility enhancement. By increasing the amount of silica, the dissolution rate measured in the USPIV apparatus was increased, which was an indirect indication for improved dispersibility due to increased surface area. Importantly, mucoadhesion was not impaired up to a silica concentration of 5% (w/w). In summary, mucoadhesive microparticles with sustained-release characteristics over several hours were manufactured at pilot scale, and dry-coating with silica nanoparticles has shown to improve the dispersibility, which is essential for better particle distribution along the intestinal mucosa in humans. Therefore, this advanced drug delivery concept bears great potential, in particular for local treatment of gastrointestinal diseases.
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Daniel
D
Preisig
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Roger
R
Roth
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Sandy
S
Tognola
Tillotts Pharma AG, Baslerstrasse 15, 4310 Rheinfelden, Switzerland.
Felipe J O
FJ
Varum
Tillotts Pharma AG, Baslerstrasse 15, 4310 Rheinfelden, Switzerland.
Roberto
R
Bravo
Tillotts Pharma AG, Baslerstrasse 15, 4310 Rheinfelden, Switzerland.
Yalcin
Y
Cetinkaya
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.
Jörg
J
Huwyler
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Maxim
M
Puchkov
D016503:Drug Delivery Systems; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D006801:Humans; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D033362:Powder Diffraction
Bioadhesion; Chitosan; Colon drug delivery; Dispersibility enhancement; Drug loading; Fluidized-bed; Microparticles; Mucoadhesion; Porous carriers