CN108129371A - Calcifediol and vitamin D3Eutectic, preparation method and application - Google Patents
Calcifediol and vitamin D3Eutectic, preparation method and application Download PDFInfo
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- CN108129371A CN108129371A CN201810129038.7A CN201810129038A CN108129371A CN 108129371 A CN108129371 A CN 108129371A CN 201810129038 A CN201810129038 A CN 201810129038A CN 108129371 A CN108129371 A CN 108129371A
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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Abstract
The present invention relates to a kind of calcifediol and vitamin Ds3Eutectic, preparation method and application.In the eutectic, calcifediol and vitamin D3Molar ratio be 1:1.With X ray single crystal diffractions, X ray powder diffractions, thermogravimetric analysis, the means such as scanning thermometric analysis, infrared spectrum analysis are checked and verify to calcifediol and vitamin D3Eutectic carried out comprehensive characterization, it is found that the eutectic can significantly improve vitamin D under illumination condition3Chemical stability.The calcifediol and vitamin D3Eutectic preparation method it is simple, repeat prepare.
Description
Technical field
The present invention relates to pharmaceutical chemistry and crystallization processes technical field, and in particular, to calcifediol and vitamin D3's
Eutectic and preparation method and application.
Background technology
When two kinds and more than drug in combined clinical in use, can generally select exploitation into compound to improve compliance.
But since two or more active constituents (active pharmaceutical ingredient, API) are objects in compound medicine
Reason mixing, brings various problems：(a) the quality control standard problem of APIs.Although two or more of compound medicine
API is mixed in a certain ratio, but the reproducibility of its content standard is poor；Because being physical mixed, the X- of different compounds
The response of ray powder diffraction has difference, can not even more establish crystal form standard.(b) in production process APIs dispersion problem.
APIs contained by the drug products of per unit dose is only milligram even microgram rank, is difficult the ratio of control API in production process.
(c) storage problem of bulk pharmaceutical chemicals.Its stability of the active constituent of physical mixed is more more unstable than single component.It is and logical hypereutectic
Two or more API are prepared into supermolecule by method by weak interaction, can well solve current compound medicine band
The problem of coming.And drug-drug eutectic may have higher dissolution rate and bioavilability than physical mixed.
Drug cocrystallization refers to active constituents of medicine and other physiologically acceptable ligand (Co-crystal Co-
Former, CCF), such as acid, alkali, salt, non-ionic compound molecule are with hydrogen bond, pi-pi accumulation effect, Van der Waals force and other are non-
Covalent bond is connected and is incorporated in same lattice.Wherein API and CCF is solid at room temperature, and exists between each component and fix
Stoichiometric ratio.The formation of cocrystallization does not need to generate new covalent bond between API and CCF or molecule is destroyed,
Self assembly after only binary or multicomponent mixture rearrange.The advantage of cocrystallization is that host molecule API can be not only acid
Property or alkali molecules or non-ionized molecules；And the selection of CCF is also very much, including food additives, preservative, medicine
With auxiliary material, minerals, vitamin, amino acid, it might even be possible to be other API.Drug formed cocrystallization after pharmacological action not by
It influences, but physicochemical property is improved.By forming cocrystallization, its crystal form on the one hand can be greatly enriched, on the other hand
Its physico-chemical property and clinical efficacy can be improved.
Calcifediol (Calcifediol), chemistry are entitled：(5Z, 7E) -9,10- open loops cholesteric -5,7,10 (19)-triolefin -
3 β, 25- glycol, molecular formula C27H44O2, water (2.2ug/mL) is practically insoluble in, is soluble in organic solvent.Its monohydrate is
White crystalline powder, structural formula are as follows：
Vitamin D3(Vitamin D3), chemistry is entitled：9,10- open loop cholesterics -5,7,10 (19)-triolefin -3- alcohol, molecule
Formula is C27H44O.Structure is as follows：
Vitamin D is a kind of indispensable liposoluble vitamin of human body, after vitamin D enters in vivo, first passes around dimension
Raw element binding protein combines, and is transported to liver, under the action of CYP2R1 enzymes, is converted into calcifediol.Calcifediol is dimension life
The main storage forms of plain D in vivo, and can be detected in blood plasma, so calcifediol level is used for evaluating in blood plasma
Whether be deficient in vitamin D in vivo.Calcifediol is further metabolized in kidney, curing three of the generation with maximum bioactivity
Alcohol, and be combined with vitamin D receptor, it is transported to each target organ.Calcitriol and parathyroid hormone, calcitonin together,
The calcium phosphorus balance of blood plasma is adjusted, prevents rickets and osteomalacia.Vitamin D activities ingredient can also increase bone density, drop
The effects that low cardiovascular and cerebrovascular risk.
At present often by calcifediol and vitamin D in Clinical practice3Combination, can quickly and significantly improve blood plasma
The level of middle calcifediol achievees the purpose that improve internal vitamin D level to treat osteoporosis.But various rule in use
The vitamin D of lattice3With calcifediol it is difficult to which Proper Match uses, and patient's poor compliance.
Present inventor is directed to clinical calcifediol and vitamin D3Be combined bring poor compliance the problem of, pass through by
It is 1 that the two, which leads to hypereutectic technological means to have synthesized molar ratio,:1 compound achievees the purpose that improve patient's compliance.This is common
Crystalline substance avoids the problem that bringing using physical mixed, and significantly improves vitamin D under illumination condition3Chemical stability.
Invention content
It is an object of the present invention to provide a kind of calcifediol and vitamin Ds3Eutectic.
The second object of the present invention is to provide a kind of calcifediol and vitamin D3Eutectic preparation method.
The third object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition includes above-mentioned calcifediol
With vitamin D3Eutectic and pharmaceutically acceptable carrier.
The fourth object of the present invention is to provide a kind of calcifediol and vitamin D3Eutectic it is each for treating preparing
The chronic bone of kind is disorderly, adult's 3-4 phases chronic kidney disease (CKD) secondary hyperparathyroidism (SHPT) and vitamin
It is applied in the drug of D deficiency diseases.
According to the first aspect of the invention, a kind of calcifediol and vitamin D are provided3Eutectic, wherein described ossified
Glycol and vitamin D3Eutectic in, calcifediol and vitamin D3Molar ratio be 1:1.
The calcifediol and vitamin D3Eutectic X-ray powder diffraction collection in 2 θ angles be about 11.18 ±
There is characteristic peak at 0.2,12.08 ± 0.2,15.15 ± 0.2,15.53 ± 0.2,16.62 ± 0.2,18.80 ± 0.2 °.
Preferably, the calcifediol and vitamin D3Eutectic X-ray powder diffraction collection in 2 θ angles about
Be 11.18 ± 0.2,12.08 ± 0.2,14.05 ± 0.2,15.15 ± 0.2,15.53 ± 0.2,16.62 ± 0.2,17.30 ±
0.2,17.86 ± 0.2,18.24 ± 0.2,18.80 ± 0.2,19.26 ± 0.2,20.06 ± 0.2,20.88 ± 0.2,21.19 ±
Have at 0.2,21.77 ± 0.2,22.65 ± 0.2,23.51 ± 0.2,24.34 ± 0.2,25.32 ± 0.2,26.30 ± 0.2 °
Characteristic peak.
Preferably, the calcifediol and vitamin D3Eutectic X-ray powder collection of illustrative plates, have substantially as attached
XRPD collection of illustrative plates shown in FIG. 1.
Due to the difference of measuring condition, each 2 θ angles of peak and relative intensity can be changed on XRPD diffraction patterns, general 2 θ angles
Variation also can slightly overflow the range within ± 0.2 °, it will be understood by those skilled in the art that the relative intensity of diffraction can depend on
In for example, sample formulation or device therefor.
Preferably, the calcifediol and vitamin D3Eutectic, the calcifediol and vitamin D3Eutectic
Check and verify scanning amount Thermal Chart has feature melting peak about 106.51 ± 2 DEG C (onset temperature).It is highly preferred that the bone
Change glycol and vitamin D3Eutectic have differential scanning calorimetric analysis (DSC) collection of illustrative plates substantially as shown in Figure 4.
Preferably, the calcifediol and vitamin D3Eutectic infrared spectrum at least about 3334,2954,
2938、2863、2847、1811、1646、1630、1603、1470、1438、1411、1374、1353、1320、1304、1277、
1246、1203、1165、1091、1059、1037、994、941、883、856、840、770、712、653、562cm-1Place has spy
Levy peak.
According to the second aspect of the invention, a kind of calcifediol and vitamin D are provided3Eutectic preparation method, institute
The method of stating includes the following steps：
(a) calcifediol and vitamin D are weighed respectively3Powder；
(b) powder in step (a) is dissolved in organic solvent, forms calcifediol and vitamin D3Unsaturated solution；
(c) the unsaturated solution volatilization concentration obtained step (b) or cooling crystallization；
(d) calcifediol and vitamin D formed in separating step (c)3Eutectic, obtain calcifediol and vitamin D3
Eutectic；
Preferably,
In step (b), the organic solvent is selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, isoamyl alcohol, acetonitrile, first
One or more of ethyl ketone, ethyl acetate, methyl iso-butyl ketone (MIBK), preferably acetonitrile；
In step (a), the calcifediol and vitamin D3Powder molar ratio fluctuated in certain range pair
The quality of eutectic is without influence, this ranging from 1.2:1~1:1.2, preferably 1.1:1~1:1.1, more preferably 1.05:1~1:
1.05, most preferably 1:1.
In step (c), the cooling is to be cooled to 0~-20 degrees Celsius from room temperature, is preferably cooled to -10~-20 and takes the photograph
Family name's degree.
In step (c), the volatilization is volatilizees at room temperature.
In step (d), the separation is selected from one of following methods：
(d1) by filtering, so as to obtain calcifediol and vitamin D3Eutectic；Or
(d2) by centrifuging and filtering, so as to obtain calcifediol and vitamin D3Eutectic；Or
(d3) calcifediol and vitamin D are being detached using (d1) or (d2) step3Eutectic after, further evaporate
Liquid solution isolated in (d1) or (d2) step is removed, so as to obtain calcifediol and vitamin D3Eutectic.
Heretofore described room temperature is 25 ± 5 DEG C.
The third aspect of the present invention is related to a kind of pharmaceutical composition, and described pharmaceutical composition includes calcifediol and vitamin
D3Eutectic and pharmaceutically acceptable carrier.
The fourth aspect of the present invention is related to a kind of calcifediol and vitamin D3Eutectic and/or drug as described above
Composition is disorderly for treating various chronic bones preparing, the secondary parathyroid gland work(of adult's 3-4 phases chronic kidney disease (CKD)
It is applied in energy hyperfunction (SHPT) or the drug of vitamin D deficiency.
Advantageous effect
The present invention provides a kind of for clinical calcifediol and vitamin D3It is combined the solution of poor compliance problem brought
Scheme is 1 by leading to hypereutectic technological means to have synthesized molar ratio the two:1 compound reaches and improves patient's compliance
Purpose, which avoids the problem of being brought using physical mixed.Calcifediol and vitamin D3Eutectic, preparation method
Simply, it is reproducible, it can obtain higher crystallinity.Compared to vitamin D3For, under identical illumination condition, Ke Yiti
Vitamin D in high eutectic3Stability.Vitamin D3For adjusting internal calcium phosphorus balance, prevention and treatment osteoporosis tool
There is very big curative effect.But the outside environmental elements such as illumination, oxygen, temperature can be to vitamin D3Stability generate very big shadow
It rings.Under illumination condition, vitamin D3It can chemically react rapidly, go bad and generate other inactive ingredients, these ingredients
The effect for the treatment of osteoporosis is not only not achieved, some side reactions can be caused instead, a degree of damage is generated to body.Cause
This, this calcifediol and vitamin D provided by the invention3Eutectic, it is poor both both to have solved combined clinical medication compliance
The problem of, and significantly increase vitamin D3Chemical stability.
Description of the drawings
Fig. 1 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic X-ray powder diffraction (XRPD) figure；
Fig. 2 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic mono-crystalline structures (S-CXRD) figure；
Fig. 3 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic thermogravimetric analysis (TG) figure；
Fig. 4 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic differential scanning calorimetric analysis (DSC)
Figure；
Fig. 5 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic infrared spectrum (IR) figure；
Fig. 6 is the calcifediol and vitamin D of the embodiment of the present invention 13Eutectic and vitamin D3Bulk pharmaceutical chemicals contain compared to residue
Amount.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated, but does not limit the present invention.
Detecting instrument and method：
Instrument used in X-ray powder diffraction (XRPD) is Bruker D8Advance diffractometer, is adopted
With Cu K alpha rays, (line is used), voltage is 40 kilovolts, and electric current is 40 milliamperes.Instrument is carried before use with instrument
Standard sample correction peak position.Acquisition software is Diffrac Plus XRD Commander, and analysis software is MDI Jade
6.0.Sample is tested at ambient temperature, and the sample that needs detect is placed on organic slide.Detailed testing conditions are as follows：2 θ angles
Spend range：3~40 °；Step-length：0.02°；Speed：0.1 second/step.Unless stated otherwise, sample is not ground before detection.
Thermogravimetric analysis (TGA) data are picked up from German Nai Chi scientific instrument Co., Ltd TG20F3 types, instrument control software
It is NETZSCH-Proteus-6, analysis software is Proteus Analysis.With the heating rate of 10 DEG C/min in 50mL/min
Sample is risen to 400 DEG C, while weight of the software records sample in temperature-rise period becomes from room temperature under the protection of dry drying nitrogen
Change.
Differential scanning calorimetric analysis (DSC) data are picked up from TA instrument companies of U.S. DSC Q2000 differential scanning calorimeters,
Instrument control software is ThermalAdvantage, and analysis software is Universal Analysis.With the heating of 10 DEG C/min
Sample is risen to 200 DEG C, while TA software records sample is heating up by speed under the protection of 50mL/min drying nitrogens from room temperature
Thermal change in the process.
Infrared analysis (IR) using U.S. Buddhist nun high-tensile strength company 750 infrared spectrometric analyzers of Nicolet-Magna FT-IR
It is detected in room temperature, detection range is：4000-350cm-1Wave number.
The reagents such as methanol are that analysis is pure, are provided by Sinopharm Chemical Reagent Co., Ltd., agents useful for same and solvent remove
It is by especially handling outside illustrating.Calcifediol, vitamin D3Bulk pharmaceutical chemicals purchase from this Reagent Company of Adama,
Purity is more than 99%.All temperature represent that room temperature refers to 20~25 DEG C with DEG C (degree Celsius).
Room temperature in embodiment is 25 degrees Celsius.
Embodiment 1
Calcifediol and vitamin D3Eutectic
At ambient temperature, calcifediol (20.32g) and vitamin D are weighed respectively3(19.23g) powder, is completely dissolved
In 500mL acetonitrile solutions, calcifediol and vitamin D are formed3Unsaturated solution.This unsaturated solution is cooled down from room temperature
To -20 degrees Celsius, after standing 24 hours, just there are calcifediol and vitamin D3Eutectic powder be precipitated.To the suspension into
Row centrifugation and filtering, obtain calcifediol and vitamin D3Eutectic (31.35g).
To calcifediol obtained and vitamin D3Eutectic spread out using X-ray powder diffraction (XRPD), X-ray monocrystalline
(S-CXRD), thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC) and infrared (IR) spectrum is penetrated to be characterized.
X-ray powder diffraction collection analysis result is shown in attached drawing 1, and X-ray single crystal diffraction analysis result is shown in attached drawing 2, thermogravimetric
Analysis result is shown in Fig. 3, and differential scanning calorimetric analysis result is shown in attached drawing 4, and infrared analysis result is shown in attached drawing 5.
Embodiment 2
At ambient temperature, calcifediol (30.48g) and vitamin D are weighed respectively3(28.85g) powder, is completely dissolved
In 700mL acetonitrile solutions, calcifediol and vitamin D are formed3Unsaturated solution.This unsaturated solution is cooled down from room temperature
To -20 degrees Celsius, after standing 24 hours, just there are calcifediol and vitamin D3Eutectic powder be precipitated.To the suspension into
Row centrifugation and filtering, obtain calcifediol and vitamin D3Eutectic (47.46g).
Embodiment 3
At ambient temperature, calcifediol (16.26g) and vitamin D are weighed respectively3(15.38g) powder, is completely dissolved
In 300mL acetonitrile solutions, calcifediol and vitamin D are formed3Unsaturated solution.This unsaturated solution is positioned over room temperature
Under the conditions of constantly volatilization concentration, be precipitated crystal, so as to obtain calcifediol and vitamin D3Eutectic.Centrifugal filtration obtains bone
Change glycol and vitamin D3Eutectic (24.63g).
Embodiment 4
At ambient temperature, calcifediol (36.58g) and vitamin D are weighed respectively3(34.62g) powder, is completely dissolved
In 500mL methanol solutions, calcifediol and vitamin D are formed3Unsaturated solution.This unsaturated solution is cooled down from room temperature
To -20 degrees Celsius, after standing 24 hours, just there are calcifediol and vitamin D3Eutectic powder be precipitated.To the suspension into
Row centrifugation and filtering, obtain calcifediol and vitamin D3Eutectic (35.69g).
Embodiment 5
At ambient temperature, calcifediol (29.26g) and vitamin D are weighed respectively3(27.70g) powder, is completely dissolved
In 300mL methyl ethyl ketone solutions, calcifediol and vitamin D are formed3Unsaturated solution.This unsaturated solution is cold from room temperature
But to -20 degrees Celsius, after standing 24 hours, just there are calcifediol and vitamin D3Eutectic powder be precipitated.To the suspension
It is centrifuged and is filtered, obtain calcifediol and vitamin D3Eutectic (30.12g).
The calcifediol and vitamin D being prepared in embodiment 2, embodiment 3, embodiment 4 and embodiment 53Eutectic,
Pass through X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC) and infrared (IR) spectrum etc.
After Solid-state Chemistry method characterization, calcifediol and vitamin D that result is prepared with embodiment 13Eutectic it is basically identical.
Test case
Calcifediol and vitamin D3Stability of the eutectic under illumination condition compare
Given the test agent source：The calcifediol and vitamin D being prepared in embodiment 13Eutectic and purchase in Ah reaching
The calcifediol and vitamin D of Ma Si Reagent Companies3Raw material.
Experimental method is as follows：
By calcifediol and vitamin D3Eutectic and vitamin D3After bulk pharmaceutical chemicals powder mull, about 15 milligrams are weighed respectively
Sample is laid on glass plate, and is gently pressed with pan paper, is paved.It is put into drug strong illumination chamber.Sample is apart from light source
About 20cm, light interval are for a period of time afterwards sampled sample.Each sample point is detected with efficient liquid-phase chromatography method
Remaining sample content, finally obtains calcifediol and vitamin D3Eutectic and vitamin D3The light durability of bulk pharmaceutical chemicals is bent
Line.
Illumination condition：
Instrument：Drug strong illumination chamber
Intensity of illumination：5500lux
Illumination temperature：25 degrees Celsius
Sample time：0 day, 2 days, 4 days, 6 days, 8 days, 10 days
High-efficient liquid phase chromatogram determining condition condition：
Instrument：Agilent 1260
Chromatography Ultraviolet Detector model：Agilent G1315D
Chromatography two-phase pump type：Agilent G1331C
Chromatographic column:Agilent Zorbax Eclipse Plus C18 columns (4.6 × 150mm, 5 μm)
Mobile phase：Water and methanol ratio are (20:80), elution time：15 minutes
Column temperature：30 degrees Celsius
Flow velocity：1.5mL/min
Sample size：20μL
Detection wavelength：265nm
Experimental result：
Calcifediol and vitamin D3Eutectic and vitamin D3Bulk pharmaceutical chemicals compare the percentage of initial content shared by remaining content
Than seeing Fig. 6.
As shown in fig. 6, calcifediol and vitamin D that the present invention is prepared3Eutectic and vitamin D3Raw material medicine phases
Than being significantly increased in terms of light durability.
The foregoing is merely highly preferred embodiment of the present invention, are not intended to limit the invention, all essences in the present invention
God and all any modification, equivalent and improvement within principle etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of calcifediol and vitamin D3Eutectic, which is characterized in that in the eutectic, calcifediol and vitamin D3
Molar ratio be 1:1.
2. calcifediol according to claim 1 and vitamin D3Eutectic, which is characterized in that the calcifediol with
Vitamin D3Eutectic X-ray powder diffraction collection in 2 θ angles be about 11.18 ± 0.2,12.08 ± 0.2,15.15 ±
There is characteristic peak at 0.2,15.53 ± 0.2,16.62 ± 0.2,18.80 ± 0.2 °.
3. calcifediol according to claim 1 and vitamin D3Eutectic, it is characterised in that：The calcifediol with
Vitamin D3Eutectic X-ray powder diffraction collection in 2 θ angles be about 11.18 ± 0.2,12.08 ± 0.2,14.05 ±
0.2,15.15 ± 0.2,15.53 ± 0.2,16.62 ± 0.2,17.30 ± 0.2,17.86 ± 0.2,18.24 ± 0.2,18.80 ±
0.2,19.26 ± 0.2,20.06 ± 0.2,20.88 ± 0.2,21.19 ± 0.2,21.77 ± 0.2,22.65 ± 0.2,23.51 ±
There is characteristic peak at 0.2,24.34 ± 0.2,25.32 ± 0.2,26.30 ± 0.2 °.
4. calcifediol and vitamin D as described in any one of claim 1-33Eutectic, which is characterized in that the bone
Change glycol and vitamin D3Eutectic X-ray powder diffraction collection, there is X-ray powder substantially as shown in Figure 1
Diffracting spectrum.
5. calcifediol and vitamin D as described in any one of claim 1-33Eutectic, which is characterized in that the bone
Change glycol and vitamin D3The differential scanning calorimetric analysis spectrogram of eutectic have feature melting peak at about 106.51 ± 2 DEG C.
6. a kind of calcifediol and vitamin D prepared as described in any one of claim 1-53Eutectic method, feature
It is, includes the following steps：
(a) calcifediol and vitamin D are weighed respectively3Powder；
(b) powder in step (a) is dissolved in organic solvent, forms calcifediol and vitamin D3Unsaturated solution；
(c) the unsaturated solution volatilization concentration obtained step (b) or cooling crystallization；
(d) calcifediol and vitamin D formed in separating step (c)3Eutectic, obtain calcifediol and vitamin D3Be total to
It is brilliant.
7. calcifediol as described in claim 6 and vitamin D3Eutectic preparation method, it is characterised in that：
In step (b), the organic solvent be selected from methanol, ethyl alcohol, isopropanol, normal propyl alcohol, isoamyl alcohol, acetonitrile, methyl ethyl ketone,
One or more of ethyl acetate, methyl iso-butyl ketone (MIBK), preferably acetonitrile；
In step (c), the cooling is to be cooled to 0~-20 degrees Celsius from room temperature, and it is Celsius to be preferably cooled to -10~-20
Degree；The volatilization is volatilizees at room temperature.
8. calcifediol as described in claim 6 and vitamin D3Eutectic preparation method, it is characterised in that：
In step (d) separation selected from one of following methods：
(d1) by filtering, so as to obtain calcifediol and vitamin D3Eutectic；Or
(d2) by centrifuging and filtering, so as to obtain calcifediol and vitamin D3Eutectic；Or
(d3) calcifediol and vitamin D are being detached using (d1) or (d2) step3Eutectic after, further evaporative removal
(d1) isolated liquid solution or in (d2) step, so as to obtain calcifediol and vitamin D3Eutectic.
9. a kind of pharmaceutical composition, described pharmaceutical composition includes the calcifediol and dimension described in any one of claim 1-5
Raw element D3Eutectic and pharmaceutically acceptable carrier.
10. calcifediol and vitamin D as described in any one of claim 1-53Eutectic or as claimed in claim 9
For pharmaceutical composition preparing for treating chronic bone disorder, the secondary parathyroid function of adult's 3-4 phase chronic kidney disease is high
Into or the drug of vitamin D deficiency in apply.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810129038.7A CN108129371A (en) | 2018-02-08 | 2018-02-08 | Calcifediol and vitamin D3Eutectic, preparation method and application |
| CN201910100972.0A CN110128312B (en) | 2018-02-08 | 2019-01-31 | Calcifediol and vitamin D3Eutectic crystal of (1), preparation method and application thereof |
| PCT/CN2019/074059 WO2019154237A1 (en) | 2018-02-08 | 2019-01-31 | Co-crystal of calcifediol and vitamin d3, preparation method therefor and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810129038.7A CN108129371A (en) | 2018-02-08 | 2018-02-08 | Calcifediol and vitamin D3Eutectic, preparation method and application |
Publications (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651479A (en) * | 2019-02-15 | 2019-04-19 | 上海共晶医药科技有限公司 | The eutectic of calcifediol and cholesterol, preparation method and application |
| WO2019154237A1 (en) * | 2018-02-08 | 2019-08-15 | 中国科学院上海药物研究所 | Co-crystal of calcifediol and vitamin d3, preparation method therefor and use thereof |
| CN114846019A (en) * | 2019-11-25 | 2022-08-02 | 晶体工程智能研究中心公司 | Co-crystals of steroids and secosteroids and compositions containing same |
| CN115181046A (en) * | 2022-07-26 | 2022-10-14 | 中国科学院上海药物研究所 | Eutectic crystal of vitamin D3 and L-menthol and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102442991B (en) * | 2010-10-12 | 2015-03-11 | 上海睿智化学研究有限公司 | Genistein vitamin B6 eutectic crystal and crystal and preparation method thereof |
| CN103819379A (en) * | 2014-02-18 | 2014-05-28 | 中国科学院上海药物研究所 | Cholestanol co crystal of vitamin D3 and its preparation method and application |
| CN104356038B (en) * | 2014-10-15 | 2016-06-01 | 中国科学院上海药物研究所 | Eutectic of vitamin D2 and D3 and its production and use |
| CN108129371A (en) * | 2018-02-08 | 2018-06-08 | 中国科学院上海药物研究所 | Calcifediol and vitamin D3Eutectic, preparation method and application |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019154237A1 (en) * | 2018-02-08 | 2019-08-15 | 中国科学院上海药物研究所 | Co-crystal of calcifediol and vitamin d3, preparation method therefor and use thereof |
| CN109651479A (en) * | 2019-02-15 | 2019-04-19 | 上海共晶医药科技有限公司 | The eutectic of calcifediol and cholesterol, preparation method and application |
| CN109651479B (en) * | 2019-02-15 | 2021-11-16 | 中国科学院上海药物研究所 | Co-crystal of ossifying glycol and cholesterol, preparation method and application thereof |
| CN114846019A (en) * | 2019-11-25 | 2022-08-02 | 晶体工程智能研究中心公司 | Co-crystals of steroids and secosteroids and compositions containing same |
| CN115181046A (en) * | 2022-07-26 | 2022-10-14 | 中国科学院上海药物研究所 | Eutectic crystal of vitamin D3 and L-menthol and preparation method and application thereof |
| CN115181046B (en) * | 2022-07-26 | 2024-01-30 | 中国科学院上海药物研究所 | Eutectic crystal of vitamin D3 and L-menthol as well as preparation method and application thereof |
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| Publication number | Publication date |
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| CN110128312A (en) | 2019-08-16 |
| CN110128312B (en) | 2021-04-13 |
| WO2019154237A1 (en) | 2019-08-15 |
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