The Application of Coarse-Grained Molecular Dynamics to the Evaluation of Liposome Physical Stability.

Physical stability is one of critical characteristics of liposome, especially to its clinical application. Vesicle fusion was one of the common physical stability phenomena that occurred during the long storage period. Because vesicle fusion could be easily checked by the change of vesicle size, it was widely applied in the evaluation of liposome physical stability. However, since the method requires the liposome to be placed under certain conditions for long-term observation, a liposome physical stability test usually takes several weeks, which greatly hinders the research efficiency. In this study, to speed up the research efficiency, coarse-grained molecular dynamics was first applied in the study of liposome physical stability. By analyzing the microprocess of vesicle fusion, two parameters including diffusion constant and the total time of the vesicle morphology transition process were employed to study the liposome physical stability. Then, in order to verify the applicability of two parameters, the physical stability of elastic liposomes and conventional liposomes was compared at 3 different temperatures. It was found that the fusion probability and speed of elastic liposomes were higher than those of conventional liposomes. Thus, elastic liposomes showed a worse physical stability compared with that of conventional liposomes, which was consistent with former research. Through this research, a new efficient method based on coarse-grained molecular dynamics was proposed for the study of liposome physical stability.

Optimal Selection of Incoming Materials from the Inventory for Achieving the Target Drug Release Profile of High Drug Load Sustained-Release Matrix Tablet.

In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.

A Multiscale Study on the Effect of Sodium Cholate on the Deformation Ability of Elastic Liposomes.

Elastic liposoxy1mes (ELs) are biocompatible bilayer vesicular systems commonly used in the transdermal delivery of drugs. Compared with conventional liposomes (CLs), the strong deformation ability conferred by edge activators (EAs) is one of the most critical properties of ELs. However, due to limited research methods, little is known about the effect of EAs on the deformation abilities of vesicles. In this study, taking sodium cholate as an example, a multiscale study was carried to study the effect of EAs on the deformability of ELs, including in vitro diffusion experiment at macroscale, "vesicle-pore" model experiment at the microscale and flat patch model experiment at the molecular scale. As a result, it was found that sodium cholate could decrease the kc of DPPC bilayer, which enabled it to remain morphologically intact during a strong deformation process. Such kind of differences on deformation ability made pogostone ELs (contain sodium cholate) present a better permeation effect compared with that of pogostone CLs. All of these provide a multiscale and thorough understanding of the effect of sodium cholate on the deformation ability of ELs.

Setting up multivariate specifications on critical raw material attributes to ensure consistent drug dissolution from high drug-load sustained-release matrix tablet.

The purpose of this study was to describe the raw material variability that influenced the in-vitro dissolution behavior of high drug-load sustained-release matrix tablet and to ensure the consistent quality of the final product. The Panax notoginseng saponins (PNS) - hydroxypropyl methylcellulose - anhydrous lactose - magnesium stearate (57:20:23:0.5%, w/w) was used as the model formulation. PNS extract powders with lot-to-lot and source-to-source differences were collected to cover the common cause variations and their physicochemical properties were characterized by the chromatographic fingerprints and the SeDeM expert system. It was found that the release behavior of active pharmaceutical ingredients (APIs) in PNS from different batches exhibited considerable variations. Latent variable modeling results demonstrated that the physical properties of raw materials played major roles in predicting the drug dissolution. PNS extracts with high specific surface area, the width of particle size distribution and hygroscopicity or low moisture content led to an increase in drug release. In order to perform efficient pass/fail judgments for incoming new materials, multivariate specifications of critical material attributes (CMAs) were established and the multivariate design space in line with the quality by design (QbD) principles was explored to achieve the release target.

[Application of quality by design in granulation process for ginkgo leaf tablet (⠣)： influence and control of raw materials' quality variation].

Raw materials' quality variation could affect the quality consistency of product and the clinical efficacy. In this paper, the high shear wet granulation (HSWG) process of the ginkgo leaf tablet was taken as the research object. Ginkgo biloba extracts and excipients microcrystalline cellulose collected from various sources and batches were used to simulate raw materials' quality variation. Real-time torque was recorded to analyze the viscosity of the wetting mass, and then by combining with physical fingerprint, the impact of physical quality variation of powders on granule properties could be investigated. Based on regime map thesis, whether the granules' nucleation mode was in mechanical dispersion regime was determined by calculating dimensionless parameters, which would lead to the unstable output in considerations of granule yield ratio and particle size distribution (PSD) curve. The orthogonal partial least square (OPLS) model was adopted to build the relationship between the micromeritic properties and the mediangranule size (D50) of Ginkgo biloba granules and then the critical material attributes (CMAs) were screened by variable importance in the projection (VIP) indexes. The results demonstrated that the properties of powders including hygroscopicity, angle of repose, Hausner ratio, Carr index, D10 and loss on drying affected the granule size. Besides, Ginkgo biloba granules were compressed into tablets. In view of tensile strength analysis, the raw materials' quality variation did not result in decrease of tensile strength of the ginkgo leaf tablets. The design space of critical quality attributes (CQAs) and the process design space which could cope with raw materials' quality variation were proved to be robust..

[Near infrared spectrum monitoring of scale up process for macroporous resin purification of Grardeniae extract].

To establish a fast detection method during the purifying process of the extracts from Grardeniae using macroporous resin based on near infrared spectroscopy. First, the ethanol eluent was collected from the purification process of small size sample; and near infrared (NIR) spectrum was collected. Then the content of the geniposide was determined by HPLC method, and partial least squares (PLS) method was used to establish the quantitative model to predict the content of geniposide by NIR spectrum. This model was used to supervise the changes of geniposide concentrations in ethanol eluent during medium scale process. Experimental results showed that the NIR small scale model can accurately predict the concentrations of geniposide in the production process of medium scale. However, with the proceeding of batch processes, the prediction performance of the model was decreased, so model updating method was employed to maintain the model. After twice updates, the NIR quantitative model can accurately predict the concentrations of the geniposide during medium scale process. Therefore, through model updates, the established NIR quantitative model can be applied in different scales of macroporous resin purification processes, to improve the data utilization efficiency of small scale process and save the cost of rebuilding the quantitative model of medium scale.

[Quality by design based high shear wet granulation process development for the microcrystalline cellulose].

The design space of the high shear wet granulation process was established and validated within the framework of quality by design (QbD). The system of microcrystalline cellulose-de-ioned water was used in this study. The median granule size and bulk density of granules were identified as critical quality attributes. Plackeet-Burmann experimental design was used to screen these factors as follows: dry mixing time, the impeller and chopper speed of dry mixing, water amount, water addition time, wet massing time, the impeller and chopper speed of wet massing and drying time. And the optimization was implemented with the central composite experimental design based on screened critical process parameters. The design space of the high shear wet granulation process was established based on the quadratic polynomial regression model. Since the P-values of both models were less than 0.05 and values of lack of fit were more than 0.1, the relationship between critical quality attributes and critical process parameters could be well described by the two models. The reliability of design space, illustrated by overlay plot, was improved with the addition of 95% confidence interval. For those granules whose process parameters were in the design space, the granule size could be controlled within 250 to 355 µm, and the bulk density could be controlled within a range of 0.4 to 0.6 g x cm(-3). The robustness and flexibility of the high shear wet granulation process have been enhanced via the establishment of the design space based on the QbD concept.

Interactions of borneol with DPPC phospholipid membranes: a molecular dynamics simulation study.

Borneol, known as a "guide" drug in traditional Chinese medicine, is widely used as a natural penetration enhancer in modern clinical applications. Despite a large number of experimental studies on borneol's penetration enhancing effect, the molecular basis of its action on bio-membranes is still unclear. We carried out a series of coarse-grained molecular dynamics simulations with the borneol concentration ranging from 3.31% to 54.59% (v/v, lipid-free basis) to study the interactions of borneol with aDPPC(1,2-dipalmitoylsn-glycero-3-phosphatidylcholine) bilayer membrane, and the temperature effects were also considered. At concentrations below 21.89%, borneol's presence only caused DPPC bilayer thinning and an increase in fluidity; A rise in temperature could promote the diffusing progress of borneol. When the concentration was 21.89% or above, inverted micelle-like structures were formed within the bilayer interior, which led to increased bilayer thickness, and an optimum temperature was found for the interaction of borneol with the DPPC bilayer membrane. These findings revealed that the choice of optimal concentration and temperature is critical for a given application in which borneol is used as a penetration enhancer. Our results not only clarify some molecular basis for borneol's penetration enhancing effects, but also provide some guidance for the development and applications of new preparations containing borneol.

Investigation on drug entrapment location in liposomes and transfersomes based on molecular dynamics simulation.

In this study, liposome and transfersome were successfully constructed using molecular dynamics simulation. Three drugs with different polarity, including 5-fluorouracil, ligustrazine, and osthole, were selected as model drugs to study the distribution of drugs in lipid vesicles by calculating the radial distribution function and the potential of mean force. The solubility parameters between drugs and different regions in lipid vesicles were calculated to characterize the compatibility of drugs in different regions in lipid vesicles, which provided the basis for the conclusion of this paper. It showed that the radial distribution function and the potential of mean force were consistent in the characterization of drug distribution in vesicles, and the drug distribution in vesicles was closely related to the compatibility between drugs and vesicles. Therefore, the radial distribution function and the potential of mean force can be used to characterize the distribution of drugs in vesicles, and molecular simulation technology has a great potential in studying the characteristics of vesicles. Graphical abstract.

Coarse-grained molecular dynamics simulations of the effect of edge activators on the skin permeation behavior of transfersomes.

Transfersomes (TRS) can provide sustained drug delivery and themselves are biocompatible, biodegradable and nontoxic. Edge activators (EAs) are key factors for increasing the deformability of TRS, and this active deformation mechanism is of commercial interest, especially at the molecular level. Accordingly, in this paper, the deformability of pure dipalmitoyl phosphatidylcholine (DPPC) vesicles, TRS with sodium cholate as an EA, and DPPC vesicles containing pogostone (POG) were compared via umbrella sampling technology. The DPPC conformation and membrane fluidity of these three types of bilayer systems were evaluated, and the changes in the membrane properties of vesicles caused by EAs were studied. EAs could increase the deformability of TRS by decreasing the deformation energy barrier due to their amphiphilic structures, which was similar to those of DPPC molecules. The membrane properties also changed via treatment with EAs including altering the tail chain angle, disturbing the ordered tail chain arrangement and prompting lateral diffusion of DPPC molecules. In addition, the impact of EAs on DPPC bilayers was further demonstrated to be concentration dependent. An ideal concentration was identified for the lowest amount of EA that offered a gel-liquid-crystalline phase transition of DPPC bilayers. Importantly, POG, a lipophobic transdermal drug, can also affect the skin permeation behavior of vesicles but had weaker effects than EA.

Dissipative particle dynamics study on self-assembled platycodin structures: the potential biocarriers for drug delivery.

Platycodin, as a kind of plant based biosurfactants, are saponins which derived from the root of Platycodon grandiflorum A. DC. It has been confirmed that platycodin have the potential to enhance the solubility of hydrophobic drugs and function as the drug carrier, which depends on their micellization over critical micelle concentration (CMC) in aqueous solutions. With the purpose of investigating the effects of influencing factors on the micellization behavior of platycodin and obtaining the phase behavior details at a mesoscopic level, dissipative particle dynamics (DPD) simulations method has been adopted in this study. The simulations reveal that a rich variety of aggregates morphologies will appear with changes of structure or the concentration of saponins, including spherical, ellipse and oblate micelles and vesicles, multilamellar vesicles (MLVs), multicompartment vesicles (MCMs), tubular and necklace-like micelle. They can be formed spontaneously from a randomly generated initial state and the result has been represented in the phase diagrams. Furthermore, deeper explorations have been done on the concentration-dependent structure variation of spherical vesicles as well as the formation mechanism of MLVs. This work provides insight into the solubilization system formed by platycodin, and may serve as guidance for further development and application in pharmaceutical field of platycodin and other saponins.

Preparation of chitosan/ethylcellulose complex microcapsule and its application in controlled release of vitamin D2.

A system which consists of chitosan (CS) microcores entrapped within enteric polymer is investigated. Vitamin D2 (VD2) used as a model drug, was efficiently entrapped in CS microcores using spray drying and was microencapsulated by coating of ethylcellulose. The morphology and release properties of microcapsules were tested. The factors which influenced the preparation, including molecular weight of CS, concentration of CS solution, concentration of acetic acid and loading of VD2, were discussed. The results of release in vitro showed that the microcapsules could realize sustained release in intestine juice.

[Preparation of complex chitosan microcapsule and its application in controlled release of vitamin D2].

In this work a system which consists of chitosan (CS) microcores entrapped within enteric polymer is presented. Vitamin D2, used as a model drug, was efficiently entrapped within CS microcores using spray-drying and then microencapsulated into ethylic cellulose(EC). The morphology and release properties of microcapsules were tested. The influential factors of preparation conditions included molecular weight of chitosan, concentration of chitosan solution, concentration of acetic acid, loading of vitamin D2 were discussed. The results of in vitro release studies showed that the microcapsules prepared in this article could realize sustained release in intestine.

Multiscale study on the interaction mechanism between ginsenoside biosurfactant and saikosaponin a.

Ginsenoside is an important class of saponin biosurfactant that is derived from ginseng. The interactions between ginsenoside Ro, Rb1, and Rg1 with saikosaponin a (SSa) were explored using multiscale methods. The order of interaction strength was found to be Ro>Rb1>Rg1. Ro markedly increased the solubility of SSa; however, Rb1 could only disperse SSa solid in aqueous medium. No significant interaction was observed between Rg1 and SSa. Ro formed vesicles in aqueous medium while Rb1 and Rg1 formed spherical micelles. The differences in the available surface area of the aggregates appear to have some influence on the interactions between ginsenoside and SSa. However, more important effects are related to their chemical structures and interaction energy. According to the molecular simulation results, glucuronic acid linked to Ro molecules significantly reduced the potential energy through its strong electrical attraction to SSa, which contributed greatly to the strong compatibility between them. The greater number of sugars in Rb1, as compared to Rg1, created more binding sites with SSa, thus resulting in stronger interaction between Rb1 with SSa than between Rg1 and SSa. Spherical and worm-like micelles were found to be formed by Rb1 and SSa molecules. This was different from Ro and SSa, which formed vesicles. The formation of worm-like micelles was through the fusion and modification of small spherical micelles. These results may guide in expanding the applications of ginsenoside.