Egg shell membrane as a substrate for optimizing in vitro transbuccal delivery of glipizide

Buccoadhesive gels for transbuccal delivery of glipizide were prepared using different bio-adhesive polymers. The gels were prepared by solution polymerization technique. An apparatus simulating the in vivo conditions of the mouth was designed in order to assess in vitro drug release kinetics of these gels. The gels were also evaluated for spreadability, buccoadhesive strength, swelling index, and viscosity. Maximum buccoadhesive strength was observed for formulation, F8 with good sustained release behavior, whereas viscosity and swelling index was highest for the formulation, F5 but with minimum buccoadhesive strength. The drug release kinetics followed Higuchi model with release mechanism being Fickian diffusion.     

格列吡嗪治疗62例非胰岛素依赖型糖尿病

应用格列吡嗪治疗62例NIDDM患者。在新近诊断未经治疗的41例中,有效35例(85％),21例各种磺脲化合物治疗失效者,有效12例(57％)。治疗有效者,治疗后血糖、GHb、GPP、24h尿糖均较治疗前显著减低,餐后2小时血清胰岛素浓度明显升高,HDL-ch、HDL_2或HDL_3也较治疗前显著增高。副反应少见。研究表明,格列吡嗪是治疗NIDDM较有效而安全的药物。     

国产与进口格列吡嗪治疗非胰岛素依赖型糖尿病比较

应用国产格列吡嗪治疗104例Ⅱ型糖尿病患者和进口格列吡嗪治疗85例Ⅱ型糖尿病患者,均口服13±7mg/d,3mo,作对照比较研究。结果表明治疗有效者空腹和餐后血糖、糖基化血红蛋白(HbA_1)、24h尿糖与血清甘油三酯水平均较治疗前明显降低,餐后2h血清胰岛素水平明显升高。2组中副作用少见。2组比较研究结果证明国产与进口格列吡嗪的疗效并无明显差异。     

格列吡嗪盐酸二甲双胍片治疗2型糖尿病的多中心、随机、双盲双模拟临床研究

目的评价格列吡嗪盐酸二甲双胍片(降血糖药)的疗效及安全性。方法用多中心、随机、双盲双模拟临床研究,试验组120例,二甲双胍组、格列吡嗪片组各60例,治疗12周。结果治疗前后试验组较二甲双胍组HbAlc多降低了0.78%,较格列吡嗪组多降低了0.41%(P<0.001);治疗前后试验组较二甲双胍组空腹血糖多降低了0.97 mmol·L~(-1),较格列吡嗪组多降低了1.36 mmol·L~(-1)(P<0.001);低血糖发生率3组相似。结论格列吡嗪盐酸二甲双胍与单药治疗相比,降低HbAlc、空腹及餐后2 h血糖均更为明显,且耐受性很好。     

Formulation and evaluation of limonene-based membrane-moderated transdermal therapeutic system of nimodipine

The aim of the present study was to design a membranemoderated transdermal therapeutic system (TTS) of nimodipine using 2% w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing 4% w/w of limonene as a penetration enhancer. The permeability flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer (9 to 28%). The effect of pressure-sensitive adhesives such as TACKWHITE A 4MED® on the permeability of nimodipine through EVA membrane 2825 (28% w/w vinyl acetate) or membrane/rat skin composite also was studied. The permeability flux of nimodipine from the chosen EVA 2825 (with 28% vinyl acetate content) was 159.72 ± 1.96 μg/cm²/hr, and this flux further decreased to 141.85 ± 1.54 μg/cm²/hr on application of pressure-sensitive adhesive (TACKWHITE A 4MED®). However, the transdermal permeability flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED®/rat skin composite was found to be 126.59 ± 2.72 μg/cm²/hr, which is 1.3-fold greater than the required flux. Thus, a new transdermal therapeutic system for nimodipine was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED® and 2% w/w HPMC gel as reservoir containing 4% w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nimodipine, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 20 hr with improved bioavailability in comparison with the immediate release tablet dosage form.     

Development of a membrane-controlled transdermal therapeutic system containing isosorbide dinitrate

The formulation of a transdermal delivery system for isosorbide dinitrate (ISDN) was examined. It was found that the target release rate should be 4.01 mg/h per 20 cm² for optimal dosing. In order to reach such this zero order release rate, a membrane permeation controlled transdermal therapeutic system (TTS) formulation was developed, with ethylene vinyl acetate copolymer (EVAC) and polyethylene (PE) membranes as rate controlling membranes; a carbomer gel was used as the drug reservoir. The release of ISDN from this drug delivery device was studied in vitro using FDA recommended method. PIB adhesive on the EVAC or PE membrane caused a decreased flux of ISDN; the release kinetics fitted Higuchi matrix kinetics. TTS with EVAC membrane release ISDN at a rate much lower than the calculated target release rate, but with PE membranes, the release rate was very close to the target. Release rate studies have revealed that, as the VA content in EVAC membrane increased, the flux of ISDN increased. All these results were compared with the commercial product Frandol^® Tape S from Japan. It was found that the release rate of Frandol was close to target release rate and fitted matrix kinetics. These results suggested that TTS that contain PE membrane as rate controlling membrane, polyisobutylene (PIB) adhesive and carbomer gel as a reservoir can be applicable as a TTS for ISDN.     

格列吡嗪控释片对磺脲类药物疗效不佳的2型糖尿病患者的疗效观察

目的:评价口服磺脲类降糖药物效果不佳改用格列吡嗪控释片或加用睡前中效胰岛素治疗对糖尿病患者的治疗效果。方法:142例口服磺脲类药物治疗的2型糖尿病患者随机分为4组:A组原磺脲类治疗组;B组改用格列吡嗪控释片治疗组;C组格列吡嗪控释片加睡前胰岛素组;D组原磺脲类加睡前胰岛素组。治疗12周后观察血糖、胰岛素水平和糖化血红蛋白的改变。结果:在4组中,格列吡嗪控释片加胰岛素组和磺脲类降糖药物加胰岛素组治疗效果最好,改用格列吡嗪控释片血糖较原治疗组有所改善,糖化血红蛋白降低,而维持原磺脲类治疗组效果不理想。格列吡嗪控释片加胰岛素组服药依从性好,不良反应少,低血糖发生率低。结论:对于原磺脲类药物治疗不达标患者,换用格列吡嗪控释片治疗具有较好的服药依从性和满意度,治疗效果优于换药前,且可以降低糖化血红蛋白水平,值得临床推广。加用胰岛素睡前注射治疗可更好地控制血糖(包括空腹和餐后血糖),降低胰岛素和糖化血红蛋白水平,但低血糖发生率增多,在临床应用中应加以注意。     

Therapeutic equivalence of once- and thrice-daily glipizide

Summary Two cross-over studies were carried out in 23 patients with Type 2 diabetes, to examine whether glipizide, a potent sulphonylurea with fast and complete absorption and rapid elimination (t_1/2<5 h), can be given once-daily without loss of therapeutic effect. In both studies, patients were randomly assigned to an initial dose of 7.5 mg once daily or 2.5 mg three-times daily, which was increased to 15 mg o.d. or 5 mg t.i.d. if the fasting plasma glucose remained over 10 mmol/l on the lower dosage. In Study 1 (n=11), administration once a day before breakfast was compared with intake before breakfast, lunch and early dinner (5 p.m.) and in Study 2 (n=12) the comparison was between intake once-daily before breakfast and dosing before breakfast, lunch, and at bedtime (10 p.m.).Neither the 24-hour urinary glucose excretion nor HbA₁, fasting plasma glucose, insulin or C-peptide levels differed between the once and three times daily administration with the third dose given before early dinner. The nadir plasma levels of glipizide were not significantly different and were often too low to be detected. Postponing the third dose until 10 p.m. did not produce any improvement in HbA₁ or in fasting plasma glucose, insulin or C-peptide. The mean nadir glipizide levels following this schedule were twice as high as those after once-daily administration.As expected, the plasma glipizide after breakfast was higher when the whole dose was taken before breakfast than when it was divided. The corresponding plasma level of insulin was higher and that of plasma glucose was lower. The after-lunch levels of glipizide did not differ significantly, and there was no after-lunch difference in plasma insulin or glucose.It appears that the major effect of glipizide is to augment insulin availability following meals, whilst it has little influence on nocturnal glucose control. In a daily dose of 7.5 mg or more, glipizide can be taken once daily without loss of efficacy, at least in areas with Northern European meal schedules.     

格列嗪及二甲胍对Ⅱ型糖尿病人血清胰岛素样生长因子—1，2的影响

目的探讨临床常用的口服降糖药物格列吡嗪及二甲双胍和对Ⅱ型糖尿病人血清胰岛素样生长因子-1,2(IGF-1,2)的影响。方法采用治疗前后自身对照研究,分别给予格列吡嗪或二甲双胍治疗2wk,比较两种药物对Ⅱ型糖尿病患者空腹IGF-1,IGF-2血清水平的影响。结果二甲双胍治疗组(25例)空腹血清IGF-1,IGF-2治疗后无明显变化;格列吡嗪(40例)治疗后空腹血清IGF-1升高[(181.8±104.5)vs(209.0±88.2)ng     

格列吡嗪乳胶处方筛选及初步药动-药效学

目的制备格列吡嗪乳胶,考察其体外经皮渗透性及其药动-药效学。方法采用改良Franz扩散池,研究6种不同的有机胺、不同的油相和促进剂对格列吡嗪经皮渗透性的影响,并选择最佳处方进行药动-药效学考察。结果当有机胺为二乙胺和油相为肉豆蔻酸异丙脂且在不含促进剂的条件下,格列吡嗪的药物累积透过量最大;在12 h内,含药质量分数为0.5%和0.125%的乳胶均随着血药浓度的不断上升血糖值下降,但是降糖效果无显著差异(P>0.05)。结论格列吡嗪乳胶降糖作用明显,值得进一步的深入研究,制成一种治疗糖尿病的新剂型。     

Rate Control in Transdermal β-Estradiol Reservoir Membrane Systems: The Role of Membrane and Adhesive Layer

Purpose. The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for -estradiol (E₂) under in vitroconditions by determination of the role of membrane and adhesive layer on E₂flux control. Methods. E₂and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined. Results. The E₂flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E₂by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in the symmetric and asymmetric configuration increased up to maximum values of 0.80 ± 0.14 (g × cm^–2× h^–1and 0.37 ± 0.02 g × cm^–2× h^–1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E₂on ethanol fluxes was observed. Conclusions. The E₂flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (>70% v/v).     

The influence of glipizide on early insulin release and glucose disposal before and after dietary regulation in diabetic patients with different degrees of hyperglycaemia

Summary An early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation.We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect.A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation.The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6–12 mmol·l^–1 of fasting blood glucose.     

格列吡嗪两种剂型治疗2型糖尿病的成本-效果分析

目的评价格列吡嗪两种剂型治疗2型糖尿病的成本-效果。方法经患者知情同意,60例2型糖尿病患者随机分为2组,分别服用格列吡嗪控释片和普通片,以为期12周的疗效观察结合药品成本评价药物的成本-效果。结果治疗12周普通片组与控释片组患者均达到理想的血糖控制效果,且与治疗前相比,治疗后空腹血糖分别下降26%和28%,餐后2 h血糖分别下降38%和36%,糖化血红蛋白分别下降23%和24%,上述指标组间差异无统计学意义,但两组成本-效果分析显示组间差异显著,普通片组成本-效果低于控释片组(P<0.05),然而控释片组服药依从性好。结论格列吡嗪普通片具有成本优势,控释片服药依从性好,两者长期用药的成本-效果评价尚待进一步研究。     

格列吡嗪控释片对2型糖尿病病人血清胰岛素样生长因子的影响

目的 :探讨格列吡嗪控释片对 2型糖尿病病人血糖、胰岛素及胰岛素样生长因子Ⅰ ,Ⅱ (IGF Ⅰ ,Ⅱ )的影响。方法 :糖尿病组初次诊断的 2型糖尿病病人 6 8例 ,对照组健康体检者 4 3例。糖尿病组予格列吡嗪控释片 5～ 10mg ,每日 1次 ,早餐前服用 ,疗程 4wk。观察治疗前后空腹血糖 (FBG)、糖化血红蛋白 (HbA1c)、空腹胰岛素 (FINS)、IGF Ⅰ和IGF Ⅱ的情况。结果 :与对照组比 ,糖尿病组治疗前FINS ,IGF Ⅰ ,IGF Ⅱ水平较低 ,FBG和HbA1c水平较高 (均P <0 .0 1)。治疗后 ,FBG和HbA1c下降 ,FINS ,IGF Ⅰ ,IGF Ⅱ升高 (P <0 .0 1)。结论 :每日服用 1次格列吡嗪控释片可以改善 2型糖尿病病人的糖代谢及血清IGF Ⅰ和IGF Ⅱ的水平。     

格列吡嗪和二甲双胍对2型糖尿病患者血清胰岛素样生长因子结合蛋白—1的影响

目的 :探讨格列吡嗪 ( Gli)及二甲双胍 ( Met)对 2型糖尿病患者血清胰岛素样生长因子结合蛋白 ( IGFBP) - 1影响。方法 :采用治疗前后自身对照 ,5 2例初诊 2型糖尿病患者 ,分为 Gli组 ( 30例 )和 Met( 2 2例 ) ,治疗 2 wk,比较两种药物对患者空腹 IGFBP- 1血清水平的影响。结果 :Met组空腹血清 IGFBP- 1治疗后无明显变化 ;Gli组治疗后空腹血清 IGFBP- 1则明显下降 ( 70 .98± 8.0 7vs5 2 .34± 5 .15 ng/m l,P<0 .0 5 ) ;治疗后 2组血糖均明显下降 ( P均 <0 .0 0 0 1) ;Gli组治疗后 C肽水平明显升高 ( P<0 .0 5 ) ,Met组治疗后 C肽水平无明显变化。结论 :Gli可明显降低 2型糖尿病患者空腹血清 IGFBP- 1水平 ,Met则无影响     

Transdermal Delivery of Levonorgestrel. V. Preparation of Devices and Evaluation in Vitro

Transdermal devices were prepared and evaluated for their ability to codeliver levonorgestrel and the permeation enhancers ethyl acetate and ethanol in vitro. The 24-hr devices were prepared with membranes composed of ethylene vinyl acetate (EVAc) copolymers. The vinyl acetate (VAc) content of the membranes (50 ± 10 or 100 ± 10 µm thick) was varied from 12 to 25% to give a range of permeabilities toward the enhancers. The reservoir used was ethyl acetate/ethanol (7:3, v/v; 0.5 ml) containing excess solid levonorgestrel and gelled with 2% hydroxypropyl cellulose. The higher VAc content membranes (18 and 25%) exhibited relatively high release rates of EtAc and EtOH leading to depletion of ethyl acetate and ethanol from the reservoir by the end of 24 hr. As a result, the transdermal flux of levonorgestrel, evaluated using rat skin, reached a maximum at about 8 hr and thereafter diminished to zero by 24 hr. The less permeable membranes (12 and 15% VAc content) led to a more sustained release of enhancers, but due to lower solvent delivery to the skin, levonorgestrel flux was substantially lower. There was a direct relationship between drug delivery through skin and the amount of solvent delivered until release of the enhancers had diminished. The potential use of ethyl acetate in transdermal drug delivery is also discussed.     

Comparison of the pharmacokinetics of glipizide and glibenclamide in man

Summary Four subjects received 5 mg¹⁴C-glipizide orally, 3 subjects 1 mg intravenously and 2 subjects 5 mg¹⁴C-glibenclamide orally. Plasma levels of radioactivity, and urinary and faecal excretion were measured. For both drugs the disappearance of radioactivity from plasma followed complex kinetics and the apparent half-lives increased steadily with time. The two sulfonylureas were extensively metabolized and were excreted in the urine as hydroxylated or conjugated metabolites. The effects of both drugs on blood glucose and immunoreactive insulin were comparable. The findings are compared with other published results.     

Synthesis and Charactersiation of Chitosan conjugate; Design and Evaluation of Membrane Moderated Type Transdermal Drug Delivery System

The purpose of the present research investigation was to synthesis, characterisation of chitosan conjugates and its effect on drug permeation from transdermal rate controlling membrane. Chitosan conjugate was synthesised by conjugation with thioglycolic acid. The prepared chitosan conjugate was characterised by determining the charring point, Fourier transmission-infrared and differential scanning calorimetric analysis. The rate controlling membranes were prepared by various proportions of chitosan and chitosan conjugate, to moderate drug permeation through rate controlling membrane. The membrane moderated transdermal system consists of reservoir to hold the drug gel was prepared by 20% w/v ethylcellulose with a cavity in its center. An impermeable backing layer was prepared by 2% w/v ethylcellulose. Gel consists of carvedilol was prepared by sodium alginate and sodium carboxymethylcellulose in ethanol:water solvent system The rate controlling membranes prepared were evaluated by various parameters like thickness, folding endurance, swelling index, moisture content, moisture uptake, water vapor transmission rate, tensile strength test, measurement of gel strength, in vitro permeation study, ex vivo permeation study, compatibility study using differential scanning calorimetry and stability studies. All physical parameters evident that prepared membranes have good folding endurance and sufficient tensile strength. As the proportion of chitosan conjugate increases in membrane swelling index, moisture content, moisture uptake and permeability coefficient increases. The gel strength of chitosan conjugate was considerable less compared with chitosan.     

格列吡嗪控释片治疗继发性磺脲类降糖药失效2型糖尿病的疗效

目的 :观察格列吡嗪控释片治疗继发性磺脲类降糖药失效 2型糖尿病的疗效。方法 :选取继发性磺脲类降糖药失效的 2型糖尿病患者 6 4例 ,随机分为 2组 ,各 32例。治疗组予格列吡嗪控释片治疗 ,对照组予格列吡嗪速效片治疗 ,观察 8wk(治疗组分成 4wk剂量调整期 ,4wk维持期 )。治疗前后行 2次口服糖耐量试验 (OGTT)和胰岛素释放试验 ,计算胰岛素释放指数 (IRG)和胰岛素敏感指数 (ISI) ;比较 2组治疗前后血糖 ,血胰岛素 ,IRG ,ISI和临床疗效。结果 :与治疗前比较 ,治疗组治疗后血糖水平下降 ,ISI增高 ,P <0 .0 1;但胰岛素水平及IRG与服药前无显著性差异。对照组各指标治疗前后均无显著性差异。治疗组总有效率 (5 6 .2 % )显著高于对照组 (9.3% ) ,P <0 .0 1,且无明显不良反应发生。结论 :格列吡嗪控释片可改善继发性磺脲类降糖药失效的 2型糖尿病患者胰岛素敏感性及血糖控制 ,可作为继发性磺脲类降糖药失效患者的治疗药物     

Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetics

Summary Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.