CN108785273B - Entecavir capsule pharmaceutical composition and preparation method thereof - Google Patents
Entecavir capsule pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN108785273B CN108785273B CN201811079954.0A CN201811079954A CN108785273B CN 108785273 B CN108785273 B CN 108785273B CN 201811079954 A CN201811079954 A CN 201811079954A CN 108785273 B CN108785273 B CN 108785273B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
The invention provides an entecavir capsule pharmaceutical composition and a preparation method thereof. The composition comprises micronized entecavir, micronized magnesium stearate, pregelatinized starch and microcrystalline cellulose, wherein the particle size distribution characteristics of the micronized entecavir and the micronized magnesium stearate are D90Less than or equal to 30 mu m, and is prepared by mixing entecavir and magnesium stearate and then carrying out co-micronization. The pharmaceutical composition has the advantages of good stability, high dissolution rate, high bioavailability, simple formula and preparation process, and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an entecavir capsule pharmaceutical composition and a preparation method thereof.
Background
Entecavir, its english name is Entecavir, its chemical name is: 2-amino-9- [ (1S,3R,4S) -4-hydroxy-3-hydroxymethyl-2-methylenepentyl ] -1, 9-dihydro-6-H-purin-6-one monohydrate.
Structural formula (xvi):
the molecular formula is as follows: c12H15N5O3·H2O, molecular weight: 295.3.
entecavir is a guanine nucleoside analogue, is an anti-hepatitis B virus medicament developed and researched by American Bezishi Guibao corporation, is clinically used for treating adult chronic hepatitis B, and comprises hepatitis virus replication activity increase, transaminase (ALT or AST) increase in blood plasma, liver tissue activity lesion, patients who are not treated by nucleoside medicaments and have positive or negative HBeAg with compensatory chronic liver diseases, and patients with lamivudine tolerance. Entecavir was approved for the market in the united states in 2005 and the countries that have been marketed to date include 30 countries and regions of canada, uk, germany, france, australia, etc. Entecavir tablets, as reported by Shi Guibao pharmaceutical Co., Ltd, Shanghai, Japan, in 11 months 2005, were approved for local production in China. The product specification is 0.5 mg. The usage and dosage are as follows: the product is orally administered to adult and teenagers of 16 years old or above, once a day, 0.5mg each time. Patients with viremia or lamivudine resistant mutations at the time of lamivudine treatment were treated once a day at 1mg each time. The product should be taken on an empty stomach (at least 2 hours before or after meal). Entecavir dispersible tablets and capsules are sold on the market in China, the specifications are 0.5mg and 1.0mg, and the indications are the same as those of the original enterprises.
CN102552210A provides an entecavir capsule, which contains entecavir, pregelatinized starch and microcrystalline cellulose, has a similar dissolution behavior in vitro to that of the original entecavir tablets, and is biologically equivalent to that of the original entecavir tablets in human body.
CN105001223A discloses an entecavir crystal compound and a capsule preparation thereof, the components of which comprise an entecavir crystal compound, a solubilizer, a filler, a disintegrant, a lubricant, an adhesive and the like.
CN103432098A discloses an entecavir capsule, which is prepared by filling a capsule shell with contents, wherein the contents are obtained by uniformly mixing medicine-containing fine powder and a lubricant, and the medicine-containing fine powder is prepared by dissolving entecavir, meglumine and a water-soluble filler in water and then spraying and drying.
CN103110608A discloses an entecavir capsule, which is prepared by uniformly mixing dry particles and talcum powder and then encapsulating the mixture into a capsule shell, wherein the dry particles are prepared by the following method: dissolving entecavir and a solid dispersion carrier in absolute ethyl alcohol, then adding a disintegrating agent insoluble in the ethyl alcohol for uniform dispersion, decompressing, drying and volatilizing the absolute ethyl alcohol to obtain a solid dispersion attached to the surface of the disintegrating agent, then granulating with a filler and an adhesive by a wet method, and drying.
CN102106856A provides a pharmaceutical composition of entecavir, comprising entecavir, a binder, a plasticizer and a pharmaceutically acceptable carrier matrix, wherein entecavir is adhered to the pharmaceutically acceptable carrier matrix.
CN102008447A provides an entecavir solid dispersion, which is mainly prepared from entecavir, a carrier and Tween-80, wherein the carrier is polyethylene glycol and/or poloxamer.
The entecavir solid preparation currently on the market at home and abroad and the prior art still have the following defects: (1) entecavir belongs to the third class of drugs of the Biopharmaceutical Classification System (BCS), and has low oral drug permeability and low bioavailability; (2) food influence, and need to be taken on an empty stomach for optimal curative effect (improved bioavailability), so that the problem of patient compliance exists; (3) the formula has more auxiliary material types, complex preparation process and higher cost.
Therefore, how to obtain an entecavir oral preparation with high bioavailability, high patient compliance, simple prescription and simple process is a problem to be solved in the field.
The inventor surprisingly discovers in the long-term research of the entecavir capsule pharmaceutical composition that the entecavir capsule pharmaceutical composition prepared by mixing the entecavir raw material and the magnesium stearate auxiliary material together to form micro powder and then mixing the micro powder with the pregelatinized starch and the microcrystalline cellulose has higher bioavailability and is not influenced by food, thereby completing the invention.
Disclosure of Invention
The invention aims to provide an entecavir capsule pharmaceutical composition and a preparation method thereof, and the entecavir capsule pharmaceutical composition is realized by the following technical scheme:
the invention provides an entecavir capsule pharmaceutical composition, which comprises micronized entecavir, micronized magnesium stearate, pregelatinized starch and microcrystalline cellulose.
Further, the entecavir capsule pharmaceutical composition contains every 1000 capsules: micronized entecavir 0.5g (as C)12H15N5O3Calculated), 0.1-2g of micronized magnesium stearate, 30-100g of pregelatinized starch and 30-100g of microcrystalline cellulose.
In one embodiment, the micronized entecavir has a particle size distribution characterized by D90≤30μm。
In one embodiment, the micronized magnesium stearate has a particle size distribution characterized by D90≤30μm。
Furthermore, the micronized entecavir and the micronized magnesium stearate are prepared by mixing an entecavir raw material and a magnesium stearate auxiliary material and then carrying out co-micronization.
In embodiments, the microcrystalline cellulose may be selected from the group consisting of microcrystalline cellulose PH102, microcrystalline cellulose PH302, microcrystalline cellulose PH301, microcrystalline cellulose PHM06, microcrystalline cellulose PHM25, microcrystalline cellulose KG-801, microcrystalline cellulose KG-802, microcrystalline cellulose 101, microcrystalline cellulose 102, and microcrystalline cellulose 200 in one or more combinations.
In one embodimentEach 1000 capsules of the entecavir capsule pharmaceutical composition contain: 0.5g of micronized entecavir, 1.0g of micronized magnesium stearate, 50g of pregelatinized starch, and microcrystalline cellulose PH 10250 g; wherein the micronized entecavir and the micronized magnesium stearate are prepared by mixing entecavir raw materials and magnesium stearate auxiliary materials and then carrying out co-micronization, and the particle size distribution characteristics are D90≤30μm。
The invention also provides a preparation method of the entecavir capsule pharmaceutical composition, which is characterized by comprising the following steps:
(1) mixing Entecavir raw material and magnesium stearate auxiliary material uniformly by a three-dimensional mixer, and putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving pregelatinized starch and microcrystalline cellulose with 80 mesh sieve respectively;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and microcrystalline cellulose for 4 times by adopting an equivalent progressive method, sieving by a 80-mesh sieve after each mixing to obtain a mixture I, performing 1 equivalent progressive mixing on the mixture I and sieved pregelatinized starch, sieving by the 80-mesh sieve for dispersing after mixing to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
The entecavir capsule pharmaceutical composition of the invention has the following advantages:
(1) the oral bioavailability of the entecavir is obviously improved;
(2) the exertion of the activity of the medicine is not influenced by food, and the medicine can be taken before or after meals without taking on an empty stomach, thereby greatly improving the compliance of patients to the entecavir capsules.
(3) Simple formula composition, low cost, simple and convenient process and easy realization of industrial preparation.
Since entecavir is a poorly soluble, low permeability drug, in vitro methods (e.g., dissolution testing) are used to assess its bioavailabilityThe degree is not feasible and must be evaluated by in vivo methods. The invention adopts the method that blood samples are collected after the rat is administrated by gastric lavage to carry out LC-MS/MS analysis for evaluation. Research shows that the bioavailability of entecavir is obviously improved after being micronized, and the inventor more surprisingly discovers that the entecavir and magnesium stearate are co-micronized to ensure that the particle size distribution of the entecavir and the magnesium stearate reaches D90The entecavir capsule pharmaceutical composition has the advantages that the bioavailability is improved more remarkably, and the effect is most remarkable when the weight ratio of magnesium stearate to entecavir is 0.2-4; meanwhile, the inventor also finds that the active ingredient of the entecavir capsule pharmaceutical composition prepared by the co-micronization has higher content uniformity, which provides a better solution for the problem of content uniformity of the low-content specification (0.5 mg/granule) oral solid preparation of the entecavir.
Detailed Description
For a better understanding of the present invention, the present invention and its advantages will be described and illustrated in detail by examples of the present invention and experimental data, which are not intended to limit the present invention.
Example 1
Prescription:
the preparation method comprises the following steps:
(1) adding entecavir and magnesium stearate with prescription dose into a three-dimensional mixer Turbula, mixing for 2 hours at the rotating speed of 100 r/min, and then putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving the pregelatinized starch and the microcrystalline cellulose in the prescription amount by a sieve of 80 meshes respectively for later use;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and microcrystalline cellulose for 4 times by adopting an equivalent progressive method, sieving by a 80-mesh sieve after each mixing to obtain a mixture I, performing 1 equivalent progressive mixing on the mixture I and sieved pregelatinized starch, sieving by the 80-mesh sieve for dispersing after mixing to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 2
Prescription:
the preparation method comprises the following steps:
(1) the entecavir and the magnesium stearate with the prescription amount are respectively micronized by an airflow pulverizer to ensure that the particle size distribution of the entecavir and the magnesium stearate reaches D90Less than or equal to 30 mu m, then putting the entecavir into a three-dimensional mixer Turbula, and mixing for 2 hours at the rotating speed of 100 r/min to prepare a mixture of entecavir magnesium stearate micropowder for later use;
(2) sieving the pregelatinized starch and the microcrystalline cellulose PH301 with a 80-mesh sieve respectively according to the prescription amount for later use;
(3) mixing the entecavir magnesium stearate micropowder mixture prepared in the step (1) and microcrystalline cellulose PH301 by an equivalent progressive method for 4 times, sieving by an 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch in an equivalent progressive manner for 1 time, sieving by the 80-mesh sieve for dispersion to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose PH301 and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 3
Prescription:
the preparation method comprises the following steps:
(1) adding entecavir and magnesium stearate with prescription dose into a three-dimensional mixer Turbula, mixing for 2 hours at the rotating speed of 100 r/min, and then putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving the pregelatinized starch and the microcrystalline cellulose PHM25 in the prescription amount by a sieve of 80 meshes respectively for later use;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and microcrystalline cellulose PHM25 by an equivalent progressive method for 4 times, sieving with a 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch for 1 time by equivalent progressive method, sieving with the 80-mesh sieve for dispersion to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose PHM25 and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 4
Prescription:
the preparation method comprises the following steps:
(1) the entecavir and the magnesium stearate with the prescription amount are respectively micronized by an airflow pulverizer to ensure that the particle size distribution of the entecavir and the magnesium stearate reaches D90Less than or equal to 30 mu m, then putting the entecavir into a three-dimensional mixer Turbula, and mixing for 2 hours at the rotating speed of 100 r/min to prepare a mixture of entecavir magnesium stearate micropowder for later use;
(2) sieving the pregelatinized starch and the microcrystalline cellulose KG-802 with a 80-mesh sieve respectively according to the prescription amount for later use;
(3) mixing the entecavir magnesium stearate micropowder mixture prepared in the step (1) and microcrystalline cellulose KG-802 by an equivalent progressive method for 4 times, sieving with a 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch 1 time by equivalent progressive method, sieving with the 80-mesh sieve for dispersion after mixing to obtain a mixture II, and putting the mixture II, the rest microcrystalline cellulose KG-802 and the rest pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 5
Prescription:
the preparation method comprises the following steps:
(1) adding entecavir and magnesium stearate with prescription dose into a three-dimensional mixer Turbula, mixing for 2 hours at the rotating speed of 100 r/min, and then putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) respectively sieving the pregelatinized starch and the microcrystalline cellulose PH101 with a 80-mesh sieve according to the prescription amount for later use;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and the microcrystalline cellulose 101 by an equivalent progressive method for 4 times, sieving with an 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch in an equivalent progressive manner for 1 time, sieving with the 80-mesh sieve for dispersion after mixing to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose 101 and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 6
Prescription:
the preparation method comprises the following steps:
(1) adding entecavir and magnesium stearate in a prescription amount into a three-dimensional mixer Turbula, mixing for 2 hours at the rotating speed of 100 r/min, and thenThen putting the mixture into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving the pregelatinized starch, the microcrystalline cellulose PH102 and the microcrystalline cellulose PH302 with a 80-mesh sieve respectively according to the prescription amount for later use;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and the microcrystalline cellulose PH102 by an equivalent progressive method for 4 times, sieving with an 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch in an equivalent progressive manner for 1 time, sieving with the 80-mesh sieve for dispersion after mixing to obtain a mixture II, and putting the mixture II, the rest microcrystalline cellulose PH102, the microcrystalline cellulose PH302 and the rest pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Example 7
Prescription:
the preparation method comprises the following steps:
(1) adding entecavir and magnesium stearate with prescription dose into a three-dimensional mixer Turbula, mixing for 2 hours at the rotating speed of 100 r/min, and then putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving the pregelatinized starch, the microcrystalline cellulose PH102 and the microcrystalline cellulose 101 with a 80-mesh sieve respectively according to the prescription amount for later use;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and the microcrystalline cellulose PH102 by an equivalent progressive method for 4 times, sieving with an 80-mesh sieve after each mixing to obtain a mixture I, mixing the mixture I and sieved pregelatinized starch in an equivalent progressive manner for 1 time, sieving with the 80-mesh sieve for dispersion after mixing to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose PH102, the microcrystalline cellulose 101 and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
Test example 1 comparative bioavailability study
The bioavailability of the product of example 1 of the present invention was compared with the bioavailability of the original entecavir tablets (boladine) and the simulated entecavir dispersible tablets (luzhong) which are commercially available. 18 male Wistar rats were selected and randomly divided into a sample group, a boldetermining group and a lubricant-crowd group of example 1 of the present invention, and each group had 6 rats. Each group of rats was gavaged with a dose of 0.5mg/kg of entecavir suspension (in saline) during normal water and food consumption. And samples were taken at 0.08, 0.17, 0.33, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 hours before and after administration, and after sample treatment, the bioavailability was assayed using LC-MS/MS. The results are shown in table 1 below.
TABLE 1 animal test results for bioavailability of the product of the invention, boldetermining, and lubricating
The analysis of the table shows that the bioavailability (AUC) of the product of the embodiment 1 of the invention is improved by 66.7% compared with that of the boldetermining tablet and is improved by 61.2% compared with that of the Runzhong dispersible tablet; half life (t)1/2) Compared with the borlidine tablets and the Runzhong dispersible tablets, the tablet prolongs the time by 7 to 8 hours. The test result shows that the product of the invention improves the curative effect compared with the boletude tablet and the Runzhong dispersible tablet under the condition of non-fasting, effectively overcomes the problem that the existing product needs to be taken on an empty stomach, and improves the compliance of patients to the medicine.
Test example 2 comparative study of dissolution uniformity
Because the specification of the entecavir oral solid preparation is 0.5 mg/grain, the entecavir oral solid preparation belongs to the low content specification, and the content uniformity is suitably inspected by adopting the dissolution uniformity index.
The inventors investigated the dissolution uniformity of the product of example 1 and the original entecavir tablets (boldine) and the simulated entecavir dispersible tablets (luzhong) which are commercially available, and the results of their dissolution uniformity (dissolution versus standard deviation RSD,%) at different time points in three different dissolution media (phosphate buffer solution of ph2.0, ph6.8 and water) are shown in table 2 below (basket method, 900mL medium, 100 rpm, n ═ 12):
table 2 dissolution uniformity (relative standard deviation of dissolution RSD,%) of inventive product, boldetermining and luzhong
As can be seen from the table above, the relative standard deviation RSD of the dissolution rate of the product of the example 1 of the invention in three different dissolution media and at different time points is obviously lower than that of the commercially available borrelidin tablets and Runzhong dispersible tablets, which indicates that the entecavir tablet pharmaceutical composition of the invention has more uniform content uniformity and more stable dissolution release rate.
Claims (3)
1. An entecavir capsule pharmaceutical composition, wherein each 1000 capsules of the pharmaceutical composition comprise:
the particle size distribution characteristic of the micronized entecavir is D90≤30μm；
The micronized magnesium stearate has a particle size distribution characteristic of D90≤30μm；
The micronized entecavir and the micronized magnesium stearate are prepared by mixing an entecavir raw material and a magnesium stearate auxiliary material and then carrying out co-micronization;
the microcrystalline cellulose is selected from one or more of microcrystalline cellulose PH102, microcrystalline cellulose PH302, microcrystalline cellulose PH301, microcrystalline cellulose PHM06, microcrystalline cellulose PHM25, microcrystalline cellulose KG-801, microcrystalline cellulose KG-802, microcrystalline cellulose 101, microcrystalline cellulose 102 and microcrystalline cellulose 200.
2. An entecavir capsule pharmaceutical composition, which is characterized in that each 1000 capsules contain: micronized entecavir 0.5g (as C)12H15N5O3Calculated), 1.0g micronized magnesium stearate, 50g pregelatinized starch, and microcrystalline cellulose PH 10250 g, wherein the particle size distribution characteristics of the micronized entecavir and the micronized magnesium stearate are D90Less than or equal to 30 mu m, and is prepared by mixing entecavir raw material and magnesium stearate auxiliary material and then carrying out co-micronization.
3. The method for preparing an entecavir capsule pharmaceutical composition of claim 1 or 2, comprising the steps of:
(1) mixing Entecavir raw material and magnesium stearate auxiliary material uniformly by a three-dimensional mixer, and putting into a jet mill for co-micronization to obtain D90Mixing entecavir magnesium stearate with particle size less than or equal to 30 μm to obtain a mixture;
(2) sieving pregelatinized starch and microcrystalline cellulose with 80 mesh sieve respectively;
(3) mixing the entecavir magnesium stearate co-micropowder mixture prepared in the step (1) and microcrystalline cellulose for 4 times by adopting an equivalent progressive method, sieving by a 80-mesh sieve after each mixing to obtain a mixture I, performing 1 equivalent progressive mixing on the mixture I and sieved pregelatinized starch, sieving by the 80-mesh sieve for dispersing after mixing to obtain a mixture II, and putting the mixture II, the residual microcrystalline cellulose and the residual pregelatinized starch into a multidirectional motion mixer to mix for 30 minutes at a speed of 10 revolutions per minute;
(4) filling into capsules, and packaging to obtain the finished product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101325945A (en) * | 2005-12-12 | 2008-12-17 | 雅戈泰克股份公司 | Powder compositions for inhalation |
| WO2011076412A1 (en) * | 2009-12-23 | 2011-06-30 | Ratiopharm Gmbh | Oral form of administration comprising entecavir |
| CN102552210A (en) * | 2012-01-10 | 2012-07-11 | 四川海思科制药有限公司 | Entecavir capsule and preparation method thereof |
| CN103435614A (en) * | 2013-08-23 | 2013-12-11 | 四川海思科制药有限公司 | Entecavir compound |
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2018
- 2018-09-18 CN CN201811079954.0A patent/CN108785273B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101325945A (en) * | 2005-12-12 | 2008-12-17 | 雅戈泰克股份公司 | Powder compositions for inhalation |
| WO2011076412A1 (en) * | 2009-12-23 | 2011-06-30 | Ratiopharm Gmbh | Oral form of administration comprising entecavir |
| CN102552210A (en) * | 2012-01-10 | 2012-07-11 | 四川海思科制药有限公司 | Entecavir capsule and preparation method thereof |
| CN103435614A (en) * | 2013-08-23 | 2013-12-11 | 四川海思科制药有限公司 | Entecavir compound |
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