CN106543256A - Stable shellfish cholic acid compound difficult to understand - Google Patents
Stable shellfish cholic acid compound difficult to understand Download PDFInfo
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- CN106543256A CN106543256A CN201510604113.7A CN201510604113A CN106543256A CN 106543256 A CN106543256 A CN 106543256A CN 201510604113 A CN201510604113 A CN 201510604113A CN 106543256 A CN106543256 A CN 106543256A
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to one hydrated compound of shellfish cholic acid difficult to understand, the shellfish cholic acid hydrate difficult to understand that the present invention is obtained, containing a crystallization water, has the advantage that：Purity is high, good stability, even if moisture absorption weightening is not also obvious under high humidity conditions.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to shellfish cholic acid hydrate difficult to understand and preparation method thereof.
Background technology
Shellfish cholic acid (Obeticholic Acid) difficult to understand also known as 6- ethyl chenodeoxycholic acids, are chenodesoxycholic acids in people's primary bile acid（CDCA）A kind of new derivatives, be method Buddhist nun's ester derivant X acceptors（FXR）Native ligand.
Shellfish cholic acid difficult to understand is researched and developed successfully by Intercept drugmakers of the U.S., is first over 20 years research and development for treating the medicine of cholestatic liver disease.Study for those to the inabundant response of old plant medicine urso or intolerable patient.In the phase iii clinical trial of placebo, shellfish cholic acid difficult to understand（OCA）Improve the level of two related to liver transfer operation risk reduction biomarker.The composite end points of clinical research are that alkaline phosphatase at least declines 15%, 1.67 times less than ULN of the activity of serum alkaline phosphatase, and bilirubin is in normal range (NR), and alkaline phosphatase is used to indicate that a kind of biomarker of the liver diseases order of severity.Its structural formula is as follows：
Shellfish cholic acid structural formula difficult to understand
Through studying to shellfish cholic acid difficult to understand, a kind of new shellfish cholic acid hydrate crystal difficult to understand of the present invention has the advantage that the present inventor：Purity is high, and maximum contaminant is less than 1 ‰；Good stability, even if moisture absorption weightening is not also obvious under high humidity conditions.
The content of the invention
One object of the present invention, discloses a kind of shellfish cholic acid monohydrate difficult to understand.
Another object of the present invention, discloses the preparation method of shellfish cholic acid monohydrate difficult to understand.
A further object of the present invention, discloses the pharmaceutical composition comprising shellfish cholic acid monohydrate difficult to understand.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of shellfish cholic acid monohydrate difficult to understand（Shown in formula I）,
（Ⅰ）
Karl_Fischer method（Karl Fischer methods）In being a kind of all kinds of chemical methodes for determining moisture in material, method the most single-minded to water, the most accurate has been listed in the standard method of determination of moisture in many materials, especially organic compound, reliable results.6 batches of Jing are determined, and the moisture that described invention compound contains is between 3.25% -5.26% (percentage by weight).In shellfish cholic acid times semihydrate difficult to understand, the theoretical content of water is 4.10%, it can be assumed that invention compound contains a crystallization water.
The shellfish cholic acid monohydrate crystal difficult to understand, is determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values.
In the present invention, the measure of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational error range, and its error range is ± 0.2 °.
Another object of the present invention, discloses the preparation method of shellfish cholic acid hydrate crystal difficult to understand, by shellfish cholic acid difficult to understand in the dissolving of acetone-acetonitrile-heated in water solution, to naturally cool to room temperature, then is incubated a period of time and obtains.
Specifically include the following steps：Shellfish cholic acid difficult to understand adds 4-5 times（Weight or measurement (WM) ratio）Acetone-acetonitrile-water=5-6：3-4：In the mixed liquor of 2-1,70 DEG C -75 DEG C are heated to, are filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hours, separate out crystallization, filtered, drying is obtained.
Shellfish cholic acid difficult to understand used can be readily obtained by commercial sources.
A further object of the present invention, there is provided the composition comprising shellfish cholic acid hydrate crystal difficult to understand and the shellfish cholic acid hydrate difficult to understand of one or more pharmaceutically acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.
The active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount can be specifically applied according to the situation of the state of an illness of patient, diagnosis, the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is the 1%～40% of composition（Weight）.
Stability test
Inventor is studied to the chemical stability of the crystal formation of the present invention, and investigation condition is high temperature（60℃±2℃）, strong illumination（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under high light, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, and illustrate that chemical stability is good, are adapted to the manufacture and long term storage of pharmaceutical preparation.
At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, the measure of moisture in hydrate crystal of the present invention：
As a result：At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, water tariff collection is constant, and explanation has good stability, and is adapted to the manufacture and long term storage of pharmaceutical preparation.
At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, the measure of moisture in shellfish cholic acid difficult to understand：
As a result：At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, shellfish cholic acid difficult to understand has moisture absorption to increase weight, to moist lability.
Specific embodiment：
With reference to embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from the present invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
In the present invention, shellfish cholic acid difficult to understand used is obtained from commercial channels, purity 99.1% (HPLC normalization methods), its chemical constitution Jing proton nmr spectra, elementary analysis confirmation, it was demonstrated that chemical constitution is correct.
It is 0.22% with the moisture that Karl_Fischer method is measured.
Embodiment
1
In equipped with stirring, thermometer, the 2000ml reaction bulbs of condenser, the acetone-acetonitrile-water of 200 Ke Aobei cholic acid and 1000ml is added（6：4：2）Mixed liquor, starts stirring, is heated to 70 DEG C -75 DEG C, treats all molten clear, filters while hot.Filtrate naturally cools to room temperature, then is incubated 8 hours, separates out crystallization, filters, Jing indoor seasonings, obtains 181.6 grams of shellfish cholic acid white crystals difficult to understand, and fusing point is 183.1 DEG C -184.6 DEG C, content 99.86%.Jing Karl_Fischer methods are determined, the moisture containing 4.10% (percentage by weight).
INSTRUMENT MODEL and condition determination：2500 type diffractometers of Rigaku D/max； CuKa 40Kv 100mA;2 θ sweep limits：0-50°。
Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.Only citing is illustrated, and is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
2
Tablet containing shellfish cholic acid monohydrate difficult to understand
Prescription：100 grams of shellfish cholic acid monohydrate difficult to understand, 160 grams of lactose, 25 grams of PEG-4000,6 grams of magnesium stearate, 30 grams of PVP K30s, 33 grams of Ac-Di-Sol distill appropriate amount of water, make 1000.
Technique：PEG-4000 is crushed jointly with shellfish cholic acid monohydrate difficult to understand, crosses 80 mesh sieves, and with distilled water softwood after mixing with other materials, the pelleting of 16 mesh sieves is mixed in adding dry particl in 40-45 DEG C of drying, 16 mesh sieve whole grains, magnesium stearate in putting drying box, compressing tablet.
Claims (5)
1. shellfish cholic acid compound difficult to understand shown in formula I,
（Ⅰ）
Determined with Karl_Fischer method, the hydrate contains the moisture of 3.25% -5.26% (percentage by weight)；
The crystal of the shellfish cholic acid hydrate difficult to understand, in being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction and D values,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of shellfish cholic acid hydrate crystal difficult to understand described in claim 1, by by shellfish cholic acid difficult to understand in acetone-acetonitrile-aqueous solution heating for dissolving, naturally cool to room temperature, then be incubated a period of time and obtain.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Shellfish cholic acid difficult to understand adds 4-5 times of weight/volume acetone-acetonitrile-water=5-6：3-4：In the mixed liquor of 2-1,70 DEG C -75 DEG C are heated to, are filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hours, separate out crystallization, filtered, drying is obtained.
4. the composition of the shellfish cholic acid hydrate difficult to understand of a kind of shellfish cholic acid hydrate crystal difficult to understand containing described in claim 1 and one or more pharmaceutically acceptable carrier composition.
5. 4 required by right described in shellfish cholic acid hydrate difficult to understand composition, it is characterised in that said composition be used for prepare oral formulations.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510604113.7A CN106543256A (en) | 2015-09-22 | 2015-09-22 | Stable shellfish cholic acid compound difficult to understand |
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| CN201510604113.7A CN106543256A (en) | 2015-09-22 | 2015-09-22 | Stable shellfish cholic acid compound difficult to understand |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
| CN109280071A (en) * | 2017-07-19 | 2019-01-29 | 东莞东阳光药物研发有限公司 | The crystal form and preparation method thereof of shellfish cholic acid difficult to understand |
-
2015
- 2015-09-22 CN CN201510604113.7A patent/CN106543256A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109280071A (en) * | 2017-07-19 | 2019-01-29 | 东莞东阳光药物研发有限公司 | The crystal form and preparation method thereof of shellfish cholic acid difficult to understand |
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
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Application publication date: 20170329 |