Bioadhesive Chitosan-Coated Cationic Nanoliposomes With Improved Insulin Encapsulation and Prolonged Oral Hypoglycemic Effect in Diabetic Mice

Oral administration of insulin is hampered by the lack of carriers that can efficiently achieve high encapsulation, avoid gastric degradation, overcome mucosal barriers, and prolong the hypoglycemic effect. Chitosan (CS)-coated insulin-loaded cationic liposomes have been developed and optimized for improved oral delivery. Liposomes were prepared cationic to improve insulin encapsulation. CS was selected as a mucoadhesive coat to prolong the system's residence and absorption. The performance of CS-coated liposomes compared with uncoated liposomes was examined in vitro, ex vivo, and in vivo in streptozotocin-induced diabetic mice. Free uncoated liposomes showed high positive zeta potential of +58.8 ± 2.2 mV that reduced (+29.9 ± 1.4 mV) after insulin encapsulation, confirming the obtained high entrapment efficiency of 87.5 ± 0.6%. CS-coated liposomes showed nanosize of 439.0 ± 12.3 nm and zeta potential of +60.5 ± 1.9 mV. In vitro insulin release was limited to 18.9 ± 0.35% in simulated gastric fluid, whereas in simulated intestinal fluid, 73.33 ± 0.68% was released after 48 h from CS-coated liposomes. Ex vivo intestinal mucoadhesion showed increased tissue residence of CS-coated liposomes compared with uncoated liposomes. A striking reduction in the glucose level was observed 1 h after oral administration of CS-coated liposomes and maintained up to 8 h (p <0.01 vs. insulin solution or uncoated liposomes) within the normal value 129.29 ± 3.15 mg/dL. In conclusion, CS-coated insulin-loaded cationic liposomes improved loading efficiency with promising prolonged pharmacological effect.     

The effect of particle structure of chitosan-coated liposomes and type of chitosan on oral delivery of calcitonin

To optimize the properties of chitosan-coated liposomes for oral administration of peptide drugs, we examined the effect of type of chitosan and the structure of liposomal systems on the mucoadhesiveness of liposomes and resultant pharmacological effects of the liposomal peptide drug. A low-molecular weight chitosan (LCS) and a high-molecular weight chitosan (CS) were used as coating polymers of liposomes containing elcatonin (eCT). The muco-penetrative behaviors across the mucous gel layer covering the intestinal epithelial cells and the pharmacological effect after intragastric administration were determined in rats. The results showed that both LCS-coated liposomes (LCS-Lips) and CS-coated liposomes (CS-Lips) could permeate the mucous layer in the small intestine. The most interesting result was that LCS-Lips containing eCT showed remarkably more prolonged effectiveness in decreasing the blood calcium concentration than did CS-Lips containing eCT, moreover, it was also found that LCS had more efficiency to protect eCT from the enzymatic degradation than CS. In comparing the area above the plasma calcium concentration time curves (AAC) values among eCT-containing liposomes with different structures, i.e. eCT adsorbed on coated liposomes (eCT-ad-CS-Lip, eCT-ad-LCS-Lips) and eCT encapsulated in coated liposomes (eCT-encap-CS-Lips, eCT-encap-LCS-Lips), eCT-encap-CS-Lip showed much higher effectiveness than eCT-ad-CS-Lip. However, the AAC value for eCT-ad-LCS-Lip was comparable to that for eCT-encap-CS-Lip, while the value for eCT-ad-CS-Lip was nearly zero. These results suggested that LCS is a good mucoadhesive polymer candidate for enhancing the bioavailability of orally administered peptide containing liposomes, while encapsulation of eCT within the liposomal particles is important to protect eCT against enzymatic degradation in the gastrointestinal (GI) tract.     

The effect of particle structure of chitosan-coated liposomes and type of chitosan on oral delivery of calcitonin

To optimize the properties of chitosan-coated liposomes for oral administration of peptide drugs, we examined the effect of type of chitosan and the structure of liposomal systems on the mucoadhesiveness of liposomes and resultant pharmacological effects of the liposomal peptide drug. A low-molecular weight chitosan (LCS) and a high-molecular weight chitosan (CS) were used as coating polymers of liposomes containing elcatonin (eCT). The muco-penetrative behaviors across the mucous gel layer covering the intestinal epithelial cells and the pharmacological effect after intragastric administration were determined in rats. The results showed that both LCS-coated liposomes (LCS-Lips) and CS-coated liposomes (CS-Lips) could permeate the mucous layer in the small intestine. The most interesting result was that LCS-Lips containing eCT showed remarkably more prolonged effectiveness in decreasing the blood calcium concentration than did CS-Lips containing eCT, moreover, it was also found that LCS had more efficiency to protect eCT from the enzymatic degradation than CS. In comparing the area above the plasma calcium concentration time curves (AAC) values among eCT-containing liposomes with different structures, i.e. eCT adsorbed on coated liposomes (eCT-ad-CS-Lip, eCT-ad-LCS-Lips) and eCT encapsulated in coated liposomes (eCT-encap-CS-Lips, eCT-encap-LCS-Lips), eCT-encap-CS-Lip showed much higher effectiveness than eCT-ad-CS-Lip. However, the AAC value for eCT-ad-LCS-Lip was comparable to that for eCT-encap-CS-Lip, while the value for eCT-ad-CS-Lip was nearly zero. These results suggested that LCS is a good mucoadhesive polymer candidate for enhancing the bioavailability of orally administered peptide containing liposomes, while encapsulation of eCT within the liposomal particles is important to protect eCT against enzymatic degradation in the gastrointestinal (GI) tract.     

Influence of magnesium stearate on the physicochemical and pharmacodynamic characteristics of insulin-loaded Eudragit entrapped mucoadhesive microspheres

Abstract

Effective oral insulin delivery has remained a challenge to the pharmaceutical industry. This study was designed to evaluate the effect of magnesium stearate on the properties of insulin-loaded Eudragit® RL 100 entrapped mucoadhesive microspheres. Microspheres containing Eudragit® RL 100, insulin, and varying concentrations of magnesium stearate (agglomeration-preventing agent) were prepared by emulsification-coacervation method and characterized with respect to differential scanning calorimetry (DSC), morphology, particle size, loading efficiency, mucoadhesive and micromeritics properties. The in vitro release of insulin from the microspheres was performed in simulated intestinal fluid (SIF, pH 7.2) while the in vivo hypoglycemic effect was investigated by monitoring the plasma glucose level of the alloxan-induced diabetic rats after oral administration. Stable, spherical, brownish, mucoadhesive, discrete and free flowing insulin-loaded microspheres were formed. While the average particle size and mucoadhesiveness of the microspheres increased with an increase in the proportion of magnesium stearate, loading efficiency generally decreased. After 12?h, microspheres prepared with Eudragit® RL 100: magnesium stearate ratios of 15:1, 15:2, 15:3 and 15:4 released 68.20?±?1.57, 79.40?±?1.52, 76.60?±?1.93 and 70.00?±?1.00 (%) of insulin, respectively. Reduction in the blood glucose level for the subcutaneously (sc) administered insulin was significantly (p?≤?0.05) higher than for most of the formulations. However, the blood glucose reduction effect produced by the orally administered insulin-loaded microspheres prepared with four parts of magnesium stearate and fifteen parts of Eudragit® RL 100 after 12?h was equal to that produced by subcutaneously administered insulin solution. The results of this study can suggest that this carrier system could be an alternative for the delivery of insulin.     

Pharmacokinetic and Pharmacological Profiles of Free and Liposomal Recombinant Human Erythropoietin After Intravenous and Subcutaneous Administrations in Rats

Purpose. Recombinant human erythropoietin (Epo) is used frequently through intravenous (i.v.) and subcutaneous (s.c.) administration for the clinical treatment of the last stage of renal anemia. We encapsulated Epo in liposomes to develop an alternative administration route. The purpose of our study was to evaluate the pharmacokinetics and the pharmacological effects of liposomal Epo in comparison with the Epo after i.v. and s.c. administration to rats. Methods. Epo was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterol mixture (SS) prepared by the reversed-phase evaporation vesicle method. After filtration through a 0.1 m polycarbonate membrane, liposomes were gel filtered (Epo/liposomes). Results. Epo/liposomes showed higher pharmacological activity than Epo/liposomes before gel filtration after i.v. administration to rats. Non-encapsulated Epo lost its activity, whereas encapsulated Epo in liposomes retained it. The pharmacological effects of Epo/liposomes were greater than those of Epo after i.v. administration. Epo/liposomes afforded 3–9 times higher AUC, lower clearance and lower steady-state volume of distribution than Epo after both i.v. and s.c. administrations. Epo/liposomes had an improved pharmacokinetic profile compared with Epo. S.c. administration of Epo/liposomes at 7 h may penetrate primarily (40% of dose) through the blood as a liposome and partly (7% of dose) in lymph. Conclusions. Epo/liposomes may reduce the frequency of injections required for a certain reticulocyte effect in comparison to Epo. The lower clearance of Epo/liposomes may increase the plasma concentrations of Epo, which increases the efficacy.     

新型国产重组甘精胰岛素对1型糖尿病模型大鼠的降糖作用研究

目的 探讨新型国产重组甘精胰岛素注射液对1型糖尿病模型大鼠的降糖作用。方法 选择健康SD大鼠和链脲佐菌素诱导的1型糖尿病大鼠,甘精胰岛素注射液（来得时）为阳性对照药,健康SD大鼠单次sc 2、4 IU/kg剂量的重组甘精胰岛素注射液,大鼠尾静脉采血,分别测定0 h（给药前）及给药后1、2、4、6、8 h空腹血糖;1型糖尿病模型大鼠连续5 d sc 4、8 IU/kg剂量的重组甘精胰岛素注射液,每天分别测定给药前（0 h）和给药后（4 h）空腹血糖,给药第1、5天测定给药后1、2、4、6、8 h空腹血糖。结果 健康大鼠sc重组甘精胰岛素注射液2、4 IU/kg后,血糖值在2 h下降到最低,与对照组比较差异显著（P<0.01）;模型大鼠连续5 d sc 4、8 IU/kg重组甘精胰岛素注射液,血糖于给药后4~6 h下降至最低点,与模型组比较差异显著（P<0.01）;每天给药4 h后血糖均呈平稳下降趋势,与模型组比较差异显著（P<0.01）,8 IU/kg血糖值与对照组接近。结论 国产重组甘精胰岛素注射液对1型糖尿病模型大鼠有较好的降糖效果,与同剂量阳性药降糖效果相当。     

Pharmacodynamics of insulin in polyethylene glycol-coated liposomes

To reduce the injection frequency and toxicity of intravenously administered protein drugs, it is necessary to develop safe and sustained injectable delivery systems. In this study, to evaluate liposomes as safe and sustained injectable delivery systems of proteins, we chose insulin as a model protein drug and tested its incorporation efficiency and pharmacodynamics in various liposomes with and without polyethylene glycol (PEG)-derivatized phospholipid. The liposomes coated with PEG showed 3-fold higher efficiency of insulin incorporation than did the liposomes without PEG. Moreover, among the liposomes coated with PEG, dipalmitoylphosphocholine (DPPC) liposomes showed higher incorporation efficiency than did dimyristoylphosphocholine (DMPC) liposomes. For pharmacodynamic study, insulin (2 IU/kg) was administered in various formulations, such as insulin alone in phosphate-buffered saline and insulin in the DPPC liposomes with and without PEG, to streptozotocin-treated diabetic rats. The pharmacodynamics of insulin alone, however, could not be measured due to the immediate death of rats caused by hypoglycemic shock. In contrast, all the rats treated with liposomal insulin survived, probably by the sustained release of insulin from liposomes. Pharmacodynamics of liposomal insulin showed that PEG-coated liposomes induced the lowest level of blood glucose-the nadir-1 h later than did the liposomes without PEG. These results indicate that PEG-coated liposomes could be developed as a relatively safe and sustained injectable delivery system for insulin with improved incorporation efficiency. Moreover, it is suggested that the liposomes coated with PEG might have a potential as safe injectable delivery systems for other protein and peptide drugs.     

Tyrphostin-8 Enhances Transferrin Receptor-Mediated Transcytosis in Caco-2 Cells and Increases Hypoglycemic Effect of Orally Administered Insulin-Transferrin Conjugate in Diabetic Rats

Purpose. To investigate the effect of tyrphostin 8 (T-8), a GTPase inhibitor, on transferrin receptor (TfR)-mediated transcytosis of insulin-transferrin (In-Tf) conjugate in cultured enterocyte-like Caco-2 cells and on gastrointestinal (GI) absorption of In-Tf in streptozotocin (STZ)-induced diabetic rats. Methods. Caco-2 cells and diabetic rats were used as in vitro and in vivo models, respectively. TfR-mediated transcytosis was measured using ¹²⁵I-In-Tf. The absorption of insulin in diabetic rats was demonstrated by the hypoglycemic effect. Rat blood glucose level was determined using a ONE TOUCH® blood glucose monitoring system. Results. T-8 increased apical-to-basolateral transport of In-Tf conjugate by enhancing TfR-mediated transcytosis in filter-grown Caco-2 cell monolayer, and this enhancement was higher and faster than the previously reported brefeldin A (BFA)-induced effect. The measurement of transepithelial electrical resistance (TEER) during the transport study showed that T-8 was less destructive on the cell tight junction than BFA. The GI absorption of In-Tf was evaluated by its hypoglycemic effect after oral administration in STZ-induced diabetic rats. The glucose-lowering effect of orally administered In-Tf in STZ-induced diabetic rats was improved by either T-8 or BFA. However, the effect of T-8 was more potent than that of BFA, especially at 7 h after administration. Either non-conjugated insulin or insulin-human serum albumin (In-HSA) conjugate by itself or in combination with T-8 did not show any hypoglycemic effect after oral administration, indicating that T-8-enhanced hypoglycemic activity of In-Tf was due to a selective enhancement of TfR-mediated transcytosis. Conclusions. Our data indicated that T-8 could be used to increase the GI absorption of insulin as a transferrin conjugate. T-8, as an enhancer of TfR-mediated transcytosis, is better than the previously reported BFA. T-8 produces a higher increase on the transport of In-Tf and a lower toxicity on epithelial cells. Our findings provide an alternative approach to promote the GI absorption of insulin, as well as other peptide or protein drugs.     

Hybrid liposomes as a drug carrier for the oral administration of insulin in diabetic rats

It is known that hybrid liposomes composed of dimyristoylphosphatidylcholine (DMPC) and micellar surfactant (Tween 20) are effective for encapsulating drugs and for the treatment of meningeal gliomatosis in vivo without toxicity. In this study, we attempted to use these hybrid liposomes as a drug carrier system for the oral administration of insulin using diabetic model rats. The noteworthy aspects were as follows: (a) The hybrid liposomes of 90 mol% DMPC/10 mol% Tween 20 were stable and uniform for more than 4 weeks. (b) The blood glucose level of diabetic model rats decreased after the oral administration of hybrid liposomes including insulin. These results suggest that the oral administration of hybrid liposomes including insulin should be effective for the treatment of diabetes.     

Effect of Freezing Rate on the Stability of Liposomes During Freeze-Drying and Rehydration

Purpose. In the present study we examined the effect of the freezing protocol on carboxyfluorescein (CF) retention in liposomes after freeze-drying and rehydration. Methods. Liposomes were frozen slowly at 0.5°C/min, or quickly by submerging the samples in boiling nitrogen before freeze-drying. The thermal behaviour of the frozen dispersions was analysed by Modulated Temperature Differential Scanning Calorimetry (MTDSC). The dried cakes were analysed by SEM, MTDSC and FTIR. The % encapsulated CF of the (re)hydrated liposomes was determined by fluorimetry after GPC, their vesicle size was measured by the Dynamic Light scattering Technique and their bilayer transition was studied by DSC. Results. Slow freezing resulted in a markedly higher CF retention after freeze-drying and rehydration as compared to quick freezing. The effect of the freezing rate depended on the lipid composition and was most pronounced for rigid liposomes. The damage caused by quick freezing did not occur after a freezing/thawing cycle. The freezing protocol did not influence the interaction between the phospholipids and the lyoprotectants (sucrose, trehalose or glucose) in the freeze-dried state. However, analysis by DSC of dipalmitoylphosphatidylcholine (DPPC): dipalmitoylphosphatidylglycerol (DPPG) =10:1 and DPPC liposome dispersions showed that the freezing protocol affected the bilayer melting characteristics of these liposomes after freeze-drying and rehydration. Conclusions. A proper design of the freezing protocol is essential to achieve optimal stability of rigid liposomes during a freeze-drying and rehydration cycle.     

Antioxidant Activity of Indian Herbal Drugs in Rats with Aloxan-induced Diabetes

Abstract

Methanol extracts (75%) of Aegle marmelos, Momordica charantia, Trigonella foenum-graecum, Eclipta prostrata, Salacia oblonga, Coriandrum sativum, Vernonia anthelmintica and Murraya koenigii, plants used extensively in the Indian system of medicine, were found to be potent inhibitors of lipid peroxide formation and scavengers of hydroxyl and superoxide radicals in vitro. Oral administration of the extracts (100 mg/kg body weight) were found to reduce the serum glucose level in normal and alloxan (120 mg/kg) diabetic rats significantly for 4h and continued administration of the drug sustained this effect. Reduction of serum glucose by activities of herbal drugs such as Aegle marmelos (56.8%), Momordica charantia (55.4%) and Trigonella foenum-graecum (52.5%) were almost as high as the activity of insulin (60.4%). The extract of Aegle marmelos showed highest activity as an antidiabetic and antioxidant, compared to other extracts. The results indicated that oxidant induced alterations in the glucose utilizing system during diabetic manifestation is partially reversed by the administration of herbal extracts having antioxidant activity.     

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。     

Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice

Abstract

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitive in situ hydrogel, consisting of chitosan (CS) and β-glycerophosphate (β-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol–gel temperature, flow behavior and viscosity of these CS/β-GP systems. The optimized formulation exhibited sol–gel transition at 40.2?±?0.4?°C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/β-GP hydrogel in phosphate buffer saline (pH?=?7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50?h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/β-GP hydrogel, was higher than that of TPT in saline and TPT in CS/β-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/β-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs.     

Rates of Systemic Degradation and Reticuloendothelial System (RES) Uptake of Thermosensitive Liposome Encapsulating Cisplatin in Rats

The systemic degradation and reticuloendothelial system (RES) uptake of cisplatin (CDDP)-encapsulated thermosensitive liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and di-stearoylphosphatidylcholine (DSPC) (DPPC/DSPC = 9/1, 7/3, and 5/5, w/w) after intravenous administration to rats were examined by measuring the platinum (Pt) levels in the blood and RES (liver and spleen). The blood liposome level profile showed first-order rate elimination for each liposome administration. The elimination rate (K _e1) was faster when the content of DSPC was lower (K _e1: 1.3/hr for 9/1-liposomes, 0.7/hr for 7/3-liposomes, 0.5/hrfor5/5-liposomes). On the other hand, the RES liposome level profile showed distribution of liposomes followed by elimination therefrom. The RES level of the liposomes was lower when the content of DSPC was smaller (maximal level: 25% for 9/1-liposomes at 1 hr, 32% for 7/3-liposomes at 1 hr, 37% for 5/5-liposomes at 2 hr). The kinetic analysis demonstrated that the RES uptake rate (K _res) was almost the same among the liposomes (0.4/hr), while the systemic degradation rate (K _deg; K _e1 – K _res) became larger as the content of DSPC decreased (0.9/hr for 9/1-liposomes, 0.3/hr for 7/3-liposomes, and 0.1/hr for 5/5-liposomes) and that the RES liposome distribution amount was dependent not only on the K _res but also on the K _deg and the rate of RES liposome degradation. The K _deg for each type of liposome corresponded with the systemic CDDP release rate.     

Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery

Considering limitations of conventional insulin therapies, the present study characterizes usefulness of novel mucoadhesive multivesicular liposomes as a mucoadhesive sustained release carrier of insulin via nasal and ocular routes, thus attempts to develop non-invasive carrier system for the controlled release of bioactives. Multivesicular liposomes (MVLs) of 26–34 μm were prepared with a high protein loading (58–62%) and were coated with chitosan and carbopol. These mucoadhesive carriers were characterized by zeta potential studies, in vitro mucoadhesion test and insulin protective ability against nasal aminopeptidase. In vitro, mucoadhesive carriers released insulin for a period of 7–9 days compared to 24 h of conventional liposomes. After intranasal administration to STZ induced diabetic rats, the mucoadhesive MVLs (chitosan coated MVLs) effectively reduced plasma glucose level up to 2 days (35% reduction), compared to non-coated MVLs (32% at 12 h) and conventional liposomes (34% at 8 h). Although the differences are statistically insignificant, chitosan coated formulation has shown a better hypoglycemic profile as the effects were prolonged compared to carbopol coated formulation. When compared to ocular route, chitosan formulation after nasal administration has shown better therapeutic profile as the hypoglycemic effects were prolonged until 72 h. The effectiveness of this chitosan coated MVLs was further demonstrated by the significant quantities of ELISA detectable insulin levels after nasal (334.6 μIu/ml) and ocular (186.3 μIu/ml) administration. These results demonstrate that mucoadhesive carrier is a viable option for a sustained release transmucosal insulin carrier, and open an avenue to develop a non-invasive carrier platform for the controlled release of bioactives.     

Formulation and Evaluation of a Folic Acid Receptor-Targeted Oral Vancomycin Liposomal Dosage Form

Purpose. To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin, via the oral route. Methods. Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitroin the Caco-2 cell model and in vivoin male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces. Results. Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution. Conclusions. The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.     

参葛定渴片对2型糖尿病大鼠糖代谢调节作用的实验研究

目的 考察参葛定渴片对2型糖尿病大鼠糖代谢的调节作用.方法 采用ig高脂高糖脂肪乳加ip小剂量链脲佐菌素(STZ)的方法,建立2型糖尿病大鼠模型.将造模成功的大鼠随机分为模型组、阳性组和参葛定渴片高、中、低剂量组.实验各组均连续给药4周.同时取健康大鼠为对照组,观察各组大鼠行为学指标,检测其血糖、糖耐量、血清胰岛素水平.结果 与对照组比较,模型组体质量下降,血糖值显著升高、糖耐量能力降低以及血清胰岛素水平升高.与模型组比较,阳性组和参葛定渴片高、中剂量组可显著降低糖尿病大鼠的血糖和血清胰岛素水平(P <0.001、0.01),且参葛定渴片高剂量组可改善糖尿病大鼠的糖耐量(P <0.01).结论 参葛定渴片对2型糖尿病大鼠的糖代谢具有调节作用,可改善糖尿病大鼠的胰岛素抵抗状态.     

盐知母不同有效部位改善链脲佐菌素诱导2型糖尿病大鼠糖代谢的研究

目的探究盐知母不同溶剂萃取物对2型糖尿病大鼠糖代谢的影响,旨在寻找盐知母降血糖作用的有效部位。方法 SD雄性大鼠ig脂肪乳10 g/kg,1次/d。4周后,ip链脲佐菌素35 mg/kg,建立2型糖尿病模型。造模成功的大鼠按血糖值随机分为模型组、阿卡波糖(0.2 g/kg)组以及石油醚萃取物、氯仿萃取物、醋酸乙酯萃取物、正丁醇萃取和萃余物组,连续ig给药14 d。于给药7、14 d后测定空腹血糖值(FBG),末次给药后测定口服葡萄糖耐量(OGTT),眼眶取血测定糖化血红蛋白(HbAlc)、血清胰岛素(FINS),计算胰岛敏感指数(ISI)和Homa胰岛素抵抗(HOMA-IR)指数。结果与模型组比较,盐知母氯仿萃取物能够明显降低FBG、HbA1c、FINS、HOMA-IR指数,升高ISI,改善OGTT;盐知母醋酸乙酯萃取物能够显著降低HbAlc、HOMA-IR指数,改善OGTT;盐知母正丁醇萃取物能够显著降低FINS;盐知母萃余物能够显著降低FBG、FINS、HOMA-IR指数,升高ISI。结论盐知母不同溶剂萃取物对2糖尿病大鼠糖代谢具有较好的改善作用,其中氯仿萃取物的作用最强。     

胰岛素柔性纳米脂质体的口腔给药研究

目的探讨柔性纳米脂质体经口腔粘膜转运蛋白多肽类药物的可能性。方法用反相蒸发法制备胰岛素柔性纳米脂质体和普通脂质体,对其包封率、形态和粒径大小进行测定。以家兔为动物模型,口腔给药(bu)后,进行体内降糖实验,同时测定胰岛素水平变化。结果胰岛素柔性纳米脂质体与普通脂质体的包封率分别为(18.9±1.8)%和(22.1±2.2)%;粒径分别为(42±20) nm和(60±34) nm。透射电镜下,胰岛素柔性纳米脂质体的指纹状结构比普通脂质体更多,其他无明显区别。以sc胰岛素溶液(1 U·kg^-1)为对照,bu胰岛素柔性纳米脂质体组(10 U·kg^-1)的药理相对生物利用度为15.59%,相对生物利用度为19.78%,高于bu胰岛素溶液对照组(P<0.05)、胰岛素普通脂质体组(P<0.05)及空白柔性纳米脂质体与胰岛素混合物组(P<0.05)。结论胰岛素柔性纳米脂质体可能成为经口腔粘膜转运蛋白多肽类药物的有效载体。     

Rates of Systemic Degradation and Reticuloendothelial System Uptake of Calcein in the Dipalmitoylphosphatidylcholine Liposomes with Soybean-Derived Sterols in Mice

The systemic degradation and the reticuloendothelial system (RES) uptake of calcein entrapped in dipalmitoylphosphatidylcholine (DPPC) liposomes with soybean-derived sterols (SS) were examined after intravenous administration to mice by measuring the free and liposomal calcein levels in the blood. The results indicate that the rates of systemic degradation and the RES uptake of liposomes decrease with the addition of SS in DPPC liposomes since the SS has the ability to stabilize the liposomes. The rate of uptake by RES is larger than the rate of systemic degradation. The rate of leakage of calcein from liposomes by incubation in plasma in vitro is almost the same as that of systemic degradation in vivo.