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101.
A. K. Gurram P. B. Deshpande S. S. Kar Usha Y. Nayak N. Udupa M. S. Reddy 《Indian journal of pharmaceutical sciences》2015,77(3):249-257
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 SMEDDSLong 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. 相似文献102.
103.
104.
目的:研究人际交互的辨识特征。方法向参与者播放19项人际互动刺激和8项非交流性对照刺激,要求参与者作答,再由评判员进行判断。结果(1)对交流行为识别率方面女性和男性点光源视频识别率做对比后发现“靠近点”这一动作识别率差异有统计学意义(χ2=21.52,P=0.001);(2)对社会动机识别率方面女性和男性点光源视频识别率做对比后发现,“不要”这一动作识别率存在显著性差异(χ2=8.66,P=0.003)。“哪一个?”这一动作存在显著性差异(χ2=8.37,P=0.004);(3)对具体姿势的识别率差异有统计学意义的是:“我很生气”(χ2=5.44, P=0.020)、“不要”(χ2=8.27,P=0.004)和“捡起来”(χ2=5.70,P=0.017)。结论我国大学生在互动交流识别方面的敏感性较高;在社会动机和姿势识别率方面部分动作和国外研究一致,部分不一致。 相似文献
105.
Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte–neuron interaction 下载免费PDF全文
Paula Pierozan Fernanda Ferreira Brbara Ortiz de Lima Regina Pessoa‐Pureur 《Journal of neuroscience research》2015,93(2):268-284
Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN‐mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N‐methyl‐D‐aspartate (50 µM DL‐AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra‐ and extracellular Ca2+ chelators (10 µM BAPTA‐AM and 1 mM EGTA, respectively) and Ca2+ influx through L‐type voltage‐dependent Ca2+ channel (10 µM verapamil) are implicated in QUIN‐mediated effects. Cells immunostained for the neuronal markers βIII‐tubulin and microtubule‐associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN‐treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron–astrocyte interaction playing a role in neuroprotection. © 2014 Wiley Periodicals, Inc. 相似文献
106.
《第三军医大学学报》2015,37(1)
目的 分析沙眼衣原体隐匿质粒编码蛋白的相互作用.方法 采用基因克隆的方法将沙眼衣原体质粒基因pgp1~4及pgp8分别克隆到pRAC和pRBR上,通过转录激活细菌双杂交系统分析蛋白相互作用.结果 Western blot结果显示Pgp1、Pgp3与大肠杆菌RpoA氨基末端功能区(α-NTD)融合蛋白及Pgp1、Pgp3、Pgp4与DNA结合蛋白λCI融合蛋白,能在大肠杆菌中表达.在报告菌株中,共表达与α-NTD融合的Pgp3蛋白(α-Pgp3)及与λCI融合的Pgp3蛋白(CI-Pgp3),导致报告基因产物β-半乳糖苷酶的活性升高.而余无明显变化.结论 pgp3编码的Pgp3能与自身相互作用. 相似文献
107.
Nora Y. Osman Jessica L. Walling Vivian G. Mitchell Erik K. Alexander 《Teaching and learning in medicine》2015,27(2):130-137
Phenomenon: Changes in the medical education milieu have led away from the apprenticeship model resulting in shorter physician–student interactions. Faculty and student feedback suggests that supervisor/student interactions may now be more cursory with increasing numbers of supervisors per student, and shorter duration of interaction. This may affect both education and student assessment. Approach: We compared inpatient attending and resident daily schedules with those of 3rd- and 4th-year medical students rotating on medicine clerkships at Brigham and Women's Hospital during academic years 2009–11 to determine the number of days of overlap. We used evaluation forms to determine the extent of evaluator's self-reported knowledge of the student. Findings: We correlated the daily schedules of 199 students and 204 resident and 187 attending physicians, which resulted in 558 resident–student pairings and 680 attending–student pairings over 2 years. During a 4-week block, students averaged 3.7 attending physicians (M = 4, range = 2–7), with 49.7% supervised by 4 or more. Attending-student overlap averaged 9 days (M = 9, range = 2–23), though 40% were 7 days or less. Students overlapped with an average 3.4 residents (M = 3, range = 1–6). Resident-student overlap averaged 12 days (M = 11, range = 3–26). There were 824 student assessment forms analyzed. Resident and attending physician supervisors describing knowledge of their student as “good/average” overlapped with students for 14 and 11 days respectively compared to resident and physician supervisors who described their knowledge as “poor” (11 days, p < .01; 6 days, p < .01). Insights: On the inpatient medicine clerkship, students have multiple supervising physicians with wide variability in the period of overlap. This leads to a disrupted apprenticeship model with fragmentation of supervision and concomitant effects on assessment, feedback, role modeling, and clerkship education. 相似文献
108.
Searching for Dual Inhibitors of the MDM2‐p53 and MDMX‐p53 Protein–Protein Interaction by a Scaffold‐Hopping Approach 下载免费PDF全文
Andrey Zaytsev Barry Dodd Matteo Magnani Chiara Ghiron Bernard T. Golding Roger J. Griffin Junfeng Liu Xiaohong Lu Iolanda Micco David R. Newell Alessandro Padova Graeme Robertson John Lunec Ian R. Hardcastle 《Chemical biology & drug design》2015,86(2):180-189
Two libraries of substituted benzimidazoles were designed using a ‘scaffold‐hopping’ approach based on reported MDM2‐p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X‐ray structure. Benzimidazole libraries were prepared using an efficient solution‐phase approach and screened for inhibition of the MDM2‐p53 and MDMX‐p53 protein–protein interactions. Key examples showed inhibitory activity against both targets. 相似文献
109.
Recent trends in preclinical drug–drug interaction studies of flavonoids — Review of case studies,issues and perspectives 下载免费PDF全文
Nuggehally R. Srinivas 《Phytotherapy research : PTR》2015,29(11):1679-1691
Because of health benefits that are manifested across various disease areas, the consumption of herbal products and/or health supplements containing different kinds of flavonoids has been on the rise. While the drug–drug interaction potential between flavonoids and co‐ingested drugs still remain an issue, opportunities exist for the combination of flavonoids with suitable anti‐cancer drugs to enhance the bioavailability of anti‐cancer drugs and thereby reduce the dose size of the anti‐cancer drugs and improve its therapeutic index. In recent years, scores of flavonoids have undergone preclinical investigation with variety of drugs encompassing therapeutic areas such as oncology (etoposide, doxorubicin, paclitaxel, tamoxifen etc.), immunosuppression (cyclosporine) and hypertension (losartan, felodipine, nitrendipine etc.). The review provides examples of the recent trends in the preclinical investigation of 14 flavonoids (morin, quercetin, silibinin, kaempferol etc.) with various co‐administered drugs. The relevance of combination of flavonoids with anti‐cancer drugs and a framework to help design the in vitro and in vivo preclinical studies to gain better mechanistic insights are discussed. Also, concise discussions on the various physiological factors that contribute for the reduced bioavailability of flavonoids along with the significant challenges in the data interpretation are provided. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
110.
目的:应用系统生物学方法模拟分析丹红注射液中丹参与红花配伍的分子机制。方法:采用TCMGene DIT和Agilent literature search(ALS)结合搜索方式,挖掘丹参、红花各自作用的蛋白,在BIND,Bio GRID等数据库中查询蛋白间关联,分别构建丹参、红花及丹红注射液蛋白相互作用网络,应用Merge程序中的difference和intersection功能比较网络间异同。结果:采用intersection分析得丹参和红花共有的高连接区蛋白网络含934个蛋白,经cluster ONE方法提取出P0.05的高连接区蛋白子网络4个,Bi NGO插件的基因本位论聚类分析表明,其主要与RNA代谢,核因子kappa B(nuclear factor kappa B,NF-κB)级联反应,脂质代谢,Rho蛋白及小GTP酶调节4类生物学途径相关。将丹红注射液蛋白相互作用网络与丹参、红花共有高连接区蛋白网络进行difference分析,得由1 431个蛋白构成的差异网络,其主要影响细胞增殖、迁移和自噬等。结论:本研究采用系统生物学方法模拟丹参和红花的配伍机制,其可能主要在RNA代谢,NF-κB级联反应以及细胞增殖、迁移和自噬等生物学途径上协同发挥防治疾病的作用。 相似文献