CN1981750A - Water-soluble coenzyme Q10Composition and preparation method - Google Patents
Water-soluble coenzyme Q10Composition and preparation method Download PDFInfo
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- CN1981750A CN1981750A CN 200510048010 CN200510048010A CN1981750A CN 1981750 A CN1981750 A CN 1981750A CN 200510048010 CN200510048010 CN 200510048010 CN 200510048010 A CN200510048010 A CN 200510048010A CN 1981750 A CN1981750 A CN 1981750A
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- ubiquinone
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- cyclodextrin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000005515 coenzyme Substances 0.000 title abstract 4
- 239000000203 mixture Substances 0.000 claims abstract description 55
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 33
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 103
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 91
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 claims description 64
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 63
- 229940035936 ubiquinone Drugs 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 33
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 26
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 26
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 12
- 238000007664 blowing Methods 0.000 claims description 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 239000008107 starch Substances 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- 238000000265 homogenisation Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012982 microporous membrane Substances 0.000 claims description 6
- 238000001694 spray drying Methods 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 230000010355 oscillation Effects 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 238000010008 shearing Methods 0.000 claims description 2
- ICFIZJQGJAJRSU-SGHXUWJISA-N ubiquinone-8 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ICFIZJQGJAJRSU-SGHXUWJISA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 8
- 239000007962 solid dispersion Substances 0.000 abstract description 8
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 208000006454 hepatitis Diseases 0.000 abstract description 2
- 231100000283 hepatitis Toxicity 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 239000007884 disintegrant Substances 0.000 abstract 1
- 230000036039 immunity Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 230000001804 emulsifying effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 208000033065 inborn errors of immunity Diseases 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- -1 clathrate Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 125000003071 maltose group Chemical group 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000008811 mitochondrial respiratory chain Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 125000001655 ubiquinone group Chemical group 0.000 description 1
- 150000003669 ubiquinones Chemical class 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a water-soluble coenzyme Q10The composition and the preparation method have good therapeutic effect on cardiovascular diseases, hepatitis, low immunity and other diseases, and belong to the technical field of medicines and health-care products. It is prepared from coenzyme Q10Gamma cyclodextrin, sugar alcohol and disintegrant in the weight ratio of 1 to 1-100 to 1-50 to 0.1-5. Stirring or ultrasonically oscillating in water medium by high speed homogenizer, homogenizing under high pressure, freeze drying to obtain solid dispersion, granulating, and making into coenzyme Q10A composition is provided. The composition has high contentThe solubility and dissolution of the compound are low, the hygroscopicity is low, the stability is good, and the relative bioavailability is high.
Description
Technical field
The present invention relates to a kind of water-soluble coenzyme Q
10Compositions and preparation method, this material has better therapeutical effect to diseases such as cardiovascular disease, hepatitis, hypoimmunities, belongs to medicine, health product technology field.
Background technology
Ubiquinone
10Have another name called ubiquinone, be also referred to as certain herbaceous plants with big flowers alkene quinone, ubiquinol, vitamin Q, vitamin ubiquinone, English name is Coenzyme Q
10, Ubiquinone, molecular formula is C
59H
90O
4, chemical formula is 2-(3,7,11,15,19,23,27,31,35,39-methyl in the last of the ten Heavenly stems-2,6,10,14,18,22,26,30,34,38-40 decene bases)-5,6-dimethoxy-3-methyl-p-benzoquinone, this material are that human body is from the body material, also extensively be present in organs such as animal hearts, can from animal hearts, extract and obtain, also can be by chemosynthesis, biosynthesis obtains.Ubiquinone
10It is indispensable important physiologically substance in the human body, its chemical constitution characteristics have determined it to have many important physiological function in human body, it is a transmitter substance important in the vital movement, it is the key material of mitochondrial respiratory chain rate-limiting reaction, generate at cellular energy, strengthen the biologos aspect and play a significant role.Contain Q in the human body
10Total amount is 500-1500mg, peaks about 20 years old, reduces rapidly then, and 70 years old reduces 57% than 20 years old youngster later on.Discover, in a lot of ill patients, ubiquinone
10Physiological level descends obviously, in heart failure patient (HF), and ubiquinone in patient's cardiac muscle and the blood
10Content obviously reduces, and replenishes ubiquinone from external source
10After, obviously improve patient symptom.Discover the patient of a lot of hypoimmunities, its ubiquinone
10Physiological level is lower, replenishes ubiquinone
10After, symptom improves.Therefore, human body replenishes ubiquinone from external source
10Treat various ubiquinones
10Physiological level lowly becomes a kind of generally acknowledged clinical treatment method.
Ubiquinone
10Be liposoluble substance, be insoluble in water, ubiquinone
10To light, heat, water unstable, the oral administration bioavailability is lower, at this situation, has developed the method for multiple raising oral administration bioavailability in recent years, as inclusion technique, self emulsifying technology, liposome etc.Aspect drug administration by injection, also developed certain methods, as adopting surfactant hydrotropy, microemulsion technology etc.But still there are some problems, though as in previous patent, adopting the clathrate dissolubility of γ cyclodextrin to be enhanced, but inclusion rate is lower, yield is also lower, and product dissolving back principal agent still has free the existence, and product is very easy to the moisture absorption simultaneously, draw moist strong, powder flowbility is poor, makes product stability descend inconvenient suitability for industrialized production.Adopt the preparation of self emulsifying technology, liposome preparation need use multiple unsafe adjuvant, edible safety is constituted influence.The document of having published at present, patent quantity is more, wherein relevant in recent years ubiquinone
10Use patent is a lot, related with this patent by retrieval have following patent and a document: 1. at document Journal Acta Poloniae Pharmaceutica (1995), vol.52, No.5, pp.379-386 and 1996, vol.53, No.3 has described the employing stirring means and has prepared ubiquinone among the pp.193-196.
10The γ cyclodextrin clathrate, but this method needs time preparation more than tens hours, is not suitable for suitability for industrialized production.2. United States Patent (USP) 6861447, this patent disclosure prepare the method for γ cyclodextrin clathrate, have shortcoming recited above but prepare medicine with this method, in addition, the preparation method of the unexposed use high pressure homogenize of this method.3. world patent WO20041080208, this patent adopts emulsifying technology, discloses to prepare a kind of milk powder and common prescription and the technology of forming of organic acid that can be oral, does not relate to water-soluble coenzyme Q
10Technology of preparing.4. Chinese patent CN1437931 discloses a kind of ubiquinone
10The technology of preparing of pro-liposome does not relate to present technique.
Summary of the invention
The present invention provides a kind of water-soluble coenzyme Q for solving the problems of the technologies described above
10Compositions and preparation method, the method that this method adopts inclusion technique to combine with solid dispersion technology is with ubiquinone
10Form a kind of new solid dispersion with cyclodextrin and sugar alcohol adjuvant, it is a kind of new thing phase, i.e. ubiquinone
10Be dispersed in cyclodextrin and the sugar alcohol solid, and with the disintegrating agent mixing granulation after, form a kind of water-soluble coenzyme Q
10Granule medicament; Thereby improved ubiquinone
10Dissolubility, draw moist little, good stability, dissolution rate is fast, and high bioavailability is arranged.
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: sugar alcohol: disintegrating agent=1: 1-100: 1-50: 0.1-5.
Water-soluble coenzyme Q of the present invention
10Compositions is made up of by preferred weight ratio following raw material: ubiquinone
10: γ cyclodextrin: sugar alcohol: disintegrating agent=1: 1-30: 1-10: 0.1-0.5.
Described sugar alcohol can be a kind of of mannitol, sorbitol or xylitol or lactose or maltose alcohol, preferred mannitol, and disintegrating agent can be a kind of of carboxymethyl starch sodium or polyvinylpolypyrrolidone (PVPP).
Water-soluble coenzyme Q of the present invention
10The preparation of compositions method comprises following processing step:
Get γ cyclodextrin and sugar alcohol by above-mentioned weight ratio, be dissolved in and be equivalent to ubiquinone
10200-1000 times of water in, be heated to 50-80 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone meet above-mentioned weight ratio
10, carrying out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, blowing advances high pressure homogenizer, with 40-100Mpa circulation 1-10 time, blowing, filtering with microporous membrane, filtrate adds the disintegrating agent dissolving, carry out spray drying or lyophilization then, exsiccant material is directly granulated, promptly.
According to above-mentioned method, also can behind the high pressure homogenizer homogenizing, add sugar alcohol, can obtain the water-soluble coenzyme Q of effect same
10Compositions.
According to above-mentioned method, disintegrating agent also can add behind dry materials, can obtain the water-soluble coenzyme Q of effect same
10Compositions.
According to above-mentioned method, use high-speed homogenization machine or cutter can adopt supersonic generator to substitute.
According to above-mentioned method, can adopt lyophilization to replace spray drying.
The water-soluble coenzyme Q that the present invention obtains
10Compositions has following feature: it is a kind of ubiquinone that contains
10, γ cyclodextrin, sugar alcohol, disintegrating agent solid dispersion, color milky or faint yellow has water solublity.
Water-soluble coenzyme Q of the present invention
10The composition levels assay method mainly adopts high performance liquid chromatography, and method is a water intaking dissolubility ubiquinone
10Compositions is an amount of,, filters to normal concentration with methanol constant volume, gets subsequent filtrate as need testing solution, sample introduction, and chromatographic condition: C18 post, mobile phase are methanol: dehydrated alcohol=1: 1, detect wavelength 275nm, external standard method is quantitative, promptly.
The stability test of the present composition:
Get ubiquinone by the previous patent preparation
10γ cyclodextrin clathrate (abbreviation clathrate) and compositions and the ubiquinone that contains mannitol of the present invention
10Raw material carries out influence factor's test and long-time stability are investigated.
1, influence of light test
Get clathrate (5%) and under 4000 LX light, placed 10 days,, the results are shown in Table 1 respectively at 0 day, 5 days, 10 days sampling and measuring with the present composition (5%).
Table 1 light is to ubiquinone
10Influence:
Table 1 shows that light is to ubiquinone
10Considerable influence is arranged, ubiquinone wherein of the present invention
10Compositions and clathrate light stability are better than ubiquinone
10Raw material.
2, temperatures involved test
Get ubiquinone
10Clathrate and ubiquinone of the present invention
10Compositions was placed 10 days at 60 ℃, respectively at 0 day, 5 days, 10 days sampling and measuring, the results are shown in Table 2.
Table 2 high temperature is to ubiquinone
10Influence (60 ℃):
Table 2 result shows that high temperature is to ubiquinone
10The raw material influence is bigger, and is little to compositions and clathrate influence.
3, high humidity influence test:
Get ubiquinone
10Clathrate and ubiquinone of the present invention
10Compositions is at 25 ℃, and relative humidity 92.5% was placed 10 days, respectively at 0 day, 5 days, 10 days sampling and measuring, the results are shown in Table 3.
Table 3 high humidity is to ubiquinone
10Influence:
Table 3 shows that humidity is to ubiquinone
10Bigger influence is arranged, wherein to ubiquinone
10γ cyclodextrin clathrate influence bigger, the present composition is better than clathrate.
Result of the test shows: ubiquinone of the present invention
10Compositions and the ubiquinone of pressing the previous patent preparation
10γ cyclodextrin clathrate and raw material ubiquinone
10Compare, stability improves a lot.
Solubility test: it is an amount of to get compositions, clathrate, raw material respectively, joins in the pure water of 10ml, and sonic oscillation 10 minutes filters, and gets filtrate as test liquid, adopts high-efficient liquid phase technique to measure, and the result shows, ubiquinone of the present invention
10Compositions (5%) is with C
59H
90O
4The meter dissolubility is 210 μ g/ml, presses the ubiquinone of previous patent preparation
10γ cyclodextrin clathrate (5%) dissolubility be 202 μ g/ml, raw material is not measured.
Dissolution determination: take by weighing compositions respectively, clathrate (contains with C in right amount
59H
90O
4Count 10mg), measure the stripping of different time medicine with digestion instrument.Medium is the 500ml distilled water, temperature (37 ℃ ± 0.5), and timing sampling 10ml adopts high-efficient liquid phase technique to measure, and the results are shown in Table 5
Table 5 ubiquinone
10Relative dissolution
| Sample | Relative dissolution (%) | |||
| 5min | 15min | 60min | 120min | |
| Ubiquinone of the present invention 10Compositions | 95 | 98 | 99 | 98 |
| Ubiquinone 10Clathrate | 75 | 85 | 90 | 96 |
| Ubiquinone 10Raw material | 0 | 0 | 0 | 0 |
Table 5 shows that present composition dissolution rate is than ubiquinone
10Clathrate is fast.
The bioavailability test:
10 healthy males, body weight 60-80 kilogram, in age 20-30 year, no hepatic and renal function and core function abnormality are not taken other drug in two weeks, no allergies, the experimenter all fills in application form in the know.Ubiquinone in the blood plasma
10Assay method adopts high performance liquid chromatography, and chromatographic condition is C
18Post, mobile phase: dehydrated alcohol-water-glacial acetic acid (90: 2: 0.7), detect wavelength 275nm.Plasma sample is handled, and in the darkroom, the blood plasma of taking heparinization is an amount of, adds ubiquinone
9Be inner mark solution (15 μ g/ml) the treated need testing solution that gets.
The cross-over experiment design is adopted in test, takes ubiquinone of the present invention respectively
10Composition capsule and ubiquinone
10Capsule was taken 5 days continuously, and blood sampling is measured and data statistics, draws ubiquinone at last
10Compositions relative bioavailability is ubiquinone
10Capsular 460%.
The technical characterictic of the present composition:
The ubiquinone that obtains by the present invention
10Compositions is a kind of solid dispersion.This mainly proves by the following method, with compositions of the present invention, various materials in the compositions, the physical mixture of various materials in the compositions, clathrate is done heat and is analyzed (DSC), the result shows that compositions thing phase DSC collection of illustrative plates of the present invention is different from other several material thing phase collection of illustrative plates, proves ubiquinone of the present invention
10Compositions has formed a kind of new thing phase.Because the sugar alcohols molecule has a plurality of hydroxyls, and the γ cyclodextrin also has a plurality of hydroxyls, therefore, ubiquinone
10With the γ cyclodextrin inclusion compound after, form solid dispersion with the sugar alcohols material by hydrogen bonded.This solid dispersion characteristics are to have good water-solubility, and then improved dissolution, and bioavailability has overcome the shortcoming that the γ cyclodextrin clathrate draws moist big, poor stability simultaneously.Bioavailability is enhanced.Formed solid dispersion is to contain the mannitol best results.
Advantageous effect of the present invention is as follows:
Compositions of the present invention shows that by a series of test said composition has good water-solubility, and dissolution rate is fast, draws moist for a short time, has improved stability, the bioavailability height.
The specific embodiment
Embodiment 1
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: carboxymethyl starch sodium=1: 1: 1: 0.1;
Get γ cyclodextrin 10g and mannitol 10g by above-mentioned weight ratio, be dissolved in the 2000ml water, be heated to 60 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone that meets above-mentioned weight ratio
1010g carried out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, and blowing advances high pressure homogenizer, with 40Mpa circulation 10 times, and blowing, with filtering with microporous membrane, filtrate adds the carboxymethyl starch sodium dissolving, carries out spray drying then, granulates, promptly.
Embodiment 2
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: carboxymethyl starch sodium=1: 100: 50: 5;
Get γ cyclodextrin 100g by above-mentioned weight ratio, be dissolved in the 1000ml water, be heated to 50 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone that meets above-mentioned weight ratio
101g and mannitol 50g carried out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, and blowing advances high pressure homogenizer, with 100Mpa circulation 1 time, and blowing, with filtering with microporous membrane, filtrate adds carboxymethyl starch sodium 5g dissolving, carries out spray drying then, granulates, promptly.
Embodiment 3
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: polyvinylpolypyrrolidone=1: 8: 3: 0.2;
Get γ cyclodextrin 80g and mannitol 30g by above-mentioned weight ratio, be dissolved in the 4000ml water, be heated to 80 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone that meets above-mentioned weight ratio
1010g carried out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, and blowing advances high pressure homogenizer, with 80Mpa circulation 5 times, and blowing, with filtering with microporous membrane, filtrate adds polyvinylpolypyrrolidone 2g dissolving, carries out lyophilization then, granulates, promptly.
Embodiment 4
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: sorbitol: carboxymethyl starch sodium=1: 30: 10: 0.5;
Get γ cyclodextrin 30g and sorbitol 10g by above-mentioned weight ratio, be dissolved in the 400ml water, be heated to 70 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone that meets above-mentioned weight ratio
101g carried out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, and blowing advances high pressure homogenizer, with 80Mpa circulation 5 times, and blowing, with filtering with microporous membrane, filtrate is carried out lyophilization, and dry back adds carboxymethyl starch sodium 0.5g, granulation then, promptly.
Embodiment 5
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: carboxymethyl starch sodium=1: 60: 20: 3;
Except that getting the various materials by above-mentioned weight ratio, other are with the method for embodiment 3.
Embodiment 6
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: carboxymethyl starch sodium=1: 10: 5: 0.5;
Except that getting the various materials by above-mentioned weight ratio, other are with the method for embodiment 3.
Embodiment 7
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: carboxymethyl starch sodium=1: 80: 30: 0.5;
Except that getting the various materials by above-mentioned weight ratio, other are with the method for embodiment 3.
Embodiment 8
Press embodiment 3, mannitol adds behind high pressure homogenize, also can obtain the compositions of effect same.
Embodiment 9
Press embodiment 3, disintegrating agent carboxymethyl base Starch Sodium adds when granulating, and also can obtain the compositions of effect same.
Embodiment 10
Water-soluble coenzyme Q of the present invention
10Compositions is made of by weight following raw material: ubiquinone
10: γ cyclodextrin: mannitol: polyvinylpolypyrrolidone=1: 10: 5: 5.
Press the preparation method of embodiment 3, disintegrating agent is replaced with polyvinylpolypyrrolidone.
Embodiment 11
Press the preparation method of embodiment 3, mannitol is replaced with xylitol.
Embodiment 12
Press the preparation method of embodiment 3, mannitol is replaced with sorbitol.
Embodiment 13
Press the preparation method of embodiment 3, mannitol is replaced with lactose.
Embodiment 14
Press the preparation method of embodiment 3, mannitol is replaced with maltose alcohol.
Embodiment 15
Press embodiment 3, spray drying method is replaced with freeze-drying.
Embodiment 16
Press embodiment 3, the method for employing high-speed homogenization or shearing also can adopt the method for ultrasonic concussion in the preparation method.
Claims (7)
1, a kind of water-soluble coenzyme Q
10Compositions is characterized in that mainly being made up of by weight following raw material: ubiquinone
40: γ cyclodextrin: sugar alcohol: disintegrating agent=1: 1-100: 1-50: 0.1-5.
2, by the described water-soluble coenzyme Q of claim 1
10Compositions is characterized in that being made up of by weight following raw material: ubiquinone
10: γ cyclodextrin: sugar alcohol: disintegrating agent=1: 1-30: 1-10: 0.1-0.5.
3, claim 1 or 2 described water-soluble coenzyme Q
10Compositions is characterized in that described sugar alcohol is a kind of in mannitol, sorbitol, xylitol, lactose, the maltose alcohol, and disintegrating agent is a kind of in carboxymethyl starch sodium and the polyvinylpolypyrrolidone.
4, a kind of water-soluble coenzyme Q
10The preparation of compositions method is characterized in that being made up of by weight following raw material: ubiquinone
10: γ cyclodextrin: sugar alcohol: disintegrating agent=1: 1-100: 1-50: 0.1-5, its preparation method comprise following processing step:
Get γ cyclodextrin and sugar alcohol by above-mentioned weight ratio, be dissolved in and be equivalent to ubiquinone
10200-1000 times of water in, be heated to 50-80 ℃, put into high-speed homogenization machine or cutter, add the ubiquinone meet above-mentioned weight ratio
10, carrying out high-speed stirred 5-10 minute with the 5000-10000 commentaries on classics, blowing advances high pressure homogenizer, with 40-100Mpa circulation 1-10 time, blowing, with filtering with microporous membrane, filtrate adds the disintegrating agent dissolving, carry out spray drying or lyophilization then, exsiccant material is directly granulated, promptly.
5, by the described water-soluble coenzyme Q of claim 4
10The preparation of compositions method is characterized in that described sugar alcohol adds behind the high pressure homogenizer homogenizing.
6, by the described water-soluble coenzyme Q of claim 4
10The preparation of compositions method is characterized in that disintegrating agent adds behind dry materials.
7, by the described water-soluble coenzyme Q of claim 4
10The preparation of compositions method is characterized in that adopting the sonic oscillation method to replace high-speed homogenization or shearing method.
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