Co-reporter:Pimchanok Charoongchit, Jiraphong Suksiriworapong, Shirui Mao, Anne Sapin-Minet, ... Varaporn Buraphacheep Junyaprasert
Acta Biomaterialia 2017 Volume 61(Volume 61) pp:
Publication Date(Web):1 October 2017
DOI:10.1016/j.actbio.2017.08.006
In this study, poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL)2-PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200–450 nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX.Statement of SignificanceThe anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.Download high-res image (286KB)Download full-size image
Co-reporter:Jian Guan;Yeli Zhang;Qiaoyu Liu;Xin Zhang;Rina Chokshi
AAPS PharmSciTech 2017 Volume 18( Issue 8) pp:3172-3181
Publication Date(Web):23 May 2017
DOI:10.1208/s12249-017-0801-6
The objective of this study was to explore the feasibility of using alginate as a potential stabilizer of nanosuspension and elaborate the corresponding stabilization mechanism. Using lovastatin as a Biopharmaceutics Classification System (BCS) II drug model, alginate-stabilized nanosuspension was fabricated by the high-pressure homogenization method. The particle size, zeta potential, short-term stability, and dissolution behavior of the nanosuspension were characterized. Thereafter, the surface morphology, crystallinity, redispersability, and stability of the spray-dried nanosuspension were investigated. The spray-dried powder was further compressed into tablets via direct compression, and stressing test was carried out to investigate the stability of nanocrystal loaded tablets. It was demonstrated that alginate could stabilize nanocrystals by providing both electrostatic and steric stabilization, and the effective concentration was much lower than that of the commonly used stabilizers. Good redispersability was achieved after spray drying of the nanosuspension, and the existing state of lovastatin was not changed as indicated by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) studies. The stress test indicated that nanocrystal-loaded tablets possessed a favorable stability. In conclusion, alginate could be used as a potential stabilizer of nanosuspension with preferable stabilizing ability at a very low concentration either in liquid or in solid state.
Co-reporter:Xiaodan Wang, Xiangqin Gu, Huimin Wang, Yujiao Sun, Haiyang Wu, Shirui Mao
European Journal of Pharmaceutical Sciences 2017 Volume 96(Volume 96) pp:
Publication Date(Web):1 January 2017
DOI:10.1016/j.ejps.2016.09.036
Recently, polymeric materials with multiple functions have drawn great attention as the carrier for drug delivery system design. In this study, a series of multifunctional drug delivery carriers, hyaluronic acid (HA)-glycyrrhetinic acid (GA) succinate (HSG) copolymers were synthesized via hydroxyl group modification of hyaluronic acid. It was shown that the HSG nanoparticles had sub-spherical shape, and the particle size was in the range of 152.6–260.7 nm depending on GA graft ratio. HSG nanoparticles presented good short term and dilution stability. MTT assay demonstrated all the copolymers presented no significant cytotoxicity. In vivo imaging analysis suggested HSG nanoparticles had superior liver targeting efficiency and the liver targeting capacity was GA graft ratio dependent. The accumulation of DiR (a lipophilic, NIR fluorescent cyanine dye)-loaded HSG-6, HSG-12, and HSG-20 nanoparticles in liver was 1.8-, 2.1-, and 2.9-fold higher than that of free DiR. The binding site of GA on HA may influence liver targeting efficiency. These results indicated that HSG copolymers based nanoparticles are potential drug carrier for improved liver targeting.Download high-res image (238KB)Download full-size image
Co-reporter:Rui Ni, Jing Zhao, Qiaoyu Liu, Zhenglin Liang, Uwe Muenster, Shirui Mao
European Journal of Pharmaceutical Sciences 2017 Volume 99(Volume 99) pp:
Publication Date(Web):1 March 2017
DOI:10.1016/j.ejps.2016.12.013
In this study, nanocrystals embedded in microparticles were designed to achieve sustained pulmonary drug delivery of hydrophobic drugs. Chitosan based microparticles were engineered to allow sustained drug release via swelling and mucoadhesive properties of the polymer. Taking cinaciguat as a hydrophobic model drug, drug nanocrystals were prepared by high pressure homogenization and then encapsulated in chitosan microparticles via spray drying. Through various in vitro characterizations, it was shown that drug loaded microparticles had a high drug loading with promising aerosolization characteristics (mean volume diameter (Dv50) 3–4 μm, experimental mass mean aerodynamic diameter (MMADe) 4–4.5 μm, fine particle fraction (FPF%) 40–45%, emitted dose (ED%) 94–95%). The microparticles showed high swelling capacity within 5 min, with various sustained drug release rates depending on chitosan concentration and molecular weight. Furthermore, aerosolization performances under various inhalation conditions were investigated. It was found that both inspiratory flow rate and volume had an influence on the aerosolization of developed microparticles, indicating actual inhalation efficiency might be compromised under disease conditions. Taken together, in vitro data indicate that chitosan based swellable microparticles could potentially be useful as nanocrystal carrier to achieve sustained pulmonary delivery. To complete the feasibility assessment of this formulation principle, future in vivo safety and efficacy studies are needed.Download high-res image (126KB)Download full-size image
Co-reporter:Ye Tian; Chenjun Shi; Yujiao Sun; Chengyun Zhu; Changquan Calvin Sun
Molecular Pharmaceutics 2015 Volume 12(Issue 3) pp:816-825
Publication Date(Web):January 14, 2015
DOI:10.1021/mp5006504
The objective of this study is to demonstrate the feasibility of using solubility parameter as guidance for the design and identification of a stable micellar system with a high drug loading capacity for oral drug delivery. Using hydroxycamptothecin (HCPT) as a model drug, the effect of three hydrophobic blocks (fatty glycerides) grafted onto chitosan on the drug loading and stability of HCPT-loaded micellar nanoparticles formed by pH precipitation method were studied systematically. The Flory–Huggins interaction parameter (χFH) calculated by the group contribution method (GCM) and molecular dynamics simulation (MDS) was used to assess the compatibility between HCPT and the copolymers. The predicted order of compatibility between three chitosan derivatives and HCPT was verified experimentally. A high drug loading and remarkably stable micellar system for oral administration based on succinylated glycerol monooleate-chitosan was discovered in this study. Our study suggests that the miscibility between drug and copolymer is crucial to drug loading and stability of the micellar system. Thus, the calculation of χFH using GCM and MDS methods is useful for guiding the design or screening of a suitable copolymer for preparing drug-loaded micellar nanocarrier systems.
Co-reporter:Linlin Wang, Yujiao Sun, Chenjun Shi, Liang Li, Jian Guan, Xin Zhang, Rui Ni, Xiaopin Duan, Yaping Li, Shirui Mao
Acta Biomaterialia 2014 Volume 10(Issue 8) pp:3675-3685
Publication Date(Web):August 2014
DOI:10.1016/j.actbio.2014.05.003
Abstract
The objective of this paper is to elucidate the influence of fatty glyceride chain length in chitosan copolymers on the peroral absorption of enoxaparin. First of all, a series of chitosan copolymers with glyceryl monocaprylate (GM8), glyceryl monolaurate (GM12) and glyceryl monostearate (GM18) as the hydrophobic part were synthesized. The structure of the copolymers was characterized using proton nuclear magnetic resonance. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that all the copolymers were non-toxic. Enoxaparin nanocomplexes were prepared by self-assembly. Mucoadhesion of the nanocomplexes was characterized using the mucin particle method. Nanocomplex uptake and transport were quantified in Caco-2 cells and cellular localization was visualized by confocal laser scanning microscopy. Enoxaparin uptake was enhanced by nanocomplex formation, and was dependent on incubation time, concentration, temperature and glyceride chain length. The GM8 grafted chitosan–enoxaparin nanocomplex exhibited the strongest bioadhesion and the best uptake and transport in both cell culture and in vivo absorption in rats. The uptake mechanism was assumed to be adsorptive endocytosis via clathrin- and caveolae-mediated processes. In conclusion, oral absorption of enoxaparin can be further enhanced by using GM8 grafted chitosan copolymer as the carrier to form nanocomplexes.
Co-reporter:Liang Li, Rui Ni, Yang Shao, Shirui Mao
Carbohydrate Polymers 2014 Volume 103() pp:1-11
Publication Date(Web):15 March 2014
DOI:10.1016/j.carbpol.2013.12.008
•The review describes general properties of carrageenan.•The review presents a comprehensive overview of carrageenan's applications in various drug delivery systems.•The review provides suggestions for future development of carrageenan in drug delivery.Carrageenan is a sulphated linear polysaccharide of D-galactose and 3, 6-anhydro-D-galactose obtained by extraction of certain red seaweeds of the Rhodophyceae class. The objective of this review is to summarize recent applications of carrageenan in drug delivery systems. So far, carrageenan has been investigated as an excipient in pharmaceutical industry, for example, as polymer matrix in oral extended-release tablets, as a novel extrusion aid for the production of pellets and as a carrier/stabilizer in micro/nanoparticles systems. Moreover, based on the special characteristics of carrageenan such as the strong negative charge and gelling, it has been used as a gelling agent/viscosity enhancing agent for controlled drug release and prolonged retention. Furthermore, carrageenan has been used for tissue regeneration with therapeutic biomacromolecules and for cell delivery. Other potential applications and safety evaluation of carrageenan are still to be undertaken in the near future.
Co-reporter:Xin Zhang;Jian Guan;Rui Ni;Luk Chiu Li
Journal of Pharmaceutical Sciences 2014 Volume 103( Issue 7) pp:2166-2176
Publication Date(Web):
DOI:10.1002/jps.24015
To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2166–2176, 2014
Co-reporter:Liang Li;Linlin Wang;Yang Shao;Ye Tian;Conghao Li;Ying Li
Journal of Pharmaceutical Sciences 2013 Volume 102( Issue 8) pp:2644-2654
Publication Date(Web):
DOI:10.1002/jps.23632
Abstract
The aim of this study was to better understand the underlying drug release characteristics from matrix tablets based on the combination of chitosan (CS) and different types of carrageenans [kappa (κ)-CG, iota (ι)-CG, and lambda (λ)-CG]. Highly soluble trimetazidine hydrochloride (TH) was used as a model drug. First, characteristics of drug release from different formulations were investigated, and then in situ complexation capacity of CG with TH and CS was studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Erosion and swelling of matrix were also characterized to better understand the drug-release mechanisms. Effects of pH and ionic strength on drug release were also studied. It was found that not only ι-CG and λ-CG could reduce the burst release of TH by the effect of TH–CG interaction, CS–ι-CG- and CS–λ-CG-based polyelectrolyte film could further modify the controlled-release behavior, but not CS–κ-CG. High pH and high ionic strength resulted in faster drug release from CS–κ-CG- and CS–ι-CG-based matrix, but drug release from CS–λ-CG-based matrix was less sensitive to pH and ionic strength. In conclusion, CS–λ-CG-based matrix tablets are quite promising as controlled-release drug carrier based on multiple mechanisms. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2644–2654, 2013
Co-reporter:Shirui Mao
Asian Journal of Pharmaceutical Sciences (October 2013) Volume 8(Issue 5) pp:267-268
Publication Date(Web):October 2013
DOI:10.1016/j.ajps.2013.12.001
Co-reporter:Liang Li, Siping Sun, Thaigarajan Parumasivam, John A. Denman, Thomas Gengenbach, Patricia Tang, Shirui Mao, Hak-Kim Chan
European Journal of Pharmaceutics and Biopharmaceutics (May 2016) Volume 102() pp:132-141
Publication Date(Web):1 May 2016
DOI:10.1016/j.ejpb.2016.02.010
l-Leucine (LL) has been widely used to enhance the dispersion performance of powders for inhalation. LL can also protect powders against moisture, but this effect is much less studied. The aim of this study was to investigate whether LL could prevent moisture-induced deterioration in in vitro aerosolization performances of highly hygroscopic spray-dried powders. Disodium cromoglycate (DSCG) was chosen as a model drug and different amounts of LL (2–40% w/w) were added to the formulation, with the aim to explore the relationship between powder dispersion, moisture protection and physicochemical properties of the powders. The powder formulations were prepared by spray drying of aqueous solutions containing known concentrations of DSCG and LL. The particle sizes were measured by laser diffraction. The physicochemical properties of fine particles were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). The surface morphology and chemistry of fine particles were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performances were evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH), and 25 °C for 24 h. Spray-dried (SD) DSCG powders were amorphous and absorbed 30–45% (w/w) water at 70–80% RH, resulting in deterioration in the aerosolization performance of the powders. LL did not decrease the water uptake of DSCG powders, but it could significantly reduce the effect of moisture on aerosolization performances. This is due to enrichment of crystalline LL on the surface of the composite particles. The effect was directly related to the percentage of LL coverage on the surface of particles. Formulations having 61–73% (molar percent) of LL on the particle surface (which correspond to 10–20% (w/w) of LL in the bulk powders) could minimize moisture-induced deterioration in the aerosol performance. In conclusion, particle surface coverage of LL can offer short-term protection against moisture on dispersion of hygroscopic powders.Download high-res image (310KB)Download full-size image
Co-reporter:Xin Zhang, Jian Guan, Rui Ni, Luk Chiu Li, Shirui Mao
Journal of Pharmaceutical Sciences (July 2014) Volume 103(Issue 7) pp:2166-2176
Publication Date(Web):1 July 2014
DOI:10.1002/jps.24015
To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility.
Co-reporter:Lan Zhang, Shirui Mao
Asian Journal of Pharmaceutical Sciences (January 2017) Volume 12(Issue 1) pp:
Publication Date(Web):1 January 2017
DOI:10.1016/j.ajps.2016.07.006
Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design (QbD) in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper, the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology (PAT), are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.Terms and tools of Quality by Design (QbD) in drug development.Download high-res image (42KB)Download full-size image
Co-reporter:Liang Li, Linlin Wang, Yang Shao, Y.E. Tian, ... Shirui Mao
Journal of Pharmaceutical Sciences (August 2013) Volume 102(Issue 8) pp:2644-2654
Publication Date(Web):1 August 2013
DOI:10.1002/jps.23632
The aim of this study was to better understand the underlying drug release characteristics from matrix tablets based on the combination of chitosan (CS) and different types of carrageenans [kappa (κ)-CG, iota (ι)-CG, and lambda (λ)-CG]. Highly soluble trimetazidine hydrochloride (TH) was used as a model drug. First, characteristics of drug release from different formulations were investigated, and then in situ complexation capacity of CG with TH and CS was studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Erosion and swelling of matrix were also characterized to better understand the drug-release mechanisms. Effects of pH and ionic strength on drug release were also studied. It was found that not only ι-CG and λ-CG could reduce the burst release of TH by the effect of TH-CG interaction, CS-ι-CG- and CS-λ-CG-based polyelectrolyte film could further modify the controlled-release behavior, but not CS-k-CG. High pH and high ionic strength resulted in faster drug release from CS-κ-CG- and CS-ι-CG-based matrix, but drug release from CS-λ-CG-based matrix was less sensitive to pH and ionic strength. In conclusion, CS-λ-CG-based matrix tablets are quite promising as controlled-release drug carrier based on multiple mechanisms. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2644-2654, 2013
Co-reporter:Linlin Wang, Liang Li, Yujiao Sun, Ye Tian, Ying Li, Conghao Li, Varaporn B. Junyaprasert, Shirui Mao
European Journal of Pharmaceutical Sciences (20 November 2013) Volume 50(Issues 3–4) pp:263-271
Publication Date(Web):20 November 2013
DOI:10.1016/j.ejps.2013.07.009
The objective of this paper is to elucidate the influence of lipophilic modification degree of chitosan on the peroral absorption of enoxaparin. A series of novel chitosan grafted glyceryl monostearate (GM) copolymers with different GM substitution degree were synthesized and the successful synthesis was confirmed by 1H NMR, FTIR and X-ray diffraction. Enoxaparin loaded nanocomplexes with different carriers were prepared by self-assembly process. Influence of GM substitution degree and chitosan molecular weight in the copolymer on the properties of the nanocomplexes was investigated. Morphology of the nanocomplexes was observed by atomic force microscopy. Mucoadhesive properties of the nanocomplexes were characterized using mucin particle method. Initially, mucoadhesion of the nanocomplexes increased with the increase of GM substitution degree and it started to decrease when the substitution degree was up to 18.6%. A good linear relationship between GM substitution degree and in vivo absorption of enoxaparin in fasted rats was established in the substitution degree range of 0–11.1%. In agreement with mucoadhesion data, further increasing GM substitution degree to 18.6% caused a decrease in oral absorption. In conclusion, oral bioavailability of enoxaparin can be enhanced by structure modification of the carriers and the bioavailability is hydrophobic modification degree dependent.Graphical abstractDownload high-res image (188KB)Download full-size image
Co-reporter:Rui Ni, Uwe Muenster, Jing Zhao, Lan Zhang, Eva-Maria Becker-Pelster, Martin Rosenbruch, Shirui Mao
Journal of Controlled Release (10 March 2017) Volume 249() pp:
Publication Date(Web):10 March 2017
DOI:10.1016/j.jconrel.2017.01.023
Sustained pulmonary drug delivery is regarded as an effective strategy for local treatment of chronic lung diseases. Despite of the progress made so far, there remains a need for respirable drug loaded porous microparticles, where porosity of the microparticles can be readily engineered during the preparation process, with tunable sustained drug release upon lung deposition. In this work, polyvinyl pyrrolidone (PVP) was used as a novel porogen to engineer PLGA-based large porous particles (LPPs) using single emulsion method, with fine tuning of the porosity, sustained drug release both in vitro and in vivo. Using cinaciguat as the model drug, influence of PVP content and PLGA type on the properties of the LPPs was characterized, including geometric particle size, drug encapsulation efficiency, tap density, theoretical and experimental aerodynamic particle size, specific surface area, morphology, and in vitro drug release. Solid state of cinaciguat in the LPPs was studied based on DSC and X-ray analysis. LPPs retention in the rat lung was carried out using bronchoalveolar lavage fluid method. Raw 264.7 macrophage cells were used for LPPs uptake study. Pharmacodynamic study was performed in mini-pigs in a well-established model of pulmonary arterial hypertension (thromboxane challenge). It was demonstrated that porosity of the LPPs is tunable via porogen content variation. Cinaciguat can be released from the LPP in a controlled manner for over 168 h. Significant reduction of macrophage phagocytosis was presented for LPPs. Furthermore, LPPs was found to have extended retention time (~ 36 h) in the rat lung and accordingly, sustained pharmacodynamics effect was achieved in mini-pig model. Taken together, our results demonstrated that this simple PLGA based LPPs engineering using single emulsion method with PVP as porogen may find extensive application for the pulmonary delivery of hydrophobic drugs to realize tunable sustained effect with good safety profile.
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