低分子肝素栓的试制与质量控制

用热熔法制备了低分子肝素栓剂,用天 青A法测定了低分子肝素的含量,考察了该栓剂的体外释放速度,并用威布尔函数进行了分析。结果表明:该栓剂的融变时限为24min,体外释药T_(50)=7.57min,Td=8.72min,证明该制剂的配制符合中国药典规定的质量要求。     

阿尼西坦栓剂的制备及其溶出速度的研究

<正>阿尼西坦(又称茴拉西坦)为γ-内酰胺类脑功能改善药,栓剂通过直肠给药,约50%～70%的药物可避免首过效应,极大地提高了药物的生物利用度,而且也可减少对肝脏的毒性。本实验通过热熔法试制了阿尼西坦的栓剂,并分别加入了不同的吸收促进剂以考察吸收促进剂对药物的体外释放速率的影响,为更深入研究阿尼西坦的栓剂提供一定的基础。     

温度敏感型布洛芬缓释液体栓的制备与体内外评价

目的:以泊洛沙姆407(P407)和泊洛沙姆188(P188)为组合基质,添加生物黏附剂卡波姆(Cabopol)以及促渗透剂氮酮(Azone)制备温敏型布洛芬(IBU)缓释液体栓剂,考察液体栓释药的体内外相关性。方法:以凝胶温度、凝胶强度、生物黏附力和液体栓剂体外释放度为指标进行体外筛选;经比格犬直肠给药测定动物体内药物释放曲线进行体内筛选;用3P97程序计算药动学参数。结果:布洛芬体外释放结果符合零级模式,R2>0.9时,体内药物释放出现平台,显示了良好的体内外相关性;药动学研究结果表明,体内过程为一室模型,药动学参数为tmax=3.551 h,Cmax=21.483μg.mL-1,t1/2(Ke)=2.740 h,AUC0→∞=210.850μg.mL-1.h,MRT=7.670 h。结论:所制备的布洛芬液体栓剂具有良好的缓控释特征。     

论药物的直肠吸收

作为直肠给药的栓剂是怎样被人体吸收而产生如此显著的疗效呢?本文着重从探讨药物的直肠吸收,来说明栓剂等直肠或药剂型的作用机理。     

药物直肠吸收的促进剂

经直肠给药以发挥全身作用的研究自1950年后才广泛进行。1980年以来对难以从直肠吸收的药物,开始了添加吸收促进剂的研究。栓剂在直肠内变软液化后,主药在直肠分泌液中溶解释出。溶解的主药被动转运而被吸收,吸收动态与pH分配假说相一致。非离解型是有效的透过形式,油水分配系数大的非离解型分子容易透过生物膜;但解离型分子吸收很差,达不到治疗目的。在     

低分子肝素非注射制剂的研究进展

低分子肝素（LMWH）是临床广泛应用的抗凝药物,常用的注射剂型存在的一些缺陷影响了临床治疗血管栓塞性疾病的疗效。为了克服这些不足,近年来很多学者开始研究LMWH的其他给药途径,包括口服制剂、舌下给药、直肠栓剂、鼻腔给药,以及经肺、经皮肤给药。LMWH非注射制剂有助于提高患者的用药依从性和减少药物不良反应。本文就LMWH非注射制剂的优缺点等方面作一综述,从而介绍更多LMWH给药途径,以供特定患者人群选择。     

延长直肠下部停留时间的双层栓剂处方设计

栓剂药物主要在直肠两个部位吸收:其一,经直肠上静脉吸收,由门静脉入肝,这和口服给药一样在肝脏代谢,对容易受首过效应的药物不利.其二由直肠下静脉吸收,药物不经过肝脏,可直接进入体循环,能避免药物首过效应.为了使栓剂药物能在直肠下部有效地被吸收,特设计了由栓剂药物(直肠内吸收分泌液形成凝胶,以抑制药物从直肠下部扩散至上部)及栓剂后端(含有药物)所组成的双层栓剂.由于栓剂前端必须在后端熔融前形成凝胶塞,因而首先筛选出膨润性好的前端处方.其基质配比为聚二乙醇4000四份、聚乙二醇1000九十六份,并加入     

浅谈给药方式对药物吸收的影响

目的探究给药方式对药物吸收的影响,以此有效地为临床给药提供依据。方法观察体内给药和体外给药两种方式的药物吸收作用。体内给药包括口服给药、注射给药;体外给药包括口腔给药、直肠给药、皮肤给药、阴道给药等。结论为了提高药物吸收,应该重视给药方式,依据患者的病情、疾病的发展情况、药物特点等建立正确的给药方式,可以更加有效地为临床给药提供依据,使临床给药更加合理有效。     

纳米给药系统中药物体外释放度测定方法及体内外相关性评价研究进展

目的:为纳米给药系统中药物体外释放度测定方法及体内外相关性评价提供参考。方法:以"纳米给药系统""体外药物释放""体内外相关性""Nanoparticles""Drug release""in vitro-in vivo correlation"等为关键词,在中国知网、维普、PubMed、Elsevier等数据库中组合查询2001年-2018年6月发表的相关文献,从纳米给药系统药物体外释放测定的挑战、药物体外释放度测定的主要方法、体外释放度的数学模型拟合以及体外释放-体内行为相关性研究等3个方面进行归纳和总结。结果与结论:共检索到相关文献4 318篇,其中有效文献41篇。目前纳米给药系统中药物体外释放度研究面临的挑战主要来源于纳米粒径的多样性和不均匀性、体内释放过程的多重性以及在体内易受到各种蛋白的影响等。纳米给药系统中药物体外释放度的主要测定方法有透析法、离心法、流通池法、凝胶法、加压超滤法、扩散池法和原位法等,各有一定的优缺点。目前针对纳米给药系统中药物的体外释放动力学数学模型进行系统研究的文献较少,对其进行体外释放-体内行为相关性研究的文献也较少。今后可通过在药物体外释放测定的介质溶液中引入体内蛋白、在释放测定过程中设计模拟纳米给药系统在体内的分布特性、控制测定装置孔隙大小等方面减小对粒径的影响,使纳米给药系统中药物体外释放度的测定方法更加完善;通过进一步体外释药模型拟合、体内外相关性研究,使纳米给药系统中药物体外释放更好地预测其体内行为。     

氨苄青霉素甲戊酯在兔直肠的吸收

由于β-内酰胺类抗生素分子结构中连接羧基,具有亲水性,通常口服和直肠给药难以吸收。盐酸氨苄青霉素甲戊酯(BAPC)是氨苄青霉素(ABPC)的前药,它的脂溶性比母体药物(ABPC)显著增强,因此BAPC口服后有较好的吸收。那么BAPC能否直肠给药呢?基于这个问题,作者以Witepsol H- 15为基质,将BAPC制成了栓剂,并且对BAPC的直肠,口服和静脉给药进行了兔体内生物利用度的研究。高压液相色谱法测不出血样的BAPC,而只能检出BAPC的母体药物(ABPC),因此以静脉注射等克分子的ABPC作为计算     

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.     

Release of drugs from fatty suppository bases I. The release mechanism

A model for drug release from fatty suppository bases is presented that explains in vitro measurements on drugs with various physicochemical characteristics, such as paracetamol (slowly dissolving in water) sodium salicylate (rapidly dissolving in water) and salicylic acid (soluble in lipid).The in vitro results are compared with in vivo experiments on rectal absorption in man. Results indicated that for suspensions of all the drugs investigated, dissolution takes place at the interface between the suppository base and the surrounding fluid. The release process therefore includes a flow of particles in the suppository base into the direction of the interface and a flow of solute away from the interface. Either of these flows may be rate limiting dependent on the water solubility of the drug, and may determine the effect of concentration and particle size on release rate.     

Reciprocating dialysis tube method: periodic tapping improved in vitro release/dissolution testing of suppositories.

The reciprocating dialysis tube (RDT) method can be used for in vitro release/dissolution testing of suppositories and has been reported to show good in vitro and in vivo correlation. However, for suppositories with viscous excipients, the result remains variable and generally under-predicts in vivo absorption. The purpose of this study was to assess whether periodic tapping of the closure of the RDT could improve in vitro release testing of suppositories. Two commercially available acetaminophen suppositories (A and B) that showed characteristic release behavior under normal rectal temperatures (37 and 38 degrees C) were chosen as test suppositories. In the absence of tapping, suppository A showed different release profiles at 37 and 38 degrees C, but the difference disappeared with periodic tapping. This finding was consistent with minimum temperature effect in the rectal absorption of suppository A in rabbits. Suppository B showed distinct release profiles at 37 and 38 degrees C irrespective of tapping, and the rectal absorption of suppository B in rabbits was affected by temperature. The test variability (CV% and ranges of release values) was substantially reduced in the presence of tapping. In conclusion, the addition of periodic tapping to RDT method developed in this study could improve in vitro release testing of suppositories.     

Effects of surfactant characteristics on drug availability from suppositories

The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.     

温控型胰岛素液体直肠栓的制备及处方筛选

目的:制备温控型胰岛素液体直肠栓。方法:以胰岛素含量为指标,以泊洛沙姆407-泊洛沙姆188的比例、壳聚糖含量、p H为因素,采用正交设计试验筛选温控型胰岛素液体直肠栓的处方;并采用无膜、动物黏膜溶出法考察所制栓剂的体外释药机制。结果:所制温控型胰岛素液体直肠栓的胰岛素含量为0.35%;泊洛沙姆407-泊洛沙姆188的比例对栓剂中胰岛素含量影响显著(P<0.05);最优处方为泊洛沙姆407-泊洛沙姆188比例为15%∶25%、壳聚糖含量为0.4%、p H为5;使用无膜和牛肠黏膜时是通过溶蚀方式释放,使用羊肠黏膜时是通过扩散与溶蚀相结合的方式释放。结论:成功制得温控型胰岛素液体直肠栓。     

赖氨酸布洛芬缓释液体栓的制备及体内外释放度研究

目的：对赖氨酸布洛芬缓释液体栓进行处方、卡波姆和氯化钠用量筛选以及液体栓剂的体内外释放度进行研究。方法：根据处方中不同比例的泊洛沙姆及不同含量的卡波姆、氯化钠制备赖氨酸布洛芬缓释液体栓,考察不同含量的卡波姆和氯化钠对液体栓凝胶温度、凝胶强度和生物粘附力以及理化性质的影响,并对适宜处方进行体外释放度的测定;测定赖氨酸布洛芬缓释液体栓在犬体内的血药浓度,并进行体内释放度研究。结果：通过筛选最终确定卡波姆的含量为0.8%,氯化钠含量为0.8%,液体栓凝胶温度、凝胶强度、生物粘附力具有适合直肠给药的性质;赖氨酸布洛芬液体栓体外释放符合零级模式,R2〉0.9,释药时限大于6 h;经3p97程序计算药动学参数,体内过程为一室模型,药代动力学参数为：Tmax=4.82 h,Cmax=42.7μg/mL,T1/2（Ke）=8.26 h,AUC0→∞=715.48 mg/（h·L）,MRT=10.68 h,显示了良好的体内相关性。结论：本研究制备的赖氨酸布洛芬液体栓具有良好的缓控释特征。     

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.     

Pharmacokinetics and bioavailability of theophylline following enema and suppository administration in man

The pharmacokinetics and bioavailability of theophylline from a commercial oral elixir of theophylline, a rectal suppository of aminophylline, and a rectal enema of theophylline monoethanolamine was compared in six normal subjects. Using a complete crossover design, the fasted subjects received a single dose of each dosage form. Blood and saliva samples were collected at frequent time intervals for 24 h, and the plasma assayed for theophylline by a specific thin-layer chromatography densitometric method. No statistically significant differences existed among the three dosage forms with respect to Cmax and AUC corrected for the elimination rate constant and the dose (mg kg-1). However, tmax was significantly larger for the suppository. While the rate of absorption was significantly slower for the suppository, no differences in the extent of absorption existed among the three dosage forms. A one-compartment open model with apparent first-order absorption adequately described the plasma concentration-time data for the elixir and enema, whereas the suppository data were best fitted by a one-compartment open model with apparent zero-order absorption and a lag time. A rate-limiting, concentration-independent release of drug from the base most likely accounts for the slow absorption of theophylline from the suppository. While the saliva:plasma ratio remained fairly constant for most of the study period, the large variability found during the absorption phase following drug administration limits the usefulness of this parameter as a monitor of theophylline plasma concentrations.     

Mucoadhesive microsphere based suppository containing granisetron hydrochloride for management of emesis in chemotherapy

The purpose of present work was to develop suppositories containing mucoadhesive microspheres of granisetron hydrochloride (GH) using combination of xanthan gum and sodium alginate. Twelve different batches of microspheres containing GH were prepared by simple emulsification method and evaluated for surface morphology, particle size, equilibrium swelling degree, drug content, in vitro mucoadhesion, and in vitro drug release. The suppositories containing optimized batch of microspheres (C2) were formulated by fusion method using hydrophilic and lipophilic polymer base. The suppositories were evaluated for weight variation, hardness, macromelting range, drug content, drug release, morphology of rectal tissues, and in vivo suppository localization. Results show that, all microsphere batches were spherical and had size range 23.56–36.76 μm. The % drug encapsulation was found in the range 61.67–92.30 %, and showed satisfactory mucoadhesion. Especially, C2 batch had 83.67 % mucoadhesion and 92.30 % drug encapsulation and showed release retardation for 4 h. The results of all suppositories were within the pharmacopoeial standard limits. Drug content of all the suppositories was in the range 93.20–98.40 %. The suppository batch (P2M) was considered best on the basis of optimum retardation up to 5 h, high drug content, optimum mechanical strength and zero order release (r² = 0.9860). The suppository of batch P2M showed no morphological changes in rectal tissues indicating its safety. In vivo localization revealed satisfactory mucoadhesion of microspheres. Hence, it can be concluded that, delivery of GH in suppository form can avoid its presystemic metabolism, thus, may be an efficient alternative to its oral dosage form and conventional suppository.     

In vitro and in vivo study in rats of rectal suppositories containing furosemide.

The aim of our experimental work was to formulate furosemide-containing rectal suppositories, to study drug release with in vitro membrane diffusion examinations and to increase drug liberation with the use of non-ionic surfactants (Solutol HS 15, Cremophor RH 60, Montanox 60 DF), which were incorporated in the suppository base in various concentrations. Suppocire AS2X proved to be the best suppository base (diffused drug: 69.78%). The use of 1% Cremophor RH 60 additive with the Witepsol H 15 base increased the quantity of the diffused drug from 62 to 75%. The membrane diffusion examinations were followed by studying the influence of suppository bases and additives exerted on the actual diuretic effect in Sprague-Dawley male rats. Once again the Suppocire AS2X suppository base gave the best results compared to the control; the quantity of the animals' urine showed a fourfold increase. Used with the Witepsol H 15 base, even 1% of all the three additives resulted in a considerable increase of diuretic effect, so their use proved to be advantageous. The comparison of the membrane diffusion examinations with the in vivo diuretic effect reveals that in vitro drug release and the pharmacological effect usually showed the same tendency, that is a greater extent of in vitro furosemide release was associated with a greater quantity of rat urine.