几种吸收促进剂和酶抑制剂对胰岛素结肠吸收的影响

以胰岛素为模型药物，分别采用体外、在体和体内的方法进行吸收促进剂或酶抑制剂的筛选。结果表明，体外试验中，同一浓度的不同吸收促进剂或酶抑制剂促进胰岛素结肠黏膜渗透的强弱顺序为：Laureth9〉Brij78〉SDC〉STGC〉STC；大鼠在体试验表明，单用胰岛素无降血糖效果，含不同吸收促进剂或酶抑制剂的胰岛素溶液降血糖效果的强弱顺序依次为：Laureth9〉SDC〉Brij78〉STC〉sTGc〉SLC〉BTC。正常大鼠灌胃给予含促进剂或抑制剂组合的胰岛素胶囊，其降血糖效果的强弱顺序为：1％Bdj78＋1％Laureth9〉1％SDC＋1％Laureth9〉1％Bdj78＋1％SDC。     

口腔粘膜内酶对胰岛素口腔吸收的影响

目的　研究口腔粘膜内酶对胰岛素口腔吸收的影响。方法　用三氯醋酸沉淀法,考察胰岛素在仓鼠口腔粘膜匀浆物中不同条件下的降解情况。在胰岛素口腔喷雾剂中加入酶抑制剂(杆菌肽、屈来赛多)和去氧胆酸钠,考察了大鼠经口腔喷入胰岛素后的血糖降低情况。结果　小肠粘膜细胞内酶活性远高于口腔粘膜细胞中的酶的活性。杆菌肽、屈来赛多和去氧胆酸钠均能抑制口腔粘膜内胰岛素的降解。在相同浓度下,去氧胆酸钠的酶抑制作用比杆菌肽弱,但比屈来赛多强。胰岛素在正常仓鼠口腔内的降解显著大于糖尿病仓鼠。胰岛素溶液中加入杆菌肽、屈来赛多及去氧胆酸钠后,给正常大鼠口腔喷雾给药,药理相对生物利用度分别有不同程度的提高。只含胰岛素的喷雾液(胰岛素空白液) ,喷雾液中加入屈来赛多(0.1% ) ,加入杆菌肽(0.5% ) ,去氧胆酸钠(1% ) ,与sc胰岛素比较药理相对生物利用度分别为2.89% ,4.84% ,7.52 %和9.60%。结论　口腔粘膜中的酶可以限制胰岛素在口腔粘膜的吸收     

口腔粘膜内酶对胰岛素口腔吸收的影响

目的：研究口腔粘膜内酶对胰岛素口腔吸收的影响。方法：采用三氯醋酸沉淀法，考察胰岛素在仓鼠口腔粘膜匀浆物中不同条件下的降解情况，在胰岛素口腔喷雾剂中加入酶抑制剂（杆菌肽，屈来赛多）和去氧胆酸钠，考察了大鼠经口腔喷入胰岛素后的血糖降低情况。结果：小肠粘膜细胞内酶活性远高于口腔粘膜细胞中的酶的活性。杆菌肽，屈来赛多和去氧胆酸钠均能抑制口腔粘膜内胰岛素的降解，在相同浓度下，去氧胆酸钠的酶抑制作用比杆菌肽弱，但比屈来赛多强，胰岛素在正常仓鼠口腔内的降解显著大于糖尿病仓鼠。胰岛素溶液中加入杆菌肽，屈来赛多及去氧胆酸钠后，给正常大鼠口腔喷雾给药，与皮下注射胰岛素比较，药理相对生物利用率分别有不同程度的提高，只含胰岛素的喷雾液（胰岛素空白液），药理相对生物利用度为2．89％，喷雾液中加入屈来赛多（0．1％），药理相对生物利用率为4．84％，加入杆菌肽（0．5％），药理相对生物利用度为6．60％，加入去氧胆酸钠（1％），药理相对生物利用度为9．60％，结论：口腔粘膜中的酶可以限制胰岛素在口腔粘膜的吸收，为了提高胰岛素口腔吸收的生物利用度，应该尽量降低口腔粘膜中的酶对胰岛素的降解。     

吸收促进剂对蚓激酶肠道吸收的影响

目的研究蚓激酶(YJM-I)和吸收促进剂合用时在大鼠肠道各段的吸收特点，寻找YJM-I经肠道吸收的最佳位置和考察吸收促进剂对YJM-I在肠道吸收过程中的影响。方法采用体外扩散池法、十二指肠部位直接给药、在体循环灌流及肠段原位结扎等方法对荧光标记的FITC-YJM-I在大鼠肠道的吸收情况进行了研究。结果十二指肠部位给药后的药代动力学和药效学评价结果显示YJM-I药物分子可被大鼠肠道吸收进入血液循环并保持生物学活性，但其绝对生物利用度较低。体外肠黏膜通透性试验及体内肠段吸收试验结果显示部分吸收促进剂表现出良好的促进YJM-I肠道吸收的作用。十二指肠、空肠和回肠段体外肠黏膜通透性均显示了相似的吸收促进剂作用强弱趋势： 1%壳聚糖>1%去氧胆酸钠>1% Na₂EDTA>1%十二烷基硫酸钠>1%辛酸钠>1%泊洛沙姆>1%羟丙基-β-环糊精。而在体内十二指肠部位给药则显示的强弱顺序为： 2.5%去氧胆酸钠>2.5% Na₂EDTA>2.0%壳聚糖>2.5%十二烷基硫酸钠>2.5%辛酸钠>2.5%泊洛沙姆>2.5%羟丙基-β-环糊精。结论吸收促进剂能有效地增加YJM-I肠道吸收程度，其中具有生物黏附作用的壳聚糖有望成为YJM-I肠道吸收的良好促进剂。     

壳聚糖及其衍生物包覆脂质体对胰岛素肠道吸收的影响

目的考察壳聚糖及其衍生物包覆脂质体对胰岛素肠道吸收的影响。方法采用逆相蒸发制备胰岛素脂质体；采用在体肠灌流法研究壳聚糖及其衍生物包覆胰岛素脂质体的肠道吸收；用酶-苯酚法测定血糖值；用放射免疫法测定血清和肠组织中胰岛素含量。结果壳聚糖(CH)、壳聚糖-EDTA轭合物(CEC)包覆胰岛素脂质体和CH-CEC双层包覆胰岛素脂质体的最佳吸收部位均集中在十二指肠，胰岛素溶液的最佳吸收部位在结肠，而未包覆胰岛素脂质体和N-三甲基壳聚糖盐酸盐(TMC)包覆胰岛素脂质体的最佳吸收部位尚不能确定。在各肠段中，以CH-CEC双层包覆胰岛素脂质体的吸收最佳。结论壳聚糖及其衍生物包覆脂质体能促进胰岛素经肠道吸收，并可提高其在肠道中的稳定性。     

糜蛋白酶抑制剂FK-448增强胰岛素在大鼠小肠的吸收

胰岛素一直是糖尿病的治疗药,口服几乎无降血糖作用,均为注射用药,这是由于胰岛素为高分子而难于吸收,且易被蛋白分解酶分解。近年来虽报道许多非注射给药,但均未达到实用化。据报道,在小肠内投与胰岛素,分解作用主要来自糜蛋白酶。在大鼠小肠内同时投与胰岛素和糜蛋白酶抑制剂,则出现血搪下降作用。作者将     

新的糜蛋白酶抑制剂FK-448用于改进胰岛素的肠道内吸收

胰岛素在肠道内可被消化酶特别是蛋白酶所降解,因此难以采取口服途径给药。FK-448是一种强力的、具特异性的糜蛋白酶抑制剂,其化学名称为1,2,3,4-四氢-1-萘甲酸4-(4-异丙基-1-哌啶基羰基)苯酯甲烷磺酸盐。作者测定了FK-448等数种蛋白水解酶抑制剂在体外的作用强度以及在动物体内改善胰岛素肠道内吸收的作用。结果表明,FK-448在大鼠和犬体内能显著提高胰岛素的肠内吸收,从而降低血糖水平。在犬体内,血浆中免疫反应性胰岛素(IRI)水平的增高与血糖水平的降低成正比例。体外试验所得数据表明,胰酶类、肠液或肝匀浆均可使胰岛素失活,FK-448则能够抑制胰酶类特别是糜蛋白酶的这一作用,从而提高胰岛素的肠道内吸收。FK-448是一种低毒性物质,据     

胰岛素肺部给药对大鼠的降血糖作用

目的:研究胰岛素溶液(INS SOL)经正常大鼠肺部给药后的降血糖作用。方法:以血糖水平为指标,考察各种吸收促进剂以及酶抑制剂经正常大鼠肺部给药后对INS SOL降血糖作用的影响。同时比较了INS SOL在两种pH条件下的降血糖作用,并以皮下注射为对照,计算不同条件下INS SOL的药理生物利用度(pharmacologicalbioavailability,PBA)。结果:05u·kg^-1的INS SOL经肺部给药后即有明显的降血糖作用,在不加吸收促进剂的条件下的PA为260%。辛酸钠、胆酸钠、苄泽35、苄泽78和酶抑制剂杆菌肽均显著地增加INS SOL的降血糖作用。INS SOL在pH3时的降血糖效果比pH7时有显著的提高。结论:INS SOL经肺部给药后有显著的降血糖效果。     

几种多肽在大鼠离体小肠中的吸收

在大鼠的离体小肠标本中比较几种多肽、蛋白质和氨基酸的吸收率。主要通过两种方法计算肽在小肠中的吸收率:一是通过测定肽吸收前后的蛋白质含量,另一种是运用HPLC测定肽吸收前后分子质量图谱。结果:小肠能吸收多种肽(白蛋白肽、大豆肽、菜籽肽、花生肽和胶原肽),被吸收的肽的相对分子质量多在1000以内。小肠对肽的吸收率高于对氨基酸和蛋白质的吸收率。小肠各段均具有吸收肽的功能。该研究为肽类生物药物的口服途径吸收提供了实验依据。     

脱氧胆酸对胰岛素聚乳酸纳米粒在大鼠小肠吸收的影响

目的 :探讨脱氧胆酸 (DOC)对胰岛素聚乳酸纳米粒 (Ins PLA NP)在小肠吸收的影响。方法 :在正常大鼠小肠分别给予含与不含吸收促进剂DOC的Ins PLA NP后 ,观察降血糖效果。结果 :Ins PLA NP小肠直接给药表现出和缓持久的降血糖效果 ,而DOC在小肠给药中能明显加快Ins PLA NP的吸收并增强药效 ,给药后 0 5h血糖下降至用药前的 (35 49± 6 6 4) % ,显著的降血糖作用可维持 2h左右。结论 :DOC对于Ins PLA NP在小肠部位的吸收具有促进作用     

Potential utility of various protease inhibitors for improving the intestinal absorption of insulin in rats

The aim of the investigation was to study the effects of protease inhibitors on the absorption of insulin in-situ from closed small and large intestinal loops in rats and to investigate the mechanism of various protease inhibitors in different intestinal loops. The intestinal absorption of insulin was evaluated by its hypoglycaemic effect and serum insulin level in the presence or absence of luminal contents. No marked hypoglycaemic effect was observed after administration of insulin alone in either region in the presence or absence of luminal contents. A significant hypoglycaemic effect of insulin was obtained in the large intestinal loop in the presence or absence of luminal contents when insulin was co-administered with bacitracin (20, 30 mM), sodium glycocholate (20, 40 mM), bestatin (29 mM), leupeptin (21 mM) and cystatin (0.8 mM). In contrast, there was no hypoglycaemic effect in the small intestinal loop in the presence of luminal contents following small intestinal co-administration of insulin with these protease inhibitors. The effectiveness of protease inhibitors was susceptible to their categories, concentrations and activity of proteolytic enzymes in different regions. The degree of improving insulin absorption in intestine was in the order of leupeptin>sodium glycocholate>bacitracin>bestatin>cystatin. At the same time, the percutaneous enhancement effect was observed in the presence of either sodium glycocholate or bacitracin. These results suggest that protease inhibitors could increase the insulin efficacy more effectively in the large intestine than in the small intestine.     

Effects of Various Protease Inhibitors on the Intestinal Absorption and Degradation of Insulin in Rats

The effects of protease inhibitors on the intestinal absorption of insulin were investigated in situ in closed small and large intestinal loops in rats, and the stability of insulin was examined in homoge-nates of the small and large intestine. The intestinal absorption of insulin was evaluated by its hypoglycemic effect. When insulin alone was administered into small or large intestinal loops, no marked hypoglycemic response was observed in either region. Of the coadministered protease inhibitors, soybean trypsin inhibitor (1.5, 10 mg/ml) marginally promoted insulin absorption from the large intestine, whereas aprotinin (10 mg/ml) did to a moderate degree. However, a significant hypoglycemic effect was obtained following large intestinal administration of insulin with 20 mM of Na-glycocholate, camostat mesilate and bacitracin, when compared with the controls. In contrast, we found little hypoglycemic effect following small intestinal coadministration of insulin with these protease inhibitors. In the stability experiment, bacitracin, camostat mesilate and Na-glycocholate were effective in reducing insulin degradation in both small and large intestinal homogenates. It was found that the reduction in the proteolytic rate of insulin was related to the decrease in plasma glucose concentration by these protease inhibitors in the large intestine. These findings suggest that coadministration of protease inhibitors would be useful for improving the large intestinal absorption of insulin.     

Absorption Enhancement of Intrapulmonary Administered Insulin by Various Absorption Enhancers and Protease Inhibitors in Rats

Abstract— The effects of absorption enhancers and protease inhibitors on the pulmonary absorption of insulin were examined by means of an in-situ pulmonary absorption experiment. Absorption enhancers used in this study were sodium glycocholate, linoleic acid-surfactant mixed micelles and N-lauryl-β-d-maltopyranoside whereas aprotinin, bacitracin and soybean trypsin inhibitor were used as protease inhibitors. The absorption of insulin from the lung was evaluated by its hypoglycaemic effect. In the absence of these additives, a slight hypoglycaemic effect was obtained following intrapulmonary administration of insulin. However, we found significant and continuous hypoglycaemic effects after the insulin administration with these additives. N-Lauryl-β-d-maltopyranoside and bacitracin appeared to be more effective for enhancing the pulmonary absorption of insulin than the other adjuvants. These findings suggest that the use of these two adjuvants would be a useful approach for improving the pulmonary absorption of insulin.     

Small Intestinal Absorption of Bropirimine in Rats and Effect of Bile Salt on the Absorption

The intestinal absorption characteristics of a poorly water-soluble drug, bropirimine, were investigated by the in-situ small intestinal loop method using male Sprague-Dawley rats. Bropirimine in solution was well absorbed in the overall small intestine, following first-order kinetics. The rate determining step for the disappearance of bropirimine from the small intestinal loop after dosing in the suspension was the dissolution process from suspension. Bropirimine was solubilized by sodium glycocholate. The disappearance of bropirimine from the small intestinal loop was suppressed by sodium glycocholate contained in the solution, because of the loss of thermodynamic activity of bropirimine after its involvement in the micellar complex, not by the direct effect of bile salt on the permeability of intestinal mucosa. The disappearance of bropirimine was also suppressed by sodium glycocholate contained in the suspension. The suppression by sodium glycocholate seemed to be caused by the greater influence of sodium glycocholate on the thermodynamic activity of bropirimine than on the dissolution from suspension.     

Use of Protease Inhibitors to Improve Calcitonin Absorption from the Small and Large Intestine in Rats

The objective of this study was to examine the effects of protease inhibitors on the absorption of calcitonin from different regions of the intestine in rats. The absorption experiments were investigated by in-situ use of closed intestinal loops in rats and stability of calcitonin was examined in mucosal homogenates and intestinal fluids. The intestinal absorption of calcitonin was evaluated by measurement of its hypocalcaemic effect. No substantial hypocalcaemic response was observed when calcitonin was administered into the jejunum or colon. A slight hypocalcaemic effect was observed after administration of calcitonin into the ileum. Of the co-administered protease inhibitors, bacitracin (20 mM) strongly promoted calcitonin absorption from the jejunum, ileum and colon. A significant hypocalcaemic effect was also obtained after intestinal administration of calcitonin with soybean trypsin inhibitor (10mgmL^?1), camostat mesylate (20mM) or aprotinin (2mgmL^?1). In the stability experiment, bacitracin reduced the degradation of calcitonin in the different intestinal homogenates. Soybean trypsin inhibitor significantly reduced the degradation of calcitonin in the fluids of the small intestine. We also examined the different endopeptidases in gut luminal fluids and the different exopeptidases in gut mucosal homogenates of rats. The ranking order for the total endopeptidase activity of the intestinal fluids was jejunum > ileum > colon. That for total exopeptidase activity of the intestinal mucosa was jejunum > ileum > colon. These results suggest that endo- and exopeptidases might be responsible for the hydrolysis of calcitonin and that protease inhibitors might usefully improve absorption of calcitonin to the systemic circulation from the large intestine.     

Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers

The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.     

Proteolytic enzymes as a limitation for pulmonary absorption of insulin: in vitro and in vivo investigations

In vitro biodegradation of insulin in lung cytosol and subcellular pellets of normal and diabetic rats was investigated. Rat lung was homogenized and subcellular fractions were isolated by ultracentrifugation. Degradations of [125I]-insulin after incubation with lung cytosol or subcellular pellets was determined using the trichloroacetic acid method. The results show that insulin is highly degraded in cytosol and subcellular pellets. Cytosolic insulin degradation was strongly inhibited by bacitracin or sodium cholate. The degradation of insulin in the lung cytosol from diabetic rats was significantly less than from normal rat. The lung protease activity reached a maximum at pH 7.4. Enzyme inhibitors like bacitracin and sodium cholate noticeably enhanced the relative pharmacological bioavailability of insulin when given intratracheally with insulin to normal rats. Acidic insulin solutions (pH 3.0) had more pronounced hypoglycaemic effects than neutrol solution (pH 7.0). These in vitro and in vivo results suggest that the proteolytic enzymes in the lung limit pulmonary delivery of insulin. The coadministration of protease inhibitors would be a useful approach for improving the pulmonary absorption of insulin.     

Characterization of human insulin microcrystals and their absorption enhancement by protease inhibitors in rat lungs

Pulmonary route appears to be an attractive alternative as a non-invasive systemic delivery for peptide and protein drugs. An appropriate formulation, however, is important for increasing their bioavailability in lung. In this study, the human insulin microcrystals were produced. The particle size analysis and scanning electron microscopy (SEM) showed that the microcrystals were uniform and had a monodispersed size distribution (mean diameter = 0.95 microm) for pulmonary delivery. The physicochemical properties of the microcrystals developed were similar to those of the commercial crystalline powder in powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses. The percentage of high molecular weight proteins (%HMWP), the percentage of other insulin related compounds (%OIRC) and the percentage of A-21 desamido insulin (%D) of the microcrystals were very low. In addition, the cytotoxicity of microcrystals developed and protease inhibitors (aprotinin, bacitracin and soybean-trypsin inhibitor) was investigated, and the enhancement of insulin absorption in the presence of these protease inhibitors at various concentrations was studied. The cell viability of A549 was over 80% at various concentrations of aprotinin and soybean-trypsin inhibitor, except for bacitracin (below 60%). The percent of decrease in blood glucose (D%) was 42.68+/-1.62% after intratracheal instillation of insulin microcrystals (5 U/kg). An enhancement of hypoglycemic effect with protease inhibitors was also found. Soybean-trypsin inhibitor (48.86+/-3.24% at 10 mg/ml; 55.78+/-0.71% at 5 mg/ml; 51.49+/-5.27% at 1 mg/ml) and aprotinin (52.57+/-8.78% at 10 mg/ml; 51.97+/-1.98% at 5 mg/ml; 56.90+/-3.42% at 1 mg/ml) were effective for absorption enhancement. These findings suggest that the use of insulin microcrystals and protease inhibitors would be useful to improve the hypoglycemic effect in pulmonary route.     

Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers: their intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-beta-D-maltopyranoside

We have examined the in-vitro permeability characteristics of insulin in the presence of various absorption enhancers across rat intestinal membranes and have assessed the intestinal toxicity of the enhancers using an in-vitro Ussing chamber method. The absorption enhancing mechanism of n-lauryl-beta-D-maltopyranoside was studied also. The permeability of insulin across the intestinal membranes was low in the absence of absorption enhancers. However, the permeability was improved in the presence of enhancers such as sodium glycocholate and sodium deoxycholate in the jejunum, and sodium glycocholate, sodium deoxycholate, n-lauryl-beta-D-maltopyranoside, sodium caprate and ethylenediaminetetraacetic acid (EDTA) in the colon. Overall, the absorption enhancing effects were greater on the colonic membrane than on the jejunal membrane. The intestinal membrane toxicity of these enhancers was characterized using the release of cytosolic lactate dehydrogenase from the colonic membrane. A marked increase in the release of lactate dehydrogenase was observed in the presence of sodium deoxycholate and EDTA. The release of lactate dehydrogenase in the presence of these absorption enhancers was similar to that seen with sodium dodecyl sulphate (SDS), used as a positive control, indicating high toxicity of these enhancers to the intestinal membrane. In contrast, sodium glycocholate and sodium caprate caused minor releases of lactate dehydrogenase, similar to control levels, suggesting low toxicity. In addition, the amount of lactate dehydrogenase in the presence of n-lauryl-beta-D-maltopyranoside was much less than that seen with sodium deoxycholate, EDTA and SDS. Therefore, sodium glycocholate, sodium caprate and n-lauryl-beta-D-maltopyranoside are useful absorption enhancers due to their high absorption enhancing effects and low intestinal toxicity. To investigate the absorption enhancing mechanisms of n-lauryl-beta-D-maltopyranoside, the transepithelial electrical resistance (TEER), voltage clamp experiments and the circular dichroism spectra were studied. n-Lauryl-beta-D-maltopyranoside decreased the TEER values in a dose-dependent manner, suggesting that the enhancer may open the tight junctions of the epithelium, thereby increasing the permeability of insulin via a paracellular pathway. This speculation was supported by the findings that 20 mM n-lauryl-beta-D-maltopyranoside produced a greater increase in the paracellular flux rate than in the transcellular flux rate by the voltage clamp studies. Evaluating the circular dichroism spectra we found that insulin oligomers were not dissociated to monomers by the addition of n-lauryl-beta-D-maltopyranoside, but dissociation did occur with the addition of sodium glycocholate. Thus, the dissociation of insulin was not a major factor in the absorption enhancing effect of n-lauryl-beta-D-maltopyranoside. These findings provide basic information to select the optimal enhancer for the intestinal delivery of peptide and protein drugs including insulin.