JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2025
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IF 4.9
Wenjing Jiang,Qiuli Wang,Xiaoyan Zhang,Husheng Yang,Xinggang Yang
Semaglutide has the advantages of high efficacy and fewer side effects in the treatment of Type 2 diabetes (T2DM). However, the marketed formulations of semaglutide have issues such as poor compliance in individuals who require repeated injections and low oral bioavailability, limiting its use. To overcome the aforementioned issues, semaglutide microspheres with single-phase zero-order release behavior were created using two methods: polymer blending and surfactant addition. Their characteristics, in vitro release, and in vivo pharmacodynamics were investigated. Two types of semaglutide microspheres show a desirable encapsulation effectiveness and smaller particle size. When compared to ordinary semaglutide microspheres (SEM-MS), due to the introduction of hydrophilic substances such as low molecular weight PLGA and Tween 20, the lag phase disappears, it exhibits zero-order release, with better in vitro release behavior. When injected subcutaneously to T2DM rats, the drug was continuously released for about a month, and the blood drug concentration fluctuated little, exhibiting good hypoglycemic and repair β cell effects. The efficacy is superior to SEM-MS and consistent with injection. The semaglutide microspheres created by two ways in this investigation can address the issues with commercial formulations while remaining safe.
研究领域:
药剂学
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糖尿病治疗
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生物医学工程
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2022
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IF 3.571
Baole Zhang,Wanglong Xu,Chuanlong Yin,Yangming Tang
Under the guideline issued by Food and Drug Administration (FDA), ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin Guidance for Industry , a synthetic Semaglutide that is intended to be a “generic” of the approved rDNA origin Semaglutide is under exploring. Thus, each peptide-related impurity that is 0.10% of the drug substance or greater need to be identified for Semaglutide covered by this guidance. Among others, characterization of the low-level D -amino acid (D form) isomeric impurities are always the most challenging ones. Reverse-phase high-performance liquid chromatography (RP-UPLC) was used to separate the impurities, followed by high resolution mass spectrometry (HRMS) to determine the molecular weight of the impurities that existed in both formulations. Following the targeted D form isomers off-line collection, the samples went through lyophilization, deuterated hydrochloric acid ( D -HCl) hydrolyzation with low level D/L form shifting suppression substrates, chiral derivatization and RP-UPLC tandem mass spectrometry analysis of different amino acids by comparing with standards. Herein, we reported an accurate, straightforward characterization method with low limit of detection for the low-level D -Ser 8 , D -His 1 and D -Asp 9 Semaglutide impurities in Semaglutide formulations. The developed UPLC tandem HRMS method entails a valuable step forward in the detection of trace levels of the D -isomers of Semaglutide and other peptide products.
研究领域:
药学
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分析化学
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Yehan Li,Fei Liu,Jiajing Che,Yu Zhang,Tian Yin,Jingxin Gou,Xing Tang,Yanjiao Wang,Haibing He
The aim of this study was to prepare sodium glycocholate liposomes (SGC-Lip) encapsulating semaglutide (Sml) to improve oral bioavailability and better exert hypoglycemic effect. In this paper, SGC-Lip was prepared by reverse-phase evaporation method with particle size around 140 nm, potential around -27 mV, rounded morphology and better stability. The hypoglycemic and intestinal uptake effects of SGC-Lip and cholesterol-containing liposomes (CH-Lip) were comparatively investigated in rats, and the oral safety of SGC-Lip was examined by cytotoxicity assay. The results indicate that SGC-Lip can achieve a hypoglycemic effect of 40% of the initial value within 12 hours, and the AAC 0-12h is approximately six times that of CH-Lip without sodium glycocholate. The results of the cytotoxicity tests indicate that SGC-Lip has good oral safety. SGC-Lip enhances the absorption of semaglutide in the small intestinal villi via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway with the highest penetration at the ileal site. In summary, the oral bioavailability of semaglutide can be improved by encapsulating semaglutide in SGC-Lip and utilizing the stabilizing and permeation-promoting effects of SGC on liposomes.
研究领域:
药剂学
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药物递送系统
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代谢病学
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ANALYTICAL BIOCHEMISTRY
·
2026
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IF 3.1
Yifan Luo,Junyan Zhang,Wenlong Chen,Hefeng Zhang,Linglong Zou
Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), is widely used in the treatment of patients with type 2 diabetes mellitus and obesity. A sensitive and reliable quantification method is essential for bioanalysis of semaglutide in clinical studies. To develop a sensitive and specific immunoassay, we have prepared a pair of highly specific anti-semaglutide monoclonal antibodies and subsequently employed them as critical reagents in the development of an electrochemiluminescence immunoassay (ECLIA) for the quantification of semaglutide levels in human serum. The assay validation data presented here demonstrate that the performance of the ECLIA method meets prespecified criteria for all validation parameters within the quantitative range of 0.5 ng/mL to 200.0 ng/mL. The intra- and inter-assay precision (%CV) are both ≤14.4%, and accuracy (%RE) ranges from −12.5% to 15.3%. No interference is found with recombinant human GLP-1 as the endogenous counterpart, confirming the assay specificity. Additional assay performance parameters, including selectivity, dilutional linearity, hook effect, and sample stability, all meet the acceptance criteria preset in accordance with international guidelines for bioanalytical method validation. The method is suitable for bioanalysis of semaglutide in human serum.
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Pharmaceutics
·
2025
·Vol. 17
·期 4
·480
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IF 5.5
Kyeong-Ju Lee,Seong-Bin Yang,Jae-Hyeon Lee,Bison Seo,Hyung-Sik Won,Jooho Park
Background: Fatty liver disease and obesity are among the most prevalent health conditions in modern society and have recently garnered significant attention. Semaglutide, a well-known anti-obesity drug, has been widely used for diabetes and obesity treatment; however, nanotherapeutics utilizing semaglutide have not yet been developed.Methods: A novel statin–lipid conjugate was synthesized using rosuvastatin and ursodeoxycholic acid, a liver-protective agent. This conjugate was then formulated with semaglutide through hydrophobic interactions to create a new nanoparticle system. The physicochemical properties of the nanoparticles were analyzed, and their therapeutic efficacy was evaluated in a high-fat diet (HFD)-induced animal model.Results: The statin–lipid conjugate was successfully synthesized, forming novel nanoparticles with semaglutide in an aqueous solution. These nanoparticles exhibited distinct properties compared to conventional semaglutide formulations. In animal experiments, the treatment group demonstrated a 30.24% reduction in body weight and a 46.80% improvement in liver function markers compared to the control group.Conclusions: This study introduces a novel semaglutide-based nanoparticle (SRLC NP) system that overcomes key limitations of conventional semaglutide therapy by providing enhanced bioavailability, extended circulation time, and improved cellular uptake. These findings highlight the potential of SRLC NPs as a clinically translatable nanotherapeutic approach for more effective, sustained, and patient-friendly obesity and fatty liver disease treatment.
研究领域:
药学
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生物医学工程
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代谢疾病研究
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2026
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IF 5
Yuhuan Zhang,Jinghan Cheng,Hanming Wang,Zhuai Zong,Wenli Zhang,Yan Shen,Yu Tian
Semaglutide (SET) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes. Although injectable formulations offer high bioavailability, they are associated with poor patient compliance. In contrast, oral tablets are more convenient but suffer from limited absorption due to SET’s hydrophilicity and enzymatic instability in the gastrointestinal tract. To address these challenges, we developed a hydrophobic ion pair (HIP) complex of SET and sodium docusate (SET-DOC), which was further incorporated into a self-emulsifying drug delivery system (SD@SEDDS) to facilitate oral delivery. The optimized SD@SEDDS produced a clear emulsion upon dilution, with a uniform particle size of 85.55 nm, high drug loading (2.64 mg/g), and excellent stability. In vitro transport studies using a Caco-2/HT-29 co-culture model demonstrated enhanced permeability and reduced P-glycoprotein-mediated efflux. In vivo studies in a type 2 diabetic rat model showed that SD@SEDDS significantly reduced blood glucose levels, improved lipid profiles, and exhibited good biocompatibility without observable toxicity. These findings suggested that the combination of HIP technology and SEDDS represented a promising strategy for enhancing the oral delivery efficiency of peptide drugs such as SET. Download: Download high-res image (123KB) Download: Download full-size image
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BIOMEDICAL CHROMATOGRAPHY
·
2026
·Vol. 40
·期 4
·e70415
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IF 1.7
Yawen Cong,Chongzhuang Tang,Zhiqiang Li,Yang Gao,Lijuan Chen,Haibo Xu,Xingxing Diao
Semaglutide, a glucagon-like peptide-1 receptor agonist, stands as a paradigm of successful peptide drug development. Although absorption, distribution, metabolism and excretion characteristics of semaglutide have been thoroughly studied in both animals and humans, a reliable in vitro screening model for evaluating metabolic behavior of semaglutide and other peptides remains an unmet need in drug development. This study established a novel ultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry method to elucidate the species-specific metabolic pathways of semaglutide. Semaglutide was incubated with liver S9 fractions from human, monkey, dog, rat, and mouse for 1 h, respectively. For the in vivo study, rats were subcutaneously injected with semaglutide (10 mg/kg) for subsequent plasma collection. Data-dependent acquisition was performed to obtain the fragment ions, enabling identification of drug-related materials. Notably, a diagnostic fragment ion at m / z 469, formed from the cleavage of side chain, facilitated metabolite screening. Consequently, a total of 31 metabolites were detected and characterized, constituting a comprehensive metabolic profile of semaglutide in liver S9 fractions and rat plasma. Major metabolic pathways involved hydrolysis of peptide backbone. Our findings provided a robust methodological framework for the screening and metabolism prediction of peptide candidates, supporting the comprehensive safety and efficacy assessment.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Han Zeng,Jiaxin Song,Yiyao Li,Chen Guo,Yu Zhang,Tian Yin,Haibing He,Jingxin Gou,Xing Tang
The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water–oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W 1 ) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = −132.20 kJ mol −1 ) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W 1 /O/W 2 ) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.
研究领域:
药剂学
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生物医学工程
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药物化学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
·
IF 3.1
Qiuxia Zhu,Yong Luo,Yuetao Wen,Ding Wang,Jing Li,Zhongcai Fan
Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.
研究领域:
心脏病学
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药理学
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分子生物学
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PROTEIN EXPRESSION AND PURIFICATION
·
2024
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IF 1.4
Dezheng Peng,Yang Li,Linlin Si,Bo Zhu,Peng Wu,Yibang Li,Dongfang Tang,Yu Liu,Yunxiao Zhang
Semaglutide is currently the most promising antidiabetic drug, especially for the treatment of type 2 diabetes mellitus, due to its excellent efficacy in glycemic control and weight loss. However, the production of semaglutide remains high cost, and high yield, low cost, and high purity still remains a challenge. Herein, we reported a convenient and high-yield strategy for the preparation of semaglutide through fragmented condensation coupling, involving solid-phase peptide synthesis of tetrapeptide and on-column refolding and on-column enzyme cleavage based inclusion body expression of Lys 26 Arg 34 GLP-1 (11–37) with fused protein tags in an X-Y-D4K-G pattern. The optimized N-terminal protein tag significantly boosts inclusion body expression level, while on-column refolding and on-column enzyme cleavage avoid precipitation, enhancing efficiency and yield together with one-step purification. The successful preparation of semaglutide is expected to achieve large-scale industrial production with low cost, high yield and high purity.
研究领域:
药学
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生物技术
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化学工程
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
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IF 8
Baisheng Sun,Lingxin Liu,He Zhang,Xiaoli Wang,Lanlan Chen,Yan Shen,Hui Liu,Hongjun Kang,Feihu Zhou
Post-traumatic septic myocardial dysfunction (PT-SIMD) is a life-threatening condition with high mortality and no specific treatment. Ferroptosis, an iron-dependent regulated cell death pathway driven by lipid peroxidation, has been implicated in septic cardiac injury, yet the endogenous mechanisms that counteract this process remain poorly understood. We aimed to identify novel cardioprotective regulators of ferroptosis in PT-SIMD using unbiased proteomics and to investigate whether the GLP-1 receptor agonist semaglutide (SEMA) confers protection through modulation of mitochondrial E3 ubiquitin ligases. In a rat model combining limb crush injury and cecal ligation and puncture (CLP), PT-SIMD was accompanied by marked myocardial ferroptosis, evidenced by elevated ACSL4, reduced GPX4/FSP1, and 4-HNE accumulation. Quantitative 4D-DIA proteomic profiling identified March5, a mitochondrial E3 ubiquitin ligase, as significantly downregulated. In primary neonatal rat ventricular myocytes, LPS exposure suppressed March5 expression in a dose- and time-dependent manner. Knockdown of March5 using siRNA exacerbated LPS-induced ferroptosis, increasing ACSL4 protein levels, labile Fe2+, and lipid peroxidation. Notably, SEMA treatment upregulated March5 expression, attenuated ACSL4 accumulation, and ameliorated ferroptotic injury. Crucially, siRNA-mediated silencing of March5 in cardiomyocytes completely abolished the anti-ferroptotic and cytoprotective effects of SEMA. Collectively, March5 functions as a critical endogenous suppressor of ferroptosis in PT-SIMD by negatively regulating ACSL4. Semaglutide exerts its cardioprotective action via March5-dependent inhibition of the ACSL4 ferroptosis axis, highlighting a promising therapeutic strategy for sepsis-associated myocardial dysfunction.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Han Zeng,Yiyao Li,Boyuan Liu,Chenxiao Chu,Yupeng Feng,Peifu Xiao,Haoyang Yuan,Xiaopeng Deng,Yu Zhang,Tian Yin,Haibing He,Jingxin Gou,Xing Tang
Nanoparticles (NPs) modified with glycocholic acid (GCA) at surfaces are considered promising tools to overcome oral drug delivery barriers. However, question on the influence of surface GCA density over delivery efficiency arises due to ligand-induced changes in surface properties of NPs. To answer this question, we engineered GCA-modified nanoparticles (GCA NPs) with different surface densities, and their surface hydrophobicity, mucus penetration, cellular uptake, apparent permeability coefficient (P app ), intracellular trafficking behavior and oral bioavailability were compared. The results turned out that GCA NPs were found with increased surface hydrophobicity, which limited their transport across mucus layer. Nanoparticles with 50 % surface GCA density (50 % GCA NPs) demonstrated optimal performance. Compared to 100 %GCA NPs, 50 %GCA NPs exhibited an 83.28 % improvement in mucosal penetration capability, while a 250.67 % increase in cellular uptake was noticed when comparing with PEG NPs. Overall, the 50 % GCA NPs significantly enhanced trans-epithelial transport across Caco-2/E-12 co-cultured monolayers, achieving a P app value of 3.30 × 10 −6 cm/s, while the P app values of 100 %GCA NPs and PEG NPs were 2.23 × 10 −6 cm/s and 1.73 × 10 −6 cm/s. In vivo studies confirmed their therapeutic potential: oral administration of semaglutide (SMG)-loaded 50 % GCA NPs increased systemic SMG bioavailability to 12.12 %, achieving sustained glycemic control in type 2 diabetic rats. The optimized formulation exhibited favorable safety profiles and prolonged pharmacological effects. This study establishes a critical equilibrium between enhanced mucosal penetration and ligand-receptor interaction, while mitigating intracellular retention issues associated with high-density GCA-functionalized nanoparticles. These findings indicate that attentions should be paid in ligand-associated surface property alterations, which could exert unexpected influence on the performance of NPs constructed for oral peptide drug delivery.
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