Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method

“…First, apart from a small amount of surfactant, no carrier is needed in nanocrystals, so theoretically the drug loading rate can reach 100%, and practically 50–90%. , In addition, high solubility and fast dissolution are obtained, considering the small size and large specific surface area, according to the Ostwald–Freundlich equation and Noyes–Whitney equation. , Adhesion to the gastrointestinal tract leads to prolonged retention of nanocrystals and extended drug release from them. , Furthermore, the food effect could be eliminated since the enhancement of solubility and the absorption process by nanocrystals is permeation-limited rather than dissolution-limited . In the past two decades, nanocrystals experienced accelerated development from bench to bedside, such as Emend, Rapamune, and so on, achieving great success. For instance, Tricor, a tablet consisting of fenofibrate nanocrystals, has achieved sales hitting $1 billion per year and is regarded as a “blockbuster” drug …”

Section: Introductionmentioning

confidence: 99%

Transmembrane Pathways and Mechanisms of Rod-like Paclitaxel Nanocrystals through MDCK Polarized Monolayer

Deng

Zhang

Wang

et al. 2017

ACS Appl. Mater. Interfaces

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Drug nanocrystals (NCs) appear to be favorable to improving oral bioavailability of poorly water-soluble drugs as evidenced by the great success they have had in the market. However, the pathway and mechanism of drug NCs through epithelial membrane are still unclear. In an attempt to clarify their transport features, paclitaxel nanocrystals (PTX-NCs), and paclitaxel hybrid NCs with lipophilic carbocyanine dyes, were prepared and characterized as the models. The endocytosis, intracellular trafficking, paracellular transport, and transcytosis of PTX-NCs were carefully investigated with Förster resonance energy transfer (FRET) analysis, as well as a colocalization assay, flow cytometry, gene silencing, Western-blot, transepithelial electrical resistance (TEER) study and other approaches on MDCK cells. It was found that rod-like PTX-NCs could transport through the monolayer intact, and the process of endocytosis proved to be time and energy dependent. Endoplasmic reticulum (ER) and Golgi complexes were colocalized with PTX-NCs in cells, so the ER-Golgi complexes/Golgi complexes-basolateral membrane pathway may be involved in the intracellular trafficking and transcytosis of PTX-NCs. It was demonstrated here that cav-1, dynamin, and actin filament modulated the endocytosis process, and Cdc 42 regulated the transcytosis process. In addition, no paracellular transport of PTX-NCs was observed. These findings demonstrated that the rod-like nanocrystals not only enhanced the transcytosis of PTX compared with microparticles of raw drug materials but also changed the pathways of drug delivery. This study certainly provides insight for the oral absorption mechanism of nanocrystals of poorly soluble drugs.

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“…The original oral administration of SRL was through a lipid-based liquid solution with a bioavailability of 14%. With the application of wet-ground in Nanocrystal ® technology, SRL is ground in a ball mill for 120 h to prepare nanosized drug dispersions, and then post-processed into a tablet formulation as Rapamune ® [ 6 , 11 ]. The bioavailability of nanotablets is increased by approximately 27%, while having no storage limitations and improved patient compliance [ 6 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Amorphous Nanoparticulate Formulation of Sirolimus and Its Tablets

Shen

2018

Pharmaceutics

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Nanocrystallization and amorphization have proven to be two effective strategies to improve the bioavailability of water-insoluble drugs. The purpose of our work was to develop a nano-formulated tablet of sirolimus (SRL) for enhanced dissolution. Amorphous SRL nanocomposites were prepared using anti-solvent precipitation via a high-gravity rotating packed bed. Various factors that affect particle size and size distribution, such as excipients, rotating speed, antisolvent/solvent flow rate, were investigated. Structure, stability and in vitro dissolution of the as-prepared SRL were evaluated. Furthermore, the nanoparticulated SRL tablet formula was screened to control drug release. Importantly, SRL tablets exhibit different dissolution profile by adjusting HPMC (hydroxypropyl methyl cellulose) content, which makes them more suitable for various formulation developments.

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Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method

Cited by 14 publications

References 17 publications

Influence of variation in molar ratio on co-amorphous drug-amino acid systems

Influence of variation in molar ratio on co-amorphous drug-amino acid systems

Transmembrane Pathways and Mechanisms of Rod-like Paclitaxel Nanocrystals through MDCK Polarized Monolayer

Amorphous Nanoparticulate Formulation of Sirolimus and Its Tablets

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