Delivery of prazosin hydrochloride from osmotic pump system prepared by coating the core tablet with an indentation

The preparation of an osmotic pump tablet was simplified by elimination of laser drilling using prazosin hydrochloride as the model drug. The osmotic pump system was obtained by coating the indented core tablet compressed by the punch with a needle. A multiple regression equation was achieved with the experimental data of core tablet formulations, and then the formulation was optimized. The influences of the indentation size of the core tablet, environmental media, and agitation rate on drug release profile were investigated. The optimal osmotic pump tablet was found to deliver prazosin hydrochloride at an approximately constant rate up to 24 hr, and independent on both release media and agitation rate. Indentation size of core tablet hardly affected drug release in the range of 0.80-1.15 mm. The method that is simplified by elimination of laser drilling may be promising for preparation of an osmotic pump tablet.     

Factors Affecting the Release of Nifedipine from a Swellable Elementary Osmotic Pump

Oral osmotic devices including an elementary osmotic pump (EOP) are efficient systems for the delivery of drugs with high/moderately water-solublility. In this study we designed a new type of EOP for the efficient delivery of poorly water-soluble and practically insoluble drugs. In this system, called swellable elementary osmotic pump (SEOP), drug is released from the delivery orifice in the form of a very fine dispersion of drug in gel which is ready for dissolution and absorption. Factors affecting the release of drug from the SEOP containing a poorly water-soluble drug, nifedipine, were explored extensively. To this end, effect of swelling and wetting agents, orifice size, concentration of osmotic agent, and hydrophobic plasticizer were investigated. Interestingly, in the absence or low concentration of a hydrophobic plasticizer (caster oil), the osmotic devices did not retain their integrity in dissolution media. Caster oil in concentration of > 1% was necessary for tablets to retain their integrity during dissolution process. A zero-order release kinetics for nifedipine was achieved following the effective optimization of the concentrations of swelling agent, osmotic agent, wetting agent, and also size of orifice and membrane thickness in SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution medium. The designed SEOP is suggested as an efficient controlled delivery system for oral delivery of a poorly water soluble drug such as nifedipine.     

Propranolol Hydrochloride Osmotic Capsule with Controlled Onset of Release

Hard gelatin capsule was coated by a cellulose acetate as a semipermeable membrane with or without castor oil and filled with propranolol hydrochloride and sorbitol as an osmotic agent. After sealing the capsule with white bees wax plug, the onset of release and dissolution rate of the drug were studied. Water penetration into the capsule from the dissolution medium increases simultaneously the osmotic and hydrostatic pressures of its content. When the hydrostatic pressure is high enough to overweigh the gravity and frictional forces of the plug, the expulsion of the plug occurs and drug release starts. The effects of thicknesses of the membrane and plug as well as the concentrations of cellulose acetate and castor oil on the onset of drug release were presented by a polynomial model. We found that the effect of plug thickness on the onset of release is more important when the membrane is thicker. The results showed that the presence of caster oil in coating formulation (cellulose acetate 10% or 15%) increased the onset of release (t_o values). The onset of release varied from 0.6 to 10.5 hr among which the onset times of 4.2, 4.8, 5.9, 5.5, 7.5, 5.0, 7.8 and 10.5 hr could be of use for either chronotherapeutic purposes in protection of patients against heart attacks and strokes during early morning hours or reducing daily frequency of dosage.     

同离子效应对盐酸普萘洛尔渗透泵片释药速率的影响

目的:研究同离子效应对盐酸普萘洛尔渗透泵片中药物释放速率的影响。方法:采用释放度测定Ⅱ法(USP28版), 应用不同pH值、不同氯离子浓度的释放介质,考察药物累积释放度,得出其释放曲线,并结合不同介质的性质进行比较。结果:盐酸普萘洛尔渗透泵片在不同pH的介质中释放速率基本相同,而在不同氯离子浓度的介质中释放速率存在较大差异。结论:由于同离子效应,释放介质及片芯中的氯离子对盐酸普萘洛尔从渗透泵片中的释放存在较大的影响。     

非诺贝特双层渗透泵片在Beagle犬体内的药动学研究

目的 研究非诺贝特双层渗透泵片在犬体内的药动学特征,并评价受试制剂和参比制剂的生物等效性。方法 采用LC-MS测定比格犬体内的血药浓度,采用DAS 2.1.1软件计算药动学参数。结果 受试制剂和参比制剂血浆中非诺贝特酸的C_max分别为（1 100.0±771.2）、（924.3±564.0）ng/mL,t_max分别为（6.7±8.5)、（2.5±0.5）h,AUC0-t分别为（17 841.1±12 220.7）、（17 615.5±12 870.2）ng·h/mL;t_1/2分别为（17.7±8.2）、（16.4±3.3）h,MRT_0-t分别为（24.7±4.0）、（24.5±5.2）h,受试制剂中非诺贝特酸的平均相对生物利用度为（104.7±12.4）%。结论 受试制剂非诺贝特渗透泵片和参比制剂非诺贝特缓释胶囊具有生物等效性。     

HPLC法测定盐酸苯环壬酯渗透泵片的含量

目的：建立高效液相色谱法测定盐酸苯环壬酯渗透泵片含量的方法。方法：采用Diamonsil C_（18）（2）（250 mm×4.6 mm,5μm）色谱柱;流动相：乙腈-水-磷酸-三乙胺（270：400：1.3：2）;检测波长：220 nm;流速：1.0 ml·min~（-1）;柱温：30℃。结果：盐酸苯环壬酯在2~6μg·ml~（-1）范围内线性关系良好,r=0.999 9;平均回收率为100.5%,RSD为1.44%（n=9）。结论：该方法专属性强,结果准确可靠,可用于盐酸苯环壬酯渗透泵片的质量控制。     

盐酸尼卡地平单层渗透泵片的制备及其体外释放行为的考察

目的:制备盐酸尼卡地平(Nic)单层渗透泵片,提高难溶性药物溶解度,实现平稳释药。方法:以吸水速率、渗透压及Nic溶解度为指标,从柠檬酸、氯化钠、乳糖和甘露醇中筛选适当的渗透压促进剂,制备Nic单层渗透泵片,并考察其体外释放行为,拟合释药模型。结果:4种渗透压促进剂中,以柠檬酸所制片剂吸水速率较高(71.83mg·h-1),渗透压值最高,可使Nic溶解度(7.90mg·mL-1)提高约10倍(80.33mg·mL-1);以柠檬酸为渗透压促进剂制备的渗透泵片,其24h药物累积释放度在95%以上,且符合零级释药模型。结论:柠檬酸能显著提高Nic溶解度;以柠檬酸为渗透压促进剂制备的Nic单层渗透泵片可平稳释药,且24h内基本释放完全。     

盐酸维拉帕米口服渗透泵制剂释药特性的研究

以盐酸维拉帕米为模型药物，制备了口服渗透泵片，通过考察渗透泵片体外释药各过程的速率，研究口服渗透泵制剂释药的基本过程及其特性，结果表明盐酸维拉帕米口服渗透泵制剂的释药过程主要包括四个步骤，其中体外释药速率与由水渗透过膜过程所控制的药物释放速率接近，从而说明水渗透过膜是控速步骤。     

多层片给药系统在定位和控制释药中的应用

多层片给药系统由含药片层及屏障层组成，通过屏障层控制药物的释放。综述近年来该给药系统在缓控释方面的研究进展，介绍其在定位释药（颊部黏膜给药、胃内定位释药和结肠定位给药）和控制释药形式（双相型释药、零级释药、双峰型释药和延时型释药）方面的应用。     

HPLC法同时测定复方盐酸二甲双胍/沙格列汀渗透泵控释片的含量

摘 要 目的： 建立高效液相色谱法同时测定复方盐酸二甲双胍/沙格列汀渗透泵控释片的含量。方法: 采用UltimateXB-CN色谱柱（250 mm×4.6 mm,5 μm）,流动相为0.01 mol·L^-1磷酸二氢钾溶液（pH=4.7） 乙腈（15∶85）,检测波长为208 nm,流速为1.0 ml·min^-1,柱温为30℃,进样量20 μl。结果: 盐酸二甲双胍和沙格列汀分别在50.0～150.0 μg·ml^-1和0.5～1.5 μg·ml^-1浓度范围内与峰面积线性关系良好（r = 0.999 9和r=0.999 1）。平均回收率分别为99.5%和100.3%,RSD分别为0.56%和1.20%（n =9）。结论:该法专属性强,结果准确可靠,可用于复方盐酸二甲双胍/沙格列汀渗透控释片的质量控制。     

甲磺酸倍他司汀微孔渗透泵控释片包衣处方的优化

目的:制备甲磺酸倍他司汀微孔渗透泵控释片,并对其包衣处方进行优化。方法:采用相似因子法考察影响释药的主要因素,采用正交试验以致孔剂聚乙二醇的用量、增塑剂邻苯二甲酸二丁酯(DBP)的用量和包衣增重为因素,以释放度的综合指标L值为指标优化包衣处方,并进行验证试验及体外释药模型拟合。结果:相似因子值均小于50,表明聚乙二醇、DBP的用量及包衣增重对制剂的释放均有显著影响;优化的最佳包衣处方中聚乙二醇为30%,DBP为20%,包衣增重为4%;验证试验中3批样品L值分别为13.99、11.15、8.37,12h累积释药百分率大于90%,释药模型特征为零级释药。结论:按最佳处方制得的甲磺酸倍他司汀微孔渗透泵控释片在12h内可稳定释药,且释放完全。     

星点设计-效应面法优化苯扎贝特渗透泵片处方

目的:制备苯扎贝特渗透泵片,运用星点设计-效应面法优化处方。方法:选择渗透泵片辅料聚氧乙烯(PEO)N80处方用量(A)、Na2CO3用量(B)和包衣增重(C)为考察因素,以该片在1h、6h的累积释药量以及累积释放量对时间进行线性拟合的相关系数为考察指标,采用星点设计-效应面法优化处方,并进行优化处方验证。结果:优化处方为A40mg、B20mg、C29mg,以该优化处方制备的渗透泵片具有较好的释药行为,各指标偏差的绝对值均小于5%。结论:星点设计-效应面法可用于苯扎贝特渗透泵片的处方优化,所建模型具有良好的预测能力。     

星点设计-效应面法优化依普利酮双层渗透泵片处方

目的:通过星点设计-效应面法优化依普利酮双层渗透泵片处方。方法:以含药层、包衣液组分用量和包衣增重为考察因素,药物释放曲线的相关系数和12h的累积释放度为考察指标,分别用3种数学模型描述考察指标与任意2个考察因素之间的关系,并绘制了二次多项式模型的效应面和等高线图,通过重叠区域确定最优处方,并通过实测值与预测值的比较进行验证。结果:二次多项式为拟合的最佳模型,优化处方考察指标的实测值与预测值非常接近,12h的累积释放度为97.38%,释放曲线相关系数为0.9968。结论:采用星点设计-效应面法得到了基于二次多项式模型的依普利酮渗透泵片处方优化的模型,实现了该渗透泵片的处方优化。     

介孔材料MCM-41与推拉式渗透泵技术联合制备尼群地平口服片的研究

目的 利用纳米介孔材料MCM-41提高尼群地平溶解度,并结合推拉式渗透泵技术使药物达到控释释放。方法 通过溶剂挥发法将药物尼群地平载入MCM-41的孔道中制备载药体系(NDP-MCM-41),并且通过体外溶出试验优化最佳比例。利用差示扫描量热法,粉末X射线衍射法,和傅里叶红外光谱法对药物存在状态进行表征。通过体外溶出实验筛选渗透泵片剂最优处方。结果 药物以无定形形式存在于载体孔道中,当药物与载体的比例为1∶5时,溶出效果最好。以PEO(10 000)作为助悬剂,PEO(600 000)作为助推剂采用直接压片法制备推拉式渗透泵。各个因素的用量,包衣增重的大小,打孔的大小都会影响药物的释放。结论 纳米介孔材料MCM-41和推拉式渗透泵技术结合显著改善了尼群地平的溶出速率,避免了突释并且延长了药效。     

Stimulation of gastrointestinal motility by cisplatin in the ferret: activation of an intrinsic cholinergic mechanism dissociated from emesis

Summary Motility was recorded from the corpus, antrum and small intestine of the urethane anaesthetised ferret. The gastrointestinal effects of the highly emetic cytotoxic anticancer agent, cisplatin were investigated following intravenous administration (10 mg/kg i. v.).Following injection, cisplatin induced a prompt onset (< 2 min) increase in motility (tone and contraction amplitude) in all regions with a duration of < 15 min. Acute vagotomy did not abolish the effect but reduced the peak amplitude in the antrum only. Chronic subdiaphragmatic vagotomy significantly enhanced the cisplatin-induced rise in tone in the corpus, the contraction amplitude in the antrum and the duration of the response in the duodenum. The stimulatory effect of cisplatin was blocked in all regions by atropine but not naloxone or the 5-HT₃ receptor antagonist ondansetron.This study reports a previously undescribed gastrointestinal motility effect of cisplatin in vivo that is temporally dissociated from emesis. It is proposed that the results provide evidence for a neuroactive effect of cisplatin on enteric cholinergic neurones.Present address: Department of Dietetrics + Nutrition, Queen Margaret College, Clermiston Terrace, Edinburgh EH12 8TS Correspondence to H.I.M. Davidson at the present address     

人工神经网络预测盐酸帕罗西汀缓释微丸的药物释放

目的利用人工神经网络对盐酸帕罗西汀缓释微丸的释药行为进行预测。方法设计20个处方,其中16个处方作为训练处方,其余4个处方作为测试处方,制备盐酸帕罗西汀膜控释微丸,进行释放度检查。以致孔剂PVPK30的用量、包衣增重作为自变量,考察药物在各个取样点的累积释放量作为输出,建立盐酸帕罗西汀缓释微丸释药行为的人工神经网络预测模型。通过线性回归法、相似因子法、AIC法评价人工神经网络的预测能力。结果通过实测数据和BP神经网络预测结果比较,验证了人工神经网络的预测精度达0.989 9。结论用人工神经网络对盐酸帕罗西汀缓释微丸的释药行为进行预测,拟合度较高,从而为盐酸帕罗西汀缓释微丸的处方优化和释药行为预测提供了可行的依据。     

Evaluation of Systemic and Mucosal Immune Responses Induced by a Nasal Powder Delivery System in Conjunction with an OVA Antigen in Cynomolgus Monkeys

An immune response for a nasal ovalbumin (OVA) powder formulation with an applied nasal delivery platform technology, consisting of a powdery nasal carrier and a device, was evaluated in monkeys with similar upper respiratory tracts and immune systems to those of humans, in order to assess the applicability to a vaccine antigen. Nasal distribution and retention studies using a 3D nasal cavity model and manganese-enhanced MRI were conducted by administering nasal dye and manganese powder formulations with the applied technology. Systemic and mucosal immune responses for the nasal OVA powder formulation were evaluated by determining serum IgG and nasal wash IgA antibody titers. The nasal dye and manganese powder formulations showed wider distribution and longer retention time than did a nasal liquid formulation. The nasal OVA powder formulation also showed comparable and higher antigen-specific IgG antibody titer to an injection and nasal liquid formulation, respectively. Furthermore, antigen-specific IgA antibody response was detected only for the nasal OVA powder formulation. The present study suggests that the technology, originally designed for drug absorption, is promising for nasal vaccines, enabling both a mucosal immunity response as the first line of defense and systemic immunity response as a second line of defense against infection.