Ternary Amorphous Solid Dispersions Containing a High-Viscosity Polymer and Mesoporous Silica Enhance Dissolution Performance

Abstract

The aim of this study was to evaluate the benefits of a ternary amorphous solid dispersion (ASD) that was designed as an immediate-release tablet with a high drug load (e.g., 40% w/w) to produce heightened maintenance of drug supersaturation during dissolution testing, which will be henceforth referred to as the “maintenance ability”. Ternary ASD granules were produced by hot melt extrusion (HME) and were comprised of itraconazole (ITZ) 50%, hypromellose (HPMC) 20%, and mesoporous silica (XDP) 30%, where amorphous ITZ incorporated into HPMC was efficiently absorbed in XDP pores. The ternary ASD granules containing a high-viscosity HPMC (AF4M) produced a significantly heightened maintenance ability of drug supersaturation in neutral pH dissolution media in which crystalline ITZ solubility is below 1 μg/mL. The final tablet formulation contained 80% w/w of the ASD granules (40% w/w ITZ), had an acceptable size, and exhibited both sufficient tablet hardness and disintegration. The dissolution behavior of the ternary ASD tablet exhibited a supersaturation maintenance ability similar to that of the ASD granules. Under neutral conditions, the ternary ASD tablet showed immediate and higher ITZ release compared with the binary ASD tablets, and this phenomenon could be explained by the difference in ITZ/AF4M particle size in the tablet. In high-resolution scanning electron microscopy (SEM), it was observed that ITZ and AF4M in the ternary formulation could easily form nano-sized particles (<1 μm) during the absorption process into/onto XDP pores prepared by HME, which contributed to the immediate ITZ release from the ternary ASD tablet under neutral pH conditions. Therefore, the ternary ASD containing high-viscosity HPMC and mesoporous silica prepared by HME made it possible to design a high ASD content, small-size tablet with an ideal dissolution profile in biorelevant media, and we expect that this technology can be applied for continuous HME ASD manufacturing.

Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion

“…One limitation of ASDs with high drug loading is the tendency for the rate and extent of drug release to decrease as drug loading increases. , It has been reported that above 15% drug loading, the drug release rates of hydrophilic polymers (e.g., Soluplus) do not exceed the pure amorphous API . In addition, the recrystallization and crashing out of the API can be accelerated if there is insufficient polymer. , In this study, an ASD-containing 50% w/w TEL drug loading was developed. Upon dissolution, it achieved a 65% drug release that was 25.9× greater than the physical mixture.…”

“…The majority of new candidates for active pharmaceutical ingredients (APIs) are poorly water-soluble, so their oral bioavailability can be insufficient for therapeutic use . One method to increase an API’s solubility is to formulate it as an amorphous solid dispersion (ASD), in which the crystalline structure of the API is disrupted and stabilized in a polymeric carrier. − Manufacturing processes for formulating ASDs as well as challenges, including physical stability and miscibility of API in polymer, have recently been reviewed . Hot-melt extrusion (HME) is a method for formulating this type of API as an ASD.…”

“…A major limitation of HME is that it can be difficult to achieve high drug loading (DL) (w/w) in dosage forms containing ASDs formulated by HME. Recent work has focused on overcoming this limitation . High drug loading is relative to the particular API and polymer chosen.…”

“…Because of this, there remains a need for techniques to increase the drug loading of thermally labile APIs (e.g., TEL) above 30% using HME. By maximizing drug loading and minimizing other excipients, more carrier polymer (w/w) can be utilized to increase the “spring and parachute” effects seen in ASDs …”

Benchmarking the Solubility Enhancement and Storage Stability of Amorphous Drug–Polyelectrolyte Nanoplex against Co-Amorphous Formulation of the Same Drug

“…For this reason, alternative amorphous drug formulations that can circumvent the issues of large dosage requirement and handling/processing of ASD have been actively investigated. Examples of such formulations are the co-amorphous (CAM) system, mesoporous silica-based ASD, amorphous nanoparticles, and hybrid systems combining different amorphization strategies [ 9 , 10 , 11 ].…”