The ongoing development of small molecule drugs underscores the urgent need for novel excipients to formulate poorly soluble drug candidates.Cucurbit[7]uril(CB[7])possesses high binding affinities for a variety of mol...The ongoing development of small molecule drugs underscores the urgent need for novel excipients to formulate poorly soluble drug candidates.Cucurbit[7]uril(CB[7])possesses high binding affinities for a variety of molecular vips.However,its moderate water solubility limits broader application.Here we report the synthesis of three CB[7]derivatives M1-M3 by modifying an average of 4.2,5.5,and 5.9 sulfonatopropoxy groups onto their"equator"carbons.Compared to CB[7],their water-solubility increased by at least 26.6-,23.6-,and 19.2-fold,respectively,while the maximum tolerated doses(MTD)of M1 and M2 improved by 2.5-and 2.3-fold.Phase solubility diagram studies demonstrate that M1 and M2 significantly enhance the water-solubility of eighteen poorly soluble drugs.In vivo experiments in rat complete Freund's arthritis reveal that M1 not only improves the anti-inflammatory efficacy of indomethacin by up to 52%,but also substantially reduces its side effect of gastric ulcer.展开更多
Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluate...Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. 〈br〉 An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82 ？ 10 ？ 3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 mg/（day？person）, the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 mg/mL and 180 mg/mL for propylene glycol and glycerol, respectively.展开更多
In order to retain structural and functional integrity, protein medicines are frequently stabilized with excipients in aqueous solutions. The goal of this investigation was to see how stable IL-2 is with excipients th...In order to retain structural and functional integrity, protein medicines are frequently stabilized with excipients in aqueous solutions. The goal of this investigation was to see how stable IL-2 is with excipients that are acceptable for cell therapy. We investigated the time-dependent stability of commercially available recombinant IL-2 in aqueous solutions (CTS, RPMI, PBS, and water) at different temperatures [2°C - 8°C, room temperature (20°C ± 2°C) and 37°C] in the presence of excipients (EDTA, methionine, histidine, and glycine) over a period of up to 30 days. To detect and quantify IL-2, reversed phase high performance liquid chromatography was employed. Electrophoresis on a sodium dodecyl sulfate polyacrylamide gel was used to assess conformational stability. We discovered that IL-2 stability was improved in aqueous solutions including excipients, and that it may have retained its biological activity and sterility in these conditions.展开更多
Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical f...Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.展开更多
Particle sizes play a major role to mediate charge transfer, both between identical and different material surfaces. The study probes into the probable mechanism that actuates opposite polarities between two different...Particle sizes play a major role to mediate charge transfer, both between identical and different material surfaces. The study probes into the probable mechanism that actuates opposite polarities between two different size fractions of the same material by analyzing the charge transfer patterns of two different sizes of microcrystalline cellulose(MCC). Quantum scale calculations confirmed alteration of charge transfer capacities due to variation of moisture content predicted by multiple surface and bulk analytical techniques. Discrete Element Method(DEM) based multi-scale computational models pertinent to predict charge transfer capacities were further implemented, and the results were in accordance to the experimental charge profiles.展开更多
When a protein is encapsulated into poly( DL -lactide-co-glycolide)(PLGA) microspheres by means of the double-emulsion method,the harsh microspheres formation process including ultrasonification,exposure to an organic...When a protein is encapsulated into poly( DL -lactide-co-glycolide)(PLGA) microspheres by means of the double-emulsion method,the harsh microspheres formation process including ultrasonification,exposure to an organic solvent and a polymer may cause the denaturation of the protein. In this study,we investigated the enzymatic activity change and the effect of the excipients on the stability of recombinant human Cu,Zn-superoxide dismutase(rhCu,Zn-SOD) during the emulsification. The specific activity recovery was found to be concentration dependent and the excipients involved such as PEG 600 and Tween 20,and trehalose were shown to increase the stability of rhCu,Zn-SOD. The protein structural integrity within the microspheres was analyzed by FTIR. The structure of rhCu,Zn-SOD within PLGA microspheres containing trehalose was found to be similar to that of the native solid state,whereas the protein encapsulated during the preparation in the absence of any excipient changed due to the possible hydrophobic interaction with the polymer. The results suggest that a rational stability strategy for protein to be encapsulated into microspheres should aim at different processes.展开更多
A series of sulfonatopropoxylated cucurbit[8]uril derivatives(SPECB8s)with water-solubility ranging from 344 mmol/L to 360 mmol/L have been prepared.One of the derivatives SPE_(5.5)CB8 bearing an average of 5.5 sulfon...A series of sulfonatopropoxylated cucurbit[8]uril derivatives(SPECB8s)with water-solubility ranging from 344 mmol/L to 360 mmol/L have been prepared.One of the derivatives SPE_(5.5)CB8 bearing an average of 5.5 sulfonatopropoxy side chains has been revealed to display high biocompatibility,with maximum tolerated dose being as high as 2500 mg/kg for mice.Phase solubility diagram investigations illustrate that SPE_(5.5)CB8 can solubilize eighteen poorly soluble drugs and,for fifteen of them including remdesivir,its solubilization efficiency is higher than that of Captisol,the most widely used β-cyclodextrin-derived excipient for drug formulation.Moreover,the improved solubilization for remdesivir,which is formulated by Captisol for clinical use,can lead to important increase of its antiviral activity as compared with Captisol.展开更多
Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including mo...Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including molecular-level protection, small sizes,fast kinetics of host-vip recognition, and modular construction. With the continuous advances in the medical field, personalized and precision medicine requires the development of excipients with low dosages, integrated modifying effects, universality,and controlled release. To meet these requirements, we have developed a new family of macrocyclic excipients based on calixarenes by integrating their covalent(broad chemical design space) and noncovalent(wide range of substrates) advantages.Accordingly, azocalixarenes(Azo CAs) were designed, showing high binding affinities to a broad spectrum of active pharmaceutical ingredients(APIs), selectivity to interferents, and responsiveness to hypoxic microenvironments. Due to their highly efficient and controllable recognition, Azo CAs serve as low-dose excipients for 30 APIs. Molecular encapsulation by Azo CAs results in the integrated modification of the physicochemical properties of APIs, including solubility, stability, bioavailability,and biocompatibility. Moreover, Azo CAs can be reduced by azoreductases overexpressed in hypoxic microenvironments,leading to the controlled release of APIs. Collectively, Azo CA excipients have broad application prospects for a series of diseases such as enteritis, arthritis, stroke, cancer, bacterial infection and kidney injury, with diverse therapeutic modalities,including chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, boron neutron capture therapy, radiotherapy, fluorescence imaging, and their combinations.展开更多
The management of chronic wounds remains a substantial challenge for healthcare providers. Inadequate wound care can result in serious complications, including infection, which may ultimately lead to amputation or eve...The management of chronic wounds remains a substantial challenge for healthcare providers. Inadequate wound care can result in serious complications, including infection, which may ultimately lead to amputation or even death. While traditional excipients exhibit some efficacy in promoting wound healing, they are not sufficiently effective in preventing wound infections. As an antimicrobial metal, copper has a long history in the antimicrobial field, and at the same time, wound auxiliaries with copper ions have also been used in the treatment of chronic wounds. To address the limitations of conventional wound dressings, including insufficient antimicrobial properties and limited capacity to promote wound healing, this study introduces a highly adhesive hydrogel with superior mechanical stability for non-invasive wound treatment. The hydrogel was composed of carboxymethyl chitosan, tannic acid and copper ions. The tannic acid solution was subjected to dropwise addition of CuCl2 solution to produce precipitation, and tannic acid/copper ions (TA/Cu2+) composite nanoparticles were prepared. Through topological adhesion, the CMCS with pH sensitivity has the ability to establish adhesive connections with a wide range of materials. The benefits of CMCS/TA/Cu2+ hydrogel, as a kind of wound closure and repair material, include efficient wound closure, and resistance against bacterial invasion while maintaining cleanliness. Additionally, it exhibits excellent tensile and mechanical stability that can facilitate effective closure and repair in dynamic areas like joint wounds. This promising hydrogel adhesive has demonstrated potential as a material for wound closure and restoration.展开更多
Objective: Pueraria total flavonids(PTF) can treat cardiovascular and cerebrovascular diseases, but it has poor membrane permeability and oral bioavailability. Some excipients, such as carbomer, chitosan, and hydroxyp...Objective: Pueraria total flavonids(PTF) can treat cardiovascular and cerebrovascular diseases, but it has poor membrane permeability and oral bioavailability. Some excipients, such as carbomer, chitosan, and hydroxypropyl methylcellulose, can improve the oral bioavailability. Traditional in vitro evaluation techniques, including the rat intestinal perfusion and cell line models, cannot evaluate PTF absorption and holistic transporters.Methods: This study evaluated excipients' adhesiveness and effect on PTF transport across Caco-2 cell monolayer. cDNA microarrays identified gene expression changes in Caco-2 cells exposed to PTF and PTF with excipients, and revealed the mechanism underlying the effect of excipients on PTF absorption.Results: In vitro adhesion and transport experiments across Caco-2 showed that excipients had higher adhesiveness to gastric mucosa and transport efficiency across Caco-2 cells than PTF alone. The interaction of PTF with excipients significantly changed the expression of some genes, which might influence the absorption rate of PTF.Conclusion: Different bioadhesive polymers can improve intestinal absorption of PTF, which was related to some genes affiliated to the ATP-binding cassette(ABC) and solute carrier transporter(SLC) to some extent.展开更多
CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS a...CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.展开更多
Using microcalorimetry, thermal metabolic curves of Tetrahymena thermophila BF5 （T. thermophila BFs） growth at 28℃ affected by three injectable solubilizing excipients （ISE） including tween 80, hydroxypro- pyl-β...Using microcalorimetry, thermal metabolic curves of Tetrahymena thermophila BF5 （T. thermophila BFs） growth at 28℃ affected by three injectable solubilizing excipients （ISE） including tween 80, hydroxypro- pyl-β-cyclodextrin （HP-β-CD） and poloxamer 188 were measured. Meanwhile, the toxicities of three ISE were evaluated by dynamic parameters of thermal metabolic curves. In addition, the irritative effects of the ISE on myoblast L6cells were investigated to show their cytotoxicities by biochemical method. The results indicated that the effects of the ISE on T. thermophila BF5 varied for different ISE. 5% inhibition concentration values （IC5） of the ISE were 1.33, 1.83 and 1.64 mg/mL for tween 80, HP-β-CD and poloxamer 188, respectively. By the principal component analysis （PCA）, the total quantity of heat （Q）, growth rate constant （k） and second maximum power （P2） were selected as the main characteristic parameters to present their toxicities, there were good linear relationships between Q, k, P2 and concentrations c, suggesting that the toxicities of the ISE on T. thermophila BF5 were closely linked to their concentrations. The results of creatine kinase （CK） bioassay of myoblast L6 cells indicated that the sequence of irritative effects of the ISE was HP-β-CD〈poloxamer 188〈tween 80, which added to the results ob- tained from microcalorimetry.展开更多
Levothyroxine is a drug with a narrow therapeutic index.Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability,which can result in major health problems.Howe...Levothyroxine is a drug with a narrow therapeutic index.Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability,which can result in major health problems.However,the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed.In this study,we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes.Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry(UHPLC-DIA-HRMS)was employed.UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products,but also the presence of non-expected components in the formulations.Among these,we identified compounds resulting from reactions between mannitol and other excipients,such as citric acid,stearate,and palmitate,or from reactions between an excipient and an active pharmaceutical ingredient,such as levothyroxine-lactose adduct.In addition to these compounds,undeclared phospholipids were also found in three formulations.This non-targeted approach is not common in pharmaceutical quality control analysis.Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.展开更多
Parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine ...Parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients,apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance.The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD,such as sublingual delivery and transdermal delivery.展开更多
Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.Antibodies are the leading entity in immunotherapy,while chimer...Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.Antibodies are the leading entity in immunotherapy,while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area.In order to enable antibody candidates or cells available as products,formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life,storage and handling conditions.Here we provide a concise and contemporary review of ongoing formulation strategies and excipients used in approved antibodies and cellular therapeutic products.Excipients are categorized,and their function in formulations are discussed.展开更多
The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments i...The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. The formation of drug excipient adducts was very common based on the sensitive chemical moieties in the drugs and the excipients. The formation of the impurities was not limited to drug related impurities but there were several possibilities of the drug-excipient adduct formations as well as excipient impurities reaction with Active Pharmaceutical Ingredients. Identification of drug degradation in presence of excipients/excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug formulation process, give you a smooth platform in establishing the finished product in the drug market. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes in solid, semisolid and parenteral dosage forms.展开更多
In this study, the application of sodium bentonite(SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol,...In this study, the application of sodium bentonite(SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol, diclofenac sodium and metformin HCl were tested. Each drug was mixed with SB at ratio of 50% and the mixtures were subsequently compressed.Compatibility studies were conducted using both Deferential Scanning Calorimeter(DSC)and Fourier Transform Infrared Spectroscopy(FTIR). The dissolution profile for each drug was determined in USP-buffers at different time intervals. Diclofenac sodium in pH 6.8 buffer and paracetamol in both pH 6.8 and pH 4.5 buffers showed extended release. However,metformin HCl showed immediate release at the different pH values. The study showed that using SB was possible to prepare tablets with different release profiles. However, these profiles differ depending on dissolution media and drug type.展开更多
A simple, precise, accurate and sensitive reverse phase high performance liquid chromatographic method for simultaneous estimation of lisinopril dihydrate and its degradation products occuring under different ICH pres...A simple, precise, accurate and sensitive reverse phase high performance liquid chromatographic method for simultaneous estimation of lisinopril dihydrate and its degradation products occuring under different ICH prescribed stress conditions has been modified. Drug was resolved on a C18 column, utilizing modified mobile phase of tetra butyl ammonium hydroxide solution and acetonitrile. Ultra violet detection was carried out at 210 nm. The method was modified with respect to linearity, precision, accuracy, selectivity, specificity and ruggedness. The results obtained revealed that lisinopril dihydrate was an active product slightly changed under stress conditions.展开更多
Freeze drying or lyophilization of aqueous solutions is widely used in pharmaceutical industry. The in-creased importance Of the process is gaining a worldwide interest of research. A growing body of literature has de...Freeze drying or lyophilization of aqueous solutions is widely used in pharmaceutical industry. The in-creased importance Of the process is gaining a worldwide interest of research. A growing body of literature has demonstrated that the scientific approach can result in improved product quality with minimum trial and error em-piricism. Formulation and process development need a systematical understanding of the physical chemistry of freezing and freeze drying, material science and mechanisms of heat and mass transfer. This paper presents an overview on freeze ding of aqueous solutions based on publications in the past few decades. The important issuesof the process are analyzed.展开更多
基金National Natural Science Foundation of China(Nos.21921003 and 22201293)the National Key R&D Program of China(No.2023YFC3503400)for financial support。
文摘The ongoing development of small molecule drugs underscores the urgent need for novel excipients to formulate poorly soluble drug candidates.Cucurbit[7]uril(CB[7])possesses high binding affinities for a variety of molecular vips.However,its moderate water solubility limits broader application.Here we report the synthesis of three CB[7]derivatives M1-M3 by modifying an average of 4.2,5.5,and 5.9 sulfonatopropoxy groups onto their"equator"carbons.Compared to CB[7],their water-solubility increased by at least 26.6-,23.6-,and 19.2-fold,respectively,while the maximum tolerated doses(MTD)of M1 and M2 improved by 2.5-and 2.3-fold.Phase solubility diagram studies demonstrate that M1 and M2 significantly enhance the water-solubility of eighteen poorly soluble drugs.In vivo experiments in rat complete Freund's arthritis reveal that M1 not only improves the anti-inflammatory efficacy of indomethacin by up to 52%,but also substantially reduces its side effect of gastric ulcer.
基金funded by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWTVlaanderen) to Jente Boonen (091257)the Special Research Fund (BOF) of Ghent University to Lien Taevernier (01D23812)
文摘Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. 〈br〉 An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82 ？ 10 ？ 3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 mg/（day？person）, the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 mg/mL and 180 mg/mL for propylene glycol and glycerol, respectively.
文摘In order to retain structural and functional integrity, protein medicines are frequently stabilized with excipients in aqueous solutions. The goal of this investigation was to see how stable IL-2 is with excipients that are acceptable for cell therapy. We investigated the time-dependent stability of commercially available recombinant IL-2 in aqueous solutions (CTS, RPMI, PBS, and water) at different temperatures [2°C - 8°C, room temperature (20°C ± 2°C) and 37°C] in the presence of excipients (EDTA, methionine, histidine, and glycine) over a period of up to 30 days. To detect and quantify IL-2, reversed phase high performance liquid chromatography was employed. Electrophoresis on a sodium dodecyl sulfate polyacrylamide gel was used to assess conformational stability. We discovered that IL-2 stability was improved in aqueous solutions including excipients, and that it may have retained its biological activity and sterility in these conditions.
文摘Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.
文摘Particle sizes play a major role to mediate charge transfer, both between identical and different material surfaces. The study probes into the probable mechanism that actuates opposite polarities between two different size fractions of the same material by analyzing the charge transfer patterns of two different sizes of microcrystalline cellulose(MCC). Quantum scale calculations confirmed alteration of charge transfer capacities due to variation of moisture content predicted by multiple surface and bulk analytical techniques. Discrete Element Method(DEM) based multi-scale computational models pertinent to predict charge transfer capacities were further implemented, and the results were in accordance to the experimental charge profiles.
文摘When a protein is encapsulated into poly( DL -lactide-co-glycolide)(PLGA) microspheres by means of the double-emulsion method,the harsh microspheres formation process including ultrasonification,exposure to an organic solvent and a polymer may cause the denaturation of the protein. In this study,we investigated the enzymatic activity change and the effect of the excipients on the stability of recombinant human Cu,Zn-superoxide dismutase(rhCu,Zn-SOD) during the emulsification. The specific activity recovery was found to be concentration dependent and the excipients involved such as PEG 600 and Tween 20,and trehalose were shown to increase the stability of rhCu,Zn-SOD. The protein structural integrity within the microspheres was analyzed by FTIR. The structure of rhCu,Zn-SOD within PLGA microspheres containing trehalose was found to be similar to that of the native solid state,whereas the protein encapsulated during the preparation in the absence of any excipient changed due to the possible hydrophobic interaction with the polymer. The results suggest that a rational stability strategy for protein to be encapsulated into microspheres should aim at different processes.
基金supported by the National Natural Science Foundation of China(21921003 and 22201293)National Key R&D Program of China(2023YFC3503400).
文摘A series of sulfonatopropoxylated cucurbit[8]uril derivatives(SPECB8s)with water-solubility ranging from 344 mmol/L to 360 mmol/L have been prepared.One of the derivatives SPE_(5.5)CB8 bearing an average of 5.5 sulfonatopropoxy side chains has been revealed to display high biocompatibility,with maximum tolerated dose being as high as 2500 mg/kg for mice.Phase solubility diagram investigations illustrate that SPE_(5.5)CB8 can solubilize eighteen poorly soluble drugs and,for fifteen of them including remdesivir,its solubilization efficiency is higher than that of Captisol,the most widely used β-cyclodextrin-derived excipient for drug formulation.Moreover,the improved solubilization for remdesivir,which is formulated by Captisol for clinical use,can lead to important increase of its antiviral activity as compared with Captisol.
基金supported by the National Natural Science Foundation of China (U20A20259, 22201141)the Fundamental Research Funds for the Central Universities+1 种基金the NCC Fund(NCC2020FH04)the China Postdoctoral Science Foundation(2022M711697)。
文摘Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including molecular-level protection, small sizes,fast kinetics of host-vip recognition, and modular construction. With the continuous advances in the medical field, personalized and precision medicine requires the development of excipients with low dosages, integrated modifying effects, universality,and controlled release. To meet these requirements, we have developed a new family of macrocyclic excipients based on calixarenes by integrating their covalent(broad chemical design space) and noncovalent(wide range of substrates) advantages.Accordingly, azocalixarenes(Azo CAs) were designed, showing high binding affinities to a broad spectrum of active pharmaceutical ingredients(APIs), selectivity to interferents, and responsiveness to hypoxic microenvironments. Due to their highly efficient and controllable recognition, Azo CAs serve as low-dose excipients for 30 APIs. Molecular encapsulation by Azo CAs results in the integrated modification of the physicochemical properties of APIs, including solubility, stability, bioavailability,and biocompatibility. Moreover, Azo CAs can be reduced by azoreductases overexpressed in hypoxic microenvironments,leading to the controlled release of APIs. Collectively, Azo CA excipients have broad application prospects for a series of diseases such as enteritis, arthritis, stroke, cancer, bacterial infection and kidney injury, with diverse therapeutic modalities,including chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, boron neutron capture therapy, radiotherapy, fluorescence imaging, and their combinations.
文摘The management of chronic wounds remains a substantial challenge for healthcare providers. Inadequate wound care can result in serious complications, including infection, which may ultimately lead to amputation or even death. While traditional excipients exhibit some efficacy in promoting wound healing, they are not sufficiently effective in preventing wound infections. As an antimicrobial metal, copper has a long history in the antimicrobial field, and at the same time, wound auxiliaries with copper ions have also been used in the treatment of chronic wounds. To address the limitations of conventional wound dressings, including insufficient antimicrobial properties and limited capacity to promote wound healing, this study introduces a highly adhesive hydrogel with superior mechanical stability for non-invasive wound treatment. The hydrogel was composed of carboxymethyl chitosan, tannic acid and copper ions. The tannic acid solution was subjected to dropwise addition of CuCl2 solution to produce precipitation, and tannic acid/copper ions (TA/Cu2+) composite nanoparticles were prepared. Through topological adhesion, the CMCS with pH sensitivity has the ability to establish adhesive connections with a wide range of materials. The benefits of CMCS/TA/Cu2+ hydrogel, as a kind of wound closure and repair material, include efficient wound closure, and resistance against bacterial invasion while maintaining cleanliness. Additionally, it exhibits excellent tensile and mechanical stability that can facilitate effective closure and repair in dynamic areas like joint wounds. This promising hydrogel adhesive has demonstrated potential as a material for wound closure and restoration.
基金supported by the national natural science fund projects(No.81274094)
文摘Objective: Pueraria total flavonids(PTF) can treat cardiovascular and cerebrovascular diseases, but it has poor membrane permeability and oral bioavailability. Some excipients, such as carbomer, chitosan, and hydroxypropyl methylcellulose, can improve the oral bioavailability. Traditional in vitro evaluation techniques, including the rat intestinal perfusion and cell line models, cannot evaluate PTF absorption and holistic transporters.Methods: This study evaluated excipients' adhesiveness and effect on PTF transport across Caco-2 cell monolayer. cDNA microarrays identified gene expression changes in Caco-2 cells exposed to PTF and PTF with excipients, and revealed the mechanism underlying the effect of excipients on PTF absorption.Results: In vitro adhesion and transport experiments across Caco-2 showed that excipients had higher adhesiveness to gastric mucosa and transport efficiency across Caco-2 cells than PTF alone. The interaction of PTF with excipients significantly changed the expression of some genes, which might influence the absorption rate of PTF.Conclusion: Different bioadhesive polymers can improve intestinal absorption of PTF, which was related to some genes affiliated to the ATP-binding cassette(ABC) and solute carrier transporter(SLC) to some extent.
基金MOHE (FRGS/1/2023/STG05/UITM/01/3) for funding support
文摘CRISPR-Cas system permanently deletes any harmful gene-of-interest to combat cancer growth.Chitosan(CS)is a potential cancer therapeutic that mediates via PI3K/Akt/mTOR,MAPK and NF-kβsignaling pathway modulation.CS and its covalent derivatives have been designed as nanocarrier of CRISPR-Cas9 alone(plasmid or ribonucleoprotein)or in combination with chemical drug for cancer treatment.The nanocarrier was functionalized with polyethylene glycol(PEG),targeting ligand,cell penetrating ligand and its inherent positive zeta potential to mitigate premature clearance and particulate aggregation,and promote cancer cell/nucleus targeting and permeabilization to enable CRISPR-Cas9 acting on the host DNA.Different physicochemical attributes are required for the CS-based nanocarrier to survive from the administration site,through the systemic circulation-extracellular matrix-mucus-mucosa axis,to the nucleus target.CRISPR-Cas9 delivery is met with heterogeneous uptake by the cancer cells.Choice of excipients such as targeting ligand and PEG may be inappropriate due to lacking overexpressed cancer receptor or availability of excessive metabolizing enzyme and immunoglobulin that defies the survival and action of these excipients rendering nanocarrier fails to reach the target site.Cancer omics analysis should be implied to select excipients which meet the pathophysiological needs,and chitosan nanocarrier with a“transformative physicochemical behavior”is essential to succeed CRISPR-Cas9 delivery.
基金Project supported by the Special Foundation of Research on the Traditional Chinese Medicine Vocation （No. 200708006）, the Special Major Foundation of National New Drug Innovation of China （Nos. 2009ZX09502-003, 2009ZX09308-005）, the Beijing Natural Science Foundation and the Open Research Foundation of State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Re- sources.
文摘Using microcalorimetry, thermal metabolic curves of Tetrahymena thermophila BF5 （T. thermophila BFs） growth at 28℃ affected by three injectable solubilizing excipients （ISE） including tween 80, hydroxypro- pyl-β-cyclodextrin （HP-β-CD） and poloxamer 188 were measured. Meanwhile, the toxicities of three ISE were evaluated by dynamic parameters of thermal metabolic curves. In addition, the irritative effects of the ISE on myoblast L6cells were investigated to show their cytotoxicities by biochemical method. The results indicated that the effects of the ISE on T. thermophila BF5 varied for different ISE. 5% inhibition concentration values （IC5） of the ISE were 1.33, 1.83 and 1.64 mg/mL for tween 80, HP-β-CD and poloxamer 188, respectively. By the principal component analysis （PCA）, the total quantity of heat （Q）, growth rate constant （k） and second maximum power （P2） were selected as the main characteristic parameters to present their toxicities, there were good linear relationships between Q, k, P2 and concentrations c, suggesting that the toxicities of the ISE on T. thermophila BF5 were closely linked to their concentrations. The results of creatine kinase （CK） bioassay of myoblast L6 cells indicated that the sequence of irritative effects of the ISE was HP-β-CD〈poloxamer 188〈tween 80, which added to the results ob- tained from microcalorimetry.
基金supported by the project EFSA-CDN(Project No.:CZ.02.01/0.0/0.0/16_019/0000841)co-funded by ERDF.
文摘Levothyroxine is a drug with a narrow therapeutic index.Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability,which can result in major health problems.However,the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed.In this study,we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes.Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry(UHPLC-DIA-HRMS)was employed.UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products,but also the presence of non-expected components in the formulations.Among these,we identified compounds resulting from reactions between mannitol and other excipients,such as citric acid,stearate,and palmitate,or from reactions between an excipient and an active pharmaceutical ingredient,such as levothyroxine-lactose adduct.In addition to these compounds,undeclared phospholipids were also found in three formulations.This non-targeted approach is not common in pharmaceutical quality control analysis.Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.
基金The Lundbeck Foundation for the financial support(R108-A10772)
文摘Parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients,apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance.The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD,such as sublingual delivery and transdermal delivery.
文摘Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.Antibodies are the leading entity in immunotherapy,while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area.In order to enable antibody candidates or cells available as products,formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life,storage and handling conditions.Here we provide a concise and contemporary review of ongoing formulation strategies and excipients used in approved antibodies and cellular therapeutic products.Excipients are categorized,and their function in formulations are discussed.
文摘The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. The formation of drug excipient adducts was very common based on the sensitive chemical moieties in the drugs and the excipients. The formation of the impurities was not limited to drug related impurities but there were several possibilities of the drug-excipient adduct formations as well as excipient impurities reaction with Active Pharmaceutical Ingredients. Identification of drug degradation in presence of excipients/excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug formulation process, give you a smooth platform in establishing the finished product in the drug market. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes in solid, semisolid and parenteral dosage forms.
文摘In this study, the application of sodium bentonite(SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol, diclofenac sodium and metformin HCl were tested. Each drug was mixed with SB at ratio of 50% and the mixtures were subsequently compressed.Compatibility studies were conducted using both Deferential Scanning Calorimeter(DSC)and Fourier Transform Infrared Spectroscopy(FTIR). The dissolution profile for each drug was determined in USP-buffers at different time intervals. Diclofenac sodium in pH 6.8 buffer and paracetamol in both pH 6.8 and pH 4.5 buffers showed extended release. However,metformin HCl showed immediate release at the different pH values. The study showed that using SB was possible to prepare tablets with different release profiles. However, these profiles differ depending on dissolution media and drug type.
文摘A simple, precise, accurate and sensitive reverse phase high performance liquid chromatographic method for simultaneous estimation of lisinopril dihydrate and its degradation products occuring under different ICH prescribed stress conditions has been modified. Drug was resolved on a C18 column, utilizing modified mobile phase of tetra butyl ammonium hydroxide solution and acetonitrile. Ultra violet detection was carried out at 210 nm. The method was modified with respect to linearity, precision, accuracy, selectivity, specificity and ruggedness. The results obtained revealed that lisinopril dihydrate was an active product slightly changed under stress conditions.
基金Supported by the National Natural Science Foundation of China(21076042)Research Grants Council of Hong Kong SAR (RGC 600704)
文摘Freeze drying or lyophilization of aqueous solutions is widely used in pharmaceutical industry. The in-creased importance Of the process is gaining a worldwide interest of research. A growing body of literature has demonstrated that the scientific approach can result in improved product quality with minimum trial and error em-piricism. Formulation and process development need a systematical understanding of the physical chemistry of freezing and freeze drying, material science and mechanisms of heat and mass transfer. This paper presents an overview on freeze ding of aqueous solutions based on publications in the past few decades. The important issuesof the process are analyzed.
