CN106668027A - Obeticholic acid pharmaceutical composition and preparation method thereof - Google Patents
Obeticholic acid pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN106668027A CN106668027A CN201510749221.3A CN201510749221A CN106668027A CN 106668027 A CN106668027 A CN 106668027A CN 201510749221 A CN201510749221 A CN 201510749221A CN 106668027 A CN106668027 A CN 106668027A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention discloses an obeticholic acid pharmaceutical composition and a preparation method thereof. The pharmaceutical composition contains obeticholic acid, a filler, a disintegrating agent, a binder and a lubricant. The obeticholic acid pharmaceutical composition overcomes the insolubility defect of raw material drugs, has high bioavailability and stability and can be used for treatment on primary biliary cirrhosis, non-alcoholic fatty liver, bile acid diarrhea, portal hypertension, alcoholic hepatitis, primary sclerosing cholangitis and so on.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, the present invention relates to a kind of shellfish cholic acid pharmaceutical composition difficult to understand and its preparation
Method.
Technical background
Shellfish cholic acid (Obeticholic Acid) difficult to understand also known as 6- ethyl chenodeoxycholic acid, are chenodeoxy cholic acids in people's primary bile acid
(CDCA) a kind of new derivatives, are the native ligand of method Buddhist nun's ester derivant X receptors (FXR).Shellfish cholic acid category difficult to understand
Farnesoid X receptor agonist, by activating farnesoid X receptor, suppresses the base of cytochrome 7A1 (CYP7A1) indirectly
Because of expression.Because CYP7A1 is the biosynthetic rate-limiting enzyme of cholic acid, therefore shellfish cholic acid difficult to understand can suppress cholic acid to synthesize, and be used for
Treatment primary biliary cirrhosiss and non-alcohol fatty liver.
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 cholestasis
The medicine of property hepatopathy.There is no abundant response or intolerable patient to old plant medicine ursodesoxycholic acid for those.
The chemical structural formula of shellfish cholic acid difficult to understand is as follows：
Shellfish cholic acid difficult to understand is a multi-crystalline compounds, and presently disclosed technical literature (patent WO2013192097) describes
A, C, D, G, F crystal formation and indefinite form of the shellfish cholic acid difficult to understand of Intercept drugmakers invention.
Because shellfish cholic acid difficult to understand is a kind of medicine of slightly solubility, the size of its crude drug is to the dissolution of medicine and absorbs and has weight
The impact wanted, therefore investigate shellfish cholic acid difficult to understand and be used for the particle diameter tool of preparation and have very important significance.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent or providing a kind of useful business
Select.For this purpose, it is an object of the present invention to proposing a kind of shellfish cholic acid pharmaceutical composition difficult to understand and preparation method thereof.The shellfish difficult to understand
Cholic acid pharmaceutical composition overcomes the characteristic of crude drug indissoluble, and the shellfish cholic acid pharmaceutical composition difficult to understand of the composition with higher
Bioavailability and stability, can be used for treat primary biliary cirrhosiss, non-alcoholic fatty liver disease, bile acid diarrhoea,
Portal blood pressure is too high, alcoholic hepatitis, primary sclerosing cholangitiss etc..
In one aspect of the invention, the invention provides a kind of shellfish cholic acid pharmaceutical composition difficult to understand, contains in the pharmaceutical composition
Shellfish cholic acid difficult to understand, filler, disintegrating agent, binding agent, lubricant.
Shellfish cholic acid pharmaceutical composition difficult to understand according to embodiments of the present invention overcomes the characteristic of crude drug indissoluble, improves shellfish cholic acid difficult to understand
Dissolubility and dissolution rate, so as to improve the speed and degree of drug absorption, and then improve shellfish cholic acid drug regimen difficult to understand
The bioavailability and stability of thing, and the pharmaceutical composition can be used for treatment primary biliary cirrhosiss, non-ethanol
Property fatty liver, bile acid diarrhoea, too high portal blood pressure, alcoholic hepatitis, primary sclerosing cholangitiss etc., and should
Pharmaceutical composition component is simple, and product is stable, and impurity is few.
Embodiments in accordance with the present invention, shellfish cholic acid difficult to understand can be the shellfish cholic acid microgranule difficult to understand Jing after micronization, tool of the invention
Body embodiment, the mean diameter of shellfish cholic acid microgranule difficult to understand is not particularly restricted, and those skilled in the art can be according to actual needs
Selected, specific example of the invention, the mean diameter of shellfish cholic acid microgranule difficult to understand can be 3.0～250 μm.Inventor
By carrying out micronization processes to shellfish cholic acid difficult to understand, have collected the sample of different average particle size ranges, and by wet granulation and
Technique of direct powder compression prepares different shellfish cholic acid pieces difficult to understand and carries out test and finally found that, when the average grain of shellfish cholic acid microgranule difficult to understand
Footpath can ensure that when being 3.0～250 μm and obtain a high and stable preparation of bioavailability.
According to one embodiment of present invention, the mean diameter of shellfish cholic acid microgranule difficult to understand is preferably 3.0～150 μm.Thus, it is possible to
It is further ensured that raw gained preparation has higher bioavailability and stability.According to a particular embodiment of the invention, Ao Bei
The mean diameter of cholic acid microgranule is more preferably 3.0～10 μm.Inventor has found, using the shellfish cholic acid microgranule difficult to understand of the particle size range,
The bioavailability and optimal stability of gained preparation.
Embodiments in accordance with the present invention, the particular type of shellfish cholic acid raw material difficult to understand is not particularly restricted, and those skilled in the art can
To be selected according to actual needs, according to a particular embodiment of the invention, crystal formation or unformed raw material can be adopted, specifically
, shellfish cholic acid crystal formation difficult to understand can adopt at least one in C, G, F crystal formation.Thus, it is possible to ensure gained drug regimen
Thing has higher bioavailability and stability.Specific example of the invention, preferably unformed raw material.Thus,
May further ensure that gained pharmaceutical composition has higher bioavailability and stability.
Embodiments in accordance with the present invention, the particular type of filler is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, filler can be selected from Microcrystalline Cellulose, Lactose, pre-
At least one in gelling starch, starch and Mannitol.Thus, it is possible to it is higher to be further ensured that gained pharmaceutical composition has
Bioavailability and stability.Specific example of the invention, filler can be in Microcrystalline Cellulose and Lactose
At least one.
Embodiments in accordance with the present invention, the particular type of disintegrating agent is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, disintegrating agent can be selected from carboxymethylstach sodium, crosslinking carboxylic first
At least one in base sodium cellulosate, low-substituted hydroxypropyl cellulose and polyvinylpolypyrrolidone.Thus, it is possible to promote the medicine fast
Instant solution, so as to actively play drug effect.Specific example of the invention, disintegrating agent can be carboxymethylstach sodium.
Embodiments in accordance with the present invention, the particular type of binding agent is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, binding agent can be selected from hydroxypropyl methylcellulose, hydroxypropyl
At least one in base cellulose, polyvidone and starch slurry.Thus, it is possible to significantly improve the stability of the pharmaceutical composition.
Specific example of the invention, binding agent can be hydroxypropyl methylcellulose.
Embodiments in accordance with the present invention, the particular type of lubricant is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, lubricant can be selected from Pulvis Talci, lauryl sulphate acid
At least one in sodium, silicon dioxide, magnesium stearate, calcium stearate and Macrogol 4000.Thus, it is possible to further protect
Card gained pharmaceutical composition has higher bioavailability and stability.Specific example of the invention, lubricant can be with
For magnesium stearate.
Embodiments in accordance with the present invention, shellfish cholic acid pharmaceutical composition difficult to understand is solid orally ingestible, preferably tablet or capsule, most
Preferably tablet.Thus, it is possible to ensure that gained pharmaceutical composition has higher bioavailability and stability.
Embodiments in accordance with the present invention, the specification of shellfish cholic acid pharmaceutical composition difficult to understand can be 1～50mg, preferably 5～25mg.
In another aspect of this invention, the present invention provides the method for preparing above-mentioned shellfish cholic acid pharmaceutical composition difficult to understand, including：(a)
By shellfish cholic acid micronization difficult to understand, to obtain the shellfish cholic acid microgranule difficult to understand that mean diameter is 3.0～250 μm；B () prepares binding agent molten
Liquid；C () mixs homogeneously shellfish cholic acid difficult to understand with filler, disintegrating agent, obtain the powder containing principal agent and excipient；D () will
Described adhesive solution obtained in step (b) is added in the powder containing principal agent and excipient, and is pelletized, done
It is dry；E () sieves the drug particles that are dried that step (d) is obtained granulate, be subsequently adding lubricant, and carries out tabletting, so as to
Obtain shellfish cholic acid pharmaceutical composition difficult to understand；E () is sieved granulate, add lubricant, determines the content of shellfish cholic acid difficult to understand in granule, pressure
Piece, get Ao Bei cholic acid pharmaceutical composition finished products.Thus, can effectively be prepared using the method above-mentioned with higher life
The shellfish cholic acid pharmaceutical composition difficult to understand of thing availability and stability, and inventor to shellfish cholic acid difficult to understand by carrying out micronization processes,
The sample of different average particle size ranges is have collected, and different Austria are prepared by wet granulation and technique of direct powder compression
Shellfish cholic acid piece carries out test and finally found that, can ensure that when the mean diameter of shellfish cholic acid microgranule difficult to understand is 3.0～250 μm and obtains one
The high and stable preparation of individual bioavailability, while the preparation method process is simple, is suitable for industrialized great production.Need
Bright, the above-mentioned feature and advantage for described by shellfish cholic acid pharmaceutical composition difficult to understand are equally applicable to preparation Austria shellfish cholic acid medicine
The method of compositions, here is omitted.
According to one embodiment of present invention, the mean diameter of shellfish cholic acid microgranule difficult to understand is preferably 3.0～150 μm.Thus, it is possible to
It is further ensured that raw gained preparation has higher bioavailability and stability.According to a particular embodiment of the invention, Ao Bei
The mean diameter of cholic acid microgranule is more preferably 3.0～10 μm.Inventor has found, using the shellfish cholic acid microgranule difficult to understand of the particle size range,
The bioavailability and optimal stability of gained preparation.
Embodiments in accordance with the present invention, the particular type of shellfish cholic acid raw material difficult to understand is not particularly restricted, and those skilled in the art can
To be selected according to actual needs, according to a particular embodiment of the invention, crystal formation or unformed raw material can be adopted, specifically
, shellfish cholic acid crystal formation difficult to understand can adopt at least one in C, G, F crystal formation.Thus, it is possible to ensure gained drug regimen
Thing has higher bioavailability and stability.Specific example of the invention, preferably unformed raw material.Thus,
May further ensure that gained pharmaceutical composition has higher bioavailability and stability.
Embodiments in accordance with the present invention, the particular type of filler is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, filler can be selected from Microcrystalline Cellulose, Lactose, pre-
At least one in gelling starch, starch and Mannitol.Thus, it is possible to it is higher to be further ensured that gained pharmaceutical composition has
Bioavailability and stability.Specific example of the invention, filler can be in Microcrystalline Cellulose and Lactose
At least one.
Embodiments in accordance with the present invention, the particular type of disintegrating agent is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, disintegrating agent can be selected from carboxymethylstach sodium, crosslinking carboxylic first
At least one in base sodium cellulosate, low-substituted hydroxypropyl cellulose and polyvinylpolypyrrolidone.Thus, it is possible to promote the medicine fast
Instant solution, so as to actively play drug effect.Specific example of the invention, disintegrating agent can be carboxymethylstach sodium.
Embodiments in accordance with the present invention, the particular type of binding agent is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, binding agent can be selected from hydroxypropyl methylcellulose, hydroxypropyl
At least one in base cellulose, polyvidone and starch slurry.Thus, it is possible to significantly improve the stability of the pharmaceutical composition.
Specific example of the invention, binding agent can be hydroxypropyl methylcellulose.
Embodiments in accordance with the present invention, the particular type of lubricant is not particularly restricted, and those skilled in the art can basis
It is actually needed and is selected, according to a particular embodiment of the invention, lubricant can be selected from Pulvis Talci, lauryl sulphate acid
At least one in sodium, silicon dioxide, magnesium stearate, calcium stearate and Macrogol 4000.Thus, it is possible to further protect
Card gained pharmaceutical composition has higher bioavailability and stability.Specific example of the invention, lubricant can be with
For magnesium stearate.
Embodiments in accordance with the present invention, are dried to loss on drying in step (d) and are not more than 3wt%.Thus it is convenient for tabletting.
In a third aspect of the present invention, the present invention provides the method for preparing above-mentioned shellfish cholic acid pharmaceutical composition difficult to understand.According to the present invention
Embodiment, the method includes：(1) it is that 3.0～250 μm of shellfish cholic acid difficult to understand are micro- by shellfish cholic acid crude drug difficult to understand process to mean diameter
Grain；(2) by the uniform rear direct compression of the shellfish cholic acid microgranule difficult to understand and filler, disintegrating agent and mix lubricant, to obtain
Shellfish cholic acid pharmaceutical composition difficult to understand.Thus, using the method can effectively prepare it is above-mentioned with higher bioavailability and
The shellfish cholic acid pharmaceutical composition difficult to understand of stability, and inventor have collected not by carrying out micronization processes to shellfish cholic acid difficult to understand
With the sample of average particle size range, and different shellfish cholic acid pieces difficult to understand are prepared by wet granulation and technique of direct powder compression enter
Row test finally found that, can ensure that when the mean diameter of shellfish cholic acid microgranule difficult to understand is 3.0～250 μm and obtain a biological utilisation
The high and stable preparation of degree, while the preparation method process is simple, is suitable for industrialized great production.It should be noted that on
State and be equally applicable to preparation Austria shellfish cholic acid pharmaceutical composition for the feature and advantage described by shellfish cholic acid pharmaceutical composition difficult to understand
Method, here is omitted.
Embodiments in accordance with the present invention, can be with root before by shellfish cholic acid microgranule difficult to understand and filler, disintegrating agent and mix lubricant
Respectively process of sieving is carried out to filler, disintegrating agent and lubricant according to needs.Thus, it is possible to the degree of scatter of each component is improved,
So as to ensure that gained pharmaceutical composition has higher bioavailability and stability.
The shellfish cholic acid pharmaceutical composition difficult to understand of the present invention compared with prior art, has the advantage that：
(1) invention formulation component is simple, and product is stable, and impurity is few, and active component content is high；
(2) present invention improves the dissolubility and dissolution rate of shellfish cholic acid difficult to understand, improves the speed and degree of drug absorption,
Improve the bioavailability of medicine；
(3) impact of the present invention by the size of investigation shellfish cholic acid crude drug difficult to understand to dissolution and the absorption of medicine, clearly
The key parameter of preparation process, is to improve the fixed basis of product formulation level pad；
(4) present invention prepares shellfish cholic acid piece difficult to understand using micronization technology first, and has carried out prescription, the work of shellfish cholic acid piece difficult to understand
Skill research, it is domestic and international unlisted product.
Additional aspect of the present invention and advantage will be set forth in part in the description, and partly will become apparent from the description below,
Or recognized by the practice of the present invention.
Description of the drawings
Accompanying drawing 1：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 1；
Accompanying drawing 2：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 2；
Accompanying drawing 3：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 3；
Accompanying drawing 4：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 4；
Accompanying drawing 5：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 5；
Accompanying drawing 6：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 6.
Accompanying drawing 7：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 7；
Accompanying drawing 8：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 8；
Accompanying drawing 9：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 9；
Accompanying drawing 10：The external stripping curve figure of shellfish cholic acid piece difficult to understand of embodiment 10.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention,
And be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to document in the art
Described technology or condition are carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are
Can pass through city available from conventional products.
Shellfish cholic acid difficult to understand, white powder is provided by Waterstone Pharmaceuticals (Wuhan) Co., Ltd..
Micronization adopts jet mill, purchased from the new powder machinery equipment company limited of Yixing City essence.
Embodiment 1
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 3.0～5 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 2
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 10～150 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 3
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 150～250 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 4
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 6.2～10 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 5
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 3.0～10 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 6
Prescription：
Preparation technology：
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 3.0～10 μm, it is standby；
2. respectively by Microcrystalline Cellulose, Lactose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3. hydroxypropylcellulose water is configured to into the solution for standby that concentration is 3% (W/V)；
4., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, Lactose and carboxymethylstach sodium mix homogeneously, binding agent soft material is added,
Granulation, in 50 DEG C～60 DEG C dryings, granulate, adds magnesium stearate to mix, and tabletting is obtained final product and meets the present invention
The shellfish cholic acid tablet a kind of difficult to understand of description.
Embodiment 7
Prescription：
Preparation technology
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 10～150 μm, it is standby；
2. respectively by Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously, tabletting, obtain final product and meet
The shellfish cholic acid tablet a kind of difficult to understand of present invention description.
Embodiment 8
Prescription：
Preparation technology
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 10～150 μm, it is standby；
2. respectively by Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously, tabletting, obtain final product and meet
The shellfish cholic acid tablet a kind of difficult to understand of present invention description.
Embodiment 9
Prescription：
Preparation technology
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 10～150 μm, it is standby；
2. respectively by Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously, tabletting, obtain final product and meet
The shellfish cholic acid tablet a kind of difficult to understand of present invention description.
Embodiment 10
Prescription：
Preparation technology
1. shellfish cholic acid crude drug difficult to understand is processed to mean diameter between 10～150 μm, it is standby；
2. respectively by Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, respectively 80 mesh sieves excessively are standby；
3., by shellfish cholic acid difficult to understand, Microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate mix homogeneously, tabletting, obtain final product and meet
The shellfish cholic acid tablet a kind of difficult to understand of present invention description.
The In Vitro Dissolution test of embodiment：
The measure of shellfish cholic acid piece In Vitro Dissolution difficult to understand：
The assay method of In Vitro Dissolution of the present invention adopts Chinese Pharmacopoeia two methods of annex XC second of version in 2010, is with pH
6.8 phosphate buffered solution 900ml are dissolution medium, and rotating speed is 50 turns per minute, and temperature is 37 DEG C.
Sampled at 5,10,15,20,30,45,60 minutes, the dissolution fluid of taking-up is filtered with 0.45 μm of filter membrane, use
HPLC methods determine the dissolution content of shellfish cholic acid difficult to understand, and calculate the stripping quantity of each time point.
The In Vitro Dissolution result of the test of embodiment 1, is shown in Table 1：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 1
The In Vitro Dissolution result of the test of embodiment 2, is shown in Table 2：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 2
The In Vitro Dissolution result of the test of embodiment 3, is shown in Table 3：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 3
The In Vitro Dissolution result of the test of embodiment 4, is shown in Table 4：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 4
The In Vitro Dissolution result of the test of embodiment 5, is shown in Table 5：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 5
The In Vitro Dissolution result of the test of embodiment 6, is shown in Table 6：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 6
The In Vitro Dissolution result of the test of embodiment 7, is shown in Table 7：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 7
The In Vitro Dissolution result of the test of embodiment 8, is shown in Table 8：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 8
The In Vitro Dissolution result of the test of embodiment 9, is shown in Table 9：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 9
The In Vitro Dissolution result of the test of embodiment 10, is shown in Table 10：
The external dissolution results of the shellfish cholic acid piece difficult to understand of table 10
The In Vitro Dissolution result of the test curve chart of embodiment 1-10 is respectively as Figure 1-10 shows.
Conclusion：Shown by the In Vitro Dissolution result of embodiment 1 to embodiment 5 (Fig. 1-5)：Austria of different mean diameters
Shellfish cholic acid raw material, using identical technique, obtained tablet, under identical leaching condition, with particle diameter reduction its
Dissolution gradually increases, but after mean diameter is less than 10 μm, particle diameter will no longer affect dissolution in vitro.At 3.0～10 μm
Particle size range in, product stripping curve is optimum.
The In Vitro Dissolution result of embodiment 5 to embodiment 10 (Fig. 5-10) shows：The shellfish cholic acid raw material difficult to understand of different crystal forms
In 3.0～150 μm selected of mean diameter, using the technique of identical (or different), i.e., by wet granule compression tablet
With tablet obtained in two methods of direct powder compression, its external dissolution is identical.
In describing the invention, it is to be understood that term " first ", " second " are only used for describing purpose, and are not understood that
To indicate or implying relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, define " first ", "
Two " one or more this feature can be expressed or be implicitly included to feature.In describing the invention, " multiple "
Two or more are meant that, unless otherwise expressly limited specifically.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example ",
Or the description of " some examples " etc. means to combine specific features, structure, material or feature bag that the embodiment or example are described
In being contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term necessarily
It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be arbitrary
Combine in an appropriate manner in individual or multiple embodiments or example.Additionally, in the case of not conflicting, the skill of this area
Art personnel can be combined the feature of the different embodiments or example described in this specification and different embodiments or example
And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment be it is exemplary,
It is not considered as limiting the invention, one of ordinary skill in the art within the scope of the invention can be to above-described embodiment
It is changed, changes, replacing and modification.
Claims (10)
1. a kind of shellfish cholic acid pharmaceutical composition difficult to understand, it is characterised in that in the shellfish cholic acid pharmaceutical composition difficult to understand containing shellfish cholic acid difficult to understand,
Filler, disintegrating agent, binding agent, lubricant.
2. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 1, it is characterised in that the shellfish cholic acid difficult to understand is Jing micropowders
Shellfish cholic acid microgranule difficult to understand after change, the mean diameter of the shellfish cholic acid microgranule difficult to understand is 3.0～250 μm.
3. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 2, it is characterised in that the shellfish cholic acid microgranule difficult to understand it is flat
Particle diameter is 3.0～150 μm, preferably 3.0～10 μm.
4. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 1, it is characterised in that the shellfish cholic acid difficult to understand adopts crystal formation
Or unformed raw material, preferably unformed raw material.
5. the shellfish cholic acid pharmaceutical composition difficult to understand according to any one of claim 1-4, it is characterised in that the filler is
At least one in Microcrystalline Cellulose, Lactose, pregelatinized Starch, starch and Mannitol；
Optionally, the disintegrating agent is selected from carboxymethylstach sodium, Croscarmellose Sodium, low-substituted hydroxypropyl cellulose
With at least one in polyvinylpolypyrrolidone；
Optionally, described adhesive be in hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone and starch slurry extremely
Few one kind；
Optionally, the lubricant is selected from Pulvis Talci, sodium lauryl sulphate, silicon dioxide, magnesium stearate, stearic acid
At least one in calcium and Macrogol 4000.
6. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 5, it is characterised in that the filler is selected from crystallite
At least one in cellulose and Lactose；
Optionally, the disintegrating agent is carboxymethylstach sodium；
Optionally, described adhesive is hydroxypropyl methylcellulose；
Optionally, the lubricant is magnesium stearate.
7. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 1, it is characterised in that the shellfish cholic acid drug regimen difficult to understand
Thing is solid orally ingestible, preferably tablet or capsule, most preferably tablet.
8. shellfish cholic acid pharmaceutical composition difficult to understand according to claim 7, it is characterised in that the shellfish cholic acid drug regimen difficult to understand
The specification of thing is 1～50mg, preferably 5～25mg.
9. a kind of method of the shellfish cholic acid pharmaceutical composition difficult to understand prepared described in any one of claim 1～8, it is characterised in that bag
Include：
(a) by shellfish cholic acid micronization difficult to understand, to obtain the shellfish cholic acid microgranule difficult to understand that mean diameter is 3.0～250 μm；
B () prepares binder solution；
C () mixs homogeneously shellfish cholic acid difficult to understand with filler, disintegrating agent, obtain the powder containing principal agent and excipient；
D () is added to described adhesive solution obtained in step (b) in the powder containing principal agent and excipient, and
Pelletized, be dried；
E () sieves the drug particles that are dried that step (d) is obtained granulate, be subsequently adding lubricant, and carries out tabletting, with
Just shellfish cholic acid pharmaceutical composition difficult to understand is obtained；
Optional, it is dried in step (d) to drug particles are weightless and is not more than 3wt%.
10. a kind of method of the shellfish cholic acid pharmaceutical composition difficult to understand prepared described in any one of claim 1～8, it is characterised in that
Including：
(1) it is 3.0～250 μm of shellfish cholic acid microgranules difficult to understand by shellfish cholic acid crude drug difficult to understand process to mean diameter；
(2) by the uniform rear direct compression of the shellfish cholic acid microgranule difficult to understand and filler, disintegrating agent and mix lubricant, to obtain
Shellfish cholic acid pharmaceutical composition difficult to understand.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510749221.3A CN106668027A (en) | 2015-11-05 | 2015-11-05 | Obeticholic acid pharmaceutical composition and preparation method thereof |
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| CN201510749221.3A CN106668027A (en) | 2015-11-05 | 2015-11-05 | Obeticholic acid pharmaceutical composition and preparation method thereof |
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Cited By (3)
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| CN109620812A (en) * | 2019-01-16 | 2019-04-16 | 浙江华海药业股份有限公司 | A kind of preparation method of Austria's shellfish cholic acid composition |
| CN110025591A (en) * | 2019-04-29 | 2019-07-19 | 郑州泰丰制药有限公司 | A kind of Austria's shellfish cholic acid self-emulsifiable preparation and its soft capsule |
| WO2024104960A1 (en) * | 2022-11-15 | 2024-05-23 | Synthon B.V. | Stable formulation comprising obeticholic acid |
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109620812A (en) * | 2019-01-16 | 2019-04-16 | 浙江华海药业股份有限公司 | A kind of preparation method of Austria's shellfish cholic acid composition |
| CN109620812B (en) * | 2019-01-16 | 2023-07-21 | 浙江华海药业股份有限公司 | Preparation method of obeticholic acid composition |
| CN110025591A (en) * | 2019-04-29 | 2019-07-19 | 郑州泰丰制药有限公司 | A kind of Austria's shellfish cholic acid self-emulsifiable preparation and its soft capsule |
| WO2024104960A1 (en) * | 2022-11-15 | 2024-05-23 | Synthon B.V. | Stable formulation comprising obeticholic acid |
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