Jing-Jing Xiang, Bi-Bo Jiang, Wen-Qing Sun, Fu-Li Zhang, Jun Yu
2-Thioadenosine monohydrate (1) is a vital intermediate in the synthesis of cangrelor. However, its industrial-scale preparation process and the analysis of the impurities formed during this process remained largely unknown. Herein, cangrelor was synthesized from oxidate adenosine, and the key step involved in the synthesis of compound 1 from intermediate 5. The effects of key synthesis parameters that influenced the reaction, including reaction temperature and time, were discussed. Moreover, four process-related impurities were purified, synthesized, and identified via nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The process can be utilized to produce 1 on a kilogram scale, with a high-performance liquid chromatography purity of 98.0%. The study sheds light on and helps drug manufacturers further understand the formation process of impurities in the preparation of cangrelor.
{"title":"Synthesis and Impurity Research of 2-Thioadenosine Monohydrate","authors":"Jing-Jing Xiang, Bi-Bo Jiang, Wen-Qing Sun, Fu-Li Zhang, Jun Yu","doi":"10.1055/s-0043-1768692","DOIUrl":"https://doi.org/10.1055/s-0043-1768692","url":null,"abstract":"2-Thioadenosine monohydrate (1) is a vital intermediate in the synthesis of cangrelor. However, its industrial-scale preparation process and the analysis of the impurities formed during this process remained largely unknown. Herein, cangrelor was synthesized from oxidate adenosine, and the key step involved in the synthesis of compound 1 from intermediate 5. The effects of key synthesis parameters that influenced the reaction, including reaction temperature and time, were discussed. Moreover, four process-related impurities were purified, synthesized, and identified via nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The process can be utilized to produce 1 on a kilogram scale, with a high-performance liquid chromatography purity of 98.0%. The study sheds light on and helps drug manufacturers further understand the formation process of impurities in the preparation of cangrelor.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"76 1","pages":"e84 - e90"},"PeriodicalIF":0.0,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90837350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhiteng Du, Zeng Zhao, Qingyan Sun, Wei-Dong Zhang
From the roots of Campylotropis hirtella (Franch.) Schindl., many natural dihydroflavonol compounds have been extracted, and they possess a structurally novel feature of chiral tertiary alcohol groups. However, the content of the compounds in the plant is extremely low. At this point, to satisfy the needs of further experimental research on these compounds, much effort has been invested in the chemical synthesis of the core structure of 3-hydroxy-3-phenylchroman-4-one. This study aimed to explore a novel method for the synthesis of dihydroflavonol (3), and its application in the production of a natural product (14). The method started with commercially available materials, and provided a foundation for total synthesis of natural compounds of dihydroflavonol.
{"title":"Study on the Synthesis of Dihydroflavonol Compounds","authors":"Zhiteng Du, Zeng Zhao, Qingyan Sun, Wei-Dong Zhang","doi":"10.1055/s-0043-1764226","DOIUrl":"https://doi.org/10.1055/s-0043-1764226","url":null,"abstract":"From the roots of Campylotropis hirtella (Franch.) Schindl., many natural dihydroflavonol compounds have been extracted, and they possess a structurally novel feature of chiral tertiary alcohol groups. However, the content of the compounds in the plant is extremely low. At this point, to satisfy the needs of further experimental research on these compounds, much effort has been invested in the chemical synthesis of the core structure of 3-hydroxy-3-phenylchroman-4-one. This study aimed to explore a novel method for the synthesis of dihydroflavonol (3), and its application in the production of a natural product (14). The method started with commercially available materials, and provided a foundation for total synthesis of natural compounds of dihydroflavonol.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"12 1","pages":"e25 - e30"},"PeriodicalIF":0.0,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77732041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The extract of Gnaphalium affine has been reported to have antihyperuricemic and renal protective effects in vivo. The plant could alleviate acute hyperuricemia by inhibiting the activity of xanthine oxidase (XOD). 3,4,5-Tri-O-caffeoylquinic acid (3,4,5-triCQA), 4,4',6'-trihydroxy-2'-methoxychalcone (Chal), and caffeic acid (CA) were identified as the main ingredients of the plant attributed to the potential to retard XOD activity. However, whether the compounds were the effective ingredient of the plant exerting antihyperuricemic activity remained largely unknown. In this study, an experimental mouse model of hyperuricemia was induced by potassium oxonate and hypoxanthine, and orally administered with 3,4,5-triCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d) for 6 consecutive days, respectively. Then, serum urate levels and liver XOD activities were assessed. The liver- or kidney-to body weight ratio was calculated. Allopurinol (AP, 50 mg/kg/d) and benzbromarone (BBR, 10 mg/kg/d) were used as controls. Our data showed that there were 52.7 to 81.0% inhibitions in XOD activities in mice treated with 3,4,5-TriCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (80 mg/kg/d), and 38.8 to 72.5% reduction in uric acid levels in mice treated with 3,4,5-TriCQA (20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d). A larger kidney-to-body weight ratio was observed in hyperuricemic mice and further enhanced by AP treatment. However, the increasing trend was significantly reversed by additional treatment of 3,4,5-triCQA (10 and 20 mg/kg/d) and CA (40 mg/kg/d). Given the above fundings, 3,4,5-triCQA, Chal, and CA may be the key component responsible for the in vivo activities of G. affine for urate-lowering therapy and even promising agents for the treatment of hyperuricemia.
{"title":"In Vivo Antihyperuricemic Activities of 3,4,5-Tri- O -caffeoylquinic acid, 4,4',6'-Trihydroxy-2'-Methoxychalcone, and Caffeic Acid from the Aerial Parts of Gnaphalium Affine","authors":"An Jia, Fei Liu, Si-yang Fan","doi":"10.1055/s-0043-1768691","DOIUrl":"https://doi.org/10.1055/s-0043-1768691","url":null,"abstract":"The extract of Gnaphalium affine has been reported to have antihyperuricemic and renal protective effects in vivo. The plant could alleviate acute hyperuricemia by inhibiting the activity of xanthine oxidase (XOD). 3,4,5-Tri-O-caffeoylquinic acid (3,4,5-triCQA), 4,4',6'-trihydroxy-2'-methoxychalcone (Chal), and caffeic acid (CA) were identified as the main ingredients of the plant attributed to the potential to retard XOD activity. However, whether the compounds were the effective ingredient of the plant exerting antihyperuricemic activity remained largely unknown. In this study, an experimental mouse model of hyperuricemia was induced by potassium oxonate and hypoxanthine, and orally administered with 3,4,5-triCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d) for 6 consecutive days, respectively. Then, serum urate levels and liver XOD activities were assessed. The liver- or kidney-to body weight ratio was calculated. Allopurinol (AP, 50 mg/kg/d) and benzbromarone (BBR, 10 mg/kg/d) were used as controls. Our data showed that there were 52.7 to 81.0% inhibitions in XOD activities in mice treated with 3,4,5-TriCQA (10 and 20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (80 mg/kg/d), and 38.8 to 72.5% reduction in uric acid levels in mice treated with 3,4,5-TriCQA (20 mg/kg/d), Chal (20 and 40 mg/kg/d), and CA (40 and 80 mg/kg/d). A larger kidney-to-body weight ratio was observed in hyperuricemic mice and further enhanced by AP treatment. However, the increasing trend was significantly reversed by additional treatment of 3,4,5-triCQA (10 and 20 mg/kg/d) and CA (40 mg/kg/d). Given the above fundings, 3,4,5-triCQA, Chal, and CA may be the key component responsible for the in vivo activities of G. affine for urate-lowering therapy and even promising agents for the treatment of hyperuricemia.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"26 1","pages":"e77 - e83"},"PeriodicalIF":0.0,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77445735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Tulobuterol is a selective β2-adrenoceptor agonist and has been widely utilized as a therapeutic agent for the treatment of asthma. Synthesis of tulobuterol has achieved many important progresses over the past decades and has gradually become one of the research hotspots in organic chemistry. This study aimed to explore a novel synthesis route to synthesize tulobuterol hydrochloride ( 1 ), an active ingredient of Chlobamolie Hydrochloride Tablets. In the study, 1 was obtained from the cost-effective, commercially available 2-chloroacetophenone through the key steps including the reactions of bromination, NaBH 4 reduction, and amination. Process-related impurities were also investigated. 1 was obtained with excellent purity (99.96%) in 53% overall yield without the need for chromatographic purification. The developed method is green, facile, and cost-effective; thus, it is suitable for the industrial-scale production of 1 .
{"title":"Development of a New Process for Tulobuterol Hydrochloride","authors":"Chuanjun Wu, Peng Peng, Lin-Tao Xia, X. Liu, Caiyun Yu, Zhibo Zheng, Chuanmeng Zhao, Fu-Li Zhang","doi":"10.1055/s-0043-1764464","DOIUrl":"https://doi.org/10.1055/s-0043-1764464","url":null,"abstract":"Abstract Tulobuterol is a selective β2-adrenoceptor agonist and has been widely utilized as a therapeutic agent for the treatment of asthma. Synthesis of tulobuterol has achieved many important progresses over the past decades and has gradually become one of the research hotspots in organic chemistry. This study aimed to explore a novel synthesis route to synthesize tulobuterol hydrochloride ( 1 ), an active ingredient of Chlobamolie Hydrochloride Tablets. In the study, 1 was obtained from the cost-effective, commercially available 2-chloroacetophenone through the key steps including the reactions of bromination, NaBH 4 reduction, and amination. Process-related impurities were also investigated. 1 was obtained with excellent purity (99.96%) in 53% overall yield without the need for chromatographic purification. The developed method is green, facile, and cost-effective; thus, it is suitable for the industrial-scale production of 1 .","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"21 1","pages":"e31 - e37"},"PeriodicalIF":0.0,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82743706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract The mometasone furoate (MF) and formoterol fumarate dihydrate (FF) inhalable microparticles prepared by different methods, such as micronized active pharmaceutical ingredients (APIs), microparticles of APIs prepared by spray-freeze drying technique (SFD APIs), and phospholipid microparticles of APIs prepared by SFD (SFD Lip-APIs), showed different inhaled drug delivery characteristics. Study on the physicochemical characteristics of those microparticles and the effect of matrix excipients on pharmacokinetic ( PK ) behaviors of inhalable microparticles is helpful for the development of new methods for inhalable microparticles with excellent performance of inhalation characteristics. In this study, the crystal state of the microparticles was investigated by powder X-ray diffraction and differential scanning calorimetry. The density was investigated by a bulk density method. The suspension and dispersion characteristics were determined by observing its state in hydrofluoroalkane (HFA). Meanwhile, the PK behaviors of SFD Lip-APIs in beagle dogs were also investigated by airway administration to evaluate the effect of phospholipids on drug release. The results indicated that the presence of phospholipids prevents the formation of solid bridges bonding to each other during SFD of pure drug solutions. In comparison to the conventional micronized microparticles, inhalable drug–phospholipid microparticles were easily dispersed and suspended in HFA. The embedded drugs were in a crystal state that endowed a better physical stability, and most interestingly, have similar PK behavior to the control (a mixed solution of MF/FF), suggesting that the phospholipids, as matrix excipients, had no effect on absorption. Given above, our designed SFD phospholipid microparticles may represent an efficient carrier for pulmonary delivery of MF and FF for further clinical treatment.
{"title":"The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part II: In Vitro and In Vivo Evaluations","authors":"Quanxin Xi, Zhen Cao, Jianbo Miao, Hao Wang","doi":"10.1055/s-0042-1758388","DOIUrl":"https://doi.org/10.1055/s-0042-1758388","url":null,"abstract":"Abstract The mometasone furoate (MF) and formoterol fumarate dihydrate (FF) inhalable microparticles prepared by different methods, such as micronized active pharmaceutical ingredients (APIs), microparticles of APIs prepared by spray-freeze drying technique (SFD APIs), and phospholipid microparticles of APIs prepared by SFD (SFD Lip-APIs), showed different inhaled drug delivery characteristics. Study on the physicochemical characteristics of those microparticles and the effect of matrix excipients on pharmacokinetic ( PK ) behaviors of inhalable microparticles is helpful for the development of new methods for inhalable microparticles with excellent performance of inhalation characteristics. In this study, the crystal state of the microparticles was investigated by powder X-ray diffraction and differential scanning calorimetry. The density was investigated by a bulk density method. The suspension and dispersion characteristics were determined by observing its state in hydrofluoroalkane (HFA). Meanwhile, the PK behaviors of SFD Lip-APIs in beagle dogs were also investigated by airway administration to evaluate the effect of phospholipids on drug release. The results indicated that the presence of phospholipids prevents the formation of solid bridges bonding to each other during SFD of pure drug solutions. In comparison to the conventional micronized microparticles, inhalable drug–phospholipid microparticles were easily dispersed and suspended in HFA. The embedded drugs were in a crystal state that endowed a better physical stability, and most interestingly, have similar PK behavior to the control (a mixed solution of MF/FF), suggesting that the phospholipids, as matrix excipients, had no effect on absorption. Given above, our designed SFD phospholipid microparticles may represent an efficient carrier for pulmonary delivery of MF and FF for further clinical treatment.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"79 1","pages":"e275 - e283"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88154846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Starch is an important excipient employed in the pharmaceutical industry but irrespective of its source, the native starch is undesirable for many applications because of its inability to withstand processing conditions and hence needs its modification to achieve the desired properties. This study aimed to synthesize starch phosphate through the modification of starch obtained from Manihot esculentus , and then explore its potential in the preparation of cream formulations. In the present study, the starch was extracted from M. esculentus (cassava), then phosphorylated by reacting with varied concentrations of disodium hydrogen phosphate, anhydrous (Na 2 HPO 4 , 0.05, 0.1, and 0.2 mol/dm 3 ) under pH 6. A standard wet chemistry method was used for the determination of the degree of substitution by phosphate (DSp) of modified starch, and Fourier transform infrared (FTIR) spectra were used for structure identification. The starch phosphate obtained was employed to develop a cream formulation. The physicochemical properties of the formulation were further evaluated. Calamine cream BP was utilized as a control. Our result indicated that a higher concentration of Na 2 HPO 4 favors a higher DSp (0.047). FTIR spectra of the modified starch suggested a new peak at 1,090 cm −1 (P-OR). The cream formulated with a high DSp of starch phosphate demonstrated good physicochemical properties with spreadability (7.84–8.65 gcm/s), pH (6.5–7.0), viscosity (267–296 cp), extrudability (2.05–2.62%) and physical stability, and were smooth, opaque, greasy, homogeneous, and easily removed on washing with water. Statistical analysis showed that there was no significant difference between the starch phosphate-based cream and the control, but a significant difference between the starch phosphate-based cream and a native starch-based cream. Given the above, starch phosphate with a high DSp can be prepared from M. esculentus starch and utilized as a promising emulsifying agent in cream formulation due to its being more widely available, more stable, and cost-effective.
{"title":"Formulation and Evaluation of Starch Phosphate-Based Cream Derived from Manihot esculentus","authors":"M. Achor, Buhari Muntaqa Abdullahi","doi":"10.1055/s-0043-1768614","DOIUrl":"https://doi.org/10.1055/s-0043-1768614","url":null,"abstract":"Abstract Starch is an important excipient employed in the pharmaceutical industry but irrespective of its source, the native starch is undesirable for many applications because of its inability to withstand processing conditions and hence needs its modification to achieve the desired properties. This study aimed to synthesize starch phosphate through the modification of starch obtained from Manihot esculentus , and then explore its potential in the preparation of cream formulations. In the present study, the starch was extracted from M. esculentus (cassava), then phosphorylated by reacting with varied concentrations of disodium hydrogen phosphate, anhydrous (Na 2 HPO 4 , 0.05, 0.1, and 0.2 mol/dm 3 ) under pH 6. A standard wet chemistry method was used for the determination of the degree of substitution by phosphate (DSp) of modified starch, and Fourier transform infrared (FTIR) spectra were used for structure identification. The starch phosphate obtained was employed to develop a cream formulation. The physicochemical properties of the formulation were further evaluated. Calamine cream BP was utilized as a control. Our result indicated that a higher concentration of Na 2 HPO 4 favors a higher DSp (0.047). FTIR spectra of the modified starch suggested a new peak at 1,090 cm −1 (P-OR). The cream formulated with a high DSp of starch phosphate demonstrated good physicochemical properties with spreadability (7.84–8.65 gcm/s), pH (6.5–7.0), viscosity (267–296 cp), extrudability (2.05–2.62%) and physical stability, and were smooth, opaque, greasy, homogeneous, and easily removed on washing with water. Statistical analysis showed that there was no significant difference between the starch phosphate-based cream and the control, but a significant difference between the starch phosphate-based cream and a native starch-based cream. Given the above, starch phosphate with a high DSp can be prepared from M. esculentus starch and utilized as a promising emulsifying agent in cream formulation due to its being more widely available, more stable, and cost-effective.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"15 1","pages":"e109 - e116"},"PeriodicalIF":0.0,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91330762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
U. Ibiam, D. E. Uti, Chris C. Ejeogo, O. U. Orji, P. M. Aja, Ezeaani N. Nwamaka, E. Alum, C. Chukwu, C. Aloke, Kate E. Chinedum, P. Agu, V. Nwobodo
Abstract Xylopia aethiopica (XAE) is a commonly used herbal medicine and contains rich active ingredients for a variety of biological activities. The study aimed to explore the role of XAE in the management of benign prostatic hyperplasia (BPH). In the study, testosterone propionate-induced BPH in albino rats was established and treated with different concentrations of ethanol extract of XAE leaf. After treatment, the rats were sacrificed, and the body and prostate weights were recorded. The prostate-specific antigen (PSA) and acid phosphatase (ACP) levels in the blood samples were also determined. Gas chromatography-mass spectrometry was conducted to assess the active chemical compounds. Docking analysis was performed to screen chemical compounds by evaluating their binding affinity with two pro-BPH protein targets (cellular prostatic ACP and PSA). Our data showed the presence of 44 chemical compounds in XAE leaf extract. The body and prostate weights, as well as the levels of PSA and ACP, were significantly increased in BPH induction, and the changing trend was significantly reversed by additional XAE treatment. Interestingly, PSA and ACP levels in XAE-treated groups were reduced to almost the same levels as those in the healthy control. Docking analysis identified four top-posed compounds: β-amyrin, α-amyrin, α-amyrenone, and lupenone with stronger binding energies to prostatic ACP being −9.8, −8.3, −8.4, and −8.6, respectively, compared with the standard drug finasteride (−8.3). Furthermore, the two-dimensional analysis revealed strong interactions through hydrogen bonding, covalent interactions, and several van der Waal forces between the lead compounds and the target proteins. Notably, there was a recurrence interaction between similar residues Asn-1062, Lys-1250, Lys-1059, and Phe-1060 on the protein targets and the lead compounds. The study first revealed the role of XAE in BPH therapy and will help in drug design based on the lead compounds discovered in this work.
{"title":"In Vivo and in Silico Assessment of Ameliorative Effects of Xylopia aethiopica on Testosterone Propionate-Induced Benign Prostatic Hyperplasia","authors":"U. Ibiam, D. E. Uti, Chris C. Ejeogo, O. U. Orji, P. M. Aja, Ezeaani N. Nwamaka, E. Alum, C. Chukwu, C. Aloke, Kate E. Chinedum, P. Agu, V. Nwobodo","doi":"10.1055/s-0043-1768477","DOIUrl":"https://doi.org/10.1055/s-0043-1768477","url":null,"abstract":"Abstract Xylopia aethiopica (XAE) is a commonly used herbal medicine and contains rich active ingredients for a variety of biological activities. The study aimed to explore the role of XAE in the management of benign prostatic hyperplasia (BPH). In the study, testosterone propionate-induced BPH in albino rats was established and treated with different concentrations of ethanol extract of XAE leaf. After treatment, the rats were sacrificed, and the body and prostate weights were recorded. The prostate-specific antigen (PSA) and acid phosphatase (ACP) levels in the blood samples were also determined. Gas chromatography-mass spectrometry was conducted to assess the active chemical compounds. Docking analysis was performed to screen chemical compounds by evaluating their binding affinity with two pro-BPH protein targets (cellular prostatic ACP and PSA). Our data showed the presence of 44 chemical compounds in XAE leaf extract. The body and prostate weights, as well as the levels of PSA and ACP, were significantly increased in BPH induction, and the changing trend was significantly reversed by additional XAE treatment. Interestingly, PSA and ACP levels in XAE-treated groups were reduced to almost the same levels as those in the healthy control. Docking analysis identified four top-posed compounds: β-amyrin, α-amyrin, α-amyrenone, and lupenone with stronger binding energies to prostatic ACP being −9.8, −8.3, −8.4, and −8.6, respectively, compared with the standard drug finasteride (−8.3). Furthermore, the two-dimensional analysis revealed strong interactions through hydrogen bonding, covalent interactions, and several van der Waal forces between the lead compounds and the target proteins. Notably, there was a recurrence interaction between similar residues Asn-1062, Lys-1250, Lys-1059, and Phe-1060 on the protein targets and the lead compounds. The study first revealed the role of XAE in BPH therapy and will help in drug design based on the lead compounds discovered in this work.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"6 1","pages":"e64 - e76"},"PeriodicalIF":0.0,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80267483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Docetaxel (DTX) is a poorly soluble drug. The purpose of this study was to explore a DTX-loaded micelle delivery system using N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt (XMeNa) as the carrier materials. In this study, amphiphilic surfactant XMeNa was synthesized. Then, the blood biocompatibility and the value of critical micelle concentration (CMC) were assessed by a hemolysis test and pyrene-based fluorescent probe techniques, respectively. The XM-DTX micelles were prepared using the method of thin-film hydration, and characterized by dynamic light scattering and transmission electron microscopy (TEM). The entrapment efficiency (EE) and drug loading efficiency (DLE) were assessed by the ultrafiltration method. In vitro release and pharmacokinetic behaviors of XM-DTX micelles were performed in rats using Taxotere (a commercialized DTX injection) as a control. Our data confirmed the excellent blood biocompatibility of XMeNa as a carrier. XMeNa can self-assemble into micelles in aqueous media with a very low CMC (6.2 μg/mL). The average size and zeta potential of the XM-DTX micelles were 17.3 ± 0.2 nm, and −41.6 ± 0.3 mV, respectively. EE and DLE reached up to 95.3 ± 0.7% and 22.4 ± 0.2%, respectively, which may account for the high solubility of DTX in normal saline. The micelles were spherical in TEM with good dispersion and no aggregation and adhesion, and exhibited good stability after reconstitution over 8 hours. Results from in vitro release assay suggested a much slower release behavior of XM-DTX micelles in comparison to Taxotere. Additionally, XM-DTX micelles prolonged DTX retention in blood circulation, increased the area under the curve by 2.4-fold, and significantly decreased the clearance of the drug. Given above, the XM-DTX micelles could improve the solubility and the release of DTX. The amphiphilic surfactant XMeNa also exhibited great potential as a vehicle for exploring delivery of poorly water soluble drugs in the future.
{"title":"Novel Docetaxel-Loaded Micelles Based on all-trans-Retinoic Acid: Preparation and Pharmacokinetic Study in Rats","authors":"Yaning Yang, Jiaqi Cheng, Jun He, Wei-gen Lu","doi":"10.1055/s-0042-1757511","DOIUrl":"https://doi.org/10.1055/s-0042-1757511","url":null,"abstract":"Docetaxel (DTX) is a poorly soluble drug. The purpose of this study was to explore a DTX-loaded micelle delivery system using N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt (XMeNa) as the carrier materials. In this study, amphiphilic surfactant XMeNa was synthesized. Then, the blood biocompatibility and the value of critical micelle concentration (CMC) were assessed by a hemolysis test and pyrene-based fluorescent probe techniques, respectively. The XM-DTX micelles were prepared using the method of thin-film hydration, and characterized by dynamic light scattering and transmission electron microscopy (TEM). The entrapment efficiency (EE) and drug loading efficiency (DLE) were assessed by the ultrafiltration method. In vitro release and pharmacokinetic behaviors of XM-DTX micelles were performed in rats using Taxotere (a commercialized DTX injection) as a control. Our data confirmed the excellent blood biocompatibility of XMeNa as a carrier. XMeNa can self-assemble into micelles in aqueous media with a very low CMC (6.2 μg/mL). The average size and zeta potential of the XM-DTX micelles were 17.3 ± 0.2 nm, and −41.6 ± 0.3 mV, respectively. EE and DLE reached up to 95.3 ± 0.7% and 22.4 ± 0.2%, respectively, which may account for the high solubility of DTX in normal saline. The micelles were spherical in TEM with good dispersion and no aggregation and adhesion, and exhibited good stability after reconstitution over 8 hours. Results from in vitro release assay suggested a much slower release behavior of XM-DTX micelles in comparison to Taxotere. Additionally, XM-DTX micelles prolonged DTX retention in blood circulation, increased the area under the curve by 2.4-fold, and significantly decreased the clearance of the drug. Given above, the XM-DTX micelles could improve the solubility and the release of DTX. The amphiphilic surfactant XMeNa also exhibited great potential as a vehicle for exploring delivery of poorly water soluble drugs in the future.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73197964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zi-Hong Zhou, Yong-Bo Xu, Shuming Wu, Wei-Jian Ling, Lei Zhang, Zhongqing Wang
This work aimed to explore a novel protocol for selective reduction of the nitro group on the aromatic ring while remaining the ester group unaffected. In this study, NaBH4-FeCl2 was disclosed as a key reductant in the process. NaBH4-FeCl2-mediated reduction showed high chemoselectivity, gave the desired products in magnificent yield (up to 96%), and was applied to synthesize a key intermediate of vilazodone (an antidepressant drug) on a hectogram scale in a total yield of 81% (two steps). The protocol is practical, and capable of synthesis of a range of aromatic amines, especially those with ester substituted in the ring.
{"title":"Selective Nitro Reduction of Ester Substituted Nitroarenes by NaBH4-FeCl2","authors":"Zi-Hong Zhou, Yong-Bo Xu, Shuming Wu, Wei-Jian Ling, Lei Zhang, Zhongqing Wang","doi":"10.1055/s-0042-1756457","DOIUrl":"https://doi.org/10.1055/s-0042-1756457","url":null,"abstract":"This work aimed to explore a novel protocol for selective reduction of the nitro group on the aromatic ring while remaining the ester group unaffected. In this study, NaBH4-FeCl2 was disclosed as a key reductant in the process. NaBH4-FeCl2-mediated reduction showed high chemoselectivity, gave the desired products in magnificent yield (up to 96%), and was applied to synthesize a key intermediate of vilazodone (an antidepressant drug) on a hectogram scale in a total yield of 81% (two steps). The protocol is practical, and capable of synthesis of a range of aromatic amines, especially those with ester substituted in the ring.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87220182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clinically available pressurized metered-dose inhalers (pMDIs) mainly directly use micronized drugs as inhalable microparticles. Although technology for preparing pMDIs has proven to obtain clinically appropriate aerosol performance, the fine particle fraction and delivered dose content uniformity (DDCU) of pMDIs still need to be improved. DDCU problem is usually exacerbated by patients' handling errors prior to taking a dose. In this study, novel phospholipid microparticle inhalation pMDIs were prepared by a spray-freeze-drying process using mometasone furoate and formoterol fumarate dihydrate as model drugs and distearoylphosphatidylcholine as an excipient. Combined with the material composition, the atomization and freeze-drying processes were also studied. Our data showed that both atomization parameters of gas–liquid ratio and freeze-drying curve settings met the requirements of drug design. According to aerodynamic performance in vitro and DDCU evaluation, the performance of the phospholipid microparticle inhalation pMDI was better than that of the micronized drug microparticle pMDI. In conclusion, preparing pMDIs with particle engineering has the potential to ensure accuracy of quantification and to improve the efficiency of drug deposition in lungs in clinical practice.
{"title":"The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part I: Study on the Preparation Method","authors":"Quanxin Xi, Jianbo Miao, Zhen Cao, Hao Wang","doi":"10.1055/s-0042-1755455","DOIUrl":"https://doi.org/10.1055/s-0042-1755455","url":null,"abstract":"Clinically available pressurized metered-dose inhalers (pMDIs) mainly directly use micronized drugs as inhalable microparticles. Although technology for preparing pMDIs has proven to obtain clinically appropriate aerosol performance, the fine particle fraction and delivered dose content uniformity (DDCU) of pMDIs still need to be improved. DDCU problem is usually exacerbated by patients' handling errors prior to taking a dose. In this study, novel phospholipid microparticle inhalation pMDIs were prepared by a spray-freeze-drying process using mometasone furoate and formoterol fumarate dihydrate as model drugs and distearoylphosphatidylcholine as an excipient. Combined with the material composition, the atomization and freeze-drying processes were also studied. Our data showed that both atomization parameters of gas–liquid ratio and freeze-drying curve settings met the requirements of drug design. According to aerodynamic performance in vitro and DDCU evaluation, the performance of the phospholipid microparticle inhalation pMDI was better than that of the micronized drug microparticle pMDI. In conclusion, preparing pMDIs with particle engineering has the potential to ensure accuracy of quantification and to improve the efficiency of drug deposition in lungs in clinical practice.","PeriodicalId":19767,"journal":{"name":"Pharmaceutical Fronts","volume":"857 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82100631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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