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.     

Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet

In this paper, a bilayer-core osmotic pump tablet (OPT) which does not require laser drilling to form the drug delivery orifice is described. The bilayer-core consisted of two layers: (a) push layer and (b) drug layer, and was made with a modified upper tablet punch, which produced an indentation at the center of the drug layer surface. The indented tablets were coated by using a conventional pan-coating process. Although the bottom of the indentation could be coated, the side face of the indentation was scarcely sprayed by the coating solution and this part of the tablet remained at least partly uncoated leaving an aperture from which drug release could occur. Nifedipine was selected as the model drug. Sodium chloride was used as osmotic agent, polyvinylpyrrolidone as suspending agent and croscarmellose sodium as expanding agent. The indented core tablet was coated by ethyl cellulose as semipermeable membrane containing polyethylene glycol 400 for controlling the membrane permeability. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f(2)). It was found that the optimal OPT was able to deliver nifedipine at an approximate zero-order up to 24 h, independent on both release media and agitation rates. The preparation of bilayer-core OPT was simplified by coating the indented core tablet, by which sophisticated technology of the drug layer identification and laser drilling could be eliminated. It might be promising in the field of preparation of bilayer-core OPT.     

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.     

Preparation of monolithic osmotic pump system by coating the indented core tablet.

A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The formulation of atenolol osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f2). The optimal formulation was evaluated in various release media and agitation rates. Indentation size of core tablet hardly affected drug release in the range of (1.00-1.14) mm. The optimal osmotic tablet was found to be able to deliver atenolol at an approximately constant rate up to 24h, independent of both release media and agitation rate. The method that is simplified by coating the indented core tablet with the elimination of laser drilling may be promising in the field of the preparation of osmotic pump tablet.     

硝苯地平双层渗透泵控释片的制备

目的 采用乙基纤维素包衣来制备难溶性药物硝苯地平单室双层渗透泵控释片.方法 测定不同时间药物的释放度,以累积释放量和与国外市售片比较的相似因子(f2)为评价指标,采用单因素实验筛选硝苯地平渗透泵控释片的处方.结果 片芯处方和包衣增重对硝苯地平渗透泵片的体外释药行为有显著影响,含药层中PEO N80与CMS-Na为5∶2,助推层中PEO Coagulant与CMS-Na为2∶1;包衣液中PEG400用量为乙基纤维素的68％,包衣增重10％.自制控释片与市售片的释放曲线相似,且批间差异小,重复性良好.结论 自制硝苯地平双层渗透泵控释片的工艺稳定,体外释药特征符合控释制剂的要求,24 h内释药完全.     

盐酸特拉唑嗪口服渗透泵控释片人体药物动力学研究(英文)

本研究进行了盐酸特拉唑嗪口服渗透泵控释片在健康人体内的药物动力学分析。运用随机交叉实验设计,20名健康受试者单剂量、多剂量口服受试制剂、参比制剂,采用HPLC法测定血浆中盐酸特拉唑嗪的浓度,使用3P97软件计算药物动力学参数。单剂量口服控释片、普通片各4 mg后,普通片的C_(max)(120.56±23.15)ng/mL明显高于控释片的C_(max)(95.27±16.35)ng/mL。控释片口服给药后的T_(max)为(2.65±0.82)h,较普通片T_(max)(1.27±0.61)h延迟,有显著性差异(P<0.05),其相对生物利用度为(105.85±6.12)%。受试者多剂量口服普通片与控释片后药物动力学参数稳态时曲线下面积(AUC_(ss))分别为(1275.17±175.35)、(1382.65±205.31)ng·h/mL;C_(max)分别为(128.15±22.37)、(98.57±18.16)ng/mL;T_(max)分别为(1.35±0.71)、(2.76±0.85)h;平均稳态血药浓度(C_(av))分别为(53.13±9.12)、(57.61±9.25)ng/mL;血药浓度波动度...     

人参总皂苷渗透泵片体外释药的影响因素

目的建立测定人参总皂苷渗透泵片体外释放度的方法,考察不同因素对该剂型体外释药行为的影响规律。方法用UV法和体外释放度试验,考察渗透泵片在不同溶出方法、释放介质、搅拌桨转速下的累积释放度。结果溶出方法、搅拌桨转速、溶出介质pH3.5~7.6对渗透泵片体外释放行为无显著影响;渗透压对体外释放行为有显著影响。结论确定了不同因素对渗透泵片体外释放度的影响规律。     

盐酸二甲双胍渗透泵控释片的制备及体外释放度考察

目的研究盐酸二甲双胍渗透泵控释片的制备工艺及体外释药的影响因素。方法通过单因素考察和正交试验,优化制备工艺。结果盐酸二甲双胍渗透泵控释片的体外释药符合零级释放规律,释药速率受PEG种类、PEG用量、包衣膜重量影响较大,在一定范围内,释药孔大小、片芯硬度、溶出介质pH值和桨转速对其影响较小。结论盐酸二甲双胍渗透泵控释片工艺稳定,能够达到9h明显的恒速释药。     

阿魏酸钠微孔渗透泵控释片的包衣对体外释药的影响

目的考察包衣处方对阿魏酸钠口服微孔渗透泵控释片体外释药性质的影响,并优选最佳包衣处方。方法根据不同时间的累积释放度,考察药物的释放情况,通过正交设计优化包衣处方。结果增塑剂、包衣膜厚度、致孔剂对阿魏酸钠口服微孔渗透泵控释片体外释药速率的影响均较大,并能通过正交设计得到控制12 h内稳定释药的包衣处方。结论通过对包衣处方的调整,可稳定地控释阿魏酸钠口服微孔渗透泵控释片。     

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.     

Rectal infusion of the model drug antipyrine with an osmotic delivery system

An osmotically-powered rectal drug delivery system, was used for the rectal infusion of the model drug antipyrine. The system, which is slightly larger than a normal suppository, has a nominal pumping rate of 43 μl h^{? 1} over at least 30 h. Four healthy volunteers kept two such systems in their rectum for a sum total of 98 h. Saliva and plasma concentrations were determined at regular intervals and in all cases a very constant steady-state saliva and plasma concentration was reached and maintained. Defecation and reinsertion of the drug delivery system did not cause any irregularities in the concentration profile. The system was very well tolerated by the volunteers.     

包衣处方对盐酸文拉法辛微孔渗透泵型控释片体外释药的影响

目的考察包衣处方对盐酸文拉法辛口服微孔渗透泵控释片体外释药的影响,并优选最佳包衣处方。方法考察聚乙二醇400(PEG400)的用量、包衣增量、邻苯二甲酸二丁酯(DBP)的种类和用量4个因素对释放的影响,并通过正交设计优化包衣处方。结果盐酸文拉法辛微孔渗透泵控释片的体外释药符合零级释放规律,释药速率受致孔剂、增塑剂、衣膜厚度的影响均较大。结论通过对包衣处方的优化,盐酸文拉法辛口服微孔渗透泵控释片能够恒速释药。     

Box-Behnken法优化渗透泵微丸丸芯的制备工艺

目的：优化渗透泵微丸丸芯的处方、制备工艺,为渗透泵载药微丸研究提供优质丸芯。方法：在单因素的基础上,以休止角、硬度为评价指标,采用Box-Behnken法优选渗透丸芯的最佳制备工艺。结果：由单因素试验及Box-Behnken试验可知,以乳糖-微晶纤维素-PVP（5∶1∶0.1,w/w）为丸芯组成,以挤出转速30 r·min^-1,挤出温度24℃,滚圆转速1 800 r·min^-1为最佳制备工艺,制得粒径为0.8 mm,休止角为28.42°,硬度为17.52 kg·cm^-2的丸芯。结论：本实验筛选出渗透泵丸芯的处方组成及制备工艺,可为以渗透压为动力的渗透泵丸芯的制备研究提供参考。     

利用难溶性药物渗透泵处方设计专家系统设计法莫替丁双层渗透泵控释片

本文目的在于利用本课题组建立的难溶性药物渗透泵处方设计专家系统设计法莫替丁双层渗透泵控释片。首先通过文献检索和实验测定获得系统所需要的参数; 然后将各参数输入系统并运行程序, 此时系统会给出设计结果; 最后根据系统设计结果制备样品并检测法莫替丁双层渗透泵控释系统体外释药情况。结果发现经过很短的周期便获得了释放24 h的法莫替丁控释片, 同时也验证了专家系统的实用性。     

Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system

Human therapeutic valproic acid (VPA) levels could be maintained in the mouse for a period of 1 week by constant rate application via subcutaneously implanted osmotic minipumps. Also, the concentrations of VPA metabolites observed in mouse plasma were similar to those seen in human plasma. The drug application could be prolonged by replacing exhausted pumps with freshly-filled devices. Removal of the implanted pumps and measurement of the decay of the drug levels revealed that the half-life of the main plasma metabolite 2-en(2-propyl-2-pentenoic acid) exceeded that of VPA. This result was confirmed by constant-rate application of this metabolite; the plasma clearance of 2-en (as calculated from the steady-state levels observed) was found to be lower than that of VPA. Brain levels of VPA and 2-en during steady-state were 3–10 per cent of corresponding plasma levels. The blood-brain kinetics of 2-en following administration of VPA were similar to those observed following application of 2-en itself. VPA was cleared faster from the brain than from the plasma, while 2-en was more persistent in the brain than in the plasma. Our results indicate that controlled, constant-rate application of drugs such as VPA, via implantable osmotic minipumps, may be a valuable procedure for a number of pharmacological and toxicological studies, particularly where persistent drug levels must be maintained for extended time periods.     

Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant

TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12?h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8?h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo–in vitro correlation.     

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     

质子泵抑制剂治疗慢性阻塞性肺疾病并发呼吸衰竭患者上消化道出血的疗效评价

目的探讨质子泵抑制剂在治疗慢性阻塞性肺疾病并发呼吸衰竭患者上消化道出血中的治疗价值。方法选择慢性阻塞性肺疾病并发呼吸衰竭患者103例,且均经大便隐血试验上消化道出血,将其分为观察组53例和对照组50例,两组均给予常规抗感染、纠正呼吸衰竭等基础治疗,观察组加用兰索拉唑30mg,每天1次,静脉滴注,对照组加用法莫替丁40mg,每天1次,静脉滴注,两组均连续使用1周,分别观察第5、7、14天大便隐血情况。结果观察组大便隐血情况分别为第5天10例,第7天5例,第14天0例;对照组大便隐血情况分别为第5天26例,第7天22例,第14天18例。观察组有效率[100．0％（53／53）]高于对照组[64．0％（32／50）],差异有统计学意义（P〈0.05）。观察组总不良反应发生率[3．8％（2／53）]低于对照组[16．0％（8／50）],差异有统计学意义（P〈0．05）。观察组患者好转率、病死亡、住院时间和气管插管率等转归情况均优于对照组（P〈0．05）。结论质子泵抑制剂治疗慢性阻塞性肺疾病并发呼吸衰竭患者上消化道出血疗效好,能缩短住院时间,降低全组病死率,不良反应少,值得临床推广。     

盐酸雷莫司琼口腔崩解片预防恶性血液疾病联合化疗所致的胃肠反应

目的：观察盐酸雷莫司琼口腔崩解片预防恶性血液疾病患者联合化疗所致胃肠反应的疗效和安全性。方法：采用随机、对照方法，将入选病例随机分为治疗组（含服盐酸雷莫司琼口腔崩解片0．1mg）和对照组（静脉注射盐酸托烷司琼5mg）。结果：可评价疗效及安全性病例110例。两种药物对控制化疗所致食欲缺乏、恶心和呕吐的有效率相似。第1～7天盐酸雷莫司琼对食欲缺乏的完全控制率（52．7％～63．6％）、第4～7天对恶心的完全控制率（43．6％～56．4％）及第3、4、6天对呕吐的完全控制率（80．0％、87．3％和90．9％）明显优于盐酸托烷司琼注射剂，差异有显著性（P〈0．05）。盐酸雷莫司琼不良反应轻，主要为便秘、头痛、体热感和疲倦，为一过性，其发生率与盐酸托烷司琼注射剂相似。结论：盐酸雷莫司琼口腔崩解片能有效预防恶性血液病患者联合化疗所致的胃肠反应，适用于因各种原因不能吞服药片的患者。