Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate t...Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.展开更多
The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequ...The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequivalent to that of the reference listed drug(RLD). Two commercial batches of APIs(API-1 and API-2) with the same polymorphism and one batch of home-made APIs(API-3) with super-small particle size were used in the present study.The in vitro dissolution profiles of the tested formulations were compared with the RLD in a series of dissolution media. Then, the impact of particle size on in vivo absorption was evaluated in Beagle dogs. Compared with the RLD, formulation A with larger API size showed slower dissolution in p H 6.0 and 7.4 medium, resulting bioinequivalent with the RLD. Conversely, formulation B with smaller API size demonstrated similar in vitro dissolution profiles with the RLD and thus exhibited bioequivalent in the present study. Furthermore, formulation C with super small particle size still exhibited identical oral absorption although rapid dissolution was observed in the tested condition. Herein, it indicated that 2–5 μm might be defined as the "inert size range" of glipizide for ensuring the bioequivalence with the RLD. The results in the present study might help to obtain a better understanding of the variability in raw materials for oral absorption, develop a bioequivalent product and thus post-market quality control.展开更多
The shapes of particles and their distribution in tablets, controlled by pretreatment and tableting process, determine the pharmaceutical performance of excipient like lubricant. This study aims to provide deeper insi...The shapes of particles and their distribution in tablets, controlled by pretreatment and tableting process, determine the pharmaceutical performance of excipient like lubricant. This study aims to provide deeper insights to the relationship of the morphology and spatial distribution of stearic acid(SA) with the lubrication efficiency, as well as the resulting tablet property. Unmodified SA particles as flat sheet-like particles were firstly reprocessed by emulsification in hot water to obtain the reprocessed SA particles with spherical morphology. The three-dimensional(3 D) information of SA particles in tablets was detected by a quantitative and non-invasive 3 D structure elucidation technique, namely, synchrotron radiation X-ray micro-computed tomography(SR-μCT). SA particles in glipizide tablets prepared by using unmodified SA(GUT), reprocessed SA(GRT), as well as reference listed drug(RLD) of glipizide tablets were analyzed by SR-μCT. The results showed that the reprocessed SA with better flowability contributed to similarity of breaking forces between that of GRT and RLD. SA particles in GRT were very similar to those in RLD with uniform morphology and particle size, while SA particles in GUT were not evenly distributed. These findings not only demonstrated the feasibility of SR-μCT as a new method in revealing the morphology and spatial distribution of excipient in drug delivery system, but also deepened insights of solid dosage form design into a new scale by powder engineering.展开更多
The theoretical study of chlorpropamide, tolazamide and glipizide was carried out by the </span><span style="font-family:Verdana;">Density Functional Theory </span><span style="font...The theoretical study of chlorpropamide, tolazamide and glipizide was carried out by the </span><span style="font-family:Verdana;">Density Functional Theory </span><span style="font-family:Verdana;">(DFT) at B3LYP/6-31G(d) level. This study</span></span><span style="font-family:""> </span><span style="font-family:Verdana;">made it possible to determine the global reactivity parameters in order to better understand the interactions between the molecules studied and the copper surface. Then, the determination of local reactivity indices (Fukui functions and dual descriptor) on these molecules resulted in the precision </span><span style="font-family:Verdana;">on </span><span style="font-family:Verdana;">the most probable center</span><span style="font-family:Verdana;">s </span><span style="font-family:Verdana;">of nucleophilic and electrophilic attacks within each molecule. The results obtained, show that chloropropamide, tolazamide and glipizide can be good inhibitors against copper corrosion. Thus, the mechanism of copper corrosion inhibition of these compounds in nitric acid solution has been explained </span><span style="font-family:Verdana;">by means of theoretical calculations</span><span style="font-family:Verdana;">.展开更多
<strong>Background:</strong> Diabetes mellitus (DM) is a syndrome of chronically elevated glucose level in the blood either due to insulin resistance, insulin deficiency or both. In addition, it may occur ...<strong>Background:</strong> Diabetes mellitus (DM) is a syndrome of chronically elevated glucose level in the blood either due to insulin resistance, insulin deficiency or both. In addition, it may occur due to defective metabolism of carbohydrates, fats and proteins. There are 3 main types of DM: Type 2 DM is more prevalent in adults and is typically due to relative insulin deficiency, deficiency of insulin in children leads to DM type 1;and lastly, gestational diabetes occurs during pregnancy resulting from an imbalance of placental hormones. <strong>Introduction:</strong> Insulin, Biguanides and Sulfonylureas are some of the drug classes used to treat DM. However, their use is complicated by numerous side effects, such as;hypoglycemia & weight gain from insulin and sulfonylureas;lactic acidosis, vitamin B12 deficiency and gastrointestinal upset with metformin. Route of administration and cost are also important factors to consider when prescribing. It is for this reason the quest for newer, safer and easier to administer drugs is ongoing. <strong>Methodology:</strong> Used all the articles available on anti Diabetic drugs on web especially in British Medical Journal, Elsevier, Pubmed, Google scholar and Wikipedia etc. Got a final review article to compare the older and newer anti Diabetic drugs. <strong>Results and Conclusion:</strong> Insulin is good for controlling acute hyperglycemic states in DM but it causes acute hypoglycemia and lipodystrophy. Metformin is good hypoglycemic and easily available but causes hypoglycemia, metallic taste, Lactic acidosis and B12 deficiency. Sulfonylureas are good hypoglycemic but causes severe hypoglycemia acutely and weight gain so contraindicated for obese or hypertensive patients. While newer antidiabetics such as GLP 1 agonists increases insulin secretions has very low risk of hypoglycemia, causes weight loss as compared to insulin and decreases risk of cardiovascular side effects but still can’t be used in renally impaired patients, causes pancreatitis and can not be given in gastroparesis patients, similarly a newer drug of this class known as LY2189265 has long halflife of 90 hours, better efficacy, but causes pancreatitis and increase diastolic BP in high doses, pancreatitis is not associated with lixisenatide (GLP 1 agonist), while DPP4 inhibitors which increases GLP 1 in body has less risk of hypoglycemia, GI side effects, are weight neutral can be used in CKD but causes headaches and Nasopharyngitis. Bromocriptine or pegvisomant are used in patients of growth hormones adenoma induced DM as a medical therapy but are associated with psychosis and hallucinations. Meglitinides increases insulin secretion and has minuscule risk of hypoglycemia but can not be used in CKD patients. Otelixizumab and Teplizumab decrease T cell functions and save beta cells from immune reactions used in DM 1 but cause immune suppression and is an orphan drug. Recombinant GAD used in vaccines decreased antibody mediated beta cell damage but is still under studies.展开更多
基金supported by the University of Macao Research Grants(MYRG2016-00038-ICMS-QRCM and MYRG2016-00040-ICMS-QRCM)in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao
文摘Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.
基金supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development"(No.2017ZX09101-001-005,Beijing,China)
文摘The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequivalent to that of the reference listed drug(RLD). Two commercial batches of APIs(API-1 and API-2) with the same polymorphism and one batch of home-made APIs(API-3) with super-small particle size were used in the present study.The in vitro dissolution profiles of the tested formulations were compared with the RLD in a series of dissolution media. Then, the impact of particle size on in vivo absorption was evaluated in Beagle dogs. Compared with the RLD, formulation A with larger API size showed slower dissolution in p H 6.0 and 7.4 medium, resulting bioinequivalent with the RLD. Conversely, formulation B with smaller API size demonstrated similar in vitro dissolution profiles with the RLD and thus exhibited bioequivalent in the present study. Furthermore, formulation C with super small particle size still exhibited identical oral absorption although rapid dissolution was observed in the tested condition. Herein, it indicated that 2–5 μm might be defined as the "inert size range" of glipizide for ensuring the bioequivalence with the RLD. The results in the present study might help to obtain a better understanding of the variability in raw materials for oral absorption, develop a bioequivalent product and thus post-market quality control.
基金The authors are grateful for the financial support from the National Science and Technology Major Project(2017ZX09101001-006)Thanks to the BL13W1 beamline of the SSRF for the precious beam time and help from the team.
文摘The shapes of particles and their distribution in tablets, controlled by pretreatment and tableting process, determine the pharmaceutical performance of excipient like lubricant. This study aims to provide deeper insights to the relationship of the morphology and spatial distribution of stearic acid(SA) with the lubrication efficiency, as well as the resulting tablet property. Unmodified SA particles as flat sheet-like particles were firstly reprocessed by emulsification in hot water to obtain the reprocessed SA particles with spherical morphology. The three-dimensional(3 D) information of SA particles in tablets was detected by a quantitative and non-invasive 3 D structure elucidation technique, namely, synchrotron radiation X-ray micro-computed tomography(SR-μCT). SA particles in glipizide tablets prepared by using unmodified SA(GUT), reprocessed SA(GRT), as well as reference listed drug(RLD) of glipizide tablets were analyzed by SR-μCT. The results showed that the reprocessed SA with better flowability contributed to similarity of breaking forces between that of GRT and RLD. SA particles in GRT were very similar to those in RLD with uniform morphology and particle size, while SA particles in GUT were not evenly distributed. These findings not only demonstrated the feasibility of SR-μCT as a new method in revealing the morphology and spatial distribution of excipient in drug delivery system, but also deepened insights of solid dosage form design into a new scale by powder engineering.
文摘The theoretical study of chlorpropamide, tolazamide and glipizide was carried out by the </span><span style="font-family:Verdana;">Density Functional Theory </span><span style="font-family:Verdana;">(DFT) at B3LYP/6-31G(d) level. This study</span></span><span style="font-family:""> </span><span style="font-family:Verdana;">made it possible to determine the global reactivity parameters in order to better understand the interactions between the molecules studied and the copper surface. Then, the determination of local reactivity indices (Fukui functions and dual descriptor) on these molecules resulted in the precision </span><span style="font-family:Verdana;">on </span><span style="font-family:Verdana;">the most probable center</span><span style="font-family:Verdana;">s </span><span style="font-family:Verdana;">of nucleophilic and electrophilic attacks within each molecule. The results obtained, show that chloropropamide, tolazamide and glipizide can be good inhibitors against copper corrosion. Thus, the mechanism of copper corrosion inhibition of these compounds in nitric acid solution has been explained </span><span style="font-family:Verdana;">by means of theoretical calculations</span><span style="font-family:Verdana;">.
文摘<strong>Background:</strong> Diabetes mellitus (DM) is a syndrome of chronically elevated glucose level in the blood either due to insulin resistance, insulin deficiency or both. In addition, it may occur due to defective metabolism of carbohydrates, fats and proteins. There are 3 main types of DM: Type 2 DM is more prevalent in adults and is typically due to relative insulin deficiency, deficiency of insulin in children leads to DM type 1;and lastly, gestational diabetes occurs during pregnancy resulting from an imbalance of placental hormones. <strong>Introduction:</strong> Insulin, Biguanides and Sulfonylureas are some of the drug classes used to treat DM. However, their use is complicated by numerous side effects, such as;hypoglycemia & weight gain from insulin and sulfonylureas;lactic acidosis, vitamin B12 deficiency and gastrointestinal upset with metformin. Route of administration and cost are also important factors to consider when prescribing. It is for this reason the quest for newer, safer and easier to administer drugs is ongoing. <strong>Methodology:</strong> Used all the articles available on anti Diabetic drugs on web especially in British Medical Journal, Elsevier, Pubmed, Google scholar and Wikipedia etc. Got a final review article to compare the older and newer anti Diabetic drugs. <strong>Results and Conclusion:</strong> Insulin is good for controlling acute hyperglycemic states in DM but it causes acute hypoglycemia and lipodystrophy. Metformin is good hypoglycemic and easily available but causes hypoglycemia, metallic taste, Lactic acidosis and B12 deficiency. Sulfonylureas are good hypoglycemic but causes severe hypoglycemia acutely and weight gain so contraindicated for obese or hypertensive patients. While newer antidiabetics such as GLP 1 agonists increases insulin secretions has very low risk of hypoglycemia, causes weight loss as compared to insulin and decreases risk of cardiovascular side effects but still can’t be used in renally impaired patients, causes pancreatitis and can not be given in gastroparesis patients, similarly a newer drug of this class known as LY2189265 has long halflife of 90 hours, better efficacy, but causes pancreatitis and increase diastolic BP in high doses, pancreatitis is not associated with lixisenatide (GLP 1 agonist), while DPP4 inhibitors which increases GLP 1 in body has less risk of hypoglycemia, GI side effects, are weight neutral can be used in CKD but causes headaches and Nasopharyngitis. Bromocriptine or pegvisomant are used in patients of growth hormones adenoma induced DM as a medical therapy but are associated with psychosis and hallucinations. Meglitinides increases insulin secretion and has minuscule risk of hypoglycemia but can not be used in CKD patients. Otelixizumab and Teplizumab decrease T cell functions and save beta cells from immune reactions used in DM 1 but cause immune suppression and is an orphan drug. Recombinant GAD used in vaccines decreased antibody mediated beta cell damage but is still under studies.
