CC BY
6[10] Sun Z. L., Gao G. L., Xia Y. F., et al. A novel hepatoprotective saponin from Celosia cristata L.[J]. Fitoterapia, 2011, 82: 591-594.
[11] Shen S., Ding X., Ouyang M. A., et al. A new phenolic glycoside and cytotoxic constituents from Celosia argentea [J]. Journal of Asian Natural Products Research, 2010, 12(9): 821-827.
[12] Gao Liangliang, Xu Xudong, Nan Haijiang, et al. Chemical constituents in Rheum tanguticum [J]. Chinese Traditional and Herbal Drugs, 2011, 42 (3): 443-446.
[13] Yoshio T., Yasushi O., Toshiya M., et al. Iridoid and eugenol glycosides from nepeta cadmea [J]. Phyrochemrsrry, 1998, 49(3):787-791.
Study on thePreparingProcess ofIntermediates of Anti-cancer Element as Colon
Targeting Dropping Pill
ZHANG Xiao-Yan1, Yu Ying1, XIE Ning2, MA Wei3, DONG Pei-liang1
(1Heilongjiang University of Chinese Medicine, Research Institute of Traditional Chinese Medicine, Harbin 150040,China The First Affiliated Hospital of Heilongjiang University of Chinese medicine;3)
Abstract: objectiveThe preparing technique of the droppingpill were established.Methods The orthogonal test was design with PEG4000, PEG6000 and Boluosham as base for the research of the dropping pill Preparation process. Resuits The best preparing technique were thedrug and matrix as 1:5, PEG4000/PEG6000 as 3:1, drug / Boluosham as 20:1, liquid temperature as88C, and dropping rate as 20 drops per min, and dropping distance as 5cm.Conclusions The dropping pill was prepared with the best hardness, roundness and weight differences. Key words :anti-cancer element; colon targeting; dropping pill
Keaisu is a colon-targeted preparations, including curcuminoids from the root of curcuma longa and quercetin from bud of sophora japonica. Quercetin is the hydrolysate which from rutin is hydrolyzed under the action of enzymes or acid. Modern pharmacological studies have shown thatQuercetin is a kind of natural flavonoid compound which can dilate coronary artery, reducing blood lipid, anti-inflammation, anti-allergy, anti-diabetes mellitus complication and other effects[1]. Curcumin is a yellow, acid, phenolic compound extracted from a plant of Zingiberaceae and Curcuma genus, the root of curcuma longa. And Curcumin is the major active ingredient pharmacology. Curcumin has extensive pharmacological effects, such as anti-tumor, anti-inflammatory, antioxidant, anti mutation, anti-hiv, etc[2]. The Chinese medicinetargeted preparations are composed of curcuminoids and quercetin (mass ratio35g: 20g) [3], which are effective components, and thiswill provide a reference for studyingon oral drug release system.
1. Material
Quercetin (Xian xiaocao zhiwukeji Co., LTD., UV purity is 98.05%); Curcuminoids (Ningbo chengtai modern Chinese medicine technology Co., LTD, total contents of curcuminoids by HPLC is 95.0%); PEG4000 * 6000 (Tianjin kemiou); dropping pill preparation device (homemade).
2. Method and Results[4] 2.1 Dropping distance
1FundHeilongjiang University of Chinese Medicine Doctor Innovation FundNOB201006
Author ProfileZHANG Xiao Yan, female, associate professor, doctor major in Chinese medicine, mainly engaged in material base of traditional Chinese medicine and novel drug delivery system. Tel045187266836.
E-mail: [email protected].
Choose different distance: 3,5,7cm; besides, fixing the following parameters: speed is 30 drops/min, solution temperature is 85°C. Based on roundness and trailing condition as evaluation index. When the dropping distance is 3cm, dropping size is too much, and dissolution has crushed slag, and color is light. When the dropping distance is 5cm, dropping is optimal. When the dropping distance is 7cm, taling or trailing cutting. So the optimal distance is 5cm.
2.2 Dropping speed
Compare different speed 20, 30, 40 drops/min, fixing the other parameters. Based on roundness and trailing condition as evaluation index. When the dropping speed is 20 drops/min, the granules and circularity behavior are better, and no trailing. When the dropping speed is 30 drops/min, the drops are granular, some dropping pills are flat shape, and the trailing is serious. When the dropping speed is 40 drops/min, the granules are more, all dropping pills are flat shape, and the trailing is more serious. So the optimal dropping speed is 20 drops/min.
2.3 Solution temperature
Compare different temperatures 80° * 85° * 88° * 90°, fixing the other parameters. Based on roundness and trailing condition as evaluation index. When the solution temperature is 80°, drop speed is slow, and trailing is serious. When the solution temperature is 85°, trailing is slight. When the solution temperature is 88°, roundness and trailing condition is optimal. 90°, temperature difference is large, roundness and trailing condition is bad. So the optimal solution temperature is 88°.
2.4 The condensate temperature
Compare different condensate temperatures 0~5°C, 6~10°C, 11~15°C, 16~20°C, fixing the other parameters. Based on roundness and trailing condition as evaluation index. Within a certain range, reducing the condensate temperature is good for dropping pill contraction, solidification and cooling rapidly. Meanwhile, it will increase the specific gravity of liquid coolant, and viscosity, and reduce the dropping speed, and easier shape. When the temperature is 0~5°C, liquid paraffin coagulates, dropping is difficult. So the optimal condensate temperature is 6~10°C.
2.5The Optimal Proportion of Drug/Substrate, PEG4000/PEG6000 and Drug/Poloxamer
Using L9(3)4 orthogonal design to research several key parameters: the optimal proportion of Drug/Substrate(A), PEG4000/PEG6000(B) and Drug/Poloxamer(C). According to the L9Q)4, weighing appropriate PEG4000,6000and Poloxamer, melting with the water bath after adding powder and mixing evenly, moving quickly to the drop head preheated, after warming 10 minters, under the specified temperature, dropping distance and dropping speed, dropping medicine into the specified temperature liquid paraffin, and drying the molding pill then paint removal liquid paraffin quickly. Getting each experimental sample to survey the limit of resolving time according to the method in Chinese Pharmacopoeia, then random sampling 20 pills, weighting each pill precisely, finding out the differences. Table1 is the particular influencing factors and levels.
Table1 Factors and Levels
Level A B C
Drug/Substrate PEG4000/PEG6000 Drug/Poloxamer
1 1:3 1:1 20:1
2 1:4 2:1 30:1
3 1:5 3:1 40:1
2.6 Results and Data
Table 2 The Orthogonal Experiment and Results_
Number ABC D The Resolving The
Difference Time Weighte of Pill's y2 (min) d Results Weight y y1 (%)_
1 1 1 1 1 7.50 6.45 96.988
2 1 2 2 2 5.76 11.00 94.958
3 1 3 3 3 3.21 8.21 97.648
4 2 1 2 3 1.62 10.30 97.030
5 2 2 3 1 4.17 7.38 97.762
6 2 3 1 2 5.16 7.54 97.270
7 3 1 3 2 8.57 7.52 95.918
8 3 2 1 3 2.72 5.36 99.554
9 3 3 2 1 4.91 5.35 98.684
K1 289. 594 289.93 6 293.812 290.668
Compre hensive K2 292. 062 292.27 4 290.672 288.146
weighted K3 294. 156 293.60 2 291.328 294.232
R 1.52 1.22 1.05 2.03
K1 16.4 8 17.69 15.38 16.58
The differenc K2 10.9 5 12.66 12.29 19.49
e of pill K3 16.2 0 13.28 15.95 7.55
R 1.84 1.68 1.22 3.98
K1 25.6 6 24.27 19.35 19.18
Resolvin K2 25.2 2 18.2 3 23.74 26.65 26.06
g time K3 21.10 23.11 23.87
R 2.48 1.06 2.43 2.29
Analysis of the results of data processing: To make the two best index as full mark, the weight difference and resolving time as the index, according to the importance of each index, confirmed weight coefficient as 0.4,0.6, got comprehensive evaluation formula y=0.4X(100+1.62-yx) +0.6X(100+5.35-y2), the minimum of the weight difference of 9 pills is 1.62, the minimum of the resolving time is 5.35.
From Table3, three factors(A,B,C) have certain effect to the result, primary and secondary order of comprehensive weighted is A3B3C1, primary and secondary order of resolving time is A3C1B3, primary and secondary order of the weight difference of pill is A2B2C2. Then comparing the above conditions and the best eighth experiment among the nine experiments, the best result is the NO.8 experiment, then the best process conditions as A3B2C1: Drug/Matrix=1:5, PEG4000 / PEG6000=3:1, Drug/Poloxamer=20:1, the temperature is 88C, drop speed is 20 drops/min, distance is 5cm. The pills can have the smooth appearance, the entire park without trail.
Table3 Analysis of variance table_
Sources of Sum of Freedom Mean F P
Variance Squares of Square
Deviations
A 3.476 2 1.738 0.477 >0.1
Comprehensive B 2.297 2 1.149 0.315 >0.1
weighted C 1.829 2 0.915 0.251 >0.1
D 7.293 2 3.647 1.000
A 6.456 2 3.228 0.250 >0.1
The difference of pill B 5.027 2 2.514 0.195 >0.1
C 2
2.585 1.293 0.100 >0.1
D 25.841 2 12.921 1.000
A 11.584 2 5.792 1.407 >0.1
Resolving time B 1.922 2 0.961 0.233 >0.1
C 8.884 2 4.442 1.079 >0.1
D 8.236 2 4.118 1.000
3. Discussion
To choose different length cooling pipes with 60cm, 80cm, 100cm, the length of cooling pipe is too short, cooling time is not enough, a part of pills happen to adhesion, trailing, and have influence to roundness and hardness, too long is not adverse to production design. Then choose the length of the cooling pipe as 80cm. The main molding problem is hardness, choosing PEG4000, the hardness is not ideal, but choosing PEG6000 is relatively good, then mixing the PEG4000 and PEG6000[5]. The difference s of condensate don' t have great influence to the result, because of making methyl silicone oil as condensate, dropping down slowly, dropping speed slightly faster may lead to bond together, not suitable for industrial production, liquid paraffin does not exist these reasons, then choosing liquid paraffin as condensate.
Drug and matrix must be mixed evenly. If the proportion of matrix in pills is too large, then the meatball shape is good, but the drug loading will also fall at the same time, the dose increase. Then we should adopt the reasonable extraction and purification technology to wipe off the invalid target as far as possible. Reference:
[1]MENG De sheng, WANG Shi-
Hang . Antitumoreffectofquercetin[J]. ChineseTraditionalandHerbatDrug, 2001, 32 (2) : 186-188.
[2]Yu Dong-qing, Deng Hua-cong. Study on the Pharmacological Activities of Curcumin [J]. Shandong Medical Journal, 2005, 45 (2) : 72-73.
[3]Zhang Xiao-yan, Xu Zeng-rong, Hu Hong-wei, etal. Study on the Anti-tumor Effect of Anti-cancer Element as Colon Targeting Dropping Pill, 2010.12 (3) : 459-460.
[4]Xie Zhao-ruing, Li Shun-xiang. StudyonmouldingtechnicsofShuxinDropPills[J]. Chinese Traditional Patent Medicine, 2002, 24(4): 249-251.
[5]zhouxiao-wen. The Applicationof PEG on Optimization of Dosage Form[J]. Chinese Journal of Pharmaceuticals , 1995, 30 (12) : 7l3-714.
Cerebral metabonomics study on Parkinson's disease mice treated with extract
of Acanthopanax senticosus harms
Xu-zhao LIa, FangLUa*, Chang-feng LIU a, Ying ZHANG a, Guang-li YANb, Yu WANGa, Yu BAI
a, Na WANGa, Shu-min LIUa*
a: Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, PR China, b:College of Pharmacology,Heilongjiang University of Chinese Medicine, Harbin 150040, PR China Corresponding author:
Shu-min LIU:Tel: +86-451-87266988; Fax: +86-451-87266988; E-mail address: [email protected]; Postal address: Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping Road 24, Harbin 150040, PR China
FangLU;Tel: +86-451-87266829; Fax:+86-451-87266829; E-mail address:[email protected]; Postal address: Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, He Ping
Road 24, Harbin 150040, PR China
Abbreviations:BPI, base peak intensity; BV/h, bed volume/hour; CPT,carnitine O-palmitoyltransferase; DA, dopamine;EAS, extract ofAcanthopanaxsenticosusharms; MPTP-HCl, 1-Methyl-4-phenyl-1,2,3,6-tetrahydro -pyridineHydrochloride; MS, Mass spectrometry; NMR, nuclear magnetic resonance; PCA, principal componentsanalysis; PD, Parkinson's disease; PLS-DA, partial least squares-discriminate analysis; RSD, relative standarddeviations;TCM, traditional Chinese medicine;TH, tyrosine hydroxylase; UPLC-QTOF-MS, ultra-performanceliquid chromatography coupled with quadrupole time-of-flight mass spectrometry; VIP, variable importance of project;VLACD, very long-chain acyl-CoAdehydrogenase
Abstract
Extract ofAcanthopanaxsenticosusharms (EAS) has neuroprotectiveeffect on Parkinson's disease (PD)mice against dopaminergic neuronaldamage. However,studies of its anti-PD mechanism arechallenging, accounted for the complex pathophysiology of PD, and complexity of EAS with multipleconstituents acting on different metabolic pathways.In this study, metabonomics based on ultra-performanceliquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used toprofile the metabolic fingerprints ofcerebrumobtained from1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineHydrochloride(MPTP-HCl)-induced PD model in mice with and withoutEAStreatment.Through partial least squares-discriminate analysis (PLS-DA), it was observed that metabolic perturbations induced byMPTPwere restoredafter treatment with EAS. Metabolites with significant changes inducedbyMPTP, including (1) L-dopa, (2) 5'-methylthioadenosine, (3)tetradecanoylcarnitine, (4) phytosphingosine-1-P, (5)Cer(d18:0/18:0),
(6)LysoPC(20:4(5Z,8Z,11Z,14Z)), (7) L-palmitoylcarnitine, (8)tetracosanoylglycine, (9) morphiceptin and (10) stearoylcarnitine,were characterized as potential biomarkers involvedin the pathogenesis of PD. The derivations of all those biomarkers can be regulated by EAS treatment except(5)Cer(d18:0/18:0), (6)LysoPC(20:4(5Z,8Z,11Z,14Z)), (9)morphiceptin, which suggested that the therapeutic effect of EAS on PD may involve in regulating thetyrosine metabolism,mitochondrial beta-oxidation of long chain saturated fatty acids, fatty acid metabolism,methionine metabolismand sphingolipid metabolism. This study indicated thatchanged metabolities can be certainly recovered by EAS, and the treatment of EAS can be connected with the regulation of related metabolic pathways.
Keywords :extract of Acanthopanaxsenticosus harms; Parkinson's disease;cerebral metabonomics; UPLC-QTOF-MS
