CN109988215A - Betulin crystal B-type substance and preparation method and its composition and purposes - Google Patents
Betulin crystal B-type substance and preparation method and its composition and purposes Download PDFInfo
- Publication number
- CN109988215A CN109988215A CN201711496821.9A CN201711496821A CN109988215A CN 109988215 A CN109988215 A CN 109988215A CN 201711496821 A CN201711496821 A CN 201711496821A CN 109988215 A CN109988215 A CN 109988215A
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- Prior art keywords
- betulin
- crystal
- solid matter
- type
- type solid
- Prior art date
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- MVIRREHRVZLANQ-UHFFFAOYSA-N betulin Natural products CC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5C(CCC5(CO)CCC34C)C(=C)C)C1(C)C MVIRREHRVZLANQ-UHFFFAOYSA-N 0.000 title claims abstract description 150
- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 title claims abstract description 148
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- 210000001215 vagina Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
- A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Botany (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses the crystal B-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 betulin in the solid state, there are crystal B-type solid matter stastus formats；The preparation method of crystal B-type solid matter sample；Various anti-inflammatory, antiviral, anticancer, anti-diabetic and/or Antiatherosclerosis medicine are being prepared using betulin crystal B-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 crystal B-type solid matter stastus format in the solid state；
It is related to having invented the preparation method of crystal B-type；It is related to having invented containing betulin crystal B-type or containing any non-zero proportions crystal B-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 " " Isostructurality Among 5Solvatomorphs of Betulin:X-Ray
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 4New 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 crystal B-type solid matter state and preparation methods, it was found that betulin
Crystal B-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 crystal B-type solid matter existence that betulin is new and
Characteristic manner.
The second technical problem to be solved by the present invention: the preparation method of betulin crystal B-type solid matter is provided.
The third technical problem to be solved by the present invention: it provides containing betulin crystal B-type sterling or contains any non-zero ratio
The solid drugs and combinations thereof of the mixing crystal form of example crystal B-type.
The four of the technical problem to be solved in the present invention: offer uses betulin crystal B-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 crystal B-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 crystal B-type sample morphology feature of betulin:
1.1 betulin crystal B-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 crystal B-type material sample of table
1.2 betulin crystal B-type solid matters of the present invention, using decaying total reflection Fourier transform infrared spectrometry into
When row analysis, 3363,3083,2940,2868,2650,2321,1768,1645,1485,1462,1451,1387,1374,
1360、1338、1300、1278、1244、1212、1188、1159、1131、1106、1083、1069、1026、984、971、944、
932、913、898、881、804、765、747、688cm-1There are infrared spectroscopy characteristic peak, middle infrared spectrum characteristic peaks to permit at place
Perhaps deviation is ± 2cm-1(Fig. 2).
1.3 betulin crystal B-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 204 DEG C ± 3 DEG C, 260 DEG C
There are 2 endothermic peaks at ± 3 DEG C.(Fig. 3)
1.4 betulin crystal B-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 B containing any non-zero proportions
Type material composition.
2. the preparation method characteristic of betulin crystal B-type material sample and mixed crystal:
The preparation method of 2.1 betulin crystal B-type solid matters of the present invention, which is characterized in that use white birch rouge
Betulin solvate sample is placed on 160 DEG C of -170 DEG C of temperature down toward complete by any one or more of alcohol solvate
Full removal solvent, prepares the crystal B-type solid matter of betulin, wherein the betulin solvate is selected from first
Alcohol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, pyridine and water, N,N-Dimethylformamide, nitrogen nitrogen dimethylacetamide
The solvate of amine and/or dimethyl sulfoxide.
2.2 betulin mixing crystal form solid matters of the invention, are the betulin crystalline substance B 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. containing white birch
Pharmaceutical preparations composition, dosage feature and the pharmaceutical applications of lipidol crystal form ingredient:
3.1 pharmaceutical compositions of the present invention, contain betulin crystal B-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 crystal B-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 crystal B-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 B 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 crystal B-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 crystal B-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 crystal B-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 crystal B-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 crystal B-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 crystal B-type ingredient, betulin mixing crystal form solid matter tablet of the present invention
Agent, glidant kind can also be used for preparing betulin crystal B-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 crystal B-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 crystal B-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 crystal B-type solid matters have dissolubility advantageous characteristic
The dissolubility of betulin crystal B-type solid matter of the invention in 0.5%SDS aqueous solution is substantially better than known
The rate of dissolution of crystal type A (marketable material contains recrystallisation solvent), crystal B-type has marked improvement compared with crystal type A, and its solubility is about crystalline substance A
1.5 times or more of type have significant dissolubility advantageous characteristic.
4.2 betulin crystal B-type solid matters have stability advantage feature
Betulin crystal B-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 crystal B-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 crystal B-type material sample is composed
The infrared absorpting light spectra of Fig. 2 betulin crystal B-type material sample
The DSC map of Fig. 3 betulin crystal B-type material sample
The TG map of Fig. 4 betulin crystal B-type material sample
Fig. 5 betulin crystal B-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 crystal B-type material sample:
Betulin sample is completely dissolved under 20 DEG C of normal temperature states using alcohol solvent, the condition for being 10 DEG C in temperature
Under obtain the ethanol solvate of betulin, the preparation of 1 hour removal solvent is placed under the conditions of which is placed in 160 DEG C
Betulin solid sample is obtained, powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, shows gained sample
Product are betulin crystal B-type solid matter.
The preparation method 2 of betulin crystal B-type material sample:
Betulin sample is completely dissolved under 20 DEG C of normal temperature states using N,N-Dimethylformamide (DMF) solvent,
The DMF solvent that betulin is obtained under conditions of temperature is 10 DEG C closes object, which is placed under the conditions of 160 DEG C and is placed
Removal solvent prepares betulin solid sample within 1 hour, carries out powder x-ray diffraction analysis to it, diffracting spectrum with
Fig. 1 is consistent, shows that gained sample is betulin crystal B-type solid matter.
The preparation method 3 of betulin crystal B-type material sample:
Betulin sample is completely dissolved under 20 DEG C of normal temperature states using isopropanol solvent, the item for being 10 DEG C in temperature
The iso-propanol solvate that betulin is obtained under part places 1 hour removal solvent under the conditions of the solvate is placed in 160 DEG C
Betulin solid sample is prepared, powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, shows institute
Obtaining sample is betulin crystal B-type solid matter.
The preparation method 4 of betulin crystal B-type material sample:
Betulin sample is completely dissolved under 20 DEG C of normal temperature states using normal propyl alcohol solvent, the item for being 10 DEG C in temperature
The n-propanol solvate that betulin is obtained under part places 1 hour removal solvent under the conditions of the solvate is placed in 160 DEG C
Betulin solid sample is prepared, powder x-ray diffraction analysis is carried out to it, diffracting spectrum is consistent with Fig. 1, shows institute
Obtaining sample is betulin crystal B-type solid matter.
Embodiment 2
Betulin crystal B-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 crystal B-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 crystal B-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 crystal B-type solid matter in illumination shadow
It rings and stablizes under factorial experiments.
Stability test the result shows that, betulin crystal B-type have stability advantage.
Embodiment 3
Betulin crystal B-type solid matter dissolubility feature:
Using 0.5%SDS aqueous solution as solvent, the dissolution sex differernce that betulin investigates crystal B-type and crystal type A is investigated, knot
Fruit shows that crystal B-type solubility is substantially better than crystal type A, sees Fig. 5.
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 crystal B-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 crystal B-type substance of this patent it can be seen from experimental data molten
Sexual clorminance is solved, embodying has better rate of dissolution and solubility, and solubility is about 1.5 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 crystal B-type substance sterling or containing appoint
The mixed crystal solid matter of meaning ratio crystal B-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 crystal B-type substance sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystal B-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 crystal B-type substance sterling or containing appoint
The mixed crystal solid matter of meaning ratio crystal B-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 crystal B-type substance sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystal B-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 crystal B-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 crystal B-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 crystal B-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 5Solvatomorphs
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
4New 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 crystal B-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 crystal B-type solid matter according to claim 1, which is characterized in that use decaying total reflection Fourier
When leaf infra-red sepectrometry is analyzed, 3363,3083,2940,2868,2650,2321,1768,1645,1485,1462,
1451、1387、1374、1360、1338、1300、1278、1244、1212、1188、1159、1131、1106、1083、1069、
1026、984、971、944、932、913、898、881、804、765、747、688cm-1There are infrared spectroscopy characteristic peaks at place, wherein
The tolerance of infrared spectroscopy characteristic peak is ± 2cm-1。
3. betulin crystal B-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 204 DEG C in DSC map
There are 2 endothermic peaks at ± 3 DEG C, 260 DEG C ± 3 DEG C.
4. betulin crystal B-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, as the decomposition weightlessness step of betulin.
5. the preparation method of betulin crystal B-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 sample is placed on 160 DEG C of -170 DEG C of temperature
Degree prepares the crystal B-type solid matter of betulin down toward solvent is completely removed, wherein the betulin solvate
Selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, pyridine and water, N,N-Dimethylformamide, nitrogen nitrogen diformazan
The solvate of yl acetamide and/or dimethyl sulfoxide.
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 crystal B-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
Type B 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 crystal B-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 |
|---|---|---|---|
| CN201711496821.9A CN109988215A (en) | 2017-12-31 | 2017-12-31 | Betulin crystal B-type substance and preparation method and its composition and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496821.9A CN109988215A (en) | 2017-12-31 | 2017-12-31 | Betulin crystal B-type substance and preparation method and its composition and purposes |
Publications (1)
| Publication Number | Publication Date |
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| CN109988215A true CN109988215A (en) | 2019-07-09 |
Family
ID=67110186
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711496821.9A Pending CN109988215A (en) | 2017-12-31 | 2017-12-31 | Betulin crystal B-type substance and preparation method and its composition and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109988215A (en) |
-
2017
- 2017-12-31 CN CN201711496821.9A patent/CN109988215A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| GEORGE WYPYCH: "《溶剂手册》", 30 June 2003, 中国石化出版社 * |
| HOOSHANG PAKDEL: "Journal of Wood Chemistry and Technology", 《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》 * |
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