De ontwikkeling van orale doseervormen gebaseerd op mesoporeuze silica voor verhoogde vrijstelling van slecht oplosbare geneesmiddelen

摘要

The interest in mesoporous silica as a drug release enhancer for poorly soluble drugs is one of the more recent and burgeoning areas of drug development research. While their abundance of silanol groups, large specific surface area and porosity are attractive from a development perspective; these features attribute to low bulk density and hygroscopicity, resulting in undesirable tablet properties. Because oral drugdelivery is undoubtedly the most attractive and extensively used approach to administer drugs, the objective of this research was to assess thedown-stream processability of mesoporous silica for the development of an immediate release solid oral dosage form. First, assessments in structure and release behavior following compression of itraconazole loaded and non-loaded ordered mesoporous silica (OMS) materials SBA-15 and COK-12 were evaluated. Due to the thicker pore walls and a higher degree of silicate condensation, COK-12 was more resistant to compression than SBA-15. This material strength translated into superior in vitro release behavior following compression. Based on these findings, COK-12 was the OMS selected for further investigations. Granulationwas identified as a necessary step to improve OMS powder flow, compression and compaction properties required for tableting. The classic approach, wet granulation, was investigated as a feasibility study using polyvinylpyrrolidone (PVP) to determine the risk of extracting the drug out of the pores during processing. This phenomenon, referred to as prematuredrug release (PDR), was determined as dependent on both compound and processing conditions. Four poorly water-soluble compounds were selected for this investigation: itraconazole (weakly basic), fenofibrate (neutral) and naproxen and ibuprofen (weakly acidic). Due to the lack of hydrogen bond donors and large molar volume, itraconazole was identified as thehighest risk for premature drug release. The usefulness of granulation techniques able to reduce or avoid the employment of waterduring the process was considered. Therefore, agglomeration with steam and melting were considered as a more suitable alternative to wet granulation. All granulates were prepared in a laboratory-scale high-shear mixer. In this two part study, we first assess the difference in granulation behavior and granule properties of disordered mesoporous silica (DMS) and OMS material, Syloid® 244 and COK-12, respectively. Granules prepared with PVP from steam resulted in the overall largest size but slowest in vitro drug release. PDR was most prevalent in melt-granulated samples. However, no additional drug extraction was observed following 6months storage at 25°C/60%RH and 40°C/75%RH. In vitro release following storage slightly increased and decreased for 244 and COK-12 melt-granulated material, respectively . Analysis of the melt granulation binder, Poloxamer 188, indicated that degradation already occurs during the granulation process itself. Compressibility between the two silica materials differed, in which granulated material from DMS resulted as the best performers. Chapter 6 identifies the key the process variables using a quarter-fraction factorial design with six factors at two levelsand compares various physicochemical properties of steam-granulated 244prepared with PVP and HPMC from six responses. Results show that granules prepared from PVP resulted in an overall higher bulk density, granulesize, increased flow properties and better compression and compaction behavior. However, PDR was most prevalent with PVP. These analyses indicate the risk of extracting the drug from the pores during processing is not only governed by the amount of solvent used but more so by the binderproperties. Due to poor binder distribution, results from granules prepared with HPMC were more variable but resulted in superior in vitro release behavior. These studies elucidate the understanding ofmesoporous silica structural and release behavior following compressionfor the advancement as a drug delivery carrier. Furthermore, factors that increase the risk of unwanted drug extraction during mesoporous silica material are identified. The key process parameters are also identified that potentially will play a significant role for preparation for a successful scaled-up manufacturing process.