Chapters 2–6 deal with the production, stabilization, and dissolution of the drug nanoparticle-based formulations, i.e., drug nanosuspensions and nanocomposite microparticles. Nanoparticle delivery relies on reduced particle size for increased dissolution rate (Möschwitzer et al., 2011),according to the Noyes–Whitney equation (Noyes and Whitney, 1897). Enhanced dissolution rate, improved bioavailability, safe dose escalation, elimination of food effects, and enhanced safety, efficacy and tolerability profiles are some of the numerous advantages of crystalline drug nanoparticles (Junghanns and Müller, 2008). Despite all the above-mentioned advantages, nanoparticle formulations have a serious drawback: the limited improvement on drug solubility. Often for drugs with very low aqueous solubility, the achieved increase in dissolution rate via size reduction is limited and insufficient to provide significant enhancement of bioavailability (Müller et al., 2001).
Another approach to enhance the bioavailability of poorly water-soluble drugs is to produce amorphous solid dispersions (ASDs). ASDs tend to exhibit high levels of supersaturation in aqueous media relative to the crystal form of the drug, and thus higher apparent solubility (Newman et al., 2012). The preparation involves combining a drug with a water-soluble polymer to produce a single-phase amorphous mixture of the drug and the polymer. Once the solid dispersion encounters dissolution media, supersaturation in solution must be maintained over a period of time that will ensure complete dissolution and potential enhancement in bioavailability (Alonzo et al., 2010; Brouwers et al., 2009). Processes for the preparation of amorphous solid dispersions can be categorized into two general types: solvent methods and fusion–
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melting methods (Brough and Williams III, 2013). With solvent methods, solid dispersions are obtained by evaporating solvent from a drug and carrier solution.
Practical applications of the solvent method are spray drying (Langham et al., 2012;
Paradkar et al., 2004) and freeze drying (Kagotani et al., 2013; Schersch et al., 2010).
On the other hand, pharmaceutical hot-melt extrusion (HME), is an evolving, solvent-less fusion technique, currently being investigated by both industry and academia as a means to produce amorphous solid oral dosages, with improved bioavailability of the poorly water-soluble drugs (Gogos et al., 2012).
It is well known that utilizing the amorphous form of a drug can be a useful approach to improve the dissolution behavior and bioavailability of poorly water-soluble drugs, as a result of supersaturation (Chiou and Riegelman, 1970; Goldberg et al., 1966; Hancock and Parks, 2000). However, the dissolution advantage of amorphous solids can be negated either by crystallization of the amorphous solid on contact with the dissolution medium or through rapid crystallization of the supersaturated solution (Alonzo et al., 2010). The majority of research work on amorphous dispersions focused on the drugs at a relatively high dose, which led to supersaturation in the dissolution media (Konno et al., 2008; Langham et al., 2012;
Yang et al., 2010), where the major research focus was to retard the recrystallization and maintain the highest level of supersaturation during dissolution (Konno et al., 2008). It is interesting to note that a head-to-head comparison of the dissolution performance between nanoparticle-based formulations and amorphous solid dispersion of poorly water-soluble drugs is not available in the open literature. Yang et al. (2010) investigated the bioavailability enhancement induced by amorphous
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versus crystalline itraconazole nanoparticles. It was found that amorphous itraconazole had higher supersaturation that increased the permeation, but dissolution performance was not investigated. Six et al. (2004) investigated the relative dissolution improvement achieved by ASD with respect to as-received itraconazole microparticles. It was found that the dissolution of itraconazole was significantly improved by producing ASD compared to the microparticles. However, it is still unknown if nanoparticles of itraconazole can also achieve similar or better dissolution improvement. Similar to Six et al. (2004), Jung et al. (1999) conducted a comparison between amorphous solid dispersion of itraconazole to commercial products as well as as-received itraconazole microparticles in tablet form. By changing different polymers during spray drying process, fast dissolution of itraconazole amorphous solid dispersion can be achieved. A comparison of the dissolution performance of nanoparticles vs. ASD does not exist. Furthermore, the drug doses in the above-mentioned dissolution studies were all above 100 mg up to 200 mg. For drugs with high potency, low dose (typically <<10 mg), is preferred to mitigate the potential side effects (Branchey et al., 1978; Law et al., 2003). Hence, a direct comparison of the dissolution enhancement imparted by nanocomposites versus ASDs for low drug dose can be of special interest for formulating high potency drugs. A commonly-held notion in pharmaceutical literature is that nanocrystals of a drug formulated in nanocomposites are not as effective as the amorphous form of the drug formulated in the form of ASDs because the latter offers significant supersaturation advantage.
Chapters 7 and 8 of this dissertation will challenge this commonly-held notion and test its limits in terms of drug dose and particle size of the nanocomposites vs. ASDs.
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Recently, a nanoextrusion process has been developed to disperse drug nanoparticles in a polymeric matrix using a modified version of the standard hot melt extrusion process (Baumgartner et al., 2014; Khinast et al., 2013). Nanoextrusion appears to be a new promising platform technology to make solid nanoparticle-based formulations (nanocomposites), thereby improving the dissolution rate and thus the bioavailability of the drug as well as enhancing patient compliance. This technique was first presented by Khinast et al. (2013) as a one-step process for drying a stabilized nanosuspension of crystalline titanium oxide. In a followed-up study by Baumgartner et al. (2014), drug nanoparticles were used to demonstrate applicability to pharmaceutical products. However, the dissolution rate of the produced nanocomposite was very low, which casts doubt about the use of the technology for immediate-release drug products. In a separate study conducted by Park et al. (2013), the same technique was explored with an emphasis on the preparation of content-wise uniform solid dosage forms with very low dose drugs. In that study, the dissolution performance of the produced nanocomposites was not studied. Ye et al. (2015) combined the use of high-pressure homogenization and extrusion for the production of nanocomposites with low drug concentration, i.e., 1‒2%. Throughout the literature, no study has been conducted on the dissolution performance comparison between drug nanocomposites and ASDs that are prepared via the same nanoextrusion process.
Extrusion processes of manufacturing drug solid dosages, including traditional hot melt extrusion and nanoextrusion, usually involve downstream processes such as milling of the extrudates, sieving, compression, and coating. Milling of extrudates into various particle (matrix) sizes opens the possibility of manipulating the drug
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dissolution performance. The majority of the literature on extrusion process ignored the matrix size effect of the milled extrudates on the dissolution performance. For examples, Fule et al. (2016) used hot melt extrusion process to produce ASD of artesunate in the matrices of Soluplus® and Kollidon® VA64. The produced extrudates were milled and passed through a 200 µm for various characterizations.
Similar to Fule et al. (2016), most literature simply passed the milled extrudate powder through a sieve without reporting the actual particle sizes and their distribution, e.g., (Ghebremeskel et al., 2006; Juluri et al., 2016; Perissutti et al., 2002; Pudlas et al., 2015). Most importantly, all the reported literature focused on only one particle size of the extrudates. Even when nanocomposites were produced by an extrusion process, i.e., nanoextrusion (Baumgartner et al., 2014; Ye et al., 2015), the impact of matrix size was not thoroughly investigated. Hence, it is not unfair to assert that the impact of particle (matrix) size of the milled extrudate powders on drug dissolution has been extensively studied neither for nanocomposites nor for ASDs produced by an extrusion process.
To address the aforementioned issues and challenges, Chapter 7 presents a first attempt to prepare both a drug nanocomposite and a drug ASD using the same nanoextrusion process by using two different extrusion polymers with different polymer–drug miscibility. As the nanoextrusion process is a newly developed process to create a dispersion of drug nanoparticles while drying the drug nanosuspensions, its comparison to conventionally used drying processes, e.g., spray drying, was also carried out for the first time in literature. As a continuation, Chapter 8 uses the nanoextrusion process as a platform enabling the systematical assessment of extrudate
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particle (matrix) size impact on the drug dissolution performance under both non-supersaturating and non-supersaturating conditions for nanocomposites as well as ASDs at two drug loading levels.