CN115671073A - Ursodeoxycholic acid capsule and preparation method thereof - Google Patents
Ursodeoxycholic acid capsule and preparation method thereof Download PDFInfo
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- CN115671073A CN115671073A CN202110830412.8A CN202110830412A CN115671073A CN 115671073 A CN115671073 A CN 115671073A CN 202110830412 A CN202110830412 A CN 202110830412A CN 115671073 A CN115671073 A CN 115671073A
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- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 82
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title claims abstract description 82
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 82
- 239000002775 capsule Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000000314 lubricant Substances 0.000 claims abstract description 28
- 238000007908 dry granulation Methods 0.000 claims abstract description 23
- 239000003085 diluting agent Substances 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims description 36
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 238000011049 filling Methods 0.000 claims description 23
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 11
- 239000011812 mixed powder Substances 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 9
- 239000008101 lactose Substances 0.000 claims description 9
- 238000007873 sieving Methods 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 6
- 235000020985 whole grains Nutrition 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 239000011361 granulated particle Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 7
- 238000000338 in vitro Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 229920002261 Corn starch Polymers 0.000 description 8
- 239000008120 corn starch Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- 239000012738 dissolution medium Substances 0.000 description 7
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- 239000000203 mixture Substances 0.000 description 7
- 238000005550 wet granulation Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 241000490229 Eucephalus Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010057969 Reflux gastritis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 239000006185 dispersion Substances 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a ursodeoxycholic acid capsule and a preparation method thereof. The content of the ursodeoxycholic acid capsule comprises: ursodeoxycholic acid, a diluent, a glidant and a lubricant, and is prepared by a dry granulation process. The ursodeoxycholic acid capsule obtained by adopting the specific components, the specific content, the specific dry granulation process and the specific preparation method is consistent with the dissolution of all in vitro media of a reference preparation, so that the cost is greatly reduced while the treatment effect is ensured, the economic burden of a patient is remarkably reduced, and unexpected technical effects are obtained.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to a ursodeoxycholic acid capsule and a preparation method thereof.
Background
Ursodeoxycholic acid is used for the treatment of cholecystolith calculi, cholestatic diseases and bile reflux gastritis, mainly based on the relative replacement of lipophilic, detergent-like toxic bile acids by hydrophilic, cytoprotective and non-cytotoxic ursodeoxycholic acid, as well as the promotion of hepatocyte secretion and immunomodulation.
The ursodeoxycholic acid is extremely bitter in sour taste, and the common ursodeoxycholic acid tablets in the market are not suitable for bitter-feared people to take; and ursodeoxycholic acid is a BCS II drug, and the extremely low solubility limits the dissolution rate of the ursodeoxycholic acid tablets, thereby affecting the treatment effect. The ursodeoxycholic acid capsule can well improve the compliance of a human body when the capsule is taken, and a multi-particle dispersion system of the capsule is favorable for dissolving out the medicine. The only approval for marketing at home at present is the imported ursodeoxycholic acid capsule (Yousifu) of Dr.Falk Pharma.GmbH in Germany, which is expensive and causes great economic burden to patients.
The patent documents disclosed so far relate to the following preparation of capsules using ursodeoxycholic acid as an active ingredient:
patent document CN202010293055.1 (applicant: anshi pharmaceutical (zhongshan) limited) discloses a ursodeoxycholic acid capsule and a preparation method thereof: and (2) preparing a soft material by using corn starch slurry as an adhesive by using a conventional wet granulation process, performing wet granulation, drying to obtain dry particles, mixing the dry particles with colloidal silicon dioxide, sieving, mixing with magnesium stearate to obtain mixed particles, and filling capsules to obtain the ursodeoxycholic acid capsules. In the patent document, corn starch slurry is used as an adhesive, the gelatinization temperature of the corn starch is about 70 ℃, and workers can be scalded due to improper operation in the preheating process of purified water; the viscosity of the corn starch paste is related to the temperature, the change of the temperature causes the viscosity difference of the corn starch paste to cause the change of the granule strength, the batch uniformity is poor, so the temperature control is strictly carried out in the production process, the process is complicated and takes longer, and the energy consumption in the wet granule drying process is larger, thereby being not beneficial to the commercial production of products.
Patent document with application number of CN202010073381.1 (applicant: aster pharmaceutical (Zhongshan) Co., ltd.) discloses a ursodeoxycholic acid capsule and a preparation method thereof, wherein the raw materials comprise the following components in parts by weight: 225-275 parts of ursodeoxycholic acid, 30-20 parts of povidone K, 25-35 parts of lactose, 25-35 parts of microcrystalline cellulose, 0.66-1.66 parts of magnesium stearate and 1.66-2.66 parts of silicon dioxide. Wherein lactose and microcrystalline cellulose are used as filling agents, polyvidone K30 is used as a binding agent, magnesium stearate and colloidal silicon dioxide are used as lubricating agents, and the ursodeoxycholic acid capsule is prepared by one-step granulation, mixing and filling. The adhesive solution is prepared by using ethanol, the temperature is strictly controlled in the granulation process, an explosion-proof device is required to be installed in a workshop for large-scale production, the requirement on equipment is high, and the process has operations such as liquid preparation and the like, so that the process is relatively complicated.
Patent document with application number of CN201910081079.8 (applicant: sichuan Diffie pharmaceutical Co., ltd.) discloses a ursodeoxycholic acid capsule and a preparation method thereof, wherein the raw materials comprise the following components in parts by weight: 3-9 parts of ursodeoxycholic acid, 0.01-4 parts of pregelatinized starch, 0.02-4 parts of starch, 0.1-0.2 part of magnesium stearate, 0.05-0.5 part of colloidal silicon dioxide and 0.05-1 part of hydroxypropyl methylcellulose, wherein the ursodeoxycholic acid is subjected to micronization treatment, and the particle size D is 90 Is less than 40 mu m. The ursodeoxycholic acid used in the patent document is subjected to micronization treatment, the scale and time of commercial batch production of the product are closely related to the production capacity of micronization equipment, the micronization granularity control of raw materials is relatively complicated, the requirement on the equipment is high, and the micronized raw material medicine has strong agglomeration and adhesion, so that the adhesion of the raw material medicine on the production equipment is difficult to avoid.
Patent document CN201710499023.5 (applicant: shijiazhuang academy) discloses a ursodeoxycholic acid capsule and a preparation method thereof, wherein the content consists of ursodeoxycholic acid, a binder and a filler. The adhesive is
Hydroxypropyl cellulose of the type or
Type hydroxypropyl cellulose, the filler is microcrystalline cellulose PH102. This patent document uses wet granulation or one-step granulation after formulating the binder solution. Wet granulation involves the steps of adhesive preparation, soft material preparation, wet granulation, fluidized bed drying and the like, and one-step granulation involves the steps of adhesive preparation and the like, so that the process is complicated and takes a long time.
In conclusion, the search and summary of the existing patent documents show that most of the preparation processes of ursodeoxycholic acid capsules are wet granulation or one-step granulation, and the preparation and drying processes of the binding agent are involved, so that the process is relatively complex.
Dry granulation refers to a method of mixing the drug powder, directly pressing into tablets with proper equipment, and then crushing into particles with required size. The prescription composition can be understood by referring to the specification of "Youshefer" in Russia or Argentina: the single dose of the ursodeoxycholic acid capsule is 330mg, wherein the active component ursodeoxycholic acid accounts for 75.76 percent and 250 mg; the filler is corn starch. Ursodeoxycholic acid and corn starch are poor in flowability and compressibility, difficult to compress and form, and indeed dry granulation is not suitable for the prescription.
Therefore, it is necessary to develop ursodeoxycholic acid capsules with simple process.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the ursodeoxycholic acid capsule and the preparation method thereof.
The technical scheme adopted by the invention is as follows:
an ursodeoxycholic acid capsule, the contents of which comprise: ursodeoxycholic acid, diluent, glidant and lubricant.
Preferably, the contents are prepared by a dry granulation process.
Preferably, the content comprises 250 parts by weight of ursodeoxycholic acid, 67.0-77.4 parts by weight of diluent, 4.6-5.4 parts by weight of glidant and 2.6-3.0 parts by weight of lubricant.
Preferably, the diluent is selected from one or more of pregelatinized starch, lactose and microcrystalline cellulose, preferably microcrystalline cellulose or lactose; the glidant is selected from colloidal silicon dioxide; the lubricant is selected from magnesium stearate.
Preferably, 86 to 90 weight percent of the lubricant is an inner blending part and is added in the dry granulation process; 10-14 wt% of lubricant is added in the total mixing process as an external part.
More preferably, 88% by weight of the lubricant is the inclusion fraction, added during dry granulation; 12% by weight of lubricant is the added part and is added during the total mixing process.
More preferably, the content comprises 250 parts by weight of ursodeoxycholic acid, 72.2 parts by weight of diluent, 5 parts by weight of glidant and 2.8 parts by weight of lubricant.
The invention also provides a preparation method of the ursodeoxycholic acid capsule, which comprises the following steps:
(1) Weighing: weighing ursodeoxycholic acid, a diluent, a glidant and a lubricant; optionally, filling the weighed materials into a container lined with a double-layer medicinal low-density polyethylene bag;
(2) Sieving: respectively sieving the ursodeoxycholic acid and the diluent with a 18-mesh sieve, and respectively sieving the glidant and the lubricant with a 30-mesh sieve;
(3) Premixing: mixing the ursodeoxycholic acid and the diluent uniformly, and then mixing with the lubricant of the inner mixing part;
(4) And (3) dry granulation: putting the uniformly mixed powder into a dry granulating machine for dry granulation;
(5) Total mixing: uniformly mixing the glidant and the lubricant of the external mixing part with the dry-granulated particles to obtain total mixed powder;
(6) And (3) filling capsules: and filling the total mixed powder into a hollow capsule to obtain the ursodeoxycholic acid capsule.
Preferably, in step (1), D of ursodeoxycholic acid 90 Is 100-140 μm.
Preferably, in the step (3), the mixing time of the ursodeoxycholic acid and the diluent is 15min, and the rotating speed is 10rpm; mixing with the lubricant of the inner blending part for 5min at the rotation speed of 10rpm.
Preferably, in step (4), the process parameters of the dry granulation machine are: hydraulic pressure 5Mpa, pinch roller spacing 0.75mm, final whole grain rotating speed 150rpm, and screen mesh aperture 1.0mm.
Preferably, in step (5), the mixing time is 5min, and the rotation speed is 10rpm.
Preferably, in the step (6), the total mixed powder is poured into a capsule filling hopper, a 0-size hard gelatin hollow capsule is filled, and the capsule filling is carried out after the filling speed and the filling amount are adjusted.
The invention has the following beneficial effects:
the invention uses ursodeoxycholic acid raw material medicines with conventional particle sizes, does not need micronization treatment, avoids the adhesion of the raw material medicines to equipment in the production process, reduces the process difficulty, and also avoids the reduction of the dissolution rate of the product caused by overlarge particle sizes of the ursodeoxycholic acid raw material medicines.
The invention adopts the dry granulation technology to granulate the medicine, avoids the preparation process of an adhesive or the boiling or flushing process of corn starch slurry, does not need drying, simplifies the production process, and has less time consumption and low energy consumption.
The dry granulation process has controllable production process parameters and good batch-to-batch uniformity; compared with wet granulation, the method is simple and easy to amplify.
The invention uses the dry granulation process to prepare the ursodeoxycholic acid capsule, greatly simplifies the process flow, ensures that the in-vitro dissolution of the product can achieve the effect consistent with that of the dissolution of a reference preparation, has good stability, ensures the product quality and can furthest reduce the economic burden of patients.
In a word, the ursodeoxycholic acid capsule obtained by adopting the specific components, the specific content, the specific dry granulation process and the specific preparation method is consistent with the dissolution of all media in vitro of a reference preparation, so that the cost is greatly reduced while the treatment effect is ensured, the economic burden of a patient is remarkably reduced, and unexpected technical effects are achieved.
Drawings
FIG. 1 is a comparison of the dissolution curves of the products prepared in examples 1-2 (250 mg) of the invention with a reference formulation at pH =7.5 (dissolution conditions: paddle method, 900ml dissolution medium, 75rpm,37 ℃).
FIG. 2 is a comparison of the dissolution curves of the products prepared in examples 1-2 (250 mg) of the invention with a reference formulation at pH =6.8 (dissolution conditions: paddle method, 900ml dissolution medium, 75rpm,37 ℃).
FIG. 3 is a comparison of the dissolution profiles of the products prepared in examples 1-2 (250 mg) of the present invention with a reference formulation in SDS media at pH =5.5 (dissolution conditions: paddle, 900ml dissolution media, 75rpm,37 ℃ C.).
Detailed Description
In order to further illustrate the present invention, the ursodeoxycholic acid capsules provided by the present invention are described in detail below by way of examples, which should not be construed to limit the scope of the present invention.
Example 1: a preparation method of ursodeoxycholic acid capsules comprises the following steps:
(1) Respectively weighing the following raw materials in parts by weight: ursodeoxycholic acid 250 parts (D) 90 100-140 μm), 72.2 parts of microcrystalline cellulose, 5 parts of colloidal silicon dioxide and 2.8 parts of magnesium stearate, wherein 2.46 parts of magnesium stearate is internally blended for dry granulation.
(2) Sieving: the ursodeoxycholic acid and the microcrystalline cellulose are respectively sieved by a 18-mesh sieve, and the colloidal silicon dioxide and the magnesium stearate are respectively sieved by a 30-mesh sieve.
(3) Premixing: mixing ursodeoxycholic acid and microcrystalline cellulose at 15min and 10rpm, adding the magnesium stearate in the inner part, and mixing at 10rpm for 5min.
(4) And (3) dry granulation: setting parameters of a dry granulating machine: hydraulic pressure 5Mpa, pinch roller spacing 0.75mm, final grading rotation speed 150rpm, and grading screen mesh 1.0mm.
(5) Total mixing: the colloidal silicon dioxide, the magnesium stearate externally added and the granulated granules were mixed for 5min at 10rpm to obtain a total mixed powder.
(6) And (3) filling capsules: and pouring the total mixed powder into a capsule filling hopper, filling a No. 0 hard gelatin hollow capsule, and filling the capsule after adjusting the filling speed and the filling amount to obtain the ursodeoxycholic acid capsule.
Example 2: a preparation method of ursodeoxycholic acid capsules comprises the following steps:
(1) Respectively weighing the following raw materials in parts by weight: ursodeoxycholic acid 250 parts (D) 90 100-140 μm), 72.2 parts of lactose, 5 parts of colloidal silicon dioxide and 2.8 parts of magnesium stearate, wherein 2.46 parts of magnesium stearate is internally mixed for dry granulation.
(2) Sieving: ursodeoxycholic acid and lactose are respectively sieved by a 18-mesh sieve, and colloidal silicon dioxide and magnesium stearate are respectively sieved by a 30-mesh sieve.
(3) Premixing: mixing ursodeoxycholic acid and lactose for 15min and 10rpm, adding the magnesium stearate of the inner mixing part, and mixing for 5min and 10rpm.
(4) And (3) dry granulation: setting parameters of a dry granulator: hydraulic pressure 5Mpa, pinch roller interval 0.75mm, final whole grain rotation speed 150rpm, whole grain screen 1.0mm.
(5) Total mixing: the colloidal silicon dioxide, the magnesium stearate externally added and the granulated granules were mixed for 5min at 10rpm to obtain a total mixed powder.
(6) And (3) filling capsules: and pouring the total mixed powder into a capsule filling hopper, filling a No. 0 hard gelatin hollow capsule, and filling the capsule after adjusting the filling speed and the filling amount to obtain the ursodeoxycholic acid capsule.
Example 3: in vitro quality study (compare the quality of ursodeoxycholic acid capsules prepared in examples 1 to 2 with a commercially available reference preparation (Yoschiff))
Ursodeoxycholic acid pKa =4.63, is an acidic drug; in the medium of pH4.5, the dissolution is only 1%, so under the medium condition, because the dissolution of the raw material medicine is incomplete and the purpose of screening prescription is difficult to achieve. The present invention employs a higher pH dissolution medium: SDS was added at pH7.5, pH6.8 and pH5.5, and the dissolution method of 75rpm by the conventional paddle method was employed.
As a result: the results of the in vitro dissolution curves of the ursodeoxycholic acid capsules prepared in examples 1 to 2 are shown in fig. 1 to 3. FIG. 1 is a comparison of the dissolution profiles of the products prepared in examples 1-2 (250 mg) of the invention with a reference formulation in pH =7.5 medium (dissolution conditions: paddle method, 900ml dissolution medium, 75rpm,37 ℃). FIG. 2 is a comparison of the dissolution profiles of the products prepared in examples 1-2 (250 mg) of the invention with a reference formulation in pH =6.8 medium (dissolution conditions: paddle method, 900ml dissolution medium, 75rpm,37 ℃). FIG. 3 is a comparison of the dissolution curves of the products prepared in examples 1-2 (250 mg) of the present invention and a reference formulation in SDS medium at pH =5.5 (dissolution conditions: paddle, 900ml dissolution medium, 75rpm,37 ℃).
The results show that: the dissolution curve of the ursodeoxycholic acid capsules prepared in the examples 1 and 2 of the present invention in the buffer solution with 75rpm and pH7.5 by the paddle method, the buffer solution with 75rpm and pH6.8 by the paddle method and the SDS buffer solution with 75rpm and pH5.5+ a certain concentration by the paddle method is substantially consistent with that of the reference preparation (Yoschiff). It is shown that the ursodeoxycholic acid capsules according to the invention have substantially the same mass as the reference preparation (eurypharov) on the market.
The above description is a specific embodiment of the present invention with better effect, and the protection scope of the present invention should also cover the technical solution and inventive concept of the present invention.
Claims (9)
1. A ursodeoxycholic acid capsule, the contents of which comprise: ursodeoxycholic acid, diluent, glidant and lubricant.
2. The ursodeoxycholic acid capsule according to claim 1, wherein said contents are prepared by a dry granulation process.
3. The ursodeoxycholic acid capsule according to claim 1, wherein the contents comprise, by weight, 250 parts of ursodeoxycholic acid, 67.0-77.4 parts of a diluent, 4.6-5.4 parts of a glidant, and 2.6-3.0 parts of a lubricant.
4. Ursodeoxycholic acid capsule according to claim 1, wherein said diluent is selected from one or more of pregelatinized starch, lactose and microcrystalline cellulose, preferably microcrystalline cellulose or lactose; the glidant is selected from colloidal silicon dioxide; the lubricant is selected from magnesium stearate.
5. The ursodeoxycholic acid capsule according to claim 2, wherein 86-90% by weight of the lubricant is an inner portion, added during dry granulation; 10-14 wt% of lubricant is added in the total mixing process as an external part.
6. The ursodeoxycholic acid capsule according to claim 5, wherein 88% by weight of the lubricant is an inner portion, added during dry granulation; 12% by weight of lubricant was included as an external portion and was added during the total blending process.
7. The ursodeoxycholic acid capsule according to claim 6, wherein the content comprises, by weight, 250 parts of ursodeoxycholic acid, 72.2 parts of a diluent, 5 parts of a glidant and 2.8 parts of a lubricant.
8. The method for preparing ursodeoxycholic acid capsules according to any one of claims 1 to 7, comprising the steps of:
(1) Weighing: weighing ursodeoxycholic acid, a diluent, a glidant and a lubricant;
(2) Sieving: respectively sieving the ursodeoxycholic acid and the diluent with a 18-mesh sieve, and respectively sieving the glidant and the lubricant with a 30-mesh sieve;
(3) Premixing: mixing the ursodeoxycholic acid and the diluent uniformly, and then mixing with the lubricant of the inner mixing part;
(4) And (3) dry granulation: putting the uniformly mixed powder into a dry granulating machine for dry granulation;
(5) Total mixing: uniformly mixing the glidant, the lubricant of the external mixing part and the dry-granulated particles to obtain total mixed powder;
(6) And (3) filling capsules: and filling the total mixed powder into a hollow capsule to obtain the ursodeoxycholic acid capsule.
9. The method for preparing ursodeoxycholic acid capsules according to claim 8,
in the step (1), D of ursodeoxycholic acid 90 100-140 μm;
in the step (3), the mixing time of the ursodeoxycholic acid and the diluent is 15min, and the rotating speed is 10rpm; mixing with the lubricant of the internal mixing part for 5min at the rotation speed of 10rpm;
in the step (4), the technological parameters of the dry granulating machine are as follows: hydraulic pressure 5Mpa, pinch roller spacing 0.75mm, final whole grain rotating speed 150rpm, screen mesh aperture 1.0mm;
in the step (5), the mixing time is 5min, and the rotating speed is 10rpm.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110830412.8A CN115671073A (en) | 2021-07-22 | 2021-07-22 | Ursodeoxycholic acid capsule and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110830412.8A CN115671073A (en) | 2021-07-22 | 2021-07-22 | Ursodeoxycholic acid capsule and preparation method thereof |
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| CN115671073A true CN115671073A (en) | 2023-02-03 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101686944A (en) * | 2007-04-19 | 2010-03-31 | 蒂斯芬阿国际私人有限公司 | The high dose composition of ursodesoxycholic acid |
| WO2013057741A2 (en) * | 2011-10-21 | 2013-04-25 | Genovo Development Services Limited | Pharmaceutical compositions of ursodeoxycholic acid |
| CN104367561A (en) * | 2014-11-14 | 2015-02-25 | 成都新恒创药业有限公司 | Preparation method of bezoar ursodesoxycholic acid preparation |
| EA201501046A1 (en) * | 2015-10-30 | 2017-05-31 | Закрытое Акционерное Общество "Афофарм" | COMPOSITION FOR THE TREATMENT AND / OR PREVENTION OF DISEASES OF THE LIVER AND / OR BILATERATED WAYS |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101686944A (en) * | 2007-04-19 | 2010-03-31 | 蒂斯芬阿国际私人有限公司 | The high dose composition of ursodesoxycholic acid |
| WO2013057741A2 (en) * | 2011-10-21 | 2013-04-25 | Genovo Development Services Limited | Pharmaceutical compositions of ursodeoxycholic acid |
| CN104367561A (en) * | 2014-11-14 | 2015-02-25 | 成都新恒创药业有限公司 | Preparation method of bezoar ursodesoxycholic acid preparation |
| EA201501046A1 (en) * | 2015-10-30 | 2017-05-31 | Закрытое Акционерное Общество "Афофарм" | COMPOSITION FOR THE TREATMENT AND / OR PREVENTION OF DISEASES OF THE LIVER AND / OR BILATERATED WAYS |
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