CNCADD – Conventional vs Novel Computer Assisted Drug Delivery

Issues related to drug delivery are of essen­tial importance to contemporary mo­le­cular pharmaceutics. Molecular modeling ap­proach is of substantial importance in the course of efficient design and development of conventional dosage forms as well as novel micro/nano carrier systemsforactive pharma­ceu­ti­cal ingredients – API(from in-silico to industrial level scaling). Namely, during the preformulation studies proper characterization of API, selected excipients/polymer sand their interactions are essential for efficient development of the new drug product. Therefore,in our application, we de­ve­lop and implement new, ro­bust com­putational modeling appro­a­c­hes to stu­dy the structural and vibrational spectroscopic properties of different API`s as well as to investigate the physics and chemistry of in­ter­ac­tions between drug mo­­­lecules and their potential carriers, un­der realistic conditions encountered in bio­lo­gical systems. The intermolecular inter­ac­tions relevant to the present application span a rather wide range, in both qua­li­ta­tive and quantitative sense. The metho­do­lo­gies that we develop are inherently hyb­rid. They are based on se­qu­e­ntial appli­ca­ti­on of statistical physics simulations and qu­an­tum mechanical calculations to the sys­tems of interest. Statistical physics pha­se is, in our approach, mostly based on ab initio mo­lecular dynamics (MD) si­mu­lations, in the framework of atom-cen­te­red density matrix propa­ga­­tion scheme (ADMP) or Born-Oppenheimer MD. In cer­ta­in cases, we also imple­ment classical MD and Monte Carlo. Quan­tum mechanical pha­se involves exact com­putation of mo­le­cular properties relevant to drug – na­no­-car­rier intermolecular interactions. Final judgment concerning the usefulness and applicability of the developed mo­dels is brought up by com­pa­ri­son with relevant expe­ri­men­tal da­ta. At the current stage of deve­lop­ment, we ha­ve prepared work­flows for most of the specific com­pu­ta­ti­o­nal purposes andwe have also written mo­st of the codes for data ana­lysis. In pa­ra­llel, we havealso car­ried out numerous tests along with some productive com­­pu­ta­tions.

To implement our application, we have be­­en given excellent opportunity to use the Supercomputing Facility at Bibliotheca Alexandrina (BA) in Cairo, Egypt. The su­per­computing facility at BA is actually a HPC cluster with peak performance of 11.8 TFLOPS, composed of 130 computing nodes, each with two Intel Quadcore Xeon 2.83 GHz CPUs, a 36-TByte storage sys­tem, dual port infiniband (10 Gbps) and a Gi­gaEthernet network port.

We have already made work­flows for some particular computational purposes, along with certain outputs and datasetsava­i­la­ble to the community and the other par­tners of the VI-SEEM pro­ject (see the re­po­si­tories site).We have also provided links to the scientific pub­li­ca­tions that ha­ve arisenup to this point from our ap­pli­ca­tion.

Up to now, we have successfully im­p­le­men­ted our hybrid computational appro­ach to study the structural and vibrational spe­ctroscopic properties of hydrophilic drug irinotecane. This actually served as a first step towards a multiscale model that would lead us to an in-depth under­stan­ding of the physics and chemistry behind the processes of incorporation of this mo­le­cular system into nanoparticles built up by poly lactic-co-clycolic acid copolymer and co-adsorbed polyethylene oxide – po­ly­propylene – polyethylene oxide. Com­pa­ri­son of our theoretical results with the ex­perimental ATR FT IR data de­mon­stra­ted the validity of the approach. Further, we have also studied the vibrational spec­tro­scopic properties of morphine as well as protonated morphine-H+ cationic speci­es and compared our theoretical predicti­ons with the experimental FT IR data. Not only that our theoretical approach has ena­bled solid support to the empirical ass­ignment of the spectral bands, but it also im­plied certain fundamental insights into the structural properties of the solid-state form of this exceptionally important com­po­und. Aside for this, the current work ser­ves as a starting point for further stu­di­es of the spectroscopic manifestations of mo­r­phine incorporation into prolonged release oral formulations, where different polymers or preparation methods are used in order to obtain suitable morphine release. In this context, we have also theoretically modeled the ki­ne­tics of the process of morphine in vitro re­le­ase from developed prolonged release formulations.

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