葡萄糖浓度感应型胰岛素控制释放膜研究

The pore size and permeability control of a glucose-responsive gating membrane with plasma-grafted poly(acrylic acid) (PAAC) gates and covalently bound glucose oxidase (GOD) enzymes were investigated systematically. The PAAC-grafted porous polyvinylidene     

Convective diffusional analysis for drug transport through a tubular polymeric membrane.

The transport of three p-aminobenzoate esters (ethyl, butyl, and hexyl) through a tubular dimethyl polysiloxane membrane into a flowing liquid was investigated. The tubular configuration permits the exact determination of the convective diffusional contribution to membrane transport with models that account for fluid hydrodynamics. The observed transport behavior ranged from complete convective diffusion control for the hexyl ester to complete membrane control for the ethyl ester; the butyl ester exhibited a change in control with flow rate. The implications of convective diffusional considerations to intestinal absorption and dissolution studies are discussed.     

Mathematical model equation of the volume flows through polymeric membrane of heterogeneous non-ionic solutions

Formalism leading to more general form of the Kedem-Katchalsky equation describing osmotic membrane transport, considering local unhomogenity of solutions called concentration boundary layers and influence of gravitational factor on membrane transport kinetics was presented. In order to test this formalism, osmotic volume flux was calculated, on the basis of experimental membrane transport parameters and aqueous glucose solutions in isothermal conditions. Obtained calculation's results are conformable to adequate experimental results presented in previous paper for flat polymeric membrane used in medicine (Biophys. Chem. 1986, 24, 173).     

Effects of concentration boundary layers in a transport of electrolyte solutions through horizontal mounted polymeric membrane

The results of experiment of diffusive transmembrane transport in a single-membrane osmotic-diffusive electrochemical cell were presented. In all experiments one of the vessels was filed with pure water, and the second one--with aqueous potassium chloride solution in aqueous ammonia solutions of constant concentration. The flux of potassium chloride was assigned according to the following measure procedure. In a first step we assigned the time dependence of potassium chloride flux in conditions of uniform mechanically stirred solution with speed of 500 rpm. In a second step those characteristics were assigned in conditions of mechanically unstirred solution. Each experiment was made for two configurations of gravitational membrane system: (i) with the water in a vessel above the membrane and solution below it (configuration A) (ii) with the solution in a vessel above the membrane and water below it (configuration B). Taking under the consideration the values of potassium chloride flux in steady state for different solution concentration of the same substances and the same configurations of membrane system, the dependencies of potassium chloride flux from the solution concentration differences were made appropriately. On the base of those experiments the solute flux concentration boundary layers effects (jCBLE) were counted. Moreover it was shown that single-membrane osmotic-diffusive electrochemical cell has rectifier and amplifying of diffusive flow features. The coefficients, appropriately, of asymmetry and amplification of diffusive flux are the measurements of those features.     

Diffusion model for the study of a drug from the hydrophilic matrix of a transdermal therapeutic system through a model polymeric membrane

Conclusions The kinetics of drug supply described above from gel-like hydrophilic matrices of a TTS through human skin, or a polymeric membrane imitating itin vitro, are analogous to the kinetics of the release of a drug from a reservoir TTS through an attached polymeric membrane controlling the rate. Studying the kinetics of drug supply from diffusion matrices of TTS through a polymeric membrane imitating skin enables modeling of the kinetics of transdermal drug supplyin vitro andin vivo. The adequacy of such modeling is determined by the correlation between the diffusion coefficients of the drug in the membrane and skin epidermis and the distribution coefficients of the drug between skin and matrix or between membrane and matrix, which are subject to experimental determination.The transdermal supply of drug with kinetics of zero order (i.e. at a rate constant with time) may be effected from a TTS of the membrane-reservoir type containing a membrane specially controlling the rate or from a matrix TTS. In the latter case the function of the membrane controlling the rate of drug supply is fulfilled by the human skin at the point of application of the TTS, while the TTS diffusion matrix acts as a reservoir containing drug on the skin surface and limits the maximally achievable rate of drug release from the TTS to the skin according to equation 12. The competence of such an approach is occasionally questioned because of fears that the permeability of skin for a drug depends markedly on the point of application of the TTS and on the special features of the patient's skin. The effect of skin permeability at the point of application on the rate of transdermal drug supply has been studied well in [21] and a standard place for the application of a TTS may be the correct choice. The vast scope for the clinical application of the various TTS available at the present time indicates that individual variability of skin permeability is not so great and may be displayed mainly by a reduced permeability of the skin for a drug. Unlike membrane-reservoir TTS the majority of matrix TTS may be divided into portions of various size without disturbing their efficiency. This raises the possibility of continuously regulating the dose (by the area of application for TTS of this type).Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 10, pp. 38–45, October, 1994.     

Toxicological assessment of orally delivered nanoparticulate insulin

Subacute toxicological assessment on diabetic rats was conducted after 15 days of daily oral administration of nanoparticulate insulin. Haematological and biochemical analyses were conducted on blood and urine, biopsies performed on organs and tissues, and histology analysed by optical microscopy. Insulin-loaded nanoparticles alone did not change liver or kidney functions. The increase of some hepatic parameters was attributed to diabetes physiopathology and to chemical inducement of diabetes and not to the nanoparticle composition since diabetic controls showed the same variations. In terms of kidney function, parameters such as urea nitrogen and creatinine, were also similar to normal rats with the exception of glycosuria. This single effect was due to diabetes physiopathology and the method of induction, and not to the nanoparticle composition, since non-dosed diabetic rats showed the same alteration. Even so, glycosuria levels of animals dosed with insulin-loaded nanoparticles were lower than control diabetic rats which may indicate an effective hypoglycaemic response. Nanoparticles did not exhibit toxicity in haematological parameters. Finally, organ histology was similar between dosed animals and normal rats with the exception of pancreas histology.     

Modification of the Katchalsky's relation between effective and real solute permeability coefficients through polymeric membrane

Using Kedem-Katchalsky equations, in which volume (J(v)) and solute (J(s)) fluxes are functions of the osmotic (delta(pi)) and hydrostatic (deltaP) driving forces, the mathematical model for zeta(s) parameter was elaborated. This parameter describes relation between effective and real solute permeability coefficients through a membrane. Calculations performed on the basis of obtained quadratic equation show that for a polymeric membrane with fixed transport properties parameter zeta(s) is nonlinear function of solution concentration. This nonlinearity is caused by a change of distance between a system and stable state of diffusion. The reason of this nonlinearity is change of distance between a system and stable diffusion state. The appearance of instability related with breaking of symmetry of concentration boundary layers relative to the gravitation direction causes increases of the coefficient value. This is the sign of appearance of diffusion-convection of mass transport.     

Application of the network thermodynamics to interpretation of transport in a microsystems: transport of homogeneous solutions through polymeric membrane

The Kedem-Katchalsky equations, derived using symmetric and hybrid transformation of the Peusner's network transformation, to interpretation of transport through Nephrophan membrane of glucose aqueous solutions were employed. The values of Rij, Lij, Hij i Pij (i does not = j = 1, 2) coefficients were calculated. From these calculations it results that, the values of coefficients R12, L11 and H11 are independent on concentration (C). The values of residual coefficients are dependent on C: values of coefficients P11, L12, L22 and H22 increases linearly, while values of coefficients R22 and P22--hiperbolic decreases together with growth of C. In turn the coefficient H12 is negative and coefficients P11 and P12 are positive. The values of these coefficients decreases together with growth of C.     

Osmotic, diffusive and convective volume and solute flows of ionic solutions through a horizontally mounted polymeric membrane

On the basis of Kedem-Katchalsky's equations in classical and modified versions, the model equations of volume and solute fluxes were presented. In this model the osmotic volume flux is a sum of: simple osmotic, osmotic connected with natural convection and osmotic connected with forced convection fluxes. The solute flux is a sum of: simple diffusion, diffusion connected with natural convection and diffusion connected with forced convection fluxes. On the basis of this model, the respective definitions of the reflection and permeability coefficients were presented. In order to verification of this model, the volume and solute flows in a single-membrane osmotic-diffusive cell, which contains a flat polymer membrane separating water and electrolyte solutions has been studied. In the experimental set-up, water was placed on one side of horizontally mounted membrane. The opposite side of the membrane was exposed to aqueous solution of KCl or NH3. Each experiment was performed for configurations A and B of the single-membrane system. In configuration A water was placed in the compartment above the membrane and solution below it. In configuration B the arrangement of water and solution was reversed. The measurements of stationary volume and solute fluxes were performed in conditions of mechanical stirring and after stopping of mechanical stirring of solutions. On the basis of experimental data of volume and solute fluxes, calculations of reflections and solute permeability coefficients for aqueous solutions of KCl and NH3 were presented.     

Enhanced enteric properties and stability of shellac films through composite salts formation

The objective of this study was to improve the properties of shellac by composite salts formation. The shellac samples were prepared in various salt forms by dissolving them with 2-amino-2-methyl-1-propanol (AMP) and ammonium hydroxide (AMN) at various ratios of AMP:AMN. The results demonstrated that aqueous solubility of the shellac salts was improved as the ratio of AMP:AMN increased. The absorbance ratio of the FTIR peaks assigned to CO stretching of carboxylate and carboxylic acid (ABS₁₅₅₆/ABS₁₇₁₆) was increased with the increase of the AMP fraction, suggesting that the solubility enhancement was due to more ionization of AMP salts. Moisture adsorption studies indicated that shellac salts were more hygroscopic as AMP content increased. After storage at 40 °C, 75% RH, the acid value and insoluble solid of AMP salts were relatively constant even after storage of up to 180 days, suggesting that AMP should protect polymerization. The ABS₁₅₅₆/ABS₁₇₁₆ values of the shellac salts were rapidly decreased after storage, especially for those consisting of a high percentage of AMN. Thus, AMP should bind much tighter at the carboxylate binding site as compared with AMN, resulting in more solubility and stability. In conclusion, optimized shellac properties could be easily accomplished by composite salts formation.     

Enhanced enteric properties and stability of shellac films through composite salts formation.

The objective of this study was to improve the properties of shellac by composite salts formation. The shellac samples were prepared in various salt forms by dissolving them with 2-amino-2-methyl-1-propanol (AMP) and ammonium hydroxide (AMN) at various ratios of AMP:AMN. The results demonstrated that aqueous solubility of the shellac salts was improved as the ratio of AMP:AMN increased. The absorbance ratio of the FTIR peaks assigned to CO stretching of carboxylate and carboxylic acid (ABS1556/ABS1716) was increased with the increase of the AMP fraction, suggesting that the solubility enhancement was due to more ionization of AMP salts. Moisture adsorption studies indicated that shellac salts were more hygroscopic as AMP content increased. After storage at 40 degrees C, 75% RH, the acid value and insoluble solid of AMP salts were relatively constant even after storage of up to 180 days, suggesting that AMP should protect polymerization. The ABS1556/ABS1716 values of the shellac salts were rapidly decreased after storage, especially for those consisting of a high percentage of AMN. Thus, AMP should bind much tighter at the carboxylate binding site as compared with AMN, resulting in more solubility and stability. In conclusion, optimized shellac properties could be easily accomplished by composite salts formation.     

Studies on the liberation behavior of insulin from polymeric matrices

The in-vitro and in-vivo liberation of insulin from embeddings in polymeric matrices was investigated dependent on the charging degree, the particle- and pore size, respectively, of the granules and the dissolution behaviour of the hormone. Polyacrylamide, agar-agar, dextrane and Sephadex G-100 were used as ground-mass. These polymers are characterized by a good swelling and a high binding capacity. If these properties quality them for insulin was investigated in model experiments. Information concerning the obtained retention effects of the matrix mould were produced by photochemical methods (application of insulin against citrate phosphate buffer; absorption region of 230 to 320 nm). The in-vitro effects yielded could be confirmed by means of representative in-vivo studies in eumetabolic insulin sensitive rabbits.     

Enteric-coated insulin microparticles delivered by lipopeptides of iturin and surfactin

Surfactin, a lipopeptide produced by Bacillus species, has been used for the oral delivery of insulin. In this study, another lipopeptide of iturin was tested for its ability to orally delivery insulin alone or plus surfactin. Iturin could form co-precipitate with insulin at acidic pH values. After treatment by ultrasonification, the structure of coprecipitate was destroyed that led to a significant decrease in hypoglycemic effect after oral administration. Iturin weakly binds to (Kd?=?257?μM) and induce insulin structure more compact that is favorable for insulin uptake by the intestine. After being coated with Acryl-Eze by lyophilization, the coprecipitate formed the spherical enteric-coated insulin microparticles delivered by iturin with a relative oral bioavailability of 6.84% in diabetic mice. For further improving oral hypoglycemic effect, surfactin was added to form the spherical enteric-coated insulin microparticles in a formulation containing insulin, Acryl-Eze, iturin and surfactin at a ratio of 1:1:0.5: 0.5 (w/w), with an insulin encapsulation efficiency of 66.22%. The enteric-coated insulin microparticles delivered by iturin plus surfactin showed a classical profile for controlled release in the intestine with a relative bioavailability of 7.67% after oral administration, which could effectively control the postprandial blood glucose at a level about 50% of the initial one just like the subcutaneous injection. Collectively, iturin plus surfactin is more efficient for oral delivering insulin than the sole one, and the resultant enteric-coated insulin microparticles are potential for the development of oral insulin to control postprandial blood glucose in diabetic patients.     

吸入型胰岛素新制剂:Afrezza

2014年6月Mann Kind公司研发的吸入型胰岛素——Afrezza经美国食品和药物管理局批准上市,为超速效吸入型餐时胰岛素新剂型,其模仿生理性胰岛素的分泌,可有效降低餐后血糖,对患者体重影响小,低血糖发生率低,与基础胰岛素联合用于1型和2型糖尿病的餐时治疗。Afrezza最常见的不良反应是咳嗽、咽喉痛或咽部刺激症状。     

注射用紫杉醇聚合物胶束稳定性的研究

目的:从聚合物胶束动力学稳定性机制出发,研究制备温度及贮存温度对以PLA-mPEG为载体的紫杉醇聚合物胶束物理稳定性的影响.方法:通过DSC法考察PLA-mPEG疏水嵌段的玻璃化温度,通过荧光偏振法、荧光光谱法及1H-NMR谱图分别考察PLA-mPEG疏水嵌段粘度、极性及其链段移动性随温度的变化;采用熔融蒸发法制备紫杉醇聚合物胶束,建立了以T1和K为参数的紫杉醇胶束稳定性考察方法,并考察其在不同制备及贮存温度下物理稳定性的变化.结果:在玻璃化温度附近,PLA-mPEG聚合物胶束疏水嵌段的粘度较小,核嵌段迁移较剧烈,极性较大;而通过熔融蒸发法制备的紫杉醇载药聚合物胶束在玻璃化温度附近,即50 ℃下水化后物理稳定性较好,贮存温度在4 ℃物理稳定性较好,符合基于紫杉醇载药聚合物胶束微观性质的结果对其物理稳定性的预测.结论:聚合物胶束动力学稳定性的机理,对制备稳定的紫杉醇载药胶束有着重要的指导意义.     

胰岛素粉雾剂肺部给药对大鼠的降血糖作用

目的:观察胰岛素吸入粉雾剂肺部给药后的降血糖效果.方法:胰岛素与合适辅料制成的干粉经大鼠肺气管切口吹入肺中,测定随后7小时的血糖浓度,以血糖曲线上面积(AAC)为指标对其药效进行评价.结果:吸入胰岛素剂量为20,10,5和2.5U/kg时,最低血糖浓度可分别降至给药前的6.5％,16.6％,24.6％和57.0％;剂量为5 U/kg吸入给药的AAC值和5U/kg皮下注射给药的AAC值相近;AAC值与对数剂量间存在线性关系.结论:胰岛素肺部给药的降血糖效果明显且作用迅速.