BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile.Erratic absorption pattern with wide fluctua...BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile.Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration(MIC)as compared to other antifungal agents.AIM To compare the oral bioavailability and bioequivalence of Fixtral SB(supra bioavailable itraconazole)with reference product R2(supra bioavailable 2×50 mg itraconazole).METHODS The study population consisted of 54 healthy volunteers,aged between 18-45 years and randomized to receive a single oral dose of either test[T;Fixtral SB(supra bioavailable itraconazole)100 mg]or reference product(R1;Sporanox 100 mg×2 capsules and R2;Lozanoc capsules 50 mg×2 capsules).Blood samples were taken pre-dose and post-dose up to 96 h.The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2.The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1.Pharmacokinetics(PK)-PD comparative analysis[area under the concentration-time curve(AUC)/minimum inhibitory concentration(MIC)>25]was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg.Adverse events(AEs)assessments were performed in each study period and post-study evaluation.RESULTS Statistical analysis of primary PK variables revealed bioequivalence,with confidence intervals being completely inside the acceptance criteria of 80%-125%.The peak concentration levels of itraconazole were achieved at 10 h(T)and 8.5 h(R2),respectively.Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL(P>0.05 and observed P=0.3196).Six AEs were observed that were mild to moderate in severity and resolved.No severe AE was reported.CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product(R2)at 100 mg dose(2 capsules of Lozanoc®50 mg)under fed conditions.Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg.Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose.Tested formulations were found to be safe and well tolerated.展开更多
Budesonide is a corticosteroid used for the treatment of asthma via various matrices and inhalation mechanisms. An unknown peak of Budesonide aqueous formulation has been investigated during stability study wherein th...Budesonide is a corticosteroid used for the treatment of asthma via various matrices and inhalation mechanisms. An unknown peak of Budesonide aqueous formulation has been investigated during stability study wherein the impurity level observed around 0.1% well below the threshold 0.5%. The approach to identify anonymous species was adopted as first to generate the impurity in sample, isolate, enrich and was subjected to LC-MS/MS and NMR for spectral studies. Based on the spectral data the anonymous species were identified as a “Lumibudesonide’’ ((5aR,5bS,5cS,6S,7aS,7bS,10aR,11aS,11bS)-6-hydroxy-7b-(2-hydroxyacetyl)-5b,7a-dimethyl-9-propyl 1,5a,5b,5c,6,7,7a,7b,10a,11,11a,11b dodecahydrocyclopenta[2'',3'']cyclopropa [1'',2'':3', 4']benzo [1',2':4,5]indeno [1,2-d][1,3]dioxol-5(2H)-one), which is observed in photolysis of Budesonide.展开更多
The spread of SARS-CoV-2 as an emerging novel coronavirus disease (COVID-19) had progressed as a worldwide pandemic since the end of 2019. COVID-19 affects firstly lungs tissues which are known for their very slow reg...The spread of SARS-CoV-2 as an emerging novel coronavirus disease (COVID-19) had progressed as a worldwide pandemic since the end of 2019. COVID-19 affects firstly lungs tissues which are known for their very slow regeneration. Afterwards, enormous cytokine stimulation occurs in the infected cells immediately after a lung infection which necessitates good management to save patients. Exosomes are extracellular vesicles of nanometric size released by reticulocytes on maturation and are known to mediate intercellular communications. The exosomal cargo serves as biomarkers in diagnosing various diseases;moreover, exosomes could be employed as nanocarriers in drug delivery systems. Exosomes look promising to combat the current pandemic since they contribute to the immune response against several viral pathogens. Many studies have proved the potential of using exosomes either as viral elements or host systems that acquire immune-stimulatory effects and could be used as a vaccine or drug delivery tool. It is essential to stop viral replication, prevent and reverse the massive storm of cytokine that worsens the infected patients’ situations for the management of COVID-19. The main benefits of exosomes could be;no cells will be introduced, no chance of mutation, lack of immunogenicity and the damaged genetic material that could negatively affect the recipient is avoided. Additionally, it was found that exosomes are static with no ability for in vivo reproduction. The current review article discusses the possibilities of using exosomes for detecting novel coronavirus and summarizes state of the art concerning the clinical trials initiated for examining the use of COVID-19 specific T cells derived exosomes and mesenchymal stem cells derived exosomes in managing COVID-19.展开更多
Arformoterol (R, R) is an enantiomer of racemic formoterol, was the first long-acting beta agonist (LABA), approved by U.S. food and Drug Administration (FDA). The Arformoterol which is used for the treatment of Chron...Arformoterol (R, R) is an enantiomer of racemic formoterol, was the first long-acting beta agonist (LABA), approved by U.S. food and Drug Administration (FDA). The Arformoterol which is used for the treatment of Chronic obstructive pulmonary disease (COPD) are inhaled bronchodilator drugs which are delivered directly to the patient’s airways through a different mechanism. The formulated drug product is kept for stability study as per ICH guideline [1] and during its stability interval analysis by HPLC (High performance liquid chromatography), an unknown peak observed at level around 0.1% which is well below the identification threshold of 0.5% but after heating it crossed the identification threshold. The approach to identify anonymous species of Arformoterol aqueous formulation was adopted as first to generate the impurity in sample, isolate, enrich and Characterize through LC-MS/MS and NMR Spectroscopy. Based on the spectral data the anonymous species was identified as an “Imine impurity”, it is secondary degradant of Amine impurity of Arformoterol formed due to reaction with leachable observed in LDPE respules.展开更多
We presented a control strategy for tablet manufacturing processes based on continuous direct compression.The work was conducted by the experts of pharmaceutical companies,machine suppliers,academia,and regulatory aut...We presented a control strategy for tablet manufacturing processes based on continuous direct compression.The work was conducted by the experts of pharmaceutical companies,machine suppliers,academia,and regulatory authority in Japan.Among different items in the process,the component ratio and blended powder content were selected as the items requiring the control method specific to continuous manufacturing different from the conventional batch manufacturing.The control and management of the Loss in Weight(LIW)feeder were deemed the most important,and the Residence Time Distribution(RTD)model were regarded effective for setting the control range and for controlling of the LIW feeder.Based on these ideas,the concept of process control using RTD was summarized.展开更多
This research work deals with formulation and evaluation of nanosized Tiagabine loaded bio-flexy films consisting of Cocos nucifera biopolymer(isolated from coconut kernels).Prepared formulations were administered thr...This research work deals with formulation and evaluation of nanosized Tiagabine loaded bio-flexy films consisting of Cocos nucifera biopolymer(isolated from coconut kernels).Prepared formulations were administered through soft palatal route for brain targeting for epilepsy treatment.Soft palate,part of oral mucosa serves as novel drug delivery platform and mucoadhesive site for systemic drug delivery.It provides sustained and controlled drug delivery system,does not interfere with patient’s regular activities like talking,eating,drinking,etc.It bypasses first-pass metabolism in the liver,reduces dose frequency and minimizes drug’s side effects.Tiagabine,anticonvulsant drug possesses t1/2:7-9 h(low);Protein binding:96%;Water solubility:22 mg/L,acts as selective gamma amino butyric acid(GABA)reuptake inhibitor.Cocos nucifera biopolymer used as bio-excipient to prepare bio-flexy films due to its biodegradability,biocompatibility,non-toxicity,non-irritantancy on soft palatal surface along with inbuilt filmability,mucoadhesive properties.Nanosized drug loaded bio-flexy films were formulated using standard solvent casting method.Bio-flexy films were prepared using varying ratios of nanosized Tiagabine:isolated Cocos nucifera biopolymer(FCT1-FCT6).These prepared formulations were compared with same ratios of nanosized Tiagabine:sodium carboxyl methyl cellulose standard polymer flexy films(FET1-FET6).The%yield of Cocos nucifera biopolymer was found to be 10.2±0.04%.Thickness of nanosized Tiagabine loaded bio-flexy films containing Cocos nucifera biopolymer(FCT1-FCT6)was ranging from 0.026±0.04 mm to 0.040±0.02 mm;Folding endurance:84-107;Surface pH:7.01±0.04 to 7.01±0.02;Weight uniformity:0.012±0.04 to 0.020±0.02;Drug content uniformity:69.5±0.35%to 72.9±0.26%;Swelling percentage:65±0.5%to 73±0.2%;Percentage moisture uptake(PTU):2.0±0.14%to 2.8±0.12%;Mucoadhesivity:20-90 min;Mucoretentivity:60-180 min.The drug release pattern for formulations FCT1-FCT6 containing Cocos nucifera biopolymer based on the T50%and T80%was found to be FCT1(1:0.5)>FCT5(1:6)>FCT3(1:3)>FCT2(1:1)>FCT4(1:5)>FCT6(1:10).Based on all above-mentioned evaluation parameters,FCT1(containing Tiagabine:Cocos nucifera biopolymer(1:0.5))bio-flexy film having R2=0.9221,Higuchi matrix as best fit model,follows anomalous transport release mechanism,T50%:38.45 h.,T80%:41.20 h.using BITS Software 1.12.Stability study revealed stable formulations.Prepared formulations were suitable for soft palatal delivery.展开更多
Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores.In this study,we demonstrate that the upregulated intestinal transporter(PCFT),whic...Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores.In this study,we demonstrate that the upregulated intestinal transporter(PCFT),which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats,mediates the uptake of the folic acid-grafted nanoparticles(FNP).Specifically,the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway,Golgi-targeting pathway and basolateral exocytosis,featuring a high oral insulin bioavailability of 14.4%in the diabetic rats.Conversely,in cells with relatively low PCFT expression,the positive surface charge contributes to the cellular uptake of FNP,and FNP are mainly degraded in the lysosomes.Overall,we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway.This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.展开更多
文摘BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile.Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration(MIC)as compared to other antifungal agents.AIM To compare the oral bioavailability and bioequivalence of Fixtral SB(supra bioavailable itraconazole)with reference product R2(supra bioavailable 2×50 mg itraconazole).METHODS The study population consisted of 54 healthy volunteers,aged between 18-45 years and randomized to receive a single oral dose of either test[T;Fixtral SB(supra bioavailable itraconazole)100 mg]or reference product(R1;Sporanox 100 mg×2 capsules and R2;Lozanoc capsules 50 mg×2 capsules).Blood samples were taken pre-dose and post-dose up to 96 h.The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2.The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1.Pharmacokinetics(PK)-PD comparative analysis[area under the concentration-time curve(AUC)/minimum inhibitory concentration(MIC)>25]was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg.Adverse events(AEs)assessments were performed in each study period and post-study evaluation.RESULTS Statistical analysis of primary PK variables revealed bioequivalence,with confidence intervals being completely inside the acceptance criteria of 80%-125%.The peak concentration levels of itraconazole were achieved at 10 h(T)and 8.5 h(R2),respectively.Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL(P>0.05 and observed P=0.3196).Six AEs were observed that were mild to moderate in severity and resolved.No severe AE was reported.CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product(R2)at 100 mg dose(2 capsules of Lozanoc®50 mg)under fed conditions.Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg.Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose.Tested formulations were found to be safe and well tolerated.
文摘Budesonide is a corticosteroid used for the treatment of asthma via various matrices and inhalation mechanisms. An unknown peak of Budesonide aqueous formulation has been investigated during stability study wherein the impurity level observed around 0.1% well below the threshold 0.5%. The approach to identify anonymous species was adopted as first to generate the impurity in sample, isolate, enrich and was subjected to LC-MS/MS and NMR for spectral studies. Based on the spectral data the anonymous species were identified as a “Lumibudesonide’’ ((5aR,5bS,5cS,6S,7aS,7bS,10aR,11aS,11bS)-6-hydroxy-7b-(2-hydroxyacetyl)-5b,7a-dimethyl-9-propyl 1,5a,5b,5c,6,7,7a,7b,10a,11,11a,11b dodecahydrocyclopenta[2'',3'']cyclopropa [1'',2'':3', 4']benzo [1',2':4,5]indeno [1,2-d][1,3]dioxol-5(2H)-one), which is observed in photolysis of Budesonide.
文摘The spread of SARS-CoV-2 as an emerging novel coronavirus disease (COVID-19) had progressed as a worldwide pandemic since the end of 2019. COVID-19 affects firstly lungs tissues which are known for their very slow regeneration. Afterwards, enormous cytokine stimulation occurs in the infected cells immediately after a lung infection which necessitates good management to save patients. Exosomes are extracellular vesicles of nanometric size released by reticulocytes on maturation and are known to mediate intercellular communications. The exosomal cargo serves as biomarkers in diagnosing various diseases;moreover, exosomes could be employed as nanocarriers in drug delivery systems. Exosomes look promising to combat the current pandemic since they contribute to the immune response against several viral pathogens. Many studies have proved the potential of using exosomes either as viral elements or host systems that acquire immune-stimulatory effects and could be used as a vaccine or drug delivery tool. It is essential to stop viral replication, prevent and reverse the massive storm of cytokine that worsens the infected patients’ situations for the management of COVID-19. The main benefits of exosomes could be;no cells will be introduced, no chance of mutation, lack of immunogenicity and the damaged genetic material that could negatively affect the recipient is avoided. Additionally, it was found that exosomes are static with no ability for in vivo reproduction. The current review article discusses the possibilities of using exosomes for detecting novel coronavirus and summarizes state of the art concerning the clinical trials initiated for examining the use of COVID-19 specific T cells derived exosomes and mesenchymal stem cells derived exosomes in managing COVID-19.
文摘Arformoterol (R, R) is an enantiomer of racemic formoterol, was the first long-acting beta agonist (LABA), approved by U.S. food and Drug Administration (FDA). The Arformoterol which is used for the treatment of Chronic obstructive pulmonary disease (COPD) are inhaled bronchodilator drugs which are delivered directly to the patient’s airways through a different mechanism. The formulated drug product is kept for stability study as per ICH guideline [1] and during its stability interval analysis by HPLC (High performance liquid chromatography), an unknown peak observed at level around 0.1% which is well below the identification threshold of 0.5% but after heating it crossed the identification threshold. The approach to identify anonymous species of Arformoterol aqueous formulation was adopted as first to generate the impurity in sample, isolate, enrich and Characterize through LC-MS/MS and NMR Spectroscopy. Based on the spectral data the anonymous species was identified as an “Imine impurity”, it is secondary degradant of Amine impurity of Arformoterol formed due to reaction with leachable observed in LDPE respules.
文摘We presented a control strategy for tablet manufacturing processes based on continuous direct compression.The work was conducted by the experts of pharmaceutical companies,machine suppliers,academia,and regulatory authority in Japan.Among different items in the process,the component ratio and blended powder content were selected as the items requiring the control method specific to continuous manufacturing different from the conventional batch manufacturing.The control and management of the Loss in Weight(LIW)feeder were deemed the most important,and the Residence Time Distribution(RTD)model were regarded effective for setting the control range and for controlling of the LIW feeder.Based on these ideas,the concept of process control using RTD was summarized.
文摘This research work deals with formulation and evaluation of nanosized Tiagabine loaded bio-flexy films consisting of Cocos nucifera biopolymer(isolated from coconut kernels).Prepared formulations were administered through soft palatal route for brain targeting for epilepsy treatment.Soft palate,part of oral mucosa serves as novel drug delivery platform and mucoadhesive site for systemic drug delivery.It provides sustained and controlled drug delivery system,does not interfere with patient’s regular activities like talking,eating,drinking,etc.It bypasses first-pass metabolism in the liver,reduces dose frequency and minimizes drug’s side effects.Tiagabine,anticonvulsant drug possesses t1/2:7-9 h(low);Protein binding:96%;Water solubility:22 mg/L,acts as selective gamma amino butyric acid(GABA)reuptake inhibitor.Cocos nucifera biopolymer used as bio-excipient to prepare bio-flexy films due to its biodegradability,biocompatibility,non-toxicity,non-irritantancy on soft palatal surface along with inbuilt filmability,mucoadhesive properties.Nanosized drug loaded bio-flexy films were formulated using standard solvent casting method.Bio-flexy films were prepared using varying ratios of nanosized Tiagabine:isolated Cocos nucifera biopolymer(FCT1-FCT6).These prepared formulations were compared with same ratios of nanosized Tiagabine:sodium carboxyl methyl cellulose standard polymer flexy films(FET1-FET6).The%yield of Cocos nucifera biopolymer was found to be 10.2±0.04%.Thickness of nanosized Tiagabine loaded bio-flexy films containing Cocos nucifera biopolymer(FCT1-FCT6)was ranging from 0.026±0.04 mm to 0.040±0.02 mm;Folding endurance:84-107;Surface pH:7.01±0.04 to 7.01±0.02;Weight uniformity:0.012±0.04 to 0.020±0.02;Drug content uniformity:69.5±0.35%to 72.9±0.26%;Swelling percentage:65±0.5%to 73±0.2%;Percentage moisture uptake(PTU):2.0±0.14%to 2.8±0.12%;Mucoadhesivity:20-90 min;Mucoretentivity:60-180 min.The drug release pattern for formulations FCT1-FCT6 containing Cocos nucifera biopolymer based on the T50%and T80%was found to be FCT1(1:0.5)>FCT5(1:6)>FCT3(1:3)>FCT2(1:1)>FCT4(1:5)>FCT6(1:10).Based on all above-mentioned evaluation parameters,FCT1(containing Tiagabine:Cocos nucifera biopolymer(1:0.5))bio-flexy film having R2=0.9221,Higuchi matrix as best fit model,follows anomalous transport release mechanism,T50%:38.45 h.,T80%:41.20 h.using BITS Software 1.12.Stability study revealed stable formulations.Prepared formulations were suitable for soft palatal delivery.
基金financial support from the National Natural Science Foundation of China(NSFC,No.81773651,82025032,and 81803445,China)NN-CAS foundation,National Key R&D Program of China(No.2020YFE0201700,China)+1 种基金Major International Joint Research Project of Chinese Academy of Sciences(No.153631KYSB20190020,China)。
文摘Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores.In this study,we demonstrate that the upregulated intestinal transporter(PCFT),which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats,mediates the uptake of the folic acid-grafted nanoparticles(FNP).Specifically,the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway,Golgi-targeting pathway and basolateral exocytosis,featuring a high oral insulin bioavailability of 14.4%in the diabetic rats.Conversely,in cells with relatively low PCFT expression,the positive surface charge contributes to the cellular uptake of FNP,and FNP are mainly degraded in the lysosomes.Overall,we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway.This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.