Study of compaction tools and parameters on critical quality attributes of high drug load minitablets.

Minitablets are prepared using multiple die openings and multi-tip punches for greater productivity. With multiple tips on the punch barrel, the overall compaction force to be applied is commonly estimated by multiplying the desired compaction force per tip by the number of punch tips. Few researchers have however examined this proportionality and the effects of the number of punch tips and punch face geometry on the critical quality attributes (CQAs) of high drug load minitablets. In this study, the minitablets prepared by multi-tip tools exhibited greater weight variation than those prepared by single-tip tools. Their compaction was accompanied by a longer dwell time that led to a higher minitablet tensile strength and consequently a longer disintegration time. The compaction forces required to achieve a consistent set of minitablet CQAs were not directly proportional to the number of punch tips used. In comparison, the effect of punch face geometry was negligible. Increasing concentration of magnesium stearate (as lubricant) from 0.75 to 1.25 %, w/w reduced weight variation, especially of minitablets prepared by the multi-tip tools. It also increased the disintegration time but had no significant effect on the tensile strength of the minitablets regardless of type of tools used. The adjustment of compaction speed was an effective compensatory method to mitigate the differences in dwell time and tensile strength between minitablets prepared by single-tip and multi-tip standard concave tools. A larger reduction in compaction speed of the single-tip tools was required at higher compaction pressures.

Study of diminutive granules as feed powders for manufacturability of high drug load minitablets.

The maximal amount of drug contained in a minitablet is limited. To reduce the total number of minitablets in a single dose, high drug load minitablets can be prepared from high drug load feed powders by various pharmaceutical processing techniques. Few researchers have however examined the influence of pharmaceutical processing techniques on the properties of high drug load feed powders, and consequently the manufacturability of high drug load minitablets. In this study, silicification of the high drug load physical mix feed powders alone did not yield satisfactory quality attributes and compaction parameters to produce good quality minitablets. The abrasive nature of fumed silica increased ejection force and damage to the compaction tools. Granulation of fine paracetamol powder was crucial for the preparation of good quality high drug load minitablets. The diminutive granules had superior powder packing and flow properties for homogenous and consistent filling of the small die cavities when preparing minitablets. Compared to the physical mix feed powders for direct compression, the granules which possessed higher plasticity, lower rearrangement and elastic energies, yielded better quality minitablets with high tensile strength and rapid disintegration time. High shear granulation demonstrated greater process robustness than fluid bed granulation, with less discernment on the quality attributes of feed powder. It could proceed without fumed silica, with the high shear forces reducing interparticulate cohesivity. An in-depth understanding on the properties of high drug load feed powders with inherently poor compactability and poor flowability is important for the manufacturability of high drug load minitablets.

Charge reduction assisted production of diminutive fluid bed granules for high drug load minitablets.

Micronized drug powders are generally unsuitable as tableting feed to produce minitablets due to their cohesivity and poor flow. The silicification of fine paracetamol powder (PCMF) with an optimal concentration range of fumed silica (fSi) [0.7-0.9%, w/w] reduced the net negative charge of PCMF and improved powder flow. The optimal fSi concentration range suitable was established through the measurement of charge and flowability of the silicified powders. Silicification of PCMF by physical mix did not satisfactorily overcome the cohesive forces between the PCMF crystals and improve powder flow sufficiently such that it will feed consistently into the smaller die orifices during tableting. Using a specialized fluid bed system with swirling air and side spray, controlled granulation of silicified PCMF packed and agglomerated the interlocking-prone needle shaped PCMF crystals into diminutive granules that are more spherical and free flowing. With optimized fSi concentration (≈ 0.8%, w/w) and granulation process parameters, high drug load diminutive granules (D50≃ 90 µm) were successfully prepared from PCMF as starter seeds (D50≃ 30 µm). Minitablets prepared from the diminutive granules had low weight variation, and were mechanically strong with disintegration time of <30 s. This study demonstrated the feasibility of producing high drug load minitablets from a cohesive, electrostatic-prone fine drug powder.

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives.

The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.