Composite membrane estradiol implant.

The diffusion and permeability of large organic molecules through polymeric films were investigated, specifically the passage of estrogen through films of polyethylene, silicone, or a composite of these two films. Such systems are of interest because of the possibility of constructing a biocompatible implant that releases a hormone at a controlled and desired rate. Diffusion and permeability coefficients through implants of a desirable size-successfully tested in rats-were measured by the "time lag" method of diffusion, and solubility coefficients were determined by the method of sorption kinetics. Independently derived values were in good agreement. An interesting observation was made with implications for the controlled release from membrane-based drug delivery systems. Permeability coefficients of estrogen are orders of magnitude higher when estrogen is present as a solid rather than in a dilute solution, while diffusion coefficients are equal. This finding is explained by the considerably higher partial vapor pressure of estrogen in the former case. In fact, control of the partial vapor pressure of the encapsulated drug is a powerful method for controlling its release rate.     

Formation of peptide impurities in polyester matrices during implant manufacturing.

Most peptides are susceptible, in vivo, to proteolytic degradation, and it is difficult to formulate and to deliver them without loss of biological activity. In addition, it is often desirable to release them continuously and at a controlled rate over a period of weeks or months. For these reasons, a controlled release system is suitable. Poly(lactic acid) (PLA) is a biocompatible and biodegradable material that can be used for many applications, including the design of injectable controlled release systems for pharmaceutical agents. Development of these delivery systems presents challenges in the assessment of stability, specially for peptide drugs. By means of an extrusion method, long-acting poly(lactic acid) implants containing vapreotide, a somatostatin analogue, were prepared. The nature of the main degradation product obtained after implant manufacturing was elucidated. It was found that the main peptide impurity was a lactoyl lactyl-vapreotide conjugate. Because lactide are found in small quantities in most commercially available PLA, the influence of residual lactide in the polymeric matrix, on the formation of peptide impurities during manufacturing, was specially investigated. This work demonstrates that the degree of purity of the carrier is of great importance with regard to the formation of peptide impurities.     

雌二醇埋植剂在家兔体内的药代动力学研究

目的 观察雌二醇埋植剂在家兔体内的释放过程,同时进行药代动力学研究.方法 将自制的雌二醇埋植剂植入家兔皮下,用RIA方法 检测血清中雌二醇含量,并用3p87软件估算了药代动力学参数.结果 雌二醇埋植剂在家兔体内释放过程符合一房审模型,Cmax为327.43pg/mL,tmax为0.2421h.取出埋植剂后,血药浓度下降迅速,t1/2为19.33h,清除率为0.1218ml/h.结论 用硅胶囊控制雌二醇在动物体内的缓慢释放是可行的.     

雌二醇阴道用缓释胶囊的制备及体外释放行为的考察

目的制备雌二醇阴道用缓释胶囊,并考察其体外释药行为。方法以聚维酮K30为载体,溶剂法制备雌二醇固体分散微粒;采用溶出度测定仪和动态透析2种方法分别评价优化后的处方及对照片剂的体外药物释放情况。结果优化的处方与雌二醇阴道片释放行为较为接近,具有良好的持续性低剂量释药的作用。结论雌二醇阴道用缓释胶囊是一种理想的阴道给药新剂型。     

Eudragits: role as crystallization inhibitors in drug-in-adhesive transdermal systems of estradiol.

A transdermal steroidal delivery system usually contains a high concentration of drug to obtain high drug fluxes. The present investigation involved the development of drug-in-adhesive transdermal systems of estradiol using synthesized acrylate copolymer (EA) of 2-ethylhexyl acrylate and acrylic acid. The effect of several variables such as varying drug polymer ratios, effect of Eudragit RL PO and Eudragit E PO and effect of drying temperatures on prevention of drug crystallization in the formulation matrix was investigated. The systems free from drug crystals were evaluated and compared with a marketed formulation with respect to its skin permeation profile. The optimized formulation was also subjected to accelerated stability testing. Eudragit RL PO and Eudragit E PO were found to be effective as crystallization inhibitors in the transdermal matrix systems tested. Formulations fabricated with Eudragit E PO gave transparent systems with good film properties and a higher skin permeation profile as compared to that of the marketed system. Higher temperature and humidity conditions facilitated the formation of drug crystals, whereas no crystals were observed in the formulation matrix at 23+/-0.5 degrees C and at 30+/-1 degrees C for the period of 6 months studied.     

甲氨蝶呤缓释植入剂体外释放方法的研究

目的:建立甲氨蝶呤缓释植入剂体外释放方法。方法:选择影响甲氨蝶呤缓释植入剂体外释放的重要影响因素进行正交试验,优选释放条件。结果:最优参数如下:介质为偏碱性等渗液,介质浓度为25%,介质体积为200mL,搅拌转速为50r·min~(-1)。结论:所定方法可用于甲氨蝶呤植入剂的体外释放测试。     

植入用缓释氟尿嘧啶的人体内血药浓度经时方程初探

目的：探讨并建立植入用缓释氟尿嘧啶的人体内血浆浓度经时模型。方法：分析体内过程，建立微分方程，求解与证明。结果：经19例试验者数据拟合，其人体内血药浓度经时模型为：单室开放式模型，血药浓度方程C＝A1e^-Ket A2e^-kat A3e^-Krt。结论：此方程为植入剂药代动力学参数的计算提供理论参数。     

Avermectin粗粉的结晶工艺研究与杂质分析

采用高效液相色谱（HPLC）-电喷雾串级质谱（ESI-MS-MS）的方法对avermectin粗粉中的杂质进行定性分析。确定了主要杂质成分为：与Bla结构相类似的B1b、A1a、A1b、A2a、A2b、B2a 6个组份，其中A1a、B1b、B2a多次结晶也不易去除。随后考察了avermectin粗粉在甲醇、乙醇、正丁醇和丙酮中的重结晶，甲醇和正丁醇对杂质的去除效果更好；乙醇与丙酮相当，但对杂质去除的选择性不同。     

气固顶空色谱法测定植入用缓释氟尿嘧啶中环己烷

目的:测定植入用缓释氟尿嘧啶中环已烧残留量。方法:研碎供试品,置针管中于60℃保温作气固顶空平衡,顶空气以气相色谱法测定,氢焰检测器,SE-30固定相,柱温80℃。结果:方法的精密度RSD为2.8％,回收率为101.4％,10～110ng·mL~(-1)范围内线性良好,检出限为3.4ng·mL~(-1)。结论:为类似难溶性固体药物的有机溶剂残留量检测提供了可靠的方法。     

HPLC法测定缓释氟尿嘧啶植入剂血药浓度

目的建立HPLC法测定直肠癌患者血浆中缓释5-氟尿嘧啶植入剂浓度的方法。方法血浆样品用乙酸乙酯提取,真空干燥,残留物用50%甲醇溶解后进样。色谱柱为C18柱(250 mm×4.6 mm),流动相为甲醇∶水(5∶95),流速1.0 ml.min-1,紫外检测波长263 nm,5-溴尿嘧啶为内标。结果血清杂质对样品测定无干扰。标准曲线的回归方程为Y=0.748 3X+0.023 6,r=0.999 7;日内和日间RSD分别为2.1%～6.9%和3.5%～7.2%(n=5);相对回收率为98.7%～104.5%,最低检测限为0.025 mg.L-1。结论试验结果表明该法经济、简便、快速、灵敏度高、重现性好,适合于缓释5-氟尿嘧啶的药代动力学研究及临床血药浓度检测。     

Pharmacokinetics of a sustained-release theophylline formulation.

1 Plasma theophylline concentrations following administration of sustained-release (SR) theophylline tablets were determined in ten healthy volunteers using a dose of 190 mg or 380 mg 12 hourly. 2 The plasma theophylline levels during the first 12 h period confirmed the sustained-release formulation characteristics, with the plasma drug concentrations reaching a plateau for the last 6 hours. 3 During the fifth 12 h dosing period the mean maximum and minimum plasma theophylline concentrations were 7.25 and 4.30 microgram/ml after 190 mg SR theophylline 12 hourly (n = 6) and 12.96 and 7.36 microgram/ml after 380 mg 12 hourly (n = 5), although there was marked between-subject variation in plasma theophylline concentrations. 4 One subject withdrew from the study due to side effects, which were more common when the higher dose of SR theophylline was given.     

Effect of omeprazole on the pharmacokinetics of sustained-release carbamazepine in healthy male volunteers.

The present study shows the effect of omeprazole administration on the pharmacokinetics of a sustained-release preparation of carbamazepine in healthy male volunteers. Multiple dose administration of omeprazole increased the Cmax, AUC0-infinity and elimination half life (t1/2e) of carbamazepine. The results suggest that drug monitoring should be carried out when carbamazepine is coadministered with omeprazole.     

Effect of N-methyl-2-pyrrolidone on skin permeation of estradiol.

N-Methyl-2-pyrrolidone (NMP) increased the skin permeation of estradiol (E2) in Yucatan micropig epidermis using a modified Franz-type diffusion cell. The addition of NMP significantly increased the fluxes of E2 from water and soybean oil. The flux and skin concentration of E2 were higher from soybean oil than from water and increased with increasing NMP concentrations in soybean oil. Correlation was observed with E2 flux and skin concentration (R(2) = 0.804) NMP enhanced E2 skin permeation because NMP made E2 skin concentration higher. Thus, NMP (10%) was added to the oily gel made by isocetyl isostearate and hydrogenated phospholipid. E2 permeation from the gel without NMP was the same as that from soybean oil suspension. The flux of E2 from the gel with NMP was 0.6 microg/h per cm(2) and might be sufficient for estrogen replacement therapy.     

Effect of a sustained-release formulation of trimazosin in mild to moderate hypertension

A single-blind study was conducted to evaluate the blood pressure (BP) reduction and side effects of a sustained-release (SR) formulation of trimazosin in patients with mild to moderate hypertension. Eighteen individuals (age, 21-65 yr; mean diastolic BP, greater than 95 mm Hg) with essential hypertension were enrolled into the study. Each patient's dose was titrated to a range of 150-900 mg/d, with polythiazide added as necessary to achieve BP control. Four hours following the maximum titrated dose of trimazosin, mean standing and supine diastolic BPs were significantly lower than baseline readings. Supine systolic BP and supine and standing heart rate were not significantly lower than baseline. At 24 hours after administration of the maximum dose, there were no significant differences in heart rate of BP compared with baseline readings. Five of 16 patients responded to trimazosin therapy alone. Of the 11 treatment failures with trimazosin alone, five were therapeutic failures and six discontinued because of side effects. Only two of these 11 patients achieved satisfactory results with the combination therapy. Trimazosin SR acutely lowers BP three to six hours after administration. It appears to have a duration of action longer than six hours, but it is not sustained for 24 hours. The proportion of patients failing to respond in this sample was very high and suggests that for similar patients, the drug does not appear to be a very useful antihypertensive agent.     

Treatment of diabetic macular edema with sustained-release glucocorticoids: intravitreal triamcinolone acetonide,dexamethasone implant,and fluocinolone acetonide implant

Introduction: Diabetic macular edema (DME) can be treated with intravitreal glucocorticoids, particularly triamcinolone acetonide, dexamethasone (DEX), and fluocinolone acetonide (FA).

Areas covered: The pathophysiology of DME includes multiple growth factors such as VEGF and also inflammatory mediators. Glucocorticoids act on DME through multiple pathways, and current research into their efficacy, safety, and therapeutic potential when administered intravitreally is discussed.

Conclusion: The intravitreal route of administration minimizes systemic side effects of glucocorticoids. Furthermore, sustained-release low-dose delivery via the DEX implant or the FA implant will limit frequent intravitreal injection and possibly some cost associated with intravitreal anti-VEGF therapy. In addition, the durable action of these treatments facilitates combination therapy. Patients can receive these implants as foundational therapy, and then receive additional treatment with laser or intravitreal anti-VEGF agents as combination therapy, which may conceivably provide some synergistic benefit. While the FA implant lasts much longer than the DEX implant, potentially decreasing the visit and treatment burden on patients and their families, the FA implant appears to have a greater risk of inducing ocular hypertension and cataract. However, these modalities have not been directly compared in a clinical trial and there is insufficient evidence to draw more elaborate conclusions.     

雌二醇对孕酮作用的影响

孕酮对充分生长的蟾蜍卵母细胞膜电位有去极化的作用.这种膜电位去极化作用可被同时应用的雌二醇所完全阻断。目前发现:孕酮作用于离体培养的卵母细胞有胚泡降解发生;给予孕烯醇酮同样可促进卵母细胞成熟;但孕酮促成熟作用却可被二丁酰CAMP(ab-CAMP)或雌二醇等所阻断。我们实验中发现,用10倍于孕酮剂量的雌二醇确实显著性减弱孕酮的去极化效应;进一步证明膜电位去极化与孕酮促成熟作用是有内在联系的。     

Effect of an enteral nutrient formula on sustained-release theophylline absorption

The effect of an enteral nutrient formula (Osmolite) on the absorption of a single oral dose of sustained-release theophylline (Slo-bid) was studied in healthy men. In a randomized, crossover design, subjects received the enteral nutrient diet (2,400 ml/day) or food diet (F) of similar caloric, fat, carbohydrate, protein, and sodium content for 7 days. On day 6 of each diet, volunteers received a single oral dose (600 mg) of sustained-release theophylline (SRT) after fasting or with hourly oral boluses (100 ml) of enteral nutrient formula (ENF). Serial blood samples were collected for 48 h and serum concentrations were analyzed by enzyme multiplied immunoassay. Slight differences (p less than 0.01; paired t test) in Cmax (7.1 +/- 1.2 versus 8.2 +/- 1.3 mg/L) and Tmax (10.7 +/- 2.4 vs. 7.1 +/- 1.1 h) were observed between the ENF and F diets, respectively. However, areas under the curve values were similar (215 +/- 72 versus 211 +/- 70 mg h/L). This study suggests that ENF does not affect the extent of absorption of SRT when administered as a single oral dose.