CRYSTENGCOMM
·
2020
·Vol. 22
·期 45
·7992-8006
·
IF 3.117
Yue-Ming Yu,Ling-Yang Wang,Fan-Zhi Bu,Lin-Lin Wang,Yan-Tuan Li,Cheng Wang,Zhi-Yong Wu
In order to give full play to the superiority of cocrystallization techniques to overcome biopharmaceutical limitations in vitro and ameliorate pharmacokinetic properties in vivo together with heightening the antitumor abilities of the anticancer drug 5-fluorouracil (FL), and to gain some further insights into the development of novel pharmaceutical cocrystals with synergetic antitumor activity between an active pharmaceutical ingredient and the former cocrystal, a new cocrystal of FL with caffeic acid (CF), namely FL-CF-2H2O, has been successfully exploited and systematically studied. Single-crystal X-ray diffraction analysis confirms that the asymmetric unit of the newly synthesized cocrystal consists of one FL, one CF and two solvent water molecules, in which the two complementary FL and CF molecules compose a planar hydrogen-bonding pair. Water molecules fill in the hole surrounded by three arrays of the pairs and link each other via hydrogen bonds to form a three-dimensional supramolecular network, which is further reinforced by aromatic packing interactions. The cocrystal characteristics in vitro and in vivo are systematically evaluated through a combination of theoretical and experimental methods. It is found that the permeability and solubility of FL from the FL-CF-2H2O cocrystal are synchronously enhanced relative to pure FL, which is supported by molecular electrostatic potential calculation and Hirshfeld surface analysis. Interestingly, the ameliorated in vitro biopharmaceutical characteristics can efficaciously change the in vivo optimized pharmacokinetics with prolonged half-life and increased bioavailability compared with FL itself. What is even more interesting is that CF and FL in the cocrystal exhibit synergistic antitumor effects on tested cell lines. Thus, this work not only provides a new crystalline form for FL with potential application prospects, but also initiates an intelligent idea for the development of synergistic antitumor pharmaceutical cocrystals.
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2022
·
IF 4.01
Su-Su Meng,Yue-Ming Yu,Fan-Zhi Bu,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
A cocrystallization tactic of double optimization and synergistic enhancement efficacy has been proposed, aiming at maximizing the benefits of phenolic acid nutriment syringic acid (HSA) to perfect biopharmaceutical features of antibacterial drug ofloxacin (OA). This strategy utilizes the salt-forming function and cocrystallization ability of HSA interplaying with OA to assemble into a salt cocrystal, thus ameliorating OA’s physicochemical properties in vitro, which, in turn, can optimize its pharmacokinetic characteristics in vivo, making OA’s pharmaceutical peculiarities be doubly optimized on both in vivo and in vitro levels. Ulteriorly, the antibacterial potency of OA is heightened by stimulating the auxiliary antibacterial ability of HSA, fulfilling the cooperativeness of OA and HSA in antibacterial efficacy. Taking this tactic as orientation, the first OA– nutriment salt cocrystal, viz., [HOA+-SA–]-HSA-H2O, is directionally synthesized and structurally identified. Single-crystal X-ray diffraction substantiates that the salt cocrystal has a bilayer hole structure, wherein, a hexahelical hydrogen-bonding motif of [HOA+-SA–] salts situates outside with a double spiral of neutral HSA and H2O molecules inside, thus endowing the salt cocrystal with the capacity to simultaneously enhance solubility and permeability compared with OA itself, which achieves positive correlations with theoretical investigations. Intriguingly, the strengthened in vitro properties of the salt cocrystal have been effectually turned into in vivo pharmacokinetic advantages, displaying an advanced peak plasma concentration and protracted half-life along with raised relative bioavailability. More meaningfully, the antibacterial capacity of the salt cocrystal has also attained significant enhancement owing to the congenerous antibacterial action of OA and HSA. Therefore, this investigation not only offers a novice strategy for optimizing in vitro/vivo pharmaceutical characteristics and concurrently elevating antibacterial efficacy of OA through formation of the salt cocrystal but also fulfills a breakthrough in developing new salt cocrystal systems of antibacterial drugs.
研究领域:
药学
·
生物医学工程
✓ 已验证
DOI
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Yulin Mo,Yanjun Yang,Jingqi Zeng,Weikun Ma,Yuxin Guan,Jingxi Guo,Xiaochun Wu,Dingkun Liu,Liang Feng,Xiaobin Jia,Bing Yang
Purpose Asperosaponin VI (ASP VI) as an active ingredient of Dipsacus asperoides, which has a wide range of biological and pharmacological activity. However, its development and application are restricted due to the poor gastrointestinal permeability and oral bioavailability. This investigation aims to reveal the influence of the self-assembled structure by the interaction between ASP VI and endogenous components NaTC and/or DOPC in the gastrointestinal environment on its biopharmaceutical properties, and novelty elucidated the molecular mechanism for the formation of self-assembled nanomicelles.Methods This change in phase state in gastrointestinal fluids is characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). UPLC-Q-TOF-MS was used to analyze the composition of phase components and the exposure of nanomicelles in vivo. Molecular dynamics simulation (MDS) was applied to preliminarily elucidate the self-assembly mechanism of ASP VI in the gastrointestinal environment. Furthermore, theS8 promoting absorption mechanism of nanomicelles were investigated through in vivo pharmacokinetic experiments, parallel artificial membrane permeability assay (PAMPA), quadruple single-pass intestinal perfusion in rats, and Caco-2 cell monolayer model.Results We demonstrated that the ASP VI could spontaneously form dynamic self-assembled structures with sodium taurocholate (NaTC) and dipalmitoyl phosphatidylcholine (DOPC) during gastrointestinal solubilization, which promoted the gastrointestinal absorption and permeability of ASP VI and increased its exposure in vivo, thus improving the biopharmacological characteristics of ASP VI. Moreover, ASP VI-NaTC-DOPC-self-assembled nanostructures (ASP VI-NaTC-DOPC-SAN) manifested higher cellular uptake in Caco-2 cells as evidenced by flow cytometry and confocal microscopy, and this study also preliminarily revealed the mechanism of self-assembly formation of ASP VI with endogenous components NaTC and DOPC driven by electrostatic and hydrogen bonding interactions.Conclusion This study provides evidence that the dynamic self-assembled phase transition may play a key role in improving the biopharmacological characteristics of insoluble or low permeability active ingredients during the gastrointestinal dissolution of Chinese medicines.
研究领域:
药理学
·
生物医学工程
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
·
2014
·
IF 4.558
Linglei Jiang,Ying Huang,Qi Zhang,Hongyan He,Yun Xu,Xuefeng Mei
Pharmaceutical co-crystals involving two active pharmaceutical ingredients are rarely revealed in the literature. In this work, crystal engineering principles were exercised to guide the design and synthesis of the Biopharmaceutics Classification System class IV drug dapsone (DAP). We reported six drug–drug co-crystals of DAP with sulfanilamide, flavone, luteolin, caffeine in 1:1 stoichiometry, caffeine in 1:2 stoichiometry, and 2(3H)-benzothiazolone. Bioactive coformers were deliberately selected. The resulting co-crystals were fully characterized by a range of analytical technologies, including X-ray powder diffraction, Fourier transform infrared spectroscopy, polarized light microscopy, differential scanning calorimetry, and thermogravimetric analysis, etc. Single-crystal structure analysis reveals that reoccurring supramolecular synthons are observed in different DAP co-crystals. Equilibrium solubility and intrinsic dissolution rates were also compared with those of the parent drug. This work expands the pharmaceutically acceptable solid forms of DAP and supplements the successful cases of drug–drug co-crystals.
研究领域:
药物化学
·
晶体学
·
制药工程
✓ 已验证
DOI
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 19
·6962
·
IF 4.6
Yanxiong Gan,Yaxin Xu,Xue Zhang,Huiling Hu,Wenke Xiao,Zheng Yu,Tao Sun,Jinming Zhang,Chuanbiao Wen,Shichao Zheng
As a subclass of the biopharmaceutical classification system (BCS) class II, basic drugs (BCS IIB) exhibit pH-dependent solubility and tend to generate supersaturation in the gastrointestinal tract, leading to less qualified in vitro–in vivo correlation (IVIVC). This study aims to develop a physiologically based multi-cup dissolution approach to improve the evaluation of the supersaturation for a higher quality of IVIVC and preliminarily explores the molecular mechanism of supersaturation and precipitation of ketoconazole affected by Polyvinylpyrrolidone–vinyl acetate copolymer (PVPVA) and hydroxypropyl methyl-cellulose (HPMC). The concentration of ketoconazole in each cup of the dynamic gastrointestinal model (DGIM) was measured using fiber optical probes. Molecular interactions between ketoconazole and PVPVA or HPMC were simulated by Materials Studio. The results demonstrated that PVPVA and HPMC improved and maintained the supersaturation of ketoconazole. PVPVA exhibited superior precipitation inhibitory effect on ketoconazole molecule aggregation due to slightly stronger van der Waals forces as well as unique electrostatic forces, thereby further enhancing in vitro drug absorption, which correlated well with in vivo drug absorption. Compared with a conventional dissolution apparatus paddle method, the DGIM improved the mean prediction error through the IVIVC from 19.30% to 9.96%, reaching the qualification criteria. In conclusion, the physiologically based multi-cup dissolution approach enables improved evaluation of supersaturation in gastrointestinal transportation of BCS IIB drug ketoconazole, enabling screening screen precipitation inhibitors and achieving qualified IVIVC for drug formulation studies.Keywords:supersaturation;precipitation inhibitor;dissolution model;molecular dynamics;in vitro–in vivo correlation
研究领域:
药剂学
·
药物递送系统
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分子模拟
·
生物药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Su-Su Meng,Yue-Ming Yu,Fan-Zhi Bu,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL’s biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA–]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA–] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.
研究领域:
药剂学
·
药物化学
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药物递送
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生物药剂学
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材料科学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 20
·15444
·
IF 5.6
Monika Michalak
Natural ingredients have been used for centuries for skin treatment and care. Interest in the health effects of plants has recently increased due to their safety and applicability in the formulation of pharmaceuticals and cosmetics. Long-known plant materials as well as newly discovered ones are increasingly being used in natural products of plant origin. This review highlights the beneficial effects of plants and plant constituents on the skin, including moisturizing (e.g.,Cannabis sativa,Hydrangea serrata,Pradosia mutisiiandCarthamus tinctorius), anti-aging (e.g.,Aegopodium podagraria,Euphorbia characias,Premna odorataandWarburgia salutaris), antimicrobial (e.g.,Betula pendulaandEpilobium angustifolium), antioxidant (e.g.,Kadsura coccinea,Rosmarinus officinalis,Rubus idaeusandSpatholobus suberectus), anti-inflammatory (e.g.,Antidesma thwaitesianum,Helianthus annuus,Oenanthe javanica,Penthorum chinense,Ranunculus bulumeiandZanthoxylum bungeanum), regenerative (e.g.,Aloe vera,Angelica polymorpha,Digitaria ciliaris,Glycyrrihza glabraandMarantodes pumilum), wound healing (e.g.,Agrimonia eupatoria,Astragalus floccosus,Bursera morelensis,Jatropha neopaucifloraandSapindus mukorossi), photoprotective (e.g.,Astragalus gombiformis,Calea fruticose,Euphorbia characiasandPosoqueria latifolia) and anti-tyrosinase activity (e.g.,Aerva lanata,Bruguiera gymnorhiza,Dodonaea viscosa,Lonicera japonicaandSchisandra chinensis), as well as their role as excipients in cosmetics (coloring (e.g.,Beta vulgaris,Centaurea cyanus,Hibiscus sabdariffaandRubia tinctiorum), protective and aromatic agents (e.g.,Hyssopus officinalis,Melaleuca alternifolia,Pelargonium graveolensandVerbena officinalis)).Keywords:plants;skin;photoprotection;wound healing;anti-aging;anti-tyrosinase;essential oils;colorants;cosmetics;pharmaceutics
研究领域:
植物学
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药理学
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化妆品科学
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皮肤病学
✓ 已验证
DOI
PubMed
高影响因子
AAPS PHARMSCITECH
·
2025
·Vol. 26
·期 7
·1-17
·
IF 4
Tan Lihua,Jing Zhongli,Li Na,Yu Xuan,Liu Yi,Wang Meng,Ren Xiaoliang
This study introduced a novel vectorized Biopharmaceutics Classification System (BCS) model designed to evaluate the biopharmaceutical properties of active pharmaceutical ingredients (APIs) and their variations under different influencing factors. The model was validated using water-soluble supramolecular p -Sulfonatocalix[n]arenes (SCnA, n = 6, 8), promising pharmaceutical adjuvants, to enhance the solubility and bioavailability of a series of APIs in vitro . The binding interactions of SCnA with 22 alkaloids were assessed for their impact on solubility and permeability using the classical shake-flask method and the parallel artificial membrane permeability assay (PAMPA). To quantify the effects, the change in directional cosine (θ) for each API was calculated by measuring the ratio of the differences in x- and y-coordinates before and after binding. The linear distance and modulus length (r) changes for each API were determined using the Pythagorean theorem, enabling a quantitative assessment of the modifications in solubility and permeability. The potential changes in oral bioavailability pre- and post-binding were visualized using heat maps based on θ and r, highlighting significant improvements in the solubility of compounds such as allicin, tetrandrine, lycorisine, and others. These changes corresponded with shifts in BCS classification, indicating a positive relationship between SCnA concentration, cavity size, and enhanced solubility. The study also evaluated the influence of pH, and concentrations of host and guest, to assess the tolerance of SCnA for further pharmaceutical applications. Based on prior safety assessments, SCnA ( n = 6, 8) demonstrated significant potential as solubilizing excipients. The vectorized BCS model enabled precise, quantitative analysis of biopharmaceutical property variations without added experimental complexity, offering a tool for high-throughput screening of excipients in pharmaceutical formulation and processing. Graphical
研究领域:
药剂学
·
药物递送
·
生物药剂学
·
超分子化学
·
药用辅料
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体外研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Jingyi Ye,Huiyi Wu,Chuanli Huang,Wanting Lin,Caifeng Zhang,Bei Huang,Banyi Lu,Hongyu Xu,Xiaoling Li,Xiaoying Long
Purpose The objective of this study was to compare the in vitro Fick’s first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption.Methods The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC).Results In the cell model, the solubility of GRI, PHE, IND, and KET increased 6–8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15–21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (Fr).Conclusion The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.
研究领域:
药理学
·
药物递送系统
·
生物药剂学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2025
·
IF 4.3
Fulin Bi,Yan Lin,Baohong Zhang,Zishan Chen,Jixia Li,Tong Yuan,Jin Yang
Prodrugs with enzymatic activation requirements, such as the weakly basic biopharmaceutical classification system (BCS) class IV compound abiraterone acetate (ABA), face considerable bioequivalence (BE) risks owing to their pH-dependent solubility, food effects, and variable intestinal hydrolysis. This study established clinically relevant dissolution specifications for ABA using biorelevant dissolution and physiologically based biopharmaceutics modelling (PBBM). Two dissolution methods, two-stage (gastrointestinal transfer simulation) and single-phase (biorelevant media), were evaluated under fasted and fed conditions. Clinical BE studies revealed non-BE for formulation A (fasted, N = 39) but compliance for formulation B (fasted/fed, N = 40). Two-stage dissolution highlighted supersaturation dynamics, with fed-state media (FeSSIF-V2) enhancing solubility by >10-fold compared to fasted conditions. Although this method is biopredictive, its complexity limits its practicality. Single-phase dissolution using biorelevant media balances discriminative power and operational feasibility for quality control. Permeability studies identified the active metabolite abiraterone as the absorption driver (apparent permeability coefficient: 1.55 × 10 −5 vs. 8.91 × 10 − ⁶ cm/s for ABA). PBBM integrating hydrolysis kinetics, food effects, and first-pass metabolism predicted clinical pharmacokinetics with a prediction error of <20 %. Virtual BE trials defined a dissolution “safe space” for bioequivalence under both fasted/fed states. This study demonstrates that combining biorelevant dissolution with mechanistic modelling mitigates BE risks for high-variability prodrugs. This single-phase approach offers a scalable and physiologically aligned strategy for guiding the generic development of complex formulations with food-dependent absorption variability.
研究领域:
药剂学
·
生物药剂学
·
药代动力学
·
药物研发
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计算建模
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溶出度测试
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY
·
2025
·
IF 1.9
Hui Wang,Rui He,Kuan Chang,Jing Xie,Jinhua Li,Guangli Wang,Xiaodong Yan,Jing Wang
Mannose erythritol lipid (MEL-B) lamellar vesicles are promising biocompatible carriers for skincare, but their tendency to form unstable, micron-sized vesicles when used alone limits their application. Herein, we introduce the Gemini surfactant sodium dilauramidoglutamide lysine (DLGL) to overcome this limitation. Highly stable MEL-B-based unilamellar nanovesicles (< 100 nm) are formulated with DLGL. At an optimal DLGL/MEL-B ratio of 0.2, the binary vesicles exhibit excellent stability, showing negligible size variation (< 3 nm) across different storage temperatures and maintaining a zeta potential absolute value consistently above 30 mV. These vesicles significantly enhance the skin permeation of hydrophilic Dendrobium officinale oligosaccharides (DOOS), achieving twice the cumulative permeation compared to the pure DOOS solution at 8 h. Moreover, the formation of ternary vesicles by incorporating lecithin further enhance transdermal delivery.
研究领域:
药剂学
·
透皮药物递送
·
胶体与界面科学
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化妆品科学
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Taotao Li,Mingzhen Cai,Qianqian Qiao,Wenjie Shi,Xin Guo,Shaoqun Tang,Xulin Jiang
Postoperative pain is a major clinic challenge and local anesthetics are preferred for use in postoperative pain management, but their short duration of analgesia limits their clinical use. Various drug carriers such as liposomes or nano/microparticles have been developed for prolonging the analgesic duration, yet how to achieve effective drug loading without using organic solvents and sustained-release local anesthetics remains a big challenge. Herein, we synthesized a pH-sensitive and biodegradable polymer to efficiently load ropivacaine (Rop-micelles) by pH-induced micellization method without using any organic solvent, avoiding the aggregation and precipitation of Rop under neutral conditions within 7 days. Subsequently, an injectable dispersion of Rop-micelles in hydroxypropyl chitin (Rop-micelles@HPCH) was developed for long-term local anesthesia. This system was prepared via a simple and solvent-free process that combined pH-sensitive micelles with thermosensitive HPCH, demonstrating proven biocompatibility and biodegradability. Importantly, the obtained Rop-micelles@HPCH composite hydrogel exhibited a much more sustained Rop release than that of drug loaded in micelles or hydrogel alone in vitro. The effective analgesic time of Rop-micelles@HPCH (20.3 h) or Rop-micelles@HPCH-Dex with only a small fraction (
研究领域:
药剂学
·
药物递送
·
生物材料
·
麻醉学
·
高分子科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）