CN109988216A - Betulin crystalline substance D type substance and preparation method and its composition and purposes - Google Patents
Betulin crystalline substance D type substance and preparation method and its composition and purposes Download PDFInfo
- Publication number
- CN109988216A CN109988216A CN201711496844.XA CN201711496844A CN109988216A CN 109988216 A CN109988216 A CN 109988216A CN 201711496844 A CN201711496844 A CN 201711496844A CN 109988216 A CN109988216 A CN 109988216A
- Authority
- CN
- China
- Prior art keywords
- betulin
- solid matter
- crystalline substance
- type solid
- type
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses the brilliant D type solid matter of betulin compound (chemical name: Lup-20 (29)-ene-3b, 28-diol, English name: Betulin) and its preparation methods and its composition and purposes.Specifically, the invention discloses betulins in the solid state there is crystalline substance D type solid matter stastus format；The preparation method of brilliant D type solid matter sample；Various anti-inflammatory, antiviral, anticancer, anti-diabetic and/or Antiatherosclerosis medicine are being prepared using betulin crystalline substance D type solid matter as active pharmaceutical ingredient; and obesity, protection hair, improve the application in the health food of damaged hair gloss and/or promotion natural on-off cycles of hair growth.
Description
Technical field
The present invention relates to have found a kind of betulin existing crystalline substance D type solid matter stastus format in the solid state；
It is related to having invented the preparation method of brilliant D type；It is related to having invented containing betulin crystalline substance D type or containing any non-zero proportions crystalline substance D type
Mix the pharmaceutical composition of crystal form；The invention further relates to betulin crystal-form substances as effective ingredient, various preparing
Anti-inflammatory, antiviral, anticancer, anti-diabetic and/or Antiatherosclerosis medicine and obesity, protection hair, improve impaired
Application in the health food of hair gloss and/or promotion natural on-off cycles of hair growth.
Background technique
Molecular structural formula is such as betulin (chemical name: Lup-20 (29)-ene-3b, 28-diol, English name: Betulin)
Under:
Shanghai Ruizhi Chemical Study Co., Ltd.'s invention is described in Chinese patent CN101200486A (publication number)
" method for extraction and purification of betulin in birch-bark "[1], it has been directed to mention from birch-bark using ethyl alcohol or ethanol water
Betulin crude product is taken, is recrystallized using dehydrated alcohol, acetone, methanol, ethyl acetate equal solvent, it is pure to obtain betulin
Product.Applicant is by repeating this experiments have shown that obtained solid should be the solvate containing corresponding recrystallization solvent.
Journal of Pharmaceutical Sciences is delivered magazine 2016 the 105th from literature search to one
Page 1867 is rolled up about " " 5 Solvatomorphs of Betulin:X-Ray of Isostructurality Among
Structure and Characterization " " article[2], 5 kinds of solvates of betulin are described, one is delivered
Volume 106 page 826 of Journal of Pharmaceutical Sciences magazine 2017 about " " Structural
and Computational Study of 4 New Solvatomorphs of Betulin:A Combined X-Ray,
Hirshfeld Surface, and Thermal Analysis " " article[3], 4 kinds of solvates of betulin are described, are prompted
The compound is the property that solvate is easily formed with organic solvent.
Through domestic and international patent and literature search, the crystal form patent or document report for closing betulin are found no.
Present invention finds a kind of new betulin crystalline substance D type solid matter state and preparation methods, it was found that betulin
Brilliant D type solid matter has the feature of good stability and significantly dissolves sexual clorminance.
Research purpose of the invention is started with from the research of the crystal form solid matter existence of betulin, is sieved by crystal form
Selecting technology, stability of crystal form assessment technique are found in the active ingredient raw materials level of drug, find that crystal form solid matter exists
Type and state feature, crystal-form substances are combined with pharmacodynamic study, have optimal clinical curative effect for searching, discovery, exploitation
Betulin advantage medicinal crystal-form solid matter provide basic science data；Meanwhile also for from betulin solid drugs
Apply for that country or international intellectual property invention patent protection provide scientific basis on the basis of raw material.
Summary of the invention
The technical problem to be solved by the present invention is to, provide a kind of new brilliant D type solid matter existence of betulin and
Characteristic manner.
The second technical problem to be solved by the present invention: the preparation method of betulin crystalline substance D type solid matter is provided.
The third technical problem to be solved by the present invention: it provides containing betulin crystalline substance D type sterling or contains any non-zero ratio
The solid drugs and combinations thereof of the mixing crystal form of example crystalline substance D type.
The four of the technical problem to be solved in the present invention: offer uses betulin crystalline substance D type solid matter as pharmaceutical activity
The pharmaceutical composition of ingredient, each dosage is within the scope of 5-3000mg.The pharmaceutical composition includes tablet, glue
Capsule, pill, injection, sustained release or controlled release preparation drug
The five of the technical problem to be solved in the present invention: betulin crystalline substance D type solid matter is being made as effective ingredient
Standby various anti-inflammatory, antiviral, anticancer, anti-diabetic and/or Antiatherosclerosis medicine and obesity, protection hair, change
Application in the health food of kind damaged hair gloss and/or promotion natural on-off cycles of hair growth.
In order to solve the above technical problems, the present invention adopts the following technical scheme:
1. the brilliant D pattern product morphological feature of betulin:
1.1 betulin crystalline substance D type solid matters of the present invention, which is characterized in that do not contain recrystallisation solvent or crystallization
Water constituent, when use powder x-ray diffraction analysis uses CuKαWhen radiation experiments condition, diffraction maximum position 2-Theta value (°) or
D valueDiffraction maximum relative intensity peak value (Height%) or peak area value (Area%) have following expression (table 1, Fig. 1).
The powder x-ray diffraction peak value of 1 betulin crystalline substance D type material sample of table
1.2 betulin crystalline substance D type solid matters of the present invention, using decaying total reflection Fourier transform infrared spectrometry into
When row analysis, 3364,3083,2941,2868,2654,1768,1644,1484,1453,1388,1375,1360,1339,
1300、1278、1244、1211、1189、1159、1131、1106、1083、1069、1027、984、972、944、932、914、
897、881、804、764、745、687cm-1There are infrared spectroscopy characteristic peak, the tolerances of middle infrared spectrum characteristic peak at place is
±2cm-1(Fig. 2).
1.3 betulin crystalline substance D type solid matters of the present invention, when being analyzed using differential canning calorimetry, performance
For within the scope of 30~320 DEG C and when heating rate is 10 DEG C per minute, in DSC map at 109 DEG C ± 3 DEG C, 137 DEG C
At ± 3 DEG C, there are 3 exothermic peaks at 197 DEG C ± 3 DEG C, and there are 1 endothermic peaks at 260 DEG C ± 3 DEG C.(Fig. 3)
1.4 betulin crystalline substance D type solid matters of the present invention, when being analyzed using thermogravimetry, show as 30~
Within the scope of 500 DEG C and when heating rate is 10 DEG C per minute, there is only 1 weightless steps, as white birch rouge in TG map
The decomposition weightlessness step (Fig. 4) of alcohol.
1.5 betulin mixing crystal form solid matters of the present invention, the betulin crystalline substance D containing any non-zero proportions
Type material composition.
2. the preparation method characteristic of betulin crystalline substance D type material sample and mixed crystal:
The preparation method of 2.1 betulin crystalline substance D type solid matters of the present invention, which is characterized in that use white birch rouge
Betulin solvate is completely removed solvent by any one or more of alcohol solvate, wherein the betulin
Solvate be selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, pyridine and water, N,N-Dimethylformamide,
The solvate of nitrogen nitrogen dimethyl acetamide and/or dimethyl sulfoxide., or the betulin without recrystallisation solvent, Place grinding machine
Interior grinding (ratio of grinding media to material 6:1w/w) prepares the brilliant D type solid matter of betulin.
2.2 betulin mixing crystal form solid matters of the invention, are the betulin crystalline substance D for preparing the above method
Type ingredient is mixed according to the method for any non-zero proportions and routine with other betulin crystal form solid matters.
3. the pharmaceutical preparations composition containing betulin crystal form ingredient, dosage feature and pharmaceutical applications:
3.1 pharmaceutical compositions of the present invention contain betulin crystalline substance D type and pharmaceutically acceptable carrier.
3.2 pharmaceutical compositions of the present invention contain betulin mixing crystal form solid matter and pharmaceutically acceptable
Carrier.
3.3 pharmaceutical compositions of the present invention, the daily dosage of betulin is within the scope of 5-3000mg.
3.4 pharmaceutical compositions of the present invention, which is characterized in that the pharmaceutical composition be various tablets, capsule,
Pill, powder-injection, sustained release preparation or controlled release preparation.
3.5 the present invention relates to betulin crystal B-type solid matters to prepare various anti-inflammatory, antiviral, anticancer, anti-diabetic
And/or Antiatherosclerosis medicine and obesity, protection hair, improve damaged hair gloss and/or promotes natural on-off cycles of hair growth
Health food in application.
The 3.6 betulin mixing crystal form solid matters of the present invention containing any non-zero proportions are preparing various disappear
Scorching, antiviral, anticancer, anti-diabetic and/or Antiatherosclerosis medicine and obesity, protection hair, improve by the lost head
Application in the health food of luminous pool and/or promotion natural on-off cycles of hair growth.
The present invention relates to betulin crystalline substance D type ingredient of the present invention, betulin mixing crystal form solid matter of the present invention work
For the pharmaceutical composition of active ingredient.The pharmaceutical composition can be prepared according to method well known in the art.It can be by will be of the invention
Betulin crystalline substance D type ingredient, betulin mixing crystal form solid matter of the present invention with it is one or more pharmaceutically acceptable solid
Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.Betulin crystalline substance D of the present invention
The content of type ingredient, betulin mixing crystal form solid matter of the present invention in its pharmaceutical composition is usually 0.1-95 weight
Measure %.
Betulin crystalline substance D type ingredient, betulin mixing crystal form solid matter of the present invention or the drug containing it of the present invention
Composition can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection,
Subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc..
Form of administration of the invention is preferably solid dosage forms.Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets,
Lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), particle
Agent, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc..
Common system can be made in betulin crystalline substance D type ingredient of the present invention, betulin mixing crystal form solid matter of the present invention
Agent, to be also made be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery systems.
It, can in order to which tablet is made in betulin crystalline substance D type ingredient of the present invention, betulin synthetic type solid matter of the present invention
To be widely used various excipient well known in the art, including diluent, binder, wetting agent, disintegrating agent, lubricant, help stream
Agent.Diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, sulphur
Sour calcium, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin,
Syrup, honey, glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose,
Hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegration
It is fine that agent can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, cross-linked carboxymethyl
Tie up plain sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate
Deng；Lubricant and glidant can be talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
It, can be by effective component betulin crystalline substance D type ingredient of the present invention, the present invention in order to which capsule is made in administration unit
Betulin mixing crystal form solid matter is mixed with diluent, glidant, and mixture is placed directly in hard capsule or soft capsule.
Effective component betulin crystalline substance D type ingredient of the present invention, betulin mixing crystal form solid matter of the present invention first and can also be diluted
Particle or pellet is made in agent, binder, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare betulin of the present invention
Various diluents, binder, the wetting agent, disintegration of brilliant D type ingredient, betulin mixing crystal form solid matter tablet of the present invention
Agent, glidant kind can also be used for preparing betulin crystalline substance D type ingredient of the present invention, betulin mixing crystal form solids of the present invention
The capsule of matter.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
Betulin crystalline substance D type ingredient of the present invention, betulin mixing crystal form solid matter pharmaceutical composition of the present invention are given
Pharmaceutical quantities are according to the property and severity to be prevented or be treated disease, the individual instances of patient or animal, administration route and
Dosage form etc. can have large-scale variation.Above-mentioned dosage with a dosage unit or can be divided into several dosage unit administrations, this takes
The certainly clinical experience of Yu doctor and include dosage regimen with other treatment means.
Betulin crystalline substance D type ingredient, betulin mixing crystal form solid matter of the present invention or composition of the present invention can be independent
It takes, or merges use with other treatment drug or symptomatic drugs.When betulin crystal B-type ingredient of the present invention, white birch of the present invention
When lipidol mixing crystal form solid matter and other therapeutic agents have synergistic effect, its dosage should be adjusted according to the actual situation.
4. advantageous effects of the invention
4.1 betulin crystalline substance D type solid matters have dissolubility advantageous characteristic
The dissolubility of betulin crystalline substance D type solid matter of the invention in 0.5%SDS aqueous solution is substantially better than known
Crystal type A (marketable material medicine contains recrystallisation solvent), the rate of dissolution of brilliant D type has marked improvement compared with crystal type A, and its solubility is about
2.1 times of crystal type A have significant dissolubility advantageous characteristic.
4.2 betulin crystal B-type solid matters have stability advantage feature
Betulin crystalline substance D type solid matter of the invention is stable under high temperature, high humidity, illumination condition, does not occur to turn crystalline substance
Phenomenon has stability advantage.
4.3 betulin crystal B-type solid matters have security advantages feature
Betulin crystalline substance D type solid matter of the invention does not contain any recrystallisation solvent, brilliant with published solvate
Type, which is compared, has substantive features and significant progress, has apparent advantageous characteristic in terms of patent medicine safety.
Detailed description of the invention
The x-ray diffractogram of powder of Fig. 1 betulin crystalline substance D type material sample is composed
The infrared absorpting light spectra of Fig. 2 betulin crystalline substance D type material sample
The DSC map of Fig. 3 betulin crystalline substance D type material sample
The TG map of Fig. 4 betulin crystalline substance D type material sample
Fig. 5 betulin crystalline substance D type material sample figure compared with the solubility of crystal type A material sample.
Specific embodiment
More preferably to illustrate technical solution of the present invention, spy provides following embodiment, but the present invention is not limited to this.
Embodiment 1
The preparation method 1 of betulin crystalline substance D type material sample:
1 hour removal solvent is placed using the solvate of betulin, under the conditions of which is placed in 160 DEG C,
Grinding is no less than 2h (ratio of grinding media to material 6:1w/w) in Place grinding machine, prepares betulin solid sample, carries out powder X-ray to it and penetrate
Line diffraction analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is betulin crystalline substance D type solid matter.
Embodiment 2
Betulin crystalline substance D type solid matter stability features:
Hot test: by crystal form samples set opening clean surface ware in, placed 10 days at a temperature of 60 DEG C, and in the 0th day,
It samples within 5th day and the 10th day.Sample obtained by above-mentioned sample point is subjected to powder x-ray diffraction analysis, diffracting spectrum is and Fig. 1
Unanimously, show that betulin crystalline substance D type solid matter is stablized under the test of high temperature influence factor.
High humidity test: crystal form samples are set in opening clean surface ware, at 25 DEG C under the conditions of relative humidity 90% ± 5%
It places 10 days, and was sampled in the 0th day, the 5th day and the 10th day.Sample obtained by above-mentioned sample point is subjected to powder x-ray diffraction point
Analysis, diffracting spectrum is consistent with Fig. 1, shows that betulin crystalline substance D type solid matter is stablized under the test of high humidity influence factor.
Exposure experiments to light: crystal form samples are set in opening clean surface ware, are placed on the lighting box equipped with fluorescent lamp, are in illumination
The condition of 4500lx ± 500lx is placed 10 days, and is sampled in the 0th day, the 5th day and the 10th day.By sample obtained by above-mentioned sample point
Powder x-ray diffraction analysis is carried out, diffracting spectrum is consistent with Fig. 1, shows betulin crystalline substance D type solid matter in illumination shadow
It rings and stablizes under factorial experiments.
Stability test the result shows that, betulin crystalline substance D type have stability advantage.
Embodiment 3
Betulin crystalline substance D type solid matter dissolubility feature:
Using 0.5%SDS aqueous solution as solvent, the dissolution sex differernce that betulin investigates crystalline substance D type and crystal type A is investigated, knot
Fruit shows that brilliant D type solubility is substantially better than crystal type A, sees Fig. 4.
Due to betulin category insoluble drug, in water or different pH value aqueous solutions, the dissolution speed of different crystal forms substance
Rate differentiation is unobvious, therefore the aqueous solution of the cosolvent containing 0.5%SDS is used to be tested, and the solvent system is to two kinds of betulin
The rate of dissolution of crystal form has good discrimination.Referring to solubility test method (" normal oral solid pharmaceutical preparation Dissolution Rate Testing
Technological guidance's principle (first draft) ", 2012.10 drugs evaluate center) measurement.Using with high-efficient liquid phase technique, the chromatography of sample is utilized
The mass percent that peak area data dissolve sample calculates, and using the time as abscissa, dissolves content for ordinate difference
Solubility curve is drawn, data are as shown in the table:
The solubility curve data of 2 crystalline substance D type of table and crystal type A (raw material) in 0.5%SDS hydrochloric acid solution
Had in 0.5%SDS aqueous solution by the betulin crystalline substance D type substance of this patent it can be seen from experimental data molten
Sexual clorminance is solved, the rate of dissolution having had and solubility, solubility are about 2.1 times of crystal type A or more.
Embodiment 4
The preparation method 1 (tablet) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine tablet, it is characterized in that using betulin crystalline substance D type substance sterling or containing appoint
The mixed crystal solid matter of meaning ratio crystalline substance D type as composition of medicine bulk pharmaceutical chemicals, use several excipient as preparing composition of medicine
The adjunct ingredient of tablet, every content of dispersion is made in the tablet samples of 5~500mg in proportion according to a certain percentage, and table 3 provides tablet
Formula rate:
The preparation formula of 3 betulin composition of medicine tablet of table
Betulin crystalline substance D type substance sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystalline substance D type are prepared into tablet formulation
Method be: several excipient are uniformly mixed with bulk pharmaceutical chemicals, be added 1% sodium cellulose glycolate solution it is appropriate, soft material is made,
Sieving granulation, the drying of wet grain, whole grain of being sieved, is added magnesium stearate and talcum powder is uniformly mixed, tabletting to get.
The preparation method 2 (capsule) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine capsule, it is characterized in that using betulin crystalline substance D type substance sterling or containing appoint
The mixed crystal solid matter of meaning ratio crystalline substance D type as composition of medicine bulk pharmaceutical chemicals, use several excipient as preparing composition of medicine
The adjunct ingredient of capsule, every content of dispersion is made in the capsule sample of 5~500mg in proportion according to a certain percentage, and table 4 provides capsule
Formula rate:
The bulk pharmaceutical chemicals and accessory formula of 4 betulin composition of medicine capsule preparations of table
Betulin crystalline substance D type substance sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystalline substance D type are prepared into tablet formulation
Method be: several excipient are uniformly mixed with bulk pharmaceutical chemicals, be added 1% sodium cellulose glycolate solution it is appropriate, wet grain is made
Drying sieving whole grain, is added magnesium stearate and is uniformly mixed, and insertion capsule is made；Or granulation step is not used, and directly by white birch
Lipidol crystalline substance D type raw material of substance medicine is uniformly mixed with several excipients, after sieving, is directly loadable into capsule and is made.
Embodiment 5
The dosage 1 (tablet) of betulin crystal form composition of medicine:
The pharmaceutical composition for using crystal form betulin sample to manufacture as active pharmaceutical ingredient, it is characterized in that using
Active constituent of the brilliant D type betulin as drug, being administered daily dosage is 5-3000mg, can be prepared into each 1-6 piece respectively
Conventional tablet type containing active constituent 5,50,100,200,300,500mg.
The dosage 2 (capsule) of betulin crystal form composition of medicine:
The pharmaceutical composition for using crystal form betulin sample to manufacture as active pharmaceutical ingredient, it is characterized in that using
Active constituent of the brilliant D type betulin as drug, being administered daily dosage is 5-3000mg, can be prepared into respectively 1-6 each
Capsule containing active constituent 5,50,100,200,300,500mg.
Need the problem of illustrating: dosage of the betulin crystal form pharmaceutical composition of the present invention in effective component
On there are many factors influences, such as: the difference of patient age, body surface area, administration route, administration number of times, therapeutic purposes
Difference that is different and causing each dosage；It is existing between crystal form samples to absorb different with blood concentration etc., also result in this hair
Bright each Suitable dosage ranges using betulin crystal form ingredient are 0.01-300mg/kg weight, preferably 10-100mg/
Kg weight.When use different betulin crystal B-type substance effective component should be formulated according to actual treatment different situations demand
Accumulated dose scheme, and the completion of multiple or single administration mode can be divided into.
Bibliography
1. Chinese patent CN101200486A.
2.Yang D,Gong N,Zhang L,et al.Isostructurality Among 5 Solvatomorphs
of Betulin:X-Ray Structure and Characterization[J].Journal of Pharmaceutical
Sciences,2016,105(6):1867-1873.
3.Yang D,Gong N,Zhang L,et al.Structural and Computational Study of 4
New Solvatomorphs of Betulin:A Combined X-Ray,Hirshfeld Surface,and Thermal
Analysis[J].Journal of Pharmaceutical Sciences,2017,106(3):826-834.
Claims (13)
1. betulin crystalline substance D type solid matter, which is characterized in that do not contain recrystallisation solvent or crystalline water content, when use powder X-ray
X ray diffraction analysis x uses CuKαWhen radiation experiments condition, diffraction maximum position 2-Theta value (°) or d valueDiffraction maximum is opposite
Intensity peak value (Height%) or peak area value (Area%) have following indicate:
2. betulin crystalline substance D type solid matter according to claim 1, which is characterized in that use decaying total reflection Fourier
When leaf infra-red sepectrometry is analyzed, 3364,3083,2941,2868,2654,1768,1644,1484,1453,1388,
1375、1360、1339、1300、1278、1244、1211、1189、1159、1131、1106、1083、1069、1027、984、
972、944、932、914、897、881、804、764、745、687cm-1There are infrared spectroscopy characteristic peak, middle infrared spectrum is special at place
The tolerance for levying peak is ± 2cm-1。
3. betulin crystalline substance D type solid matter according to claim 1, which is characterized in that use differential scanning calorimetry skill
It when art is analyzed, shows as within the scope of 30~320 DEG C and when heating rate is 10 DEG C per minute, at 109 DEG C in DSC map
At ± 3 DEG C, at 137 DEG C ± 3 DEG C, there are 3 exothermic peaks at 197 DEG C ± 3 DEG C, and there are 1 endothermic peaks at 260 DEG C ± 3 DEG C.
4. betulin crystalline substance D type solid matter according to claim 1, which is characterized in that when being analyzed using thermogravimetry,
It shows as within the scope of 30~500 DEG C and when heating rate is 10 DEG C per minute, there is only 1 weightless platforms in TG map
Rank is the decomposition weightlessness step of betulin.
5. the preparation method of betulin crystalline substance D type solid matter of any of claims 1-4, which is characterized in that make
With any one or more of betulin solvate, betulin solvate is completely removed into solvent, wherein described
Betulin solvate is selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, pyridine and water, nitrogen nitrogen dimethyl
The solvate of formamide, nitrogen nitrogen dimethyl acetamide and/or dimethyl sulfoxide., or the betulin without recrystallisation solvent, it sets
(ratio of grinding media to material 6:1w/w) is ground in ball mill, prepares the brilliant D type solid matter of betulin.
6. a kind of mixing crystal form solid matter of betulin, which is characterized in that claim 1 institute containing any non-zero proportions
The betulin crystalline substance D type solid matter stated.
7. a kind of pharmaceutical composition, which is characterized in that the betulin of any one of claim 1-4 containing effective dose is brilliant
D type solid matter and pharmaceutically acceptable carrier.
8. a kind of pharmaceutical composition, which is characterized in that betulin mix-crystal described in the claim 6 containing effective dose
Type solid matter and pharmaceutically acceptable carrier.
9. according to the pharmaceutical composition of any one of claim 7 or 8, which is characterized in that the daily dosage of betulin exists
Within the scope of 5-3000mg.
10. according to the pharmaceutical composition of any one of claim 7 or 8, which is characterized in that the dosage form of described pharmaceutical composition is piece
Agent, capsule, pill, powder-injection, sustained release preparation or controlled release preparation.
11. betulin crystalline substance D type solid matter of any of claims 1-4 is preparing various anti-inflammatory, antiviral, anti-
Cancer, anti-diabetic, Antiatherosclerosis medicine, and prevention or treatment obesity, protection hair, improvement damaged hair light
Application in pool, promotion natural on-off cycles of hair growth health food.
12. betulin mixing crystal form solid matter as claimed in claim 6 is preparing various anti-inflammatory, antiviral, anticancer, anti-sugar
Urine disease and/or Antiatherosclerosis medicine, and prevention or treatment obesity, protection hair, improve damaged hair gloss and/
Or the application in the health food of promotion natural on-off cycles of hair growth.
13. pharmaceutical composition described in any one of claim 7-8 is preparing various anti-inflammatory, antiviral, anticancer, anti-diabetic
And/or Antiatherosclerosis medicine, and prevention or treatment obesity, protection hair, improve damaged hair gloss and/or rush
Application into the health food of natural on-off cycles of hair growth.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496844.XA CN109988216B (en) | 2017-12-31 | 2017-12-31 | Betulin crystal D-type substance, preparation method, composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496844.XA CN109988216B (en) | 2017-12-31 | 2017-12-31 | Betulin crystal D-type substance, preparation method, composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109988216A true CN109988216A (en) | 2019-07-09 |
| CN109988216B CN109988216B (en) | 2023-01-06 |
Family
ID=67110191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711496844.XA Active CN109988216B (en) | 2017-12-31 | 2017-12-31 | Betulin crystal D-type substance, preparation method, composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109988216B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200486A (en) * | 2006-12-13 | 2008-06-18 | 上海睿智化学研究有限公司 | Method for abstracting and purifying betulin in birch bark |
| CN103183587A (en) * | 2013-02-21 | 2013-07-03 | 西安力邦制药有限公司 | Novel 3,3',5,5'-tetraisopropyl-4,4'-2-diphenol crystal forms I, II and III and preparation methods thereof |
| CZ2015670A3 (en) * | 2015-09-30 | 2016-11-16 | Univerzita Karlova V Praze | Purification process of betulin and lupeol and betulin and lupeol prepared thereby |
-
2017
- 2017-12-31 CN CN201711496844.XA patent/CN109988216B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200486A (en) * | 2006-12-13 | 2008-06-18 | 上海睿智化学研究有限公司 | Method for abstracting and purifying betulin in birch bark |
| CN103183587A (en) * | 2013-02-21 | 2013-07-03 | 西安力邦制药有限公司 | Novel 3,3',5,5'-tetraisopropyl-4,4'-2-diphenol crystal forms I, II and III and preparation methods thereof |
| CZ2015670A3 (en) * | 2015-09-30 | 2016-11-16 | Univerzita Karlova V Praze | Purification process of betulin and lupeol and betulin and lupeol prepared thereby |
Non-Patent Citations (3)
| Title |
|---|
| GEORGE WYPYCH: "《溶剂手册》", 30 June 2003, 中国石化出版社 * |
| HOOSHANG PAKDEL: "Extraction of betulin by vacuum pyrolysis of birch bark", 《JOURNAL OF WOOD CHEMISTRY AND TECHNOLOGY》 * |
| PAVEL ŠIMAN: ""Effective Method of Purification of Betulin from Birch Bark: The Importance of Its Purity for Scientific and Medicinal Use"", 《PLOS ONE》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109988216B (en) | 2023-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013060258A1 (en) | Clavatine a-c, preparation method thereof and pharmaceutical composition and use thereof | |
| CN110054624A (en) | Berberine hydrochloride and caffeic acid eutectic object and preparation method and its composition and purposes | |
| CN101434593B (en) | Two crystal substances of baicalin, and preparations, pharmaceutical composition and uses thereof | |
| CN104844591A (en) | Tropisetron hydrochloride crystal form II substance, preparation method, composition and uses thereof | |
| US11236041B2 (en) | Type-G crystal form of fenolamine, preparation method, composition and use thereof | |
| CN101747305A (en) | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof | |
| US11059773B2 (en) | Type-B fenolamine crystal form, preparation method, composition and use thereof | |
| CN101899041B (en) | Superior medicinal crystal-form solid substance of puerarin as well as preparation method and application thereof | |
| CN113214207B (en) | Hesperetin and betaine eutectic A, preparation method, composition and application thereof | |
| CN109988216A (en) | Betulin crystalline substance D type substance and preparation method and its composition and purposes | |
| CN109988104A (en) | Kaempferol and Pyrazinamide eutectic object and preparation method and its pharmaceutical composition and purposes | |
| CN113214209B (en) | Hesperetin and carbamazepine eutectic, preparation method, composition and application thereof | |
| CN109988215A (en) | Betulin crystal B-type substance and preparation method and its composition and purposes | |
| CN109988214A (en) | Betulin crystal C type substance and preparation method and its composition and purposes | |
| CN109721557A (en) | Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes | |
| CN113214208A (en) | Hesperetin and isonicotinamide eutectic crystal, preparation method, composition and application thereof | |
| CN113214206B (en) | Hesperetin and betaine eutectic substance B, preparation method, composition and application thereof | |
| CN111662355B (en) | Mifepristone crystal W-type solid matter, preparation method, pharmaceutical composition and application thereof | |
| CN111662354B (en) | Mifepristone crystal N-type solid matter, preparation method, pharmaceutical composition and application thereof | |
| CN113214065B (en) | Gossypol crystal III substance, preparation method, composition and application thereof | |
| CN113214066B (en) | Gossypol crystal II substance, preparation method, composition and application thereof | |
| CN105237607B (en) | Uliprista acetate crystalline substance K-type substance and preparation method and its composition and purposes | |
| CN101899052B (en) | B-crystal form solid matter of bergenin and preparation method and application thereof | |
| CN108239079B (en) | Mangiferin crystal V-shaped substance, preparation method, composition and application thereof | |
| CN109721558A (en) | Letrozole crystalline substance type III solid matter and preparation method and its pharmaceutical composition and purposes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |