不同厂家的茶碱缓释片三维释放特性及释放机制考察

目的对不同厂家生产的茶碱缓释片进行pH、时间、释放度考察,探讨其体外释放机制。方法采用搅拌桨法,以紫外分光光度法检测,描绘其三维释放图像,对释放数据分别以相似因子法分析,并以零级、一级,及Peppas,Higuchi,Hopfenberg等释放模型的数学方程进行拟合。结果B片释放行为受pH变化的影响;A片、B片、C片均以一级方程为最佳拟合方程;当释放度小于40％时,A片、B片、C片均属于整块骨架系统释放模型;A片在pH=3．6及pH=8．0、B片在pH=6．8及pH=8．0、C片在pH=8．0时分别以Higuchi方程为最佳拟舍方程。结论不同厂家茶碱缓释片的体外释放机制有所不同,且受pH影响。     

丙戊酸钠缓释片体外释放特性

目的：研究自制丙戊酸钠缓释片的体外释放特性，并与市售丙戊酸钠片和丙戊酸钠缓释片（德巴金）体外释放特性进行比较。方法；按中国药典2000年版二部附录XD释放度测定第一法，以磷酸缓冲液为释放介质，采用HPLC测定介质中丙戊酸钠含量，并计算其累积释放度。对三种制剂的释放数据分别以零级释放、单指数模型、希古切（Higuchi）方程、威布尔（Weibull）分布模型和Regter-pappes模型进行拟合，求出相应的特征参数，探讨其体外释放规律。结果：丙戊酸钠片以希古切（Higuchi）为最佳拟合模型；自制丙戊酸钠缓释片与德巴金释放度的最佳拟合模型均为威布尔（Weibull）分布模型。结论：从Ritger-peppas模型拟合结果表明，丙戊酸钠缓释片释放为骨架溶蚀机制，德巴金为Fick扩散机制。     

琥珀酸美托洛尔缓释片体外释药特性评价

以进口的琥珀酸美托洛尔缓释片为参比制剂,采用f2相似因子法评价自研制剂和参比制剂在不同pH值的释放介质中体外释放行为的相似性,结果显示f2值均大于50,两种制剂体外释放行为相似.运用药物释放动力学模型拟合琥珀酸美托洛尔的释放过程,释放动力学特征以Higuchi模型拟合较好,根据Peppas方程,其释放机制是药物扩散和骨架溶蚀的共同作用.     

美乐托宁缓释片在不同介质中的释放试验

目的:制备美乐托宁缓释片,以国外上市制剂美乐托宁缓释片为参比制剂,考察自研制剂和参比制剂在不同pH释放介质中体外释放行为的相似性及体外释药机制。方法:采用释放度测定法转篮法的装置进行体外释放实验,用HPLC法测定释放度,采用f2相似因子对2种制剂释放曲线的相似度进行评价,并进行释放行为模型的拟合。结果:在不同pH的释放介质中,自制制剂释放度曲线与参比制剂比较,f2相似因子均大于50;美乐托宁缓释片在4种释放介质中体外释药拟合模型更接近一级方程、Higuchi方程和Peppas方程。结论:参比制剂与自制制剂在不同pH释放介质中的体外释放一致,释放机制为扩散释药。     

不同厂家生产的盐酸曲马多缓释片整片与半片的三维释放特性考察

目的:对不同厂家(A、B、C)的盐酸曲马多缓释片的整片与半片进行pH-时间-释放度考察,探讨整片与半片体外释放机制的差异.方法:转篮法,用紫外分光光度法检测,描绘其三维释放图像,将释放数据用相似因子法、Peppas方程进行分析.结果:在同一pH条件下,A、C的整片与半片释放曲线不相似,释放机制也不相同;B的整片与半片释放曲线相似,释放机制相同.结论:不同厂家盐酸曲马多缓释片整片与半片的体外释放不尽相同.     

盐酸曲马多缓释片的体外释放度研究

目的考察盐酸曲马多缓释片物体外释放度,探讨其体外释放机制。方法参照《中华人民共和国药典》(2000版)二部附录释放度测定法转篮法,以0.1m ol.L-1盐酸溶液为溶剂,转速为100r.m in-1,温度为(37±0.5)℃,采用紫外分光光度法测定,检测波长为270nm。并将释放数据分别用Peppas方程、H iguch i方程、一级方程、零级方程进行拟合。结果线性范围为20~100μg.mL-1,r=0.9998。1h累积释放25.42±0.81%,4h累积释放58.37±1.36%,10h累积释放92.67±1.08%,以H iguch i方程为最佳释药模型,并且释药机制为非F ick ian扩散。结论盐酸曲马多缓释片的体外释放符合缓释制剂要求。     

富马酸喹硫平缓释片在不同释放介质中的体外释放研究

目的:考察自制富马酸喹硫平缓释片的体外释放情况及其释放机制。方法:以国外上市制剂为参比,采用篮法进行2种制剂分别在3种释放介质(水、0.1mol/L盐酸溶液、pH6.8磷酸盐缓冲液)中体外释放行为的相似性比较;采用紫外分光光度法测定释放度,以相似因子(f2)进行相似度评价;并对自制制剂进行释放行为模型的拟合。结果:在3种释放介质中,2种制剂比较,f2值均大于50;自制制剂在水和pH6.8磷酸盐缓冲液中体外释放拟合模型更接近Higuchi方程和Peppas方程,在0.1mol/L盐酸溶液中更接近一级方程和Peppas方程。结论:自制制剂与参比制剂在不同释放介质中的体外释放行为一致,释放机制以扩散为主。     

双氯芬酸钠—乙基纤维素固体分散物释放动力学研究

目的：研究双氯芬酸钠-乙基纤维素固体分散物颗粒及其缓释胶囊的药物释放动力学特征。方法：测定不同粒径、不同浓度的双氯芬酸钠-乙基纤维素固体分散物颗粒及其缓释胶囊在pH6.8磷酸盐缓冲液中的释放曲线,以零级动力学方程、一级动力学方程及Higuchi方程分别对释放曲线进行拟合,根据所得方程的相关系数,探讨不同粒径、不同浓度的固体分散物颗粒及其缓释胶囊的释放特征。结果：固体分散物颗粒释放动力学拟合优劣顺序为：Higuchi模型方程、一级动力学方程、零级动力学方程;缓释胶囊释放动力学拟合结果的优劣顺序为：Higuchi模型方程、零级动力学方程、一级动力学方程、零级动力学方程;缓释胶囊释放动力学拟合结果的优劣顺序为：Higuchi模型方程、零级动力学方程、零级动力学方程、一级动力学方程。结论：不同浓度、不同粒度的双氯芬酸钠-乙基纤维素固体分散物颗粒及缓释胶囊释放均遵从Higuchi方程,为骨架扩散机制。     

左羟丙哌嗪缓释骨架片的制备及体外释药行为评价

［摘要］　目的：制备左羟丙哌嗪缓释骨架片,考察其体外释放度,探讨其释药机制。方法：以亲水性高分子材料HPMC为骨架,采用湿法制粒,制备左羟丙哌嗪缓释骨架片,评价不同pH值条件下的释放度,并将释放数据拟合方程。结果：HPMC用量增加,左羟丙哌嗪释放速度下降;溶出介质pH对药物的释放特性有一定影响。在本实验条件下,HPMC用量对水溶液中药物的释放机制无明显影响,释药过程符合Higuchi方程(R2=0.988 9~0.990 4)或一级方程(R2=0.987 5~0.990 2),释药机制为非Fickian扩散(n=0.615 3~0.633 9)。结论：左羟丙哌嗪缓释骨架片的体外释放符合缓释要求,释放表现为药物扩散和凝胶溶蚀的协同作用。     

藤甲酰苷缓释片的处方优化及释药机制研究

目的：制备藤甲酰苷缓释片并探讨其药物释放机理。方法：以羟丙基甲基纤维素（HPMC）为缓释材料、乙基纤维素（EC）为凝胶骨架材料,以及乳糖等为填充剂制备藤甲酰苷缓释片,采用正交设计法进行处方优化。使用DDslover软件拟合释放曲线。结果：采用压片法制得的骨架型藤甲酰苷缓释片具有良好的缓释效果。藤甲酰苷缓释片的体外释药行为符合 Higuchi 模型,是扩散和溶蚀协同作用的结果,其释药过程用 Higuchi 平面扩散模式方程,相关系数 r = 0.9993（1～12小时）。结论：制备出体外释放度符合要求的藤甲酰苷缓释片。     

Effect of γ-hydroxybutyrate on the release of monoamines from the rat striatum

A simple in vitro system was developed to study the effect of gamma-hydroxybutyrate on nerve cell depolarization-induced release of labelled DA and 5-hydroxytryptamine. The release of (3)H-dopamine formed in rat striatal slices incubated with (3)3H-tyrosine was followed. A three minute exposure to K+ (53.0 mM) caused a thirty-fold increase in the release of newly synthesized (3)H-dopamine. This K + -induced release was antagonized when gamma-hydroxybutyrate (1 mM) was present in the medium. Potassium (53.0 mM) increased (eighteen-fold) the release of (3)H-dopamine from striatal slices initially loaded by preincubation with (3)H-dopamine. The K + -induced release of this pool of DA was, however, not antagonized by gamma-hydroxybutyrate.Potassium (53.0 mM) also increased the release from striatal slices of (3)H-5-hydroxytryptamine (5-HT) newly synthesized from (3)H-tryptophan. This K + -induced release of 5-HT was also not inhibited by gamma-hydroxybutyrate. The ability of gamma-hydroxybutyrate to antagonize only the K + -induced release of newly formed DA may explain why this agent causes a rapid and selective increase in brain dopamine.     

Influence of catecholamines on the in vivo release of histamine in the hypothalamus.

The hypothalamus of conscious, freely moving rats was superfused with artificial CSF through push-pull cannulae and the release of endogenous histamine was determined radioenzymatically in the superfusate. Superfusion with potassium chloride enhanced the release rate of histamine. The effect of potassium chloride was abolished by alpha-fluoromethylhistidine. Noradrenaline (alpha 1- and alpha 2-agonist) and clonidine (alpha 2-agonist) decreased the release rate of histamine and inhibited the potassium-induced histamine release. In preliminary experiments, yohimbine (alpha 2-antagonist) seemed to increase the release rate of histamine in the superfusate. beta-Agonists and antagonists (isoprenaline, salbutamol, propranolol) did not influence the release of histamine.     

Studying the factors that impact the dissolution characteristic of complex drug product

This article summarizes the critical factors involved in product development of a single dosage form formulated by compacting ethyl cellulose (EC) coated controlled release pellets into a tablet. The greatest challenge associated with this type of complex system is to minimize the effect of compression on the drug release. The effects of compression on the drug release were optimized with combination of the following factors (1) particle size of the core pellets, (2) the selection of the coating polymer’s viscosity grade, and (3) emergence of cushioning agents. The optimization of these factors provided superior protection for the controlled release coated pellets; therefore, the desired drug release from the tablet was successfully achieved as designed. However, the drug release rates from the coated pellets before and after the compression were minimized and exhibited only a slight difference.     

Analysis of formulation and food effect on the absorption of metoclopramide

OBJECTIVES: Assessment of the relative and absolute bioavailability of immediate release and sustained release formulations of metoclopramide. Assessment of the effect of a high-fat meal on the pharmacokinetics of sustained release metoclopramide. MATERIAL AND METHODS: In a balanced 4-way crossover study in 16 healthy male volunteers, a sustained release (SR) formulation of metoclopramide was compared with a solution for injection (A) and an immediate release tablet (B). The SR formulation was administered after a fasting period (C) as well as after a high-fat meal (D). A single dose of 30 mg metoclopramide was investigated in each treatment. Metoclopramide concentrations were determined by HPLC. RESULTS: The absolute bioavailability of the sustained release formulation (fasting state) was 58% and thus about 17% lower than the bioavailability of the immediate release formulation. Comparing the treatments C (sustained release, fasting state) and D (sustained release, high-fat meal) no significant influence of food on the absorption of sustained release metoclopramide could be detected.     

GABA receptors are involved in the modulation of the release of 5-hydroxytryptamine from the vascularly perfused small intestine of the guinea-pig

Isolated small intestinal segments of the guinea-pig were perfused arterially and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent was determined by HPLC with electrochemical detection. Test substances were applied intraarterially. Muscimol (1 microM) time dependently first increased then decreased the release of 5-HT and 5-HIAA. The stimulatory effect was prevented by tetrodotoxin (TTx) or scopolamine, indicating that it was mediated by the release of acetylcholine. Bicuculline concentration dependently decreased (1 microM) or increased (10, 50 microM) the release of 5-HT and 5-HIAA, indicating that endogenous GABA also activates stimulatory and inhibitory GABAA receptors. Bicuculline antagonized the stimulatory and inhibitory effect of muscimol. (-)-Baclofen, but not its (+) enantiomer, inhibited the release of 5-HT in the absence and presence of TTx. It was concluded that the release of 5-HT from enterochromaffin cells is directly inhibited by GABAA and GABAB receptors. In addition, acetylcholine released after activation of GABAA receptors stimulates 5-HT release.     

Modulation of acetylcholine release in the guinea-pig trachea by the nitric oxide donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP)

The effects of the nitric oxide (NO) donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) and the NO synthase inhibitor L-N(G)-nitroarginine (L-NOARG) on the electrically evoked [(3)H]-acetylcholine release were studied in an epithelium-free preparation of guinea-pig trachea that had been preincubated with [(3)H]-choline. SNAP (100 and 300 microM) caused small but significant increases of the electrically evoked [(3)H]-acetylcholine release (121+/-4% and 124+/-10% of control). Resting outflow of [(3)H]-ACh was not affected by SNAP. The increase by SNAP was abolished by the specific inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 1 microM). The facilitatory effect of SNAP (100 and 300 microM) was reversed into inhibition of release (to 74+/-4% and to 78+/-2%) after pretreatment of the trachea with capsaicin (3 microM). ODQ prevented the inhibition. Capsaicin pretreatment alone did not significantly alter the release of [(3)H]-acetylcholine. A significant inhibition by SNAP (100 microM) of [(3)H]-acetylcholine release (78+/-3%) was also seen in the presence of the NK(2) receptor antagonist SR 48968 (30 nM). L-NOARG (10 and 100 microM) significantly enhanced the electrically-evoked smooth muscle contractions, but caused no significant increases of the evoked release from capsaicin pretreated trachea strips. This might indicate that the inhibitory effect of endogenous NO on acetylcholine release is too small to be detected by overflow studies. It is concluded that NO has dual effects on the evoked acetylcholine release. NO enhances release in the absence of modifying drugs, but NO inhibits acetylcholine release after blockade of the NK(2) receptor or after sensory nerve depletion with capsaicin. This suggests that NO and endogenous tachykinins act in series to produce an increase in acetylcholine release.     

Release of dynorphin, somatostatin and substance P from the vascularly perfused small intestine of the guinea-pig during peristalsis.

The release of dynorphin-(1-17), somatostatin and substance P into the venous effluate of the isolated and vascularly perfused guinea-pig small intestine was measured during rest and peristaltic activity. The peptides were determined by specific radioimmunoassays. Increasing the intraluminal pressure by 5 mbar increased the release of dynorphin-(1-17), somatostatin and substance P. A substantial increase in the release of substance P was only seen in the presence of naloxone (1.5 microM) indicating an inhibitory influence of opioid peptide-containing neurones on the release of substance P. The pressure-induced release of substance P and dynorphin-(1-17) was completely prevented by tetrodotoxin (1.3 microM), which suggests a neural origin of these two peptides. The pressure-induced release of somatostatin was only partially inhibited by tetrodotoxin (1.3 microM) suggesting that somatostatin may also be released from non-neuronal sources, i.e. endocrine mucosal cells. Dimethylphenylpiperazinium (32 microM) increased the release of somatostatin and substance P and this effect was inhibited by tetrodotoxin (1.3 microM). Cholecystokinin-octapeptide (38 nM) induced a large increase in the release of somatostatin but only a minute increase in the release of substance P; these effects of cholecystokinin-octapeptide were not blocked by tetrodotoxin (1.3 microM). Noradrenaline (59 microM) inhibited the pressure-induced release of substance P but not that induced by dimethylphenylpiperazinium (32 microM). Neither the pressure-induced nor the dimethylphenylpiperazinium-evoked release of somatostatin was significantly diminished by noradrenaline. These results indicate that dynorphin-(1-17), somatostatin and substance P may be transmitters involved in the coordination of the peristaltic reflex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the dihydropyridine Bay K 8644 on the release of [3H]-noradrenaline from the rat isolated vas deferens.

The effects of Bay K 8644 on the release of [3H]-noradrenaline evoked by potassium, electrical stimulation or tyramine from the rat isolated vas deferens labelled with [3H]-noradrenaline were investigated. Bay K 8644 (1 microM) by itself did not affect the spontaneous release of tritium from the rat isolated vas deferens. However, it increased the calcium-dependent release of tritium elicited by both high potassium (59 mM) and electrical field stimulation. The exposure of rat vas deferens to phentolamine (10 microM) increased the release of tritium induced by potassium (59 mM) and electrical field stimulation. Bay K 8644 (1 microM) failed to increase further the release of tritium elicited by both stimuli in preparations previously treated with phentolamine (10 microM). The calcium-independent release of [3H]-noradrenaline evoked by tyramine (10 microM) was not affected by Bay K 8644 (1 microM). The results of our study support the view that alpha2-adrenoceptors modulate noradrenaline release by restricting calcium influx into sympathetic nerve terminals through voltage-dependent channels.     

The pharmacology of the neurochemical transmission in the midbrain raphe nuclei of the rat

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [(3)H]serotonin ([(3)H]5-HT), superfused and the release of [(3)H]5-HT was determined at rest and in response to electrical stimulation. Compartmental analysis of [(3)H]5-HT taken up by raphe tissue indicated various pools where the neurotransmitter release may originate from these stores differed both in size and rate constant. 5-HT release originates not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process establishing synaptic and non-synaptic neurochemical transmission in the serotonergic somatodendritic area. Manipulation of 5-HT transporter function modulates extracellular 5-HT concentrations in the raphe nuclei: of the SSRIs, fluoxetine was found 5-HT releaser, whereas citalopram did not exhibit this effect. Serotonergic projection neurons in the raphe nuclei possess inhibitory 5-HT(1A) and 5-HT(1B/1D) receptors and facilitatory 5-HT(3) receptors, which regulate 5-HT release in an opposing fashion. This observation indicates that somatodendritic 5-HT release in the raphe nuclei is under the control of several 5-HT homoreceptors. 5-HT(7) receptors located on glutamatergic axon terminals indirectly inhibit 5-HT release by reducing glutamatergic facilitation of serotonergic projection neurons. An opposite regulation of glutamatergic axon terminals was also found by involvement of the inhibitory 5-HT(7) and the stimulatory 5-HT(2) receptors as these receptors inhibit and stimulate glutamate release in raphe slice preparation, respectively, Furthermore, postsynaptic 5-HT(1B/1D) heteroreceptors interact with release of GABA in inhibitory fashion in raphe GABAergic interneurons. Serotonergic projection neurons also possess glutamate and GABA heteroreceptors; NMDA and AMPA receptors release 5-HT, whereas both GABAA and GABAB receptors inhibit somatodendritic 5-HT release. Evidence was found for reciprocal interactions between serotonergic and glutamatergic as well as serotonergic and GABAergic innervations in the raphe nuclei. Serotonergic neurons in the raphe nuclei also receive noradrenergic innervation arising from the locus coeruleus and alpha-1 and alpha-2 adrenoceptors inhibited [(3)H]5-HT release in our experimental conditions. The close relation between 5-HT transporter and release-mediating 5-HT autoreceptors was also shown by addition of L-deprenyl, a drug possessing inhibition of type B monoamine oxidase and 5-HT reuptake. L-Deprenyl selectively desensitizes 5-HT(1B) but not 5-HT(1A) receptors and these effects are not related to inhibition of 5-HT metabolism but rather to inhibition of 5-HT transporter.     

Alterations in the potassium-evoked release of substance P from the spinal cord of streptozotocin-induced diabetic rats in vitro.

1. The release of SPLI evoked by high levels of K+ (50 mM) from the spinal cord of diabetic rats was greater than in the case of spinal cord from control rats. 2. Morphine (10(-5) M) significantly inhibited the K(+)-evoked release of SPLI release in both the groups. However, in spinal cord from diabetic rats, morphine reduced the K(+)-evoked release of SPLI only to the levels that were observed in material from control rats prior to treatment with morphine. 3. Glucose (20 mM) and dibutyryl cyclic-AMP (10(-4) M) significantly potentiated the K(+)-evoked release of SPLI in spinal cord from control rats. 4. These findings suggest that excessive release of SPLI from the spinal cord may be associated with the reported abnormalities in nociceptive transmission in diabetic rats, and that excessive release of SPLI may be modulated by levels of glucose and/or cyclic-AMP in the spinal cord.