尼扎替丁氯化钠注射液的制备、质量控制、稳定性及安全性考察

目的 制备尼扎替丁氯化钠注射液,建立质量控制方法并考察其稳定性和安全性。方法 优化处方组成与制备工艺,并进行性状、鉴别、检查等质量研究,采用高效液相色谱法测定尼扎替丁含量,滴定法测定氯化钠含量,影响因素试验、加速试验和长期试验考察其稳定性,并进行生物安全性评价。结果 尼扎替丁在0.55～1.31mg·mL^-1与峰面积线性关系良好,其平均回收率为99.9%,RSD为0.44%。恒温加速试验6个月和长期留样试验12个月,其性状、pH值、溶液颜色、有关物质、不溶性微粒、无菌、内毒素、主药含量等均未见明显改变,安全性良好。结论 该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全。     

尼扎替丁注射液的制备及质量控制

目的:根据临床需要,制备尼扎替丁注射液,考察其稳定性,并建立质量控制方法。方法:拟定处方组成与制备工艺,并进行性状、鉴别、pH、有关物质检查。采用高效液相色谱法测定尼扎替丁含量,影响因素试验、加速试验和长期试验考察其稳定性。结果:尼扎替丁在2．0-20．0μg·ml~(-1)的浓度范围内与峰面积的线性关系良好(r=0．999 7);平均回收率为100．50％,RSD为0．64％;3批尼扎替丁注射液的含量均符合规定。结论:该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好。     

藻酸双酯钠氯化钠注射液的制备、质量控制、稳定性及安全性考察

目的：制备藻酸双酯钠氯化钠注射液,建立其质量控制方法,并考察其稳定性和安全性。方法：优化处方组成与制备工艺,并进行性状、鉴别、检查等质量研究,采用滴定法测定藻酸双酯钠和氯化钠的含量,影响因素试验、加速试验和长期试验考察其稳定性,血管刺激性试验、溶血性试验以及过敏性试验评价其用药的安全性。结果：藻酸双酯钠和氯化钠的平均回收率分别为99.73%、100.93%,RSD分别为0.34%、0.17%。恒温加速试验6个月和长期留样试验12个月,其性状、pH值、溶液颜色、不溶性微粒、无菌、热原、主药含量等均未见明显改变。结论：该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全。     

聚乙烯醇滴眼液的质量标准研究

目的制备聚乙烯醇滴眼液,建立其质量控制方法并考察其稳定性及安全性。方法优化处方组成与制备工艺,并进行性状、鉴别、检查等质量研究,采用紫外分光光度法测定聚乙烯醇的含量,影响因素试验、加速试验和长期留样试验考察其稳定性,局部刺激性试验评价其用药的安全性。结果聚乙烯醇检测浓度在12.0~28.0μg·mL^-1与吸光度线性关系良好（r=0.999 9）,平均回收率为99.4%,RSD为0.85%。恒温加速试验6个月和长期留样试验12个月,其性状、pH值、溶液颜色、可见异物、黏度、渗透压摩尔浓度、微生物限度、含量等均未见明显改变。结论该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全。     

法莫替丁注射液的研制

目的：制备法莫替丁注射液,建立其质量控制方法,并考察其稳定性和安全性。方法：优化处方组成与制备工艺,并进行性状、鉴别、检查等质量研究,采用高效液相色谱法测定有关物质和含量,影响因素试验、加速试验和长期试验考察其稳定性,血管刺激性试验、溶血性试验以及过敏性试验评价其用药的安全性。结果：样品经酸、碱、氧化、热、光照破坏后所产生的杂质峰均能与主峰有效分离,最低检测限为1.0ng。法莫替丁在80.32～120.48μg/ml的浓度范围内与峰面积成良好的线性关系,平均回收率为99.76%,RSD为0.73%。恒温加速试验6个月和长期留样试验12个月,其性状、pH值、有关物质、可见异物、含量等均未见明显改变。结论：该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全。     

富马酸伊布利特注射液的研制及质量控制

目的 制备富马酸伊布利特注射液,建立有关物质和含量测定方法,并考察其稳定性和安全性.方法 优化处方组成与制备工艺,采用高效液相色谱法测定有关物质和含量,影响因素试验、加速试验和长期试验考察其稳定性,血管刺激性试验、溶血性试验以及过敏性试验评价其用药的安全性.结果 富马酸伊布利特检测浓度在4.2～20.1 μg·mL-1线性关系良好(r=0.999 7),其平均回收率为99.9％,RSD为0.61％.恒温加速试验6个月和长期留样试验12个月,其性状、pH值、溶液颜色、有关物质、可见异物、含量等均未见明显改变.结论 该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全.     

注射用氨酪酸的研制

目的研制注射用氨酪酸并建立其质量控制方法．考察其稳定性和安全性。方法拟订处方组成与制备工艺，进行性状、鉴别、pH值、有关物质检查等研究，采用非水滴定法测定氨酪酸含量，通过影响因素试验、加速试验和长期试验考察其稳定性，以其血管刺激性、溶血性及全身过敏性试验评价用药安全性。结果确定了不加赋形剂的处方，以及将氨酪酸直接冻干的工艺；影响因素试验（10d）、恒温加速试验（6个月）和长期留样试验（24个月）表明。主药含量及其他氨基酸无明显改变。结论处方工艺合理可行，制剂质量可控、稳定性良好、安全。     

氨酪酸氯化钠注射液的研制

目的根据临床需要,研究开发氨酪酸氯化钠注射液,建立其质量控制方法,考察其稳定性和用药的安全性。方法优化处方组成与制备工艺,并进行性状、鉴别、pH值、有关物质检查等质量研究,氨酪酸含量采用非水滴定法测定,氯化钠含量采用银量法测定,影响因素试验、加速试验和长期试验考察其稳定性。结果按照优化出来的最佳处方及工艺,制备3批中试样品,并对其产品质量进行检测,结果均合格。结论该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好,用药安全。     

盐酸赖氨酸注射液的研制

目的研究开发盐酸赖氨酸注射液，建立其质量控制方法，考察其稳定性，并进行其血管刺激性、溶血性及全身过敏性试验，以此评价药品的安全性。方法优化处方组成与制备工艺，进行性状、鉴别、pH值、其他氨基酸检查等质量研究，用电位滴定法测定盐酸赖氨酸含量，通过影响因素试验、加速试验和长期试验考察其稳定性。结果按照优化出来的最佳处方及工艺制备3批中试样品，其质量均合格。结论制剂处方合理，制备工艺简便可行，质量可控，稳定性良好，用药安全。     

阿替洛尔滴剂的制备与质量研究

目的研制阿替洛尔滴剂,满足儿童用药需求。方法拟定处方组成与制备工艺,进行性状、鉴别、检查、含量测定等质量控制,采用影响因素试验、加速试验、长期试验考察其稳定性。结果样品的各项质量检测结果均符合规定,经稳定性试验暂定其有效期为2年。结论该制剂处方合理,制备工艺简便可行,质量可控,稳定性良好。     

Nizatidine, and H2-receptor antagonist: disposition and safety in the elderly

Nizatidine is an orally active H2-receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vd beta/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.     

Stability of nizatidine in total nutrient admixtures.

The stability of nizatidine in total nutrient admixtures (TNAs) and the effect of the drug on the stability of lipid emulsions in the TNAs were studied. Duplicate 1476-mL amino acid-dextrose base solutions were prepared; nizatidine 300 mg was added to one. TNAs were prepared by adding to 75-mL samples of the base solutions Intralipid (KabiVitrum) or Liposyn II (Abbott) and sterile water as needed to achieve final lipid concentrations of 3% and 5%. Triplicate 100-mL samples for each lipid product and concentration were prepared; fat-free samples containing nizatidine were also studied. The theoretical final nizatidine concentration was 150 micrograms/mL. Samples were stored at 22 degrees C for 48 hours. Initially and at 12, 24, and 48 hours, the samples were visually inspected, tested for pH and particle-size distribution, and assayed by high-performance liquid chromatography for nizatidine concentration. No color change, precipitation, creaming, or oiling out was noted. For the 12 TNAs containing nizatidine, mean solution pH during the study was 5.88; stability of the lipid products requires pH values greater than or equal to 5.5. Particle-size distribution did not differ appreciably between the nizatidine-containing and drug-free TNAs. Nizatidine concentrations remained greater than 90% of the initial concentration. Nizatidine at a theoretical concentration of 150 micrograms/mL was stable for 48 hours at 22 degrees C in TNA solutions containing 3% and 5% Intralipid or Liposyn II and did not appear to affect lipid emulsion stability.     

Stability of nizatidine in commonly used intravenous fluids and containers

The stability of nizatidine in commonly used i.v. fluids stored in glass and plastic containers was studied. Stock solutions of nizatidine 0.75, 1.5, and 3.0 mg/mL in 15 i.v. fluids were prepared using nizatidine injection 25 mg/mL. Six 50-mL aliquots of each solution were transferred to separate glass infusion bottles and stored at room temperature or under refrigeration. Twenty-one 40-mL aliquots of additional stock solutions of nizatidine 0.75 and 3.0 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection were transferred to polyvinyl chloride (PVC) bags and stored at room or refrigerated temperature; some of these solutions were frozen, thawed, and refrigerated before analysis. Samples of each admixture were analyzed after 0.5, 1, 2, 3, and 7 days of storage for nizatidine concentration using a stability-indicating high-performance liquid chromatographic assay and also for visible changes and pH. The concentration of nizatidine in each admixture remained within 92%-106% of actual initial storage concentration throughout the study period, with the exception of nizatidine 3.0 mg/mL in 8.5% amino acid injection. The stability of nizatidine in admixtures stored in polyvinyl chloride bags was similar to that of admixtures stored in glass bottles. In the i.v. fluids, concentrations, and containers studied, nizatidine admixtures are stable for at least 7 days at either room or refrigerated temperature and 30 days when stored frozen in polyvinyl chloride bags. Admixtures of nizatidine 3.0 mg/mL in 8.5% amino acid injection should not be stored at room temperature for longer than four days.     

三种尼扎替丁制剂在中国健康人体的药动学及生物等效性

目的：评价健康受试者单剂量口服受试尼扎替丁片剂、胶囊以及参比尼扎替丁片剂的人体药动学与生物等效性。方法：采用3种制剂3周期随机交叉试验设计，HPLC法测定18例男性健康受试者单剂量口服150mg受试尼扎替丁片剂、胶囊和参比尼扎替丁片后的血药浓度；采用非室模型计算药动学参数；AUC，Cmax经对数转换后进行方差分析并计算90％置信区间。结果：受试尼扎替丁片剂、胶囊和参比尼扎替丁片剂的Cmax分别为（1280±359），（1377±438）和（1140±269）ng·mL^-1；tmax分别为（0．986±0．358），（1．069±O．362）和（1．125±O．464）h；tl/2分别为（1，556±O．312），（1．441±O．309）和（1．51l±O．259）h：AUC 0-t分别为（3864．50±662．77），（3775．06±596．18）和（3685．83±561．46）ng·h·mL^-1；AUC0-∞分别为（3896．55±668．89），（3798．17±605．86）和（3711．37±563．63）ng·h·mL^-1。结论：受试制剂尼扎替丁片、胶囊与参比尼扎替丁片具有生物等效性。     

Nonisothermal stability tests of famotidine and nizatidine

Nonisothermal stability tests have been proposed as an attractive and alternative method to the conventional isothermal stability tests. The stability and the degradation properties of famotidine and nizatidine were investigated using both isothermal and nonisothermal stability test techniques. Linear and logarithmic temperature programs were used and the degradation rate constant and activation energies were calculated using a computer program, which was written in BASIC. Also the advantages and disadvantages of these temperature programs are compared. The method to estimate parameters is based on nonlinear curve fitting the nonisothermal concentration-time-temperature curve equation. The nonisothermal stability test results were compared with the results of isothermal stability tests and similar results were obtained.     

Stability of nizatidine in extemporaneous oral liquid preparations

The stability of nizatidine in extemporaneous oral liquid preparations stored at room and refrigerated temperatures was studied. Preparations containing nizatidine in a final concentration of approximately 2.5 mg/mL were made by mixing the contents of a 300-mg nizatidine capsule with commercial juices (Gatorade, Stokely-Van Camp; Cran-Grape, Ocean Spray; apple juice, Sundor Brands; and V8 vegetable juice, Campbell Soup) and with aluminum hydroxide-magnesium hydroxide suspension (Maalox, Rorer). A control solution was prepared in water. Samples of each preparation were stored at 15-30 degrees C and at 5 degrees C. Initially and after 4, 8, 24, and 48 hours of storage, the samples were visually inspected, tested for pH, and analyzed in triplicate by high-performance liquid chromatography for nizatidine content. No appreciable changes in appearance or pH occurred. The only extemporaneous preparations with greater than 10% loss of nizatidine potency at 48 hours were the Cran-Grape and V8 preparations at room temperature. There was no correlation between pH of the preparations and changes in drug concentration. In the Maalox and V8 preparations, the drug powder did not dissolve uniformly. In all the preparations tested, nizatidine was stable for at least eight hours at refrigerated and room temperatures. In all except the Cran-Grape and V8 preparations, the drug was stable for 48 hours under both storage conditions.     

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.     

Nocturnal doses of ranitidine and nizatidine do not affect the disposition of diazepam

The disposition of diazepam (D) after a single oral dose of 10 mg was evaluated in nine healthy male volunteers under the following conditions (randomized, double-blind, crossover design): D + comedication of placebo and D + nocturnal dosing with 300 mg ranitidine or 300 mg nizatidine. Plasma concentrations of D and its major active metabolite, desmethyldiazepam (DD), were monitored by a gas-liquid chromatography-electron-capture detection assay for 84 hours. Neither ranitidine nor nizatidine had any significant effect on the hepatic elimination of D as characterized by its terminal half-life (mean +/- SD) of 35.3 +/- 24.2 hours (+ ranitidine: 30.1 +/- 9.9 hr; + nizatidine: 37.3 +/- 18.3 hr) or total plasma clearance of 28.2 +/- 12.0 mL/min (+ ranitidine: 26.5 +/- 7.9 mL/min; + nizatidine: 26.7 +/- 10.4 mL/min). Likewise, the formation of DD as measured by its AUC was not affected by ranitidine or nizatidine. Thus, it can be concluded that concomitant once-daily dosing (300 mg nocturnally) with ranitidine or nizatidine does not impair hepatic drug metabolism.     

Gastroprokinetic activity of nizatidine during the digestive state in the dog and rat.

The present study was undertaken to clarify a prokinetic activity of nizatidine (CAS 76963-41-2) during the digestive state as well as gastric emptying of a solid test meal in comparison with cimetidine (CAS 51481-61-9), famotidine (CAS 76842-35-6) and cisapride (CAS 81098-60-4). Intravenous administration of nizatidine (0.3-3 mg/kg) enhanced the motility of the gastric antrum and duodenum during the digestive state. With cimetidine (1-10 mg/kg) and famotidine (0.1-1 mg/kg) enhancement of gastric motility was observed only with the highest dose of cimetidine, and famotidine had no effect. Marked enhancement of gastric motility was observed with cisapride (0.1-0.5 mg/kg). After intraduodenal administration of nizatidine (10 and 20 mg/kg) and cisapride (0.25 and 0.5 mg/kg), they also amplified the contractile activity of the gastric antrum. Gastric emptying of a solid test meal was accelerated by intraperitoneal administration of nizatidine (1-10 mg/kg) to the same extent as cisapride (0.1-1 mg/kg). In addition, even in a model of delayed gastric emptying induced by clonidine, nizatidine, like cisapride, improved the rate of gastric emptying. Neither cimetidine (3-30 mg/kg) nor famotidine (0.3-3 mg/kg) affected the gastric emptying of a solid meal or delayed gastric emptying. These results suggest that nizatidine enhanced gastric motility even during the digestive state, and accelerated gastric emptying of a solid meal, similar to cisapride. Furthermore, nizatidine improved clonidine-induced delayed gastric emptying. These prokinetic activities of nizatidine may by useful for the treatment of abdominal symptoms due to dysmotility and delayed gastric emptying in patients with gastritis and non-ulcer dyspepsia (NUD). In comparison with famotidine and cimetidine, nizatidine may be different from other histamine H2-receptor antagonists and has unique properties other than its gastric antisecretory activity.