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Peptide drugs exhibit an irreplaceable role in clinics due to their high specificity, efficiency and low toxicity. At present, more than 80 peptide drugs have been approved for marketing with global sales exceeding $50 billion in 2019. However, with large molecular weights, high hydrophilicity and instability in digestive tract, oral peptide drugs encounter substantial physiological barriers leading to low oral bioavailability. Therefore, peptide drugs are mostly administered by parenteral routes. Although parenteral delivery of peptide drugs achieves high bioavailability, this is associated with inconvenience and discomfort, even causing severe side effects compared with the oral route possessing a high degree of patient compliance. Therefore, numerous studies concentrate on novel strategies to improve the oral bioavailability of peptide drugs. Some delivery technologies such as Eligen™ and Axcess™ have been successfully applied to the oral dosage form of therapeutic peptides and have accelerated relevant oral formulations for Food and Drug Administration (FDA) approval and clinical treatment. In this review, we focus on the oral peptide delivery, mainly summarizing the progress of recent strategies used to overcome oral barriers and the commercialization applications of related patents, which could facilitate the research and development (R&D) of clinical applications of oral delivery techniques for peptide drugs.
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Aim To prepare evodiamine butyryl deriva-tive (EBD) and evodiamine butyryl derivative-loaded solid lipid nanoparticles (EBDLN), and study its re-lease in vitro,and to investigate its in situ gastrointesti-nal absorption. Methods EBD was prepared by a one-step synthetized method, and then EBDLN was prepared by a film dispersion method. Dynamic dialy-sis was used to evaluate drug release in vitro,and sin-gle-pass gastrointestinal perfusion was employed to study the gastrointestinal absorption of EDM,EBD and EBDLN. Results In identical release media, there were identical drug release tendencies of EBD and EB-DLN, but the release rate of EBDLN was faster than EBD. Compared with EDM and EBD, the Kavalues and Pappvalues of EBDLN in every perfusion segment increased significantly. The Kaof EBDLN in stomach, duodenum, jejunum, ileum and colon was 110.14-fold,56.70-fold,51.23-fold,45.70-fold and 127.23-fold of free EDM respectively. The Pappvalue of EB-DLN was 9.74-fold, 4.48-fold, 3.82-fold and 11.3-fold of that of free EDM. Conclusion EBDLN has sustained effect and can enhance the gastrointestinal absorption of EDM and EBD.
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Aim To prepare the novel pyridostigmine bromide nanoemusion(PPNE)and study its release in vitro, and to investigate the intestinal absorption. Methods Pyridostigmine bromide (PB)and PPNE were tested by HPLC in pH 1 .2 HCl,pH 6.8,pH 7.4,pH 7.8 PBS.Rat single pass intestinal perfusion method was employed to investigate the absorption mechanism of PB and PPNE.Results PB release rate was faster than PB in the four release media;the intes-tinal absorption rate constant(Ka )and apparent perme-ability coefficient(Papp)of PPNE were increased in the duodenum,jejunum,ileum and colon segments.PB and PPNE had significant difference in the duodenum, jejunum,ileum and colon segments by t test (P <0.05).Conclusions PPNE can improve the bioavail-ability of drugs,increase the drugs permeability,sig-nificantly improve the absorption of the drugs in the in-testinal segments. PPNE has obviously sustained effects.
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Introdução: as doenças osteometabólicas ocorrem quando a reabsorção do osso excede a formação. Os bisfosfonatos são fármacos antirreabsortivos usados no tratamento e prevenção da perda de massa óssea decorrente da osteoporose, doença de Paget e outras condições. Os bisfosfonatos são considerados tratamento de primeira escolha na prevenção da perda de massa óssea e do aumento da susceptibilidade a fraturas, associadas ao envelhecimento. Os bisfosfonatos orais são pouco absorvidos pelo trato gastrointestinal. Devido à sua alta tendência em formar complexos com o cálcio, as bulas advertem que os mesmos não devem ser ingeridos com água mineral, que pode conter altos teores de cálcio. Os bisfosfonatos orais alendronato e risedronato integram os Protocolos Clínicos e Diretrizes Terapêuticas (PCDT) do SUS. Porém, estes não mencionam a necessidade de evitar ingerir os comprimidos com água mineral. O efeito protetor dos bisfosfonatos depende do uso correto. Objetivo: conduzir uma revisão dos estudos sobre a influência da água mineral na absorção dos bisfosfonatos. Resultados e Discussão: o cálcio e os bisfosfonatos formam complexos relativamente insolúveis de alto peso molecular em pH fisiológico. Quanto maior a concen tração de cálcio da água mineral, menor a absorção desses fármacos. Os complexos formados podem ser mais citotóxicos do que as formas livres. A filtração da água pode remover em média 89% do cálcio nela presente. Conclusão: bisfosfonatos devem ser ingeridos preferencialmente com água filtrada. A ingestão com água mineral contendo altos teores de cálcio não é recomendada.
Introduction: bone diseases occur when bone resorption exceeds bone formation. Bisphosphonates are bone antiresorptive agents used in the treatment and prevention of bone loss due to osteoporosis, Paget's disease and other conditions. Bisphosphonates are used as first-line medications for the prevention of bone loss and susceptibility to fractures associated with aging. Oral bisphosphonates are only poorly absorbed from the gastrointestinal tract. Because of their high tendency to complex with calcium, the informational packages state that they should not be ingested with mineral water, which may contain high level of calcium. The oral bisphosphonates alendronate and risedronate are included in the Clinical Protocols and Therapeutic Guidelines (PCDT) of the Brazilian Health System (SUS). However, PCDT do not refer to the need to avoid the intake of tablets with mineral water. The protective effect of bisphosphonates depends on the correct use. Objective: the objective of this research was to conduct a review of the studies regarding the influence of mineral water on the absorption of bisphosphonates. Results and Discussion: calcium ions and bisphosphonates interact to form high molecular weight polynuclear and relatively insoluble complexes in the physiological pH range. The higher the calcium concentration of mineral water, the lower proportion of bisphosphonates is absorbed. The complexes may be more cytotoxic than their free forms. Filtration was found to remove 89% of calcium from the water on average. Conclusion: oral bisphosfonates must be taken with filtered water whenever possible. Mineral water containing high levels of calcium is not recommended when taking bisphosphonates.
Subject(s)
Diphosphonates , Bone Resorption , Drug Therapy , Gastrointestinal AbsorptionABSTRACT
@#To prepare tacrolimus solid dispersion to increase the solubility and bioavailability of tacrolimus. Tacrolimus solid dispersions were prepared by different water-soluble carriers, which were evaluated by in vitro drug dissolutions to select the optimal formulation. The optimal tacrolimus solid dispersion was evaluated by scanning electron microscopy(SEM), X-ray diffraction(XRD)and differential scanning calorimetry(DSC), and its gastrointestinal absorption kinetics was studied in rats. The results showed that tacrolimus solid dispersion with HPMC E3 as carrier had the fastest dissolution rate. SEM, XRD and DSC studies indicated that tacrolimus was distributed within the carrier HPMC E3 in amorphous form. Gastrointestinal absorption experiments in rats demonstrated that the optimal formulation remarkably increased oral absorption of tacrolimus. These results demonstrate that a novel tacrolimus solid dispersion with HPMC E3 as carrier may be an advantageous dosage form of tacrolimus, boosting the solubility and absorption in gastrointestinal tract.
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OBJECTIVE: To study the absorption kinetics of baicalin phospholipid complex in rats stomach and intestine. METHODS: Using rats in vivo stomach and intestinal absorption mode, the drug concentration by in situpefusion in rats were determined by HPLC to comparise the stomach, whole intestine absorption and metabolism characteristics among baicalin, baicalin phospholipid complex and physical mixture, and the sub-bowel absorption and metabolism characteristics of baicalin phospholipid complex. RESULTS: The percentage of per hour absorpion in the stomach of baicalin, baicalin phospholipid complex and physical mixture shows little difference among them. The whole intestine absorption of baicalin phospholipid complex was better than the baicalin and physical mixture, which is (2 940.87±1.45) μg,(1 373.23±3.21) μg, (992.66±3.65) μg, respectively. Baicalin phospholipid complex has extensive absorption window in the whole intestine and duodenum is the best. The absorption percentage of duodenum, jejunum, ileum and colon is 51.81%, 32.29%, 29.56%, 11.80%,respectively. CONCLUSION: Baicalin phospholipid complex can significantly enchance absorption of baicalin in rat gastrointestinal tract.
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OBJECTIVE:To establish physiological pharmacokinetic (PBPK) model of cefdinir in healthy volunteers,and to predict pharmacokinetic process of cefdinir in volunteers after oral administration. METHODS:Using“toubao dini”“cefdinir”“logP”“pKa”as keywords,related literatures about physico-chemical constants of cefdinir were retrieved from CNKI,ScienceDi-rect,PubMed and other databases;according to related guidelines and preliminary clinical trial plan of FDA,GastroPlusTM 8.6 soft-ware was used to establish PBPK model of oral administration of cefdinir;the effectiveness of the model was evaluated by multiple error. The model was used to simulate the absorption of cefdinir in the gastrointestinal tracts. The bioequivalence of test preparation and reference preparation were evaluated through single and population(n=500)simulation tests using cmax and AUC0-∞ of cefdinir reference preparation (capsule and granular formulation) as factors when release rate t85%=15 min (i.e. accumulatively released 85% within 15 min). RESULTS:The blood concentration-time curves of cefdinir predicted by PBPK model fitted well with mea-sured value(R2≥0.95);the pharmacokinetic parameters(cmax,tmax,AUC0-∞)were close to measured results,and the multiple er-rors were less than 2. After oral administration,cefdinir was mainly absorbed by the intestinal tract (45.6%),especially by seg-ment 1 of jejunum(14.8%);the absorption amount was significantly lower than the release amount of absorption site,and reached the maximal value(about 40%)within 4 h. The results of single simulation test showed that there was no statistical significance in cmax and AUC0-∞ between cefdinir test and reference preparations (P>0.05). The results of population simulation test showed that the relative bioavailability of cefdinir test particle and test capsule respectively were 99.01%-102.99% and 97.60%-105.90%;90%CI of cmax and AUC0-∞ values were within 80%-125% of reference preparation. CONCLUSIONS:The PBPK model is accurate and reliable in this study,can provide reference for pharmacokinetic study and bioequivalence evaluation of cefdinir preparations. Test preparation and reference preparation are equivalent.
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AIM To investigate the effect of DO C(deoxycholic acid) on the absorption of INS-PLA-NP[insulin-loaded poly(lactic acid) nanoparticles] in different sites of gastrointestinal tracts. METHODS After INS-PLA-NP that contained or did not contain DOC was adminitered to different sites in gastrointestianl tracts(stomach, small intestine and colon)of normal rats, the hypoglycemic effect was observed. RESULTS The hypoglycemic effect did not exist after intragastric administration of INS-PLA-NP whether or not DOC was added. The alleviatory hypoglycemic effect was evident after intraintestinal absorption of INS-PLA-NP. After DOC was added, the absorption of INS-PLA-NP was accelerated obviously and the hypoglycemic effect was strengthened significantly. Glucose levels hardly changed after INS-PLA-NP was administered to colon. With the use of DOC, a little hypoglycemic effect appeared. CONCLUSIONS The absorption of INS-PLA-NP in small intestine was accelerated and enhanced by DOC. DOC could be used as absorption enhancer of INS-NP in the future.