双氢青蒿素磷脂复合物的研究

目的 优化双氢青蒿素与磷脂形成复合物的制备工艺。方法 以双氢青蒿素磷脂复合物的复合率为评估标准,采用单因素和正交设计试验考察各因素对复合率的影响;并用高效液相色谱法测定双氢青蒿素磷脂复合物中双氢青蒿素的含量。结果 确定双氢青蒿素磷脂复合物的最优制备条件,即在55℃制备温度下,以氯仿为反应溶剂,双氢青蒿素与磷脂的投料比为1∶3,药物浓度为5%,反应时间为3 h。结论 在55℃制备温度下双氢青蒿素磷脂复合物的形成受溶剂、反应物投料比、药物浓度及反应时间的影响较大。     

正交试验优选山楂叶总黄酮磷脂复合物的制备工艺

目的优选山楂叶总黄酮磷脂复合物的制备工艺。方法以山楂叶总黄酮磷脂复合物的综合评分(外观及复合率)为指标,以投料比、反应物浓度、温度、搅拌时间等因素对复合率的影响,据此设计5因素4水平正交试验,系统考察山楂叶总黄酮磷脂复合物的最佳制备工艺。结果 4个因素影响程度排列为投料比>反应物浓度>搅拌时间>温度。结论最佳制备工艺条件为山楂叶总黄酮∶磷脂1∶2,反应物质量物浓度40 g/L,温度60℃,搅拌时间1 h。     

阿魏酸-磷脂复合物的制备及其物理特性

目的制备阿魏酸-磷脂复合物,提高阿魏酸的脂溶性,以期进行进一步的制剂研究。方法采用溶剂挥发法制备阿魏酸-磷脂复合物,并以单因素法优化制备工艺,对复合物进行红外及X-衍射分析,考察阿魏酸表观油水分配系数的变化。结果阿魏酸磷脂复合物的制备工艺为:以无水乙醇为溶剂,药物-磷脂投料摩尔比为1∶1,室温下磁力搅拌4 h,真空干燥;红外及X-衍射图谱验证了复合物的形成;阿魏酸-磷脂复合物在0.1 mol.L-1HCl中的表观油水分配系数显著提高。结论阿魏酸磷脂复合物提高了阿魏酸的脂溶性。     

甘草黄酮磷脂复合物制备工艺研究

目的 采用正交试验法优化甘草黄酮磷脂复合物的制备工艺,改善其理化性质.方法 以甘草黄酮与磷脂的复合率为指标,在单因素法考察复合溶剂、复合温度、复合时间、初始浓度和投料比例对复合率的影响的基础上,采用正交设计法优化复合物制备工艺;并对所得磷脂复合物的表观溶解度进行考察.结果 甘草黄酮磷脂复合物的最佳制备工艺为:甘草黄酮与磷脂按1∶1.5 的质量比投料,于30 ℃ 乙醇中复合1.5 h,甘草黄酮的浓度为5 g· L-1.验证试验表明,在优化得到的工艺条件下,甘草黄酮与磷脂的复合率在96% 以上.复合物在水中的表观溶解度是甘草黄酮原料药的10.7倍.结论 优化得到的工艺稳定,磷脂复合物改善了甘草黄酮的溶解性质.     

丹酚酸B磷脂复合物制备工艺研究

［摘要］目的确定制备丹酚酸B磷脂复合物的最佳工艺。方法以丹酚酸B与磷脂的结合率为指标,采用单因素考察和正交实验筛选工艺参数。结果制备丹酚酸B磷脂复合物的最佳工艺条件：以四氢呋喃为溶剂,每克丹酚酸B其用量为40 mL,丹酚酸B与磷脂的投料量比为1：2,40 ℃下反应时间为1.5 h。结论丹酚酸B磷脂复合物的形成受反应溶剂及其用量以及反应物投料比影响较大,反应温度和时间对其亦有影响。     

淫羊藿黄酮提取工艺的优化及其磷脂复合物的制备

目的　优化淫羊藿黄酮的提取工艺 ,制备淫羊藿黄酮磷脂复合物 (EFP)。方法　优化淫羊藿黄酮的提取工艺 ,并用聚酰胺柱分离纯化淫羊藿黄酮 ,溶剂挥发法制备EFP ,摇瓶法测定淫羊藿黄酮及其磷脂复合物中黄酮的油 /水表观分配系数 ,电镜观察淫羊藿黄酮磷脂复合物的水中分散状态。结果　黄酮提取的优化条件为 :80 %乙醇 ,10倍量 ,提 2次 ,每次 2h ;制备淫羊藿黄酮磷脂复合物后 ,淫羊藿黄酮的表观分配系数提高 3 5倍 ,正辛醇中溶解量提高约 30倍 ;水中能均匀分散呈胶团状 ,与脂质体类似。结论　提取优化条件简单可行 ;磷脂的加入可有效提高淫羊藿黄酮的油 /水表观分配系数     

淫羊藿黄酮提取工艺的优化及其磷脂复合物的制备

目的优化淫羊藿黄酮的提取工艺,制备淫羊藿黄酮磷脂复合物(EFP).方法优化淫羊藿黄酮的提取工艺,并用聚酰胺柱分离纯化淫羊藿黄酮,溶剂挥发法制备EFP,摇瓶法测定淫羊藿黄酮及其磷脂复合物中黄酮的油/水表观分配系数,电镜观察淫羊藿黄酮磷脂复合物的水中分散状态.结果黄酮提取的优化条件为:80%乙醇,10倍量,提2次,每次2h;制备淫羊藿黄酮磷脂复合物后,淫羊藿黄酮的表观分配系数提高3.5倍,正辛醇中溶解量提高约30倍;水中能均匀分散呈胶团状,与脂质体类似.结论提取优化条件简单可行;磷脂的加入可有效提高淫羊藿黄酮的油/水表观分配系数.     

淫羊藿黄酮提取工艺的优化及其磷脂复合物的制备

目的：优化淫羊藿黄酮的提取工艺，制备淫羊藿黄酮磷脂复合物（EFP）。方法：优化淫羊藿黄酮的提取工艺，并用聚酰胺柱分离纯化淫羊藿黄酮，溶剂挥发法制备EFP，摇瓶法测定淫羊藿黄酮及其磷脂复物中黄酮的油／水表观分配系数，电镜观察淫羊藿黄酮脂复合物的水中分散状态。结果黄酮提取的优化条件为：80％乙醇，10倍量，提2次，每次2h；制备淫羊藿黄酮磷脂复合物后，淫羊藿黄酮的表观分配系数提高3．5倍，正辛醇中溶解量提高约30倍；水吕能均匀分散呈胶团状，与脂质体类似。结论：提取优化简单可行，磷脂的加入有效提高淫羊藿黄酮的油／水表观分配系数。     

人参皂苷Rb1磷脂复合物的制备及其理化性质研究

目的:制备人参皂苷Rb1磷脂复合物,并研究其理化性质。方法:以人参皂苷Rb1与磷脂的复合率为评价指标,对制备工艺进行单因素考察,并采用正交实验设计对处方进行优化。利用紫外光谱法、差示扫描量热法等对所得的磷脂复合物进行鉴定。测定磷脂复合物中Rb1的含量,并考察磷脂复合物在不同体系中的表观油水分配系数。结果:人参皂苷Rb1与磷脂形成了分子型复合物。最佳制备方法的复合率为99.92%±0.14%,其中Rb1的含量在99.00%以上。磷脂复合物在不同体系中的表观油水分配系数与原药相比均显著增加。结论:确定了人参皂苷Rb1磷脂复合物的最佳制备工艺,并且其磷脂复合物明显的提高了原药的脂溶性。     

阿司匹林磷脂复合物的制备及其表征

目的:制备阿司匹林磷脂复合物(ASP-PC)并进行表征。方法:以ASP与PC的复合率为指标,采用单因素试验筛选ASP-PC的制备方法、PC种类、溶剂种类、反应时间、反应温度、溶剂体积和药脂比,并进行验证。采用紫外分光光度法、热重分析法、X射线衍射法和傅里叶红外光谱分析对所制ASP-PC进行表征。结果:采用磁力搅拌-冷凝回流法,药物-大豆磷脂比为1∶3(mol/mol),溶剂为四氢呋喃(50 m L),58℃下反应3 h,所制ASP-PC的平均复合率为83.52%(RSD=1.16%,n=3)。与ASP、ASP和PC的物理混合物比较,紫外光谱显示ASP-PC没有出现新的吸收峰;热重分析、X射线衍射分析和傅里叶红外光谱分析显示ASP-PC中的ASP与PC发生了相互作用,且ASP-PC在0~300℃范围内质量变化较小。结论:成功制得ASP-PC,其中ASP与PC复合成功,但仍有微量ASP以晶体形式存在。     

醋酸氯地孕酮平衡溶解度及表观油水分配系数的测定

目的:测定醋酸氯地孕酮(CA)的平衡溶解度及表观油水分配系数,为CA新剂型的体外评价进行处方前研究。方法:采用高效液相色谱法测定CA在水及不同pH(1·2、2·0、3·0、4·5、5·5、6·8、7·4、8·0)介质及常用9种有机溶剂(包括甲醇、乙醇等)中的平衡溶解度;采用摇瓶法测定其在正辛醇与水及各pH介质组成的体系中的表观油水分配系数(P)。结果:37℃时,CA在水及9种pH值介质中的平衡溶解度依次为0·473、0·533、0·423、0·056、0·309、0·428、0·447、0·428、0·448μg·mL-1,在甲醇、乙醇等中的平衡溶解度为7320·61～344248·70μg·mL-1;CA在水中的lgP值为4·05,不同pH条件下的lgP值差别不大(4·11～4·25)。结论:CA不溶于水,易溶于有机溶剂,在弱酸环境下有一定程度的降解;且其lgP值较大,提示在制剂研究中需采用适当的增溶手段。     

胶态二氧化硅固化的银杏黄酮组分磷脂复合物微丸的制备工艺研究

目的：制备胶体二氧化硅固化粉末微丸,并对制备工艺进行研究。方法：首先制备银杏黄酮组分磷脂复合物,并利用胶体二氧化硅进行固化得到固化粉末。以其为主药,通过单因素实验筛选制备微丸的润湿剂、载药量和崩解剂,以微丸的圆整度和收率为评价指标,采用正交实验设计筛选出最佳制备工艺。结果：选择30%乙醇作为润湿剂,确定载药量为70%,选择CMC-Na作为崩解剂。最佳制备工艺确定为滚圆时间为4min,滚圆频率30Hz,挤出频率为30Hz。结论：制备的微丸稳定,验证试验结果表明制备工艺科学合理。     

金银花提取条件对绿原酸含量的影响

目的 研究金银花中有效成分绿原酸的最佳提取条件。方法 采用正交实验法以乙醇浓度(A)、溶剂量(B)、提取时间(C)和提取次数(D)4个因素,每个因素选取3个水平进行实验。结果 因素A,因素D对绿原酸的含量有极显著影响。结论 以10倍量70％乙醇为溶剂,85℃提取两次,每次1h为最佳提取条件。     

白头翁皂苷B3的溶解度及油水分配系数与大鼠在体肠吸收研究

目的 测定白头翁皂苷B3的表观溶解度及油水分配系数,并研究其大鼠在体肠吸收机制。方法 HPLC-ELSD法测定B3的表观溶解度和油水分配系数,重量法计算大鼠在体单向肠灌流实验中吸收速率常数(K_a)和表观吸收系数(P_app)。结果 白头翁皂苷B3在37℃有机溶剂中的表观溶解度较低,在碱性磷酸盐缓冲液中的表观溶解度较高;白头翁皂苷B3在不同磷酸盐缓冲液中的油水分配系数相差不大;白头翁皂苷B3在大鼠十二指肠、空肠、回肠和结肠的K_a和P_app没有显著性差异(P > 0.05);白头翁皂苷B3在0.05~2.5 mg/mL随着浓度提高出现过饱和现象;加入P-糖蛋白抑制剂维拉帕米和P-糖蛋白底物地高辛后,都能显著提高白头翁皂苷B3的K_a值。结论 在实验浓度范围内,溶解度和油水分配系数能够较好地预测肠吸收情况;白头翁皂苷B3不完全依赖浓度梯度转运,细胞膜上的载体蛋白参与了药物的转运过程,其小肠吸收机制并不完全为被动转运;受吸收部位影响较小,无特殊的吸收窗;P-糖蛋白介导了白头翁皂苷B3的小肠吸收。     

磷脂复合物一自乳化释药系统研究进展

磷脂复合物一自乳化释药系统是一种新型的释药系统,它结合了磷脂复合物与自乳化技术,能发挥二者的协同作用,提高生物利用度。磷脂复合物一自乳化释药系统为中药剂型的研究开辟了一条新的道路。该剂型具有广阔的市场前景,现将有关此类释药系统的研究情况做一介绍。     

增强绿原酸水溶液稳定性的方法研究

目的以含量变化为指标,对绿原酸水溶液的稳定剂进行研究。方法采用经典恒温加速试验法,研究各个影响因素对绿原酸含量的变化规律。结果将亚硫酸氢钠和EDTA-2Na作为稳定剂,调节溶液pH2～4之间,所得到的绿原酸水溶液按含量变化计算,室温贮存期为97d,放于4℃冰箱贮存期可达到613d。而不加稳定剂的绿原酸水溶液的室温贮存期为29d,4℃冰箱贮存期为160d。结论此方法可为含绿原酸成分的液体制剂提供参考。     

以磷脂复合物为载体的泊沙康唑亚微乳处方及制备工艺研究

确定泊沙康唑磷脂复合物亚微乳的最佳处方及制备工艺,并对其进行确证。以磷脂复合物为载体,利用高压均质技术制备泊沙康唑磷脂复合物亚微乳。以外观性状、粒径、Zeta电位、离心稳定常数(Ke)、含量和包封率为主要评价指标,对影响亚微乳剂的处方因素及制备工艺因素进行单因素考察和正交优化,确定泊沙康唑磷脂复合物亚微乳的处方及制备工艺,并对其进行确证。按确定的处方工艺制备3批样品,各质量评价指标的平均值分别为：粒径0.186μm、Zeta电位-34.69mV、pH7.01、含量98.12%、包封率91.41%、渗透压302mOsmol/L,符合亚微乳剂质量要求。本处方及制备工艺简单可行,重现性好,制得的亚微乳包封率高,质量均匀、可控。     

大孔吸附树脂对绿原酸吸附性能的研究

目的为了纯化金银花中的绿原酸,优选绿原酸的吸附树脂及工艺参数。方法用HPLC法测定绿原酸含量;采用静态吸附法,考察大孔树脂的吸附、解吸性能,吸附动力学及影响吸附性能的因素。结果HPD 100树脂综合性能最佳;HPD 450解吸率虽然最高,但吸附量和吸附率均低;提取液酸性条件下吸附量佳。结论以HPD 100树脂在pH 3条件下吸附为最佳。     

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems

Components:In order to formulate a successful SMEDDS for maximum therapeutic effect, due consideration must be given to various factors such as physicochemical properties of the active moiety as well as excipients, potential for drug excipient interaction (in vitro and in vivo) and physiological factors that promote or inhibit the bioavailability. Further, other important factors such as regulatory status, solubilization capacity, miscibility, physical state of the excipients at room temperature, digestibility and compatibility with capsule shell, chemical stability and cost of the materials should also be considered during the formulation[15]. Such a rationale approach not only helps in reducing the time involved in the formulation development but also reduces the cost of its development[11].

Oil/lipid phase:

The function of oil phase in self-microemulsifying system is to solubilize the hydrophobic/lipophilic active moiety in order to improve both drug loading and bioavailability of the hydrophobic active moiety. Selection of oil plays a vital role in the formulation as it determines the amount of drug that can be solubilized in the system[16]. A lipid molecule with a large hydrophobic portion compared to hydrophilic portion is desirable as it maximizes the amount of drug that can be solubilized. Open in a separate windowLIST OF OILS USED IN FORMULATION OF SMEDDS

Long chain triglycerides:

Lipids that have fatty acid chains of 14-20 carbons are categorized as LCTs[17]. Fixed oils i.e., vegetable oils contain a mixture of glyceride esters of unsaturated long chain fatty acids. These are considered safe as they are commonly present in daily food and are easily digestible[15]. Large hydrophobic portion of triglycerides is responsible for their high solvent capacity for lipophilic moieties. Though it is difficult to microemulsify, some marketed formulations such as Neoral^® (composed of olive oil which, has shown superior oral bioavailability) and Topicaine^® gel (composed of Jojoba oil for transdermal application) have been successfully practicing the microemulsification of LCTs[18].

Medium chain triglycerides and related esters:

Lipids that have fatty acid chains of 6-12 carbons are categorized as MCTs[17]. MCTs are the most common choice of oil for SMEDDS as they are resistant to oxidation and possess high solvent capacity compared to LCT because of their high effective concentration of ester group. MCTs produced from the distillation of coconut oil are known as glyceryl tricaprylate and comprises of saturated C8 and C10 fatty acids in the liquid state[15]. Labrafac CM 10, a MCT, has shown superior solubility for fenofibrate and produced wider microemulsion region at all surfactant/co-surfactant combinations than Maisine 35, which, is a LCT[19]. Drug substance should possess minimum solubility of 50 mg/ml in LCTs for lymphatic absorption[20]. Upon digestion, products of short and medium chain triglycerides are directed towards portal vein whereas chylomicrons formed from LCTs triggers the lymphatic transport. Further, highly hydrophobic drug substances are easily soluble in vegetable oils and can easily be formulated as simple oil solutions which are readily emulsified in the gut. However, most conventional hydrophobic drug substances do not exhibit superior solubility in LCT such as vegetable oil[21,22].Moderately hydrophobic drug substances, on the other hand, cannot be formulated into simple oil solutions as their solubility is limited. In such cases, SMEDDS are promising alternative where the drug solubility in the oil will be enhanced due to microemulsification of oil by surfactants. It is well accepted that oils with long hydrocarbon chains (high molecular volume) such as soybean oil, castor oil are difficult to microemulsify compared to MCT (low molecular volume) such as capmul MCM and Miglyol. However, solubilizing capacity of oil for lipophilic moiety increases with chain length (hydrophobic portion) of the oil. Hence the selection of oil is a compromise between the solubilizing potential and ability to facilitate the formation of microemulsion[23]. Malcolmson et al. studied the solubility of testosterone propionate in various oils for the formulation of O/W microemulsion and concluded that oils with larger molecular volume such as triglycerides show superior solubility than the corresponding micellar solution containing only surfactants without oil[24,25]. Enhancement of drug solubility in SMEDDS not only relies on the solubility of the drug in the oil but also on the surfactant(s). For instance, ethyl butyrate, small molecular volume oil, has shown higher solubility for testosterone propionate but its ME formulation has only improved the solubility slightly than the corresponding micellar solution. On the contrary, Miglyol 812 which is a larger molecular volume oil has shown improved solubilization in the ME formulation though the solubility of testosterone propionate is less in the individual components compared to ethyl butyrate[24].

Drug solubility in lipid:

Oil component alters the solubility of the drug in SMEDDS by penetrating into the hydrophobic portion of the surfactant monolayer. Extent of oil penetration varies and depends on the molecular volume, polarity, size and shape of the oil molecule. Overall drug solubility in SMEDDS is always higher than the solubility of drug in individual excipients that combine to form SMEDDS. However, such higher solubility considerably depends on the solubility of drug in oil phase, interfacial locus of the drug and drug-surfactant interactions at the interface[26]. In light scattering experiments, it was observed that oils with small molecular volume act like co-surfactants and penetrate into the surfactant monolayer. This forms thinner polyoxyethylene chains near the hydrophobic core of the micelle disrupting the main locus of the drug solubilization due to which, a higher solubility of drug is not observed. Large molecular volume oils, however, forms a distinct core and do not penetrate effectively into the surfactant monolayer. The locus of drug solubilization was found to be effected by the microstructure and solubility of the drug in the excipients. The locus of drug solubilization was found to be at the interface of micelle for phytosterols whereas the same for cholesterol was found to be between the hydrophobic head groups of surfactant molecules. This is attributed to altered side chain flexibility of phytosterol due to the additional substitution of alkyl side chain compared to cholesterol[27].In addition to molecular volume and polarity of the oil, drug solubility in oil is affected by physicochemical properties of drug molecule itself. Consideration of BCS classification and Lipinski''s rule of 5 for the selection of drug is only useful during initial screening stages. As per BCS classification, some of the acidic drugs are listed in Class II despite having good absorption and disposition as they do not satisfy the requirement of higher solubility at low pH values. Lipinski''s rule of 5, on the other hand, holds good only when the drug is not a substrate for the active transporter[4]. This suggests that aqueous solubility and log P alone are not sufficient to predict the solubility of drug in the oil. This further indicates that the solubility of any two drugs with similar log P would not be the same due to their different physicochemical properties.To demonstrate this, a study was conducted in our laboratory with two antihypertensive drugs having close partition coefficient (log P) values, different aqueous solubility and varying physicochemical properties. Candesartan cilexetil is hydrophobic and has log P value of 7.3, molecular weight 610.66 g/mol with a polar surface area 135.77 whereas, valsartan is slightly soluble in aqueous phase with log P value of 5.3, molecular weight 434.53 g/mol with a polar surface area 103.48 (clogP and polar surface area were calculated using chembiodraw ultra 11.0). Unlike candesartan cilexetil, valsartan exhibits pH dependent solubility[28].If only log P and aqueous solubility of these two drugs are considered, it is only natural to assume that candesartan cilexetil would be highly soluble in lipid phase whereas valsartan would be less soluble. A specific and sensitive HPLC-UV method was developed and validated to measure the super saturation solubility of these two drugs in various oils and the results showed a completely different solubility profiles. Solubility profile of these two drugs in different oil phase is given in fig. 2.Open in a separate windowFig. 2Solubility of active ingredients in various oils. Valsartan, candesartan cilexetil.Although log P and polar surface area of valsartan and candesartan cilexetil are closer, their solubility with triacetin, castor oil and capmul MCM C8 differs significantly. This may be attributed to the hydrogen bonding capacity and electrostatic interaction of both the scaffold with the oils. Nevertheless, valsartan is having aliphatic carboxylic group which is expected to be involved in hydrogen bond interaction with the hydrogen acceptor functionality of the triacetin as well as castor oil. We assume that the branched chain aliphatic ester moiety of triacetin, capmul MCM C8 and castor oil gets involved in the electrostatic repulsion with cilexetil part of candesartan. In case of valsartan, such electrostatic interactions are not possible. Furthermore, aliphatic ester chain of triacetin and castor oil may solvate the lipophilic chain of valsartan more favorably than candesartan in the absence of any electrostatic repulsion (proposed interaction is shown in fig. 3). However, significant difference was not observed with other oils such as olive oil, peanut oil, corn oil, miglyol 810, sunflower oil and soybean oil (data not shown).Open in a separate windowFig. 3Proposed interactions of valsartan and candesartan cilexetil with triacetin.