A novel granulation non-solvent addition method containing hydrophilic and lipophilic drugs

Atenolol and simvastatin were granulated in combination by non-solvent addition coacervation method to treat hypertension orally. Dissolution test was performed in water containing 0.5% sodium dodecyl sulfate at 37 0.05 degrees C. FTIR spectrometry, X-ray diffractometry and thermal analysis confirmed the absence of any chemical interaction between polymer and the entrapped drugs. The granules size was about 280-619 μm. Scanning electron microscopy reported irregular morphology of granules. The entrapment efficiency was approximately 90% for atenolol and 70% for simvastatin. A controlled release behavior of both drugs but a burst release phenomenon of simvastatin from the formulations were observed. In conclusion, granules loaded with a hydrophilic and a lipophilic drug were successfully prepared.     

复方丹参口服液的制备及质量控制

目的　研究复方丹参口服液的制备工艺。方法采用薄层扫描法对复方丹参口服液中丹参酮 A 进行含量测定。结果　丹参酮 A在 0 .4 5 45～ 2 .2 72 5g· L-1浓度范围内呈良好线性关系 (r =0 .9984 ) ,平均回收率为 99.78%。结论　该工艺可行 ,其质量控制方法可对制剂质量进行有效控制     

一测多评法测定冠心丹参颗粒中4种成分的含量

目的：建立以丹参酮Ⅱ_A内参物,同时测定冠心丹颗粒中丹参素钠、原儿茶醛、丹酚酸B、丹参酮Ⅱ_A的一测多评HPLC法。方法：以丹参酮Ⅱ_A为内参物,确定其他3种成分相对于丹参酮Ⅱ_A的校正因子,通过相对校正因子（RCF）对丹参素钠、原儿茶醛、丹酚酸B进行定量,实现一测多评（计算法）;同时采用外标法测定冠心丹参粒中4种成分的含量（实测法）,并比较一测多评法与外标法测定结果的差异。结果：在一定的线性范围内,丹参酮Ⅱ_A与丹参素钠、原儿茶醛、丹酚酸B的相对校正因子分别为0.299 9,1.991 7,0.424 4;且在不同实验条件下重复性良好（RSD分别为1.33%、1.44%、4.00%）;3批冠心丹参颗粒中4种成分按一测多评方法与外标法测定结果基本一致（RSD<3.0%）。结论：可有效地控制冠心丹参颗粒的内在质量。     

复方丹参片中5种活性成分的溶出度比较

目的 研究复方丹参片中5种活性成分的体外溶出特点.方法 采用HPLC法测定复方丹参片中5种活性成分在不同溶出介质中的体外溶出度,计算活性成分的累积溶出百分率,采用相似因子(f2)进行释放曲线的相似性比较.结果 在0.5%十二烷基硫酸钠水溶液中,原儿茶醛、三七皂苷R1、丹酚酸B、丹参酮ⅡA与丹参素的相似因子分别为60、61、73、17;在0.1 mol·L-1的HC1溶液中,原儿茶醛、三七皂苷R1、丹酚酸B与丹参素的相似因子分别为70、40、36.结论 在0.5%十二烷基硫酸钠水溶液与0.1 mol·L-1HC1溶液中,复方丹参片的活性成分不具有同步溶出的特点.     

Isotropic systems of medium-chain mono- and diglycerides for solubilization of lipophilic and hydrophilic drugs

The aim of this study was to investigate isotropic mono- and diglyceride-based (MCMDG) systems, which are potential vehicles for injectable products containing both hydrophilic and lipophilic drugs. For two-component systems, MCMDG was mixed with various masses of water. For three-component systems, the samples were prepared by mixing propylene glycol or glycerol formal or short-chain alcohols with MCMDG prior to the addition of water. The isotropic region was examined by visual inspection and confirmed using polarized light microscopy. Viscosities of formulations were measured. Solubilities of levamisole phosphate (hydrophilic) and abamectin (lipophilic) were determined in the isotropic formulations using high-performance liquid chromatography assay. The isotropic region in the two-component systems had a water content of up to 18% at 25 degrees C. Solvents such as propylene glycol (PG), glycerol formal (FG), and ethyl alcohol increased the isotropic region. The area of isotropic region in these three-component systems increased with increasing temperature. The area of the isotropic region became larger with decreasing dielectric constant and solubility parameter of the series of short-chain alcohols, except n-butyl alcohol, at 25 degrees C. The systems exhibited Newtonian behavior. The solubility of both hydrophilic and lipophilic drugs was high in formulations at 25 degrees C. It was concluded that more water was solubilized in MCMDG/short-chain alcohols/water systems, and the isotropic region in the short-chain alcohol systems enlarged compared with MCMDG/PG/water or MCMDG/GF/water systems, except the n-butyl alcohol system. Hydrophilic and lipophilic drugs solubilize in the systems. The isotropic formulations containing MCMDG may represent an alternative to more traditional formulations for injectable formulations containing both lipophilic and hydrophilic drugs.     

Age-related changes in skin permeability of hydrophilic and lipophilic compounds in rats

The effect of age on intact and stripped skin permeability of lipophilic (ketoprofen and isosorbide dinitrate) and hydrophilic permeants (deuterium oxide and diclofenac sodium) was investigated using STD: Wistar male rats aged 5 to 180 days. The permeability of permeants through intact skin increased with increasing lipophilicity of the permeants at each age, indicating that the permselective property of rat skin is revealed even at 5-days-old. The permeability coefficients through intact skin decreased with increasing age, and the extent of these decreases was higher for lipophilic permeants than that for hydrophilic permeants. On the other hand, the stripped skin permeability of permeants was almost the same at each age, and with aging each permeability coefficient through stripped skin decreased up to 21 days, dramatically during 21-90 days and then gradually again to 180 days. The thickness of the stratum corneum and stripped skin increased according to age with faster growth during 21-90 days. The reciprocal of the mean thickness of stratum corneum and stripped skin correlated well with intact skin and stripped skin permeability (r > 0.9), respectively. These results clarified that the permselectivity of rat skin against lipophilicity of permeant exists at the latest from 5 days after birth. In addition, it is speculated that the thickness of skin is a large factor in the decrease of its permeability with age.     

丹参活性成分或制剂对CYP450活性的影响及药物相互作用研究进展

丹参是一种传统医疗的草本植物，临床上广泛应用于心脑血管疾病的辅助治疗。丹参活性成分复杂，部分成分可影响肝脏中细胞色素P450酶（CYP450）的活性，可能导致药物相互作用的发生。探讨丹参对CYP450活性的影响及药物相互作用机制，对指导临床合理联用丹参与其他药物具有重要的意义。     

Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes

Purpose: Topical administration is the preferred route of drug delivery for ophthalmic ailments. However, poor permeation through ocular surface and significant systemic absorption, makes the topical drug delivery challenging. Furthermore, distribution of topically delivered drugs varies with their physicochemical properties and the type of formulation used. Hence, this study was done to understand the pattern of ocular drug distribution of topically applied hydrophilic and lipophilic substances in two different formulations.

Methods: 5-Carboxyfluorescein and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate were used as representative candidates for hydrophilic and lipophilic substances, respectively. They were formulated in solution and liposomes. Single drop of either formulation containing hydrophilic or lipophilic substance was instilled topically, unilaterally to rat eyes. Subsequently, rats were sacrificed at 10, 30 and 120?min post-instillation. Eyes were cryosectioned and examined under confocal microscope to determine the fluorescence intensity in ocular tissues.

Results: Corneal permeation of hydrophilic and lipophilic substances in both formulations peaked at 30?min post-instillation. Liposomal–lipophilic dye and non-liposomal–hydrophilic dye showed better corneal distribution. Fluorescence was absent in contralateral eyes of non-liposomal–hydrophilic dye-treated animals but was present in contralateral eyes of liposomal–hydrophilic dye-treated animals. Fluorescence in contralateral eyes of liposomal–lipophilic dye-treated animals was significantly higher compared to non-liposomal–lipophilic dye-treated animals.

Conclusions: Topically applied liposomal formulation of lipophilic substance provides higher corneal concentration of drug with lesser systemic absorption compared to its solution. For hydrophilic substance, topical use of solution provides greater corneal concentration compared to liposomes which is more likely to be absorbed systemically.     

Isotropic medium chain mono-diglyceride/oil/water formulations for solubilization of lipophilic and hydrophilic drugs

The aim of the study was to investigate isotropic mono- and diglyceride (MCMDG)/oil/water systems as vehicles for combinations of hydrophilic and lipophilic drugs. For two-component systems, MCMDG was mixed with various masses of water. For MCMDG/oily vehicles/water systems, mixtures were prepared by mixing oil and MCMDG prior to the addition of the appropriate masses of water. The isotropic region was examined by visual inspection and confirmed using polarized light microscopy. Viscosities of the systems were determined. Solubilities of hydrophilic (levamisole HCl) and lipopohilic (abamectin) drugs were determined in the isotropic formulations by HPLC analysis. The isotropic regions in the two-component and three-component systems had water contents of up to 18% at 25 °C. The isotropic formulations exhibited Newtonion flow. The viscosity of formulations having the same percentage of water increased with increasing ratio of MCMDG to oil in three-component systems. The solubilities of the levamisole HCl and abamectin were higher in the isotropic MCMDG/sesame oil/water formulations than in equivalent MCMDG/water formulations. In some formulations, the solubility of levamisole HCl was higher in the absence of abamectin than in combination with abamectin. Isotropic MCMDG/oil/water systems were obtained without the use of co-surfactants. Increasing water content in the system did not proportionally increase the solubility of hydrophilic drug. Solubilization of hydrophilic drug was affected by lipophilic drug in the presence or absence of SO and lipophilic drug solubility was affected by hydrophilic drug in the absence of SO. These systems are suitable vehicles to deliver both hydrophilic and lipophilic drugs and could be of interest for pharmaceutical formulations.     

左旋沙丁胺醇的合成工艺改进及有关物质研究

目的借助HPLC对左旋沙丁胺醇合成过程中的主要中间体、有关物质和终产品进行检测,建立HPLC检测方法,优化左旋沙丁胺醇的合成工艺。方法以水杨醛为起始原料,经傅克反应、选择性还原醛羰基、丙叉基保护、叔丁胺氨解、酮羰基还原、脱保护和成盐等步骤得到沙丁胺醇。针对特定路线,制备了5种可能的有关物质。并在此基础上以化合物7为前体,经L-(+)-酒石酸拆分得到左旋沙丁胺醇。结果目标产物结构经MS和~1H-NMR确证。反应总收率为42.1%(以水杨醛计),终产品纯度达到99.4%,拆分收率为34.7%(以化合物7计)。结论本文建立了沙丁胺醇合成过程中涉及的主要中间体、有关物质和终产品的HPLC检测方法,可以有效监控产品质量。反应路线原料易得,操作简便,适合工业化生产。该研究将为该药的一致性评价奠定研究基础。     

盐酸罗沙替丁醋酸酯的合成工艺优化及初步质量研究

目的优化盐酸罗沙替丁醋酸酯合成工艺,制备合成过程中有关物质及建立相应的HPLC检测方法。方法以间羟基苯甲醛为起始原料,经与哌啶还原胺化、3-氯丙胺盐酸盐成醚、氯乙酰氯酰化、醋酸盐取代成酯、成盐,得盐酸罗沙替丁醋酸酯。针对选定的特定路线,制备了4种可能的有关物质。结果目标产物结构经MS和1H-NMR确证。反应总收率为31.0%(以间羟基苯甲醛计),终产品纯度达到99.6%。结论本文还建立了涉及该合成过程中的起始原料、中间体、主要有关物质和终产品的HPLC检测方法,可以有效监控产品质量。反应路线原料廉价易得,溶剂可回收套用,操作简便稳定,适合工业化生产。     

麦白霉素的组分分析与质量控制

目的:考察国产麦白霉素组分含量,为提高中国药典2005年版麦白霉素质量标准提供依据。方法:采用 HPLC—MS 联用仪推测麦白霉素标准品中的8个主要组分,采用 HPLC 法测定12批样品的8个组分的含量情况。结果:12批样品中麦迪霉素 A_1和吉他霉素 A_6两个组分的含量分别为30%～50%和10%～20%,其它组分含量较低,各厂家产品组分的种类和含量不同。结论:建议修订麦白霉素组分质量标准,控制产品质量。     

冠心丹参颗粒质量标准探讨

目的　建立冠心丹参颗粒的质量标准。方法　采用TLC法测定冠心丹参颗粒中丹参酮IIA的含量。结果　冠心丹参颗粒中丹参酮IIA的含量平均为 0 .376mg/g ,回收率为 96 .6 8%。 结论　方法准确可靠 ,重复性好。     

冠心丹参颗粒质量标准探讨

目的建立冠心丹参颗粒的质量标准.方法采用TLC法测定冠心丹参颗粒中丹参酮IIA 的含量.结果冠心丹参颗粒中丹参酮IIA 的含量平均为0.376 mg/g,回收率为96.68%.结论方法准确可靠,重复性好.     

Chemical and in vitro enzymatic stability of newly synthesized celecoxib lipophilic and hydrophilic amides

Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP-HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were ≤13.6 and ≤40 ng/mL, respectively. The solubility and log P_app of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80 °C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY-CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53 h at 60, 70 and 80 °C, respectively, with extrapolated half-lives of 2060 and 443 h at 25 and 37 °C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79 h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis.     

Crosslinked poly(methyl vinyl ether-co-maleic anhydride) as topical vehicles for hydrophilic and lipophilic drugs

Poly(methyl vinyl ether-co-maleic anhydride) crosslinked with ethylene glycol (GZ-ET), 1,4-butanediol (GZ-BUT), 1,6-exandiol (GZ-EX), 1,8-octanediol (GZ-OCT), 1,10-decanediol (GZ-DEC) or 1,12-dodecanediol (GZ-DOD) was prepared and employed as a supporting material for aqueous topical gels containing pyridoxine hydrochloride (PYCL) chosen as a hydrophilic model molecule or for O/A emulsion containing β-carotene chosen as a hydrophobic model molecule. We analyzed the effect of the nature of the crosslinker on the permeation of hydrophilic and lipophilic vitamins through porcine skin by in vitro permeation studies. The vehicles formed by crosslinked poly(methyl vinyl ether-co-maleic anhydride) showed enhanced vitamins permeation with respect to the same vehicles formed by noncrosslinked poly(methyl vinyl ether-co-maleic anhydride) (GZ). The decrease in the crosslinker acyl chain length provides vehicles accelerating the drug permeability through the skin.     

毒性中药蟾酥质量检测方法研究

目的:建立蟾蜍中多种药效及毒性成分蟾蜍毒素的定性定量检测方法。方法:采用液相色谱-质谱/质谱联用方法检测蟾酥中多种蟾蜍毒素成分。结果:建立了华蟾毒它灵、蟾蜍灵、华蟾毒配基及脂蟾毒配基的LC-MS/MS检测方法。比较了蟾酥样本的液相色谱-质谱/质谱联用分析数据。对4个不同来源中华大蟾蜍及黑眶蟾蜍的蟾酥样本进行检测,检出华蟾毒它灵、蟾蜍灵、华蟾毒配基及脂蟾毒配基的含量范围为0.05%~5.12%(w/w)。结论:液相色谱-质谱/质谱联用方法可用于蟾酥定性定量检测,并为质量评价提供参考。