CN104098621A - Beta-arbutin crystal type III substance, and preparation method, composition and application thereof - Google Patents
Beta-arbutin crystal type III substance, and preparation method, composition and application thereof Download PDFInfo
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- CN104098621A CN104098621A CN201310121528.XA CN201310121528A CN104098621A CN 104098621 A CN104098621 A CN 104098621A CN 201310121528 A CN201310121528 A CN 201310121528A CN 104098621 A CN104098621 A CN 104098621A
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- PYLTVHIGOJZXAM-UHFFFAOYSA-N OCC(C(C1O)O)OC(CCc(cc2)ccc2O)C1O Chemical compound OCC(C(C1O)O)OC(CCc(cc2)ccc2O)C1O PYLTVHIGOJZXAM-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a beta-arbutin crystal type III (with a chemical name of 4-hydroxyphenyl-beta-D-glucopyranoside monohydrate and an English name of arbutin monohydrate), and a preparation method, a composition and application thereof. Specifically speaking, the invention discloses a crystal type III solid substance state form of a beta-arbutin compound in a solid state, a preparation method for a crystal type III solid substance sample and application of the beta-arbutin crystal type III substance as an active component in preparation of antibacterial and anti-inflammatory drugs and cosmetics. The molecular structural formula of the beta-arbutin crystal type III is described in the specification.
Description
Technical field
The present invention relates to find a kind of brilliant III type solid matter stastus format that β-arbutin exists under solid state; Relate to the preparation method who has invented brilliant III type sample; Relate to and invented pharmaceutical composition or the makeup that contain the brilliant III type of β-arbutin and contain the mixing crystal formation of the brilliant III type of arbitrary proportion; The invention still further relates to β-arbutin crystal-form substances as medicine or makeup effective constituent, the application in preparing antimicrobial antiphlogistic medicine and makeup.
Background technology
The brilliant III type of β-arbutin (chemical name: 4-hydroxyphenyl-β-D-glucopyranoside monohydrate, English name: Arbutin monohydrate) molecular structural formula is as follows:
At Chinese patent CN1302599A(publication number) in recorded " make-up composition that contains N-ethoxycarbonyl-4-amino-phenol and arbutin or derivatives thereof and/or ellagic acid or derivatives thereof " of the invention of III She Waliye DM method nurse
[1], wherein relate to a kind of preparation method of arbutin make-up composition.
At Chinese patent CN1481233A(publication number) in recorded Cotde Inc.'s invention " comprise arbutin and Polyglucosidase as the skin whitening composition of activeconstituents "
[2], wherein relate to a kind of skin whitening composition that comprises arbutin.
At Chinese patent CN1228300A(publication number) in recorded " a kind of preparation method of freckle-removing pretty gel cosmetics " of Luo Xiuying, Liang Yuzhen invention
[3], wherein relate to a kind of preparation method of the freckle-removing pretty gel cosmetics that comprises arbutin.
At Chinese patent CN1208608A(publication number) in recorded " arbutin monoesters is as the application of depigmenting agent " of M Fei Lipei invention
[4], wherein relate in the composition of topical application and use arbutin monoesters as the depigmenting agents such as human body skin or SYNTHETIC OPTICAL WHITNER.
At Chinese patent CN1608693A(publication number) in recorded Ding Jiayi invention " a kind of ginseng that contains arbutin, Radix Panacis Quinquefolii and preparation method thereof "
[5], wherein relate to a kind of ginseng that contains arbutin, Radix Panacis Quinquefolii and preparation method thereof.
At Chinese patent CN1633980A(publication number) in recorded " makeup of the ginseng preparation that a kind of use contains arbutin " of Ding Jiayi invention
[6], wherein relate to the cosmetics of being made by the ginseng that contains arbutin.
At Chinese patent CN1635139A(publication number) in recorded " method of preparing alpha-arbutin through fermentation " of Liu Chunqiao invention
[7], wherein relate to the preparation method of alpha-arbutin.
At Chinese patent CN1724551A(publication number) in record the honor of Liao Chen state, imperial court's rosy clouds, execute little neoteric " a kind of preparation method of alpha-arbutin "
[8], wherein relating to a kind of preparation method of alpha-arbutin, final step recrystallization solvent adopts sherwood oil (60～90 ℃): ethyl acetate=9～7:1.
At Chinese patent CN1727493A(publication number) in recorded " free cell or immobilized cell catalyze and synthesize the method for alpha-arbutin " of the inventions such as Zhang Peng, Zhang Shurong, Liu Chunqiao
[9], wherein relating to the preparation method who utilizes xanthomonas campestris CGMCC NO.1243 free cell or immobilized cell to catalyze and synthesize alpha-arbutin, final step recrystallization solvent adopts water.
At Chinese patent CN101247816A(publication number) in recorded the invention of M figure Dinon " comprise arbutin, xitix, the molecular complex of Oleuropein and derivative thereof and in the related application of field of medicaments "
[10], wherein relate to a kind of fruit glycosides that comprises, xitix, the molecular complex of Oleuropein or its derivative, and in the related application of field of medicaments.
At Chinese patent CN101732169A(publication number) in recorded " a kind of arbutin multi-functional skin moisturizer " of Wang Juan invention
[11], wherein relate to a kind of multifunctional skin-care fluid that comprises arbutin.
At Chinese patent CN101597631A(publication number) in recorded " a kind of method of producing A-arbutin that transforms with root arrhizus fermentation " of Liang Jingjuan, Pang Zongwen, the invention of Feng's ancient flag with yak's tail
[12], wherein relate to a kind of method of producing A-arbutin that transforms with root arrhizus fermentation.
At Chinese patent CN102040636A(publication number) in recorded " method for synthesizing beta-arbutin by adopting alpha-D-glucose pentaacetate " of Li Anliang, Yang Shuqin, Guo Xiuru invention
[13]thereby, wherein relating to and take alpha-D-glucose pentaacetate and be the method for the synthetic β-arbutin of the synthetic key intermediate of raw material, final step recrystallization solvent adopts ethanol, water.
At Chinese patent CN102093442A(publication number) in recorded " separation purification method of arbutin in a kind of blueberry " of Zhao Yuhong, Wang Zhenyu, Wang Jinling invention
[14], wherein relating to a kind of method of the arbutin extracting in blueberry pomace being carried out to separation and purification, final step recrystallization solvent adopts water.
At Chinese patent CN102505031A(publication number) in " utilizing the method for the synthetic arbutin of hairy roots of scutellaria baicalensis Resorcinol " of having recorded Qi Xiangjun, Peng Feiyu, Qian Weidong, having executed spring sun-light invention
[15], wherein relate to a kind of method of utilizing the synthetic arbutin of hairy roots of scutellaria baicalensis Resorcinol.
At Chinese patent CN102329838A(publication number) in recorded " a kind of technique of producing alpha-arbutin by microbial transformation " of Du Gang, Yang Haiying invention
[16], wherein relate to a kind of method of producing alpha-arbutin that transforms with Aspergillus niger strain.
At Chinese patent CN102517361A(publication number) in recorded " method of catalytic synthesis of arbutin by using lipase " of Deng Li, Liu Chunqiao, Wang Fang, Tan Tianwei, Nie Kaili, Cao Xi invention
[17], wherein relate to the preparation method who utilizes free or immobilized porcine pancreatic lipase to catalyze and synthesize arbutin.
At Chinese patent CN102517362A(publication number) in recorded " a kind of method of utilizing lipase-catalyzed synthesis alpha-arbutin " of Wang Fang, Liu Chunqiao, Deng Li, Tan Tianwei, Nie Kaili, Cao Xi invention
[18], wherein relating to a kind of preparation method who utilizes free or immobilized candida sp.lipase to catalyze and synthesize alpha-arbutin, final step recrystallization solvent adopts water.
At Chinese patent CN102697672A(publication number) in recorded strong, Chen Yanling invention of summer " arbutin multiple emulsion and preparation method thereof "
[19], wherein relate to a kind of arbutin multiple emulsion, the described carrier loaded arbutin active ingredient that has.
In periodical < < Journal of Molecular Structure > >, recorded the article " Arbutin:Isolation, X-ray structure and computional studies " that the people such as Jacek E.Nycz deliver abroad
[20], wherein relate to the β-arbutin crystal formation that contains 0.5 water molecules.
The present invention has found a kind of β-arbutin brilliant III type solid matter state and the preparation method that contain 1 molecular crystal water different from above-mentioned patent or literature research Reporting.
Research purpose of the present invention is to start with from the crystal formation solid matter existence research of β-arbutin, by crystal formation triage techniques, crystal formation evaluated biological activity technology, in the active ingredient raw materials aspect of D&C, find, find that crystal formation solid matter exists kind and status flag, crystal-form substances is combined with biologically effective Journal of Sex Research, for the advantage medicinal crystal-form solid matter of finding, finding, exploitation has the β-arbutin of optimal clinical curative effect provides basic science data; Meanwhile, also for providing scientific basis from β-arbutin solid pharmaceutical raw material basis application country or international intellecture property invention patent protection.
Summary of the invention
One of the object of the invention: the brilliant III type solid matter existence of β-arbutin and describing mode are provided.
Two of the object of the invention: the preparation method that the brilliant III type of β-arbutin solid matter sample is provided.
Three of the object of the invention: the solid pharmaceutical and the composition thereof that are to provide the mixing crystal formation that contains the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion.
Four of the object of the invention: provide and use the brilliant III type of β-arbutin solid matter as the pharmaceutical composition of active constituents of medicine, its, dosage was within the scope of 10～500mg every day; Provide and use β-arbutin crystal formation solid matter as the makeup of effective constituent, its every daily dosage is within the scope of 100～1000mg.
Five of the object of the invention: provide and use the brilliant III type solid matter of β-arbutin to manufacture out for clinical tablet, capsule, pill, injection, slowly-releasing or controlled release preparation medicine as active constituents of medicine raw material; Provide and use β-arbutin crystal formation solid matter to be solid, suspension, emulsion or paste as the makeup of effective constituent.
Six of the object of the invention: provide the brilliant III type of β-arbutin material to bring into play the effective therapeutic action of medicine because crystal-form substances improves Plasma Concentration in organism in treatment lysis.
Seven of the object of the invention: provide and use the brilliant III type solid matter of β-arbutin as active raw materials, the application in preparing antimicrobial antiphlogistic medicine and makeup.
The invention provides the brilliant III type solid matter form of β-arbutin compound under solid state, the preparation method of brilliant III type sample; The medicine that the different crystal forms material of discovery use β-arbutin is developed as active fraction preparation and composition thereof are for the preparation of the application in antimicrobial antiphlogistic medicine and makeup.
Technical characterictic
1. the brilliant III type solid sample morphological specificity of β-arbutin:
The brilliant III type solid matter of the 1.1 β-arbutin that the present invention relates to, is characterized in that, contains crystal water composition, and the intermolecular ratio of β-arbutin molecule and crystal water is 1:1, when using single-crystal X-ray diffraction analysis, show as rhombic system symmetry, spacer is P2
12
12
1, unit cell parameters value is
α=90.00 °, β=90.00 °, γ=90.00 °,
z=8.Accompanying drawing 1 provides the brilliant III type of β-arbutin molecule stereo structure sciagraph, and accompanying drawing 2 provides the brilliant III type of β-arbutin sample molecule along the structure cell accumulation graph of a axle, and table 1 provides the brilliant III type of β-arbutin non-hydrogen atom coordinate parameters.
The brilliant III type non-hydrogen atom coordinate parameters of table 1 β-arbutin and equivalent temperature factor values
The brilliant III type of 1.2 β that the present invention relates to-arbutin solid matter, is characterized in that, when using powder x-ray diffraction analysis to adopt CuK
αduring radiation experiments condition, show as diffraction peak position: 2-Theta value (°) or d value (
) and diffraction peak relative intensity: solid matter when peak height value (Height%) or peak area value (Area%) have following characteristic peaks (table 2, Fig. 3):
The powder x-ray diffraction peak value of the brilliant III type of table 2 β-arbutin solid sample
The brilliant III type of 1.3 β that the present invention relates to-arbutin solid matter, it is characterized in that, while using infrared spectra to analyze 3527,3371,3324,3219,3040,2945,2910,2820,2692,2111,1999,1967,1862,1650,1510,1440,1400,1372,1351,1328,1308,1270,1254,1207,1194,1110,1100,1095,1080,1063,1033,997,945,908,892,858,830,776,719cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1(Fig. 4).
2. the preparation method characteristic of the brilliant III type of β-arbutin sample:
The preparation method of the brilliant III type of 2.1 β that the present invention relates to-arbutin sample, it is characterized in that, make the mixed solvent of water, aqueous ethanol, ethanol or above-mentioned solvent and methyl alcohol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran (THF), n-propyl alcohol, Virahol, propyl carbinol composition, β-arbutin sample is dissolved completely and go down to desolventize through 4 ℃～80 ℃ of envrionment temperatures, ambient relative humidity 10%～75%, normal pressure or vacuum experiment condition the brilliant III type of the β-arbutin solid matter of acquisition at 15 ℃～60 ℃ temperature.
The brilliant III type solid matter preparation method of the 2.2 β-arbutin that the present invention relates to, is characterized in that using anhydrous type β-arbutin sample to be greater than 10 hours in ambient relative humidity 50%～100%, storage period and can obtain the brilliant III type of β-arbutin solid matter.
3. the crystal formation composition of β-arbutin, dosage and pharmaceutical preparations composition feature:
3.1 β-arbutin mixing crystal formation the solid matters that the present invention relates to, is characterized in that, the brilliant III type of the β that contains arbitrary proportion-arbutin composition.
3.2 pharmaceutical composition the present invention relates to or makeup, is characterized in that, contain the brilliant III type of β-arbutin, or contain β-arbutin mixed crystal solid matter and pharmaceutically acceptable carrier.
3.3 pharmaceutical compositions that the present invention relates to, β-arbutin every day dosage within the scope of 10～500mg.
3.4 makeup that the present invention relates to, the every daily dosage of β-arbutin is within the scope of 100～1000mg.
3.5 pharmaceutical compositions that the present invention relates to, is characterized in that, described pharmaceutical composition is various tablets, capsule, pill, injection, sustained release preparation, controlled release preparation.
3.6 makeup that the present invention relates to, is characterized in that, described makeup are solid, suspension, emulsion or paste.
3.7 application of the brilliant III type of the β-arbutin mixed crystal composition that the present invention relates to the brilliant III type of β-arbutin or contain arbitrary proportion in preparing antimicrobial antiphlogistic medicine and makeup.
Accompanying drawing explanation
The brilliant III type of Fig. 1 β-arbutin molecule stereo structure sciagraph
The brilliant III type of Fig. 2 β-arbutin sample molecule is along the structure cell accumulation graph of a axle
The x-ray diffractogram of powder spectrum of the brilliant III type of Fig. 3 β-arbutin solid sample
The infrared absorpting light spectra of the brilliant III type of Fig. 4 β-arbutin sample
Embodiment
For better explanation technical scheme of the present invention, spy provides following examples, but the present invention is not limited to this.
Embodiment 1
The brilliant III type sample preparation methods 1 of β-arbutin:
β-arbutin bulk drug of 200mg is dissolved in ethanol/ethyl acetate (2:1) 20ml, under 50 ℃ of water bath condition, sample is dissolved completely under 20 ℃ of conditions and obtains single crystal after standing 15 days, crystal is water white transparency bulk.The crystal prototype obtaining is carried out to single-crystal X-ray diffraction analysis, show as rhombic system symmetry, spacer is P2
12
12
1, unit cell parameters value is
α=90.00 °, β=90.00 °, γ=90.00 °,
z=8, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 2 of β-arbutin:
By 50 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 20ml water, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 60 ℃ of rotating speed 90rpm of bath temperature, and the time is 20min, sample obtains β-arbutin solid matter of 173mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 3 of β-arbutin:
By 45 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 25ml ethanol, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 45 ℃ of rotating speed 90rpm of bath temperature, and the time is 15min, sample obtains β-arbutin solid matter of 174mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 4 of β-arbutin:
By 55 ℃ of heating for dissolving of β-arbutin bulk drug of 100mg in 30ml acetone, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 50 ℃ of rotating speed 90rpm of bath temperature, and the time is 18min, sample obtains β-arbutin solid matter of 82mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 5 of β-arbutin:
By 55 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 25ml ethanol/water (1:1) mixed solvent system, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 55 ℃ of rotating speed 90rpm of bath temperature, and the time is 15min, sample obtains β-arbutin solid matter of 176mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 6 of β-arbutin:
By 60 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 25ml isopropanol/water (1:1) mixed solvent system, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 60 ℃ of rotating speed 90rpm of bath temperature, and the time is 20min, sample obtains β-arbutin solid matter of 171mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 7 of β-arbutin:
By 50 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 30ml acetonitrile/water (1:1) mixed solvent system, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 60 ℃ of rotating speed 90rpm of bath temperature, and the time is 15min, sample obtains β-arbutin solid matter of 176mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 8 of β-arbutin:
By 60 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 50ml methyl alcohol/chloroform (1:1) mixed solvent system, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 55 ℃ of rotating speed 90rpm of bath temperature, and the time is 20min, sample obtains β-arbutin solid matter of 173mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 9 of β-arbutin:
By 50 ℃ of heating for dissolving of β-arbutin bulk drug of 200mg in 40ml acetone/water (1:1) mixed solvent system, filtered while hot obtains settled solution, with Rotary Evaporators, revolve steaming, pressure is 0.01Mpa, 50 ℃ of rotating speed 90rpm of bath temperature, and the time is 20min, sample obtains β-arbutin solid matter of 170mg through drying under reduced pressure, the sample obtaining is carried out to powder x-ray diffraction analysis, and its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 10 of β-arbutin:
By 50 ℃ of heating for dissolving of β-arbutin bulk drug of 100mg in 15ml acetone/water (1:1) mixed solvent system, filtered while hot obtains settled solution, and under 10 ℃ of envrionment temperatures, ambient moisture 30%, condition of normal pressure standing crystallization, obtain β-arbutin solid sample of 92mg, the sample obtaining is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 11 of β-arbutin:
By 60 ℃ of heating for dissolving of β-arbutin bulk drug of 100mg in 18ml dioxane/water (1:1) mixed solvent system, filtered while hot obtains settled solution, and under 25 ℃ of envrionment temperatures, ambient moisture 15%, condition of normal pressure standing crystallization, obtain β-arbutin solid sample of 91mg, the sample obtaining is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 12 of arbutin:
By 45 ℃ of heating for dissolving of β-arbutin bulk drug of 100mg in 20ml ethanol/tetrahydrofuran (THF) (2:1) mixed solvent system, filtered while hot obtains settled solution, and under 20 ℃ of envrionment temperatures, ambient moisture 25%, condition of normal pressure standing crystallization, obtain β-arbutin solid sample of 90mg, the sample obtaining is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
The brilliant III type sample preparation methods 13 of arbutin:
Anhydrous type β-arbutin bulk drug of 100mg is positioned under ambient moisture 95% condition, within 3 days, obtain afterwards β-arbutin solid sample of 105mg, the sample obtaining is carried out to powder x-ray diffraction analysis, its diffracting spectrum is consistent with Fig. 3, shows that gained sample is the brilliant III type of β-arbutin solid matter.
Embodiment 2
The preparation method 1(tablet of combined pharmaceutical formulation):
A kind of preparation method of medicinal composition tablet, the mixed crystal solid matter that it is characterized in that using the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion as the bulk drug of medicinal composition, use several vehicle as the adjunct ingredient of preparing medicinal composition tablet, proportioning is made every content of dispersion in the tablet samples of 10～300mg according to a certain percentage, and table 3 provides tablet formulation ratio:
The preparation formula of table 3 β-arbutin composite medicine tablet
The method that the brilliant III type sterling of β-arbutin or the mixed crystal bulk drug that contains the brilliant III type of arbitrary proportion is prepared into tablet formulation is: several vehicle are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make soft material, the granulation of sieving, wet grain is dried, and the whole grain that sieves, adds Magnesium Stearate and talcum powder to mix, compressing tablet, obtains.
The preparation method 2(capsule of combined pharmaceutical formulation):
A kind of preparation method of medicinal composition capsule, the mixed crystal solid matter that it is characterized in that using the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion as the bulk drug of medicinal composition, use several vehicle as the adjunct ingredient of preparing medicinal composition capsule, proportioning is made every content of dispersion at the capsule sample of 10～200mg according to a certain percentage, and table 4 provides capsule formula ratio:
Bulk drug and the accessory formula of the brilliant III type of table 4 β-arbutin medicinal composition capsule preparations
The method that the brilliant III type sterling of β-arbutin or the mixed crystal bulk drug that contains the brilliant III type of arbitrary proportion is prepared into tablet formulation is: several vehicle are mixed with bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and make; Or do not use granulation step, and directly β-arbutin bulk drug is mixed with several vehicle auxiliary materials, after sieving, directly incapsulate and make.
The preparation method 3(pulvis of makeup):
A kind of preparation method of makeup, the mixed crystal solid matter that it is characterized in that using the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion as cosmetic material medicine, use several vehicle as the adjunct ingredient of preparing makeup, proportioning is made content at the pulvis of 100～500mg according to a certain percentage, and table 5 provides makeup wp formula ratio:
The brilliant III type of table 5 β-arbutin makeup wp formula
Above-mentioned system component was pulverized to 200 mesh sieves, and after evenly mixing, compressing tablet mounted box is made muffin.
The preparation method 4(suspension of makeup):
A kind of preparation method of makeup, the mixed crystal solid matter that it is characterized in that using the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion as cosmetic material medicine, use several vehicle as the adjunct ingredient of preparing makeup, proportioning is made content at the suspension of 100～500mg according to a certain percentage, and table 6 provides makeup suspension formula rate:
The brilliant III type of table 6 β-arbutin makeup suspension formula
Above-mentioned system component was pulverized to 200 mesh sieves, added glycerine, water constituent, and through the ultrasonic suspension of evenly making, bottled and get final product.
Preparation method 5(emulsion or the paste of makeup):
A kind of preparation method of makeup, the mixed crystal solid matter that it is characterized in that using the brilliant III type sterling of β-arbutin or contain the brilliant III type of arbitrary proportion as cosmetic material medicine, use several vehicle as the adjunct ingredient of preparing makeup, proportioning is made content at emulsion or the paste of 100～500mg according to a certain percentage, and table 7 provides cosmetic emulsions or paste ingredient ratio:
The brilliant III type cosmetic emulsions of table 7 β-arbutin or paste ingredient
Above-mentioned system component was pulverized to 200 mesh sieves, added appropriate glycerine, a little moisture, and through stirring sample blending, bottled and get final product.
Embodiment 3
The dosage 1(tablet of β-arbutin crystal formation medicinal composition):
The pharmaceutical composition that uses crystal formation β-arbutin sample to manufacture as active constituents of medicine, it is characterized in that using brilliant III type β-arbutin as the activeconstituents of medicine, every day, dosage was 30mg, can be prepared into respectively 3 times/each 1 10mg conventional tablet every day, every day 2 times/each 1 15mg conventional tablet or every day 1 time/each 1 30mg tablet type.
The dosage 2(capsule of β-arbutin crystal formation medicinal composition):
The pharmaceutical composition that uses crystal formation β-arbutin sample to manufacture as active constituents of medicine, it is characterized in that using brilliant III type β-arbutin as the activeconstituents of medicine, every day, dosage was 60mg, can be prepared into respectively 2 times/each 1 30mg capsule every day, every day 1 time/each 1 60mg capsule.
The problem that needs explanation: the β-arbutin crystal formation pharmaceutical composition the present invention relates to has multifactor impact perhaps on the dosage of effective constituent, for example: for preventing different with the purposes for the treatment of, cause the difference of dosage every day; Ill character is different from ill severity and cause the different of dosage every day; The difference of Gender, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, the absorption existing between crystal form samples and Plasma Concentration are not equal, and also causing the present invention is 0.01-300mg/kg body weight using appropriate dose scope every day of β-arbutin crystal formation composition, is preferably 10-100mg/kg body weight.During use, should formulate different brilliant III type β-arbutin effective constituent total dose schemes from treatment different situations demand according to actual prevention, and can be divided into repeatedly or single administration mode completes.
The using dosage of β-arbutin crystal formation makeup:
Use crystal formation β-arbutin sample as the makeup late frost of active fraction preparation exploitation, it is characterized in that using brilliant III type β-arbutin as the activeconstituents of makeup, every daily dosage portion is 200mg, and used night.
Use crystal formation β-arbutin sample as the makeup foundation cream of active fraction preparation exploitation, it is characterized in that using brilliant III type β-arbutin as the activeconstituents of makeup, every daily dosage portion is 100mg, and used morning.
Embodiment 4
The brilliant III type of β-arbutin stability advantage:
The brilliant III type of β-arbutin solid matter belongs to a kind of stable superiority crystal formation, and under high temperature, high humidity, illumination condition, crystal-form substances is in stable condition, difficultly turns brilliant phenomenon, as medicine and makeup exploitation, has the in stable condition advantage of crystal-form substances.
The brilliant III type of β-arbutin absorbs advantage:
The brilliant III type of β-arbutin solid matter belongs to a kind of absorption advantage crystal formation, in the oral or outer used time, all has the absorption advantageous characteristic higher compared with anhydrous crystal forms.
Reference
1. Chinese patent, publication number CN1302599A
2. Chinese patent, publication number CN1481233A
3. Chinese patent, publication number CN1228300A
4. Chinese patent, publication number CN1208608A
5. Chinese patent, publication number CN1608693A
6. Chinese patent, publication number CN1633980A
7. Chinese patent, publication number CN1635139A
8. Chinese patent, publication number CN1724551A
9. Chinese patent, publication number CN1727493A
10. Chinese patent, publication number CN101247816A
11. Chinese patents, publication number CN101732169A
12. Chinese patents, publication number CN101597631A
13. Chinese patents, publication number CN102040636A
14. Chinese patents, publication number CN102093442A
15. Chinese patents, publication number CN102505031A
16. Chinese patents, publication number CN102329838A
17. Chinese patents, publication number CN102517361A
18. Chinese patents, publication number CN102517362A
19. Chinese patents, publication number CN102697672A
20.Jacek?E.Nycz,Grzegorz?Malecki,Monika?Morag,et?al.Arbutin:Isolation,X-ray?structure?and?computional?studies.Journal?of?Molecular?Structure.2010,980:13-17.
Claims (13)
1. the brilliant III type of β-arbutin solid matter, is characterized in that, contains crystal water composition, and β-arbutin molecule is 1:1 with the intermolecular ratio of crystal water, when use single-crystal X-ray diffraction analysis, shows as rhombic system symmetry, and spacer is P2
12
12
1, unit cell parameters value is
α=90.00 °, β=90.00 °, γ=90.00 °,
z=8.
2. the brilliant III type of β-arbutin solid matter, is characterized in that, when using powder x-ray diffraction analysis to adopt CuK
aduring radiation experiments condition, diffraction peak position 2-Theta value (°) or d value (
), diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
3. according to the brilliant III type of the arbitrary described β-arbutin of claim 1-2 solid matter, it is characterized in that, while using infrared spectra to analyze 3527,3371,3324,3219,3040,2945,2910,2820,2692,2111,1999,1967,1862,1650,1510,1440,1400,1372,1351,1328,1308,1270,1254,1207,1194,1110,1100,1095,1080,1063,1033,997,945,908,892,858,830,776,719cm
-1there is diffuse reflectance infrared spectroscopy peak in place, the permissible variation at its mid-infrared spectral behavior peak is ± 2cm
-1.
4. the brilliant III type solid matter preparation method of the arbitrary described β-arbutin of claim 1-2, it is characterized in that, make the mixed solvent of water, aqueous ethanol, ethanol or above-mentioned solvent and methyl alcohol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran (THF), n-propyl alcohol, Virahol, propyl carbinol composition, β-arbutin sample is dissolved completely and go down to desolventize through 4 ℃～80 ℃ of envrionment temperatures, ambient relative humidity 10%～75%, normal pressure or vacuum experiment condition the brilliant III type of the β-arbutin solid matter of acquisition at 15 ℃～60 ℃ temperature.
5. the brilliant III type solid matter preparation method of the arbitrary described β-arbutin of claim 1-2, is characterized in that using anhydrous type β-arbutin sample to be greater than 10 hours in ambient relative humidity 50%～100%, storage period and can obtain the brilliant III type of β-arbutin solid matter.
6. a mixing crystal formation solid matter for β-arbutin, is characterized in that, the brilliant III type of arbitrary described β-arbutin composition in the claim 1-2 that contains arbitrary proportion.
7. pharmaceutical composition or makeup, is characterized in that, contains the brilliant III type sterling of arbitrary described β-arbutin and pharmaceutically acceptable carrier in claim 1-2.
8. pharmaceutical composition or makeup, is characterized in that, contains β-arbutin mixing crystal formation solid matter and the pharmaceutically acceptable carrier described in claim 5.
9. according to the pharmaceutical composition of claim 7 or 8, it is characterized in that, β-arbutin every day dosage within the scope of 10～100mg.
10. according to the makeup of claim 7 or 8, it is characterized in that, the every daily dosage of β-arbutin is within the scope of 100～1000mg.
11. according to the pharmaceutical composition of claim 7 or 8, it is characterized in that, the formulation of described composition is tablet, capsule, pill, injection, sustained release preparation or controlled release preparation.
12. according to the makeup of claim 7 or 8, it is characterized in that, described makeup are solid, suspension, emulsion or paste.
The brilliant III type composition of arbitrary described β-arbutin and/or the application of mixing crystal formation solid matter claimed in claim 6 in preparing antimicrobial antiphlogistic medicine and makeup in 13. claim 1-2.
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