CN104771376B - Dronedarone hydrochloride tablet and preparation method thereof - Google Patents
Dronedarone hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN104771376B CN104771376B CN201410016892.4A CN201410016892A CN104771376B CN 104771376 B CN104771376 B CN 104771376B CN 201410016892 A CN201410016892 A CN 201410016892A CN 104771376 B CN104771376 B CN 104771376B
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Abstract
The invention relates to a dronedarone hydrochloride tablet containing poloxamer surfactants and a preparation method thereof. The tablet comprises dronedarone hydrochloride, a molten skeleton material, poloxamer, a disintegrating agent and a lubricating agent; wherein the molten matrix material is a pharmaceutically acceptable polymeric material; the disintegrant is one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more of magnesium stearate, calcium stearate and superfine silica gel powder. The preparation method comprises the following steps: the poloxamer and the molten skeleton material are firstly melted and granulated, and then mixed with the dronedarone hydrochloride and other proper auxiliary materials for granulation to prepare the tablet. The technical scheme of the invention effectively solves the problem that the dronedarone hydrochloride tablet containing the poloxamer surfactant is easy to stick and dash in the preparation process, improves the dissolution rate of the dronedarone hydrochloride, is simple and easy to operate, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of medicinal preparations, particularly relates to a dronedarone hydrochloride tablet and a preparation method thereof, and more particularly relates to a dronedarone hydrochloride tablet containing a surfactant and a preparation method thereof.
Background
Dronedarone hydrochloride (dronedarone hydrochloride) with the chemical name 2-n-butyl-3- [4- (3-di-n-butyl-aminopropoxy) benzoyl ] -5-methylsulfanylbenzofuran hydrochloride, CAS: 141625-93-6, is a drug for treating arrhythmia which is newly developed by the company Cenoffy-Anthrate. Approved by the FDA and europe in the united states for the treatment of paroxysmal or persistent atrial fibrillation in 2009.
Dronedarone hydrochloride has a very low solubility in aqueous media, in particular a solubility which is pH dependent at room temperature, having a maximum solubility in the pH range 3 to 5, about 1-2mg/ml, becoming very low at pH about 6 to 7, and a solubility of only 10 μ g/ml at pH = 7.
Because of the dissolution characteristics, in the process of gradually increasing the pH from the stomach to the intestinal tract, the solubility of dronedarone hydrochloride gradually decreases, and dronedarone hydrochloride cannot be dissolved out or has low dissolution rate from a solid preparation in an intestinal tract environment with higher pH, so that the bioavailability of dronedarone hydrochloride in gastrointestinal tract administration is low, and therefore a method for improving the dissolution rate of dronedarone hydrochloride must be found to improve the bioavailability of dronedarone hydrochloride.
WO9858643A1 discloses a solid pharmaceutical composition containing benzofuran derivatives, and the discovery shows that the addition of poloxamer nonionic surfactant in the preparation can prevent dronedarone hydrochloride from precipitating under the condition of pH6-7, thereby improving the bioavailability of dronedarone hydrochloride. The process comprises mixing all the components except lubricant, heating to 60-65 deg.C, hot granulating, cooling, sieving, lubricating, and tabletting. The adopted poloxamer nonionic surfactant has a low melting point, so that the tabletting is easy to stick and impact in the process.
CN102078307A discloses a dronedarone hydrochloride pharmaceutical composition, which is a tablet prepared by micronizing dronedarone hydrochloride by using a solid dispersion technology and then adding auxiliary materials, and improves the solubility of a main drug. The solvent precipitation technology is used to deposit the drug on the surface of the inert carrier to increase the surface area and thus increase the dissolution rate, but the micronization and solvent precipitation technology adopted in the process is complex and finally causes the solvent residue.
CN100560067C provides a solid pharmaceutical composition comprising micronized dronedarone hydrochloride, a surfactant and a hydrophilic polymer as a co-solvent. However, the micronization technology requires special equipment, and after micronization, the surface energy is increased and easy to gather, which results in increased mixing difficulty.
CN1091593C provides a process which can be prepared by mixing all ingredients except lubricant, including active ingredient and surfactant, together at the initial stage by wet granulation, and then wetting, drying and sieving the granules with purified water for tabletting or encapsulating; it is also possible to mix all the ingredients except the lubricant at the beginning of the process, heat them to 60-65 ℃, then carry out the hot granulation operation, sieve after cooling, lubricate and tablet or fill capsules. However, in both processes, the poloxamer comes into contact with the punch or plunger as the process progresses, causing the poloxamer to melt, thereby causing the poloxamer to stick during the tableting or capsule filling process.
Disclosure of Invention
In order to solve the problems of poor solubility and easy sticking and punching in the production process, the inventor conducts a large number of experiments and unexpectedly finds that the solubility of the medicine can be improved and the problem of easy sticking and punching in the production process of the preparation is solved by adopting a hot-melting extrusion technology to melt and granulate the molten skeleton material and the poloxamer, then mixing the molten skeleton material and the medicine, granulating the mixture, and tabletting the mixture.
The invention provides a dronedarone hydrochloride tablet. The tablet comprises dronedarone hydrochloride, a molten skeleton material, poloxamer, a disintegrating agent and a lubricating agent; the mass ratio of the components is 400:20-400:20-200:10-100: 2-10.
Wherein, the melting framework material is a medicinal polymer material, preferably one or more of copovidone, acrylic resin E and hydroxypropyl cellulose;
the disintegrant is one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone;
the lubricant is one or more of magnesium stearate, calcium stearate and superfine silica gel powder, preferably magnesium stearate.
The dosage of the molten framework material is preferably 30-200 parts; further preferably 80 parts;
the amount of poloxamer is preferably 20 to 100 parts, more preferably 40 parts.
The invention provides a preparation method of dronedarone hydrochloride tablets, in particular to a preparation method of dronedarone hydrochloride tablets containing dronedarone hydrochloride, a molten framework material and poloxamer; more specifically, the invention provides a dronedarone hydrochloride tablet prepared by adopting a hot-melt extrusion technology, which comprises the following steps: the poloxamer and the molten skeleton material are firstly melted and granulated, and then mixed with the dronedarone hydrochloride and other proper auxiliary materials for granulation to prepare the tablet.
The melting framework material is a medicinal polymer material, preferably one or more of copovidone, acrylic resin E and hydroxypropyl cellulose;
other suitable excipients are those pharmaceutical excipients other than poloxamer and molten matrix materials commonly used in the development of oral forms of pharmaceuticals and are well known to those skilled in the art. Other suitable excipients include disintegrants, lubricants; and may further contain a binder, a diluent, etc.;
the disintegrant can be one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone and sodium carboxymethyl starch, preferably crospovidone;
the lubricant can be one or more of magnesium stearate, calcium stearate and aerosil, preferably magnesium stearate;
the binder can be cellulose derivative, such as at least one of methylcellulose, hydroxyethyl cellulose, methylhydroxypropyl cellulose, polyethylene glycol;
the diluent may be at least one of lactose, mannitol, and starch.
The poloxamers and the molten framework material are melted and granulated firstly, so that the poloxamers can be uniformly attached to the molten framework material, sticking can be effectively prevented in the later-stage tabletting process, and the solubility of the tablet can be improved.
The invention has the technical effects that:
(1) the technical scheme provided by the invention obviously improves the dissolution rate of dronedarone hydrochloride.
(2) The technical scheme provided by the invention avoids the problems of low melting point and easy sticking of the surfactant in the production process of the preparation.
(3) The technical scheme provided by the invention has the advantages of simple preparation process and convenient operation, and is suitable for industrial mass production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those skilled in the art to which the present invention pertains are also included in the scope of the present invention. The technical contents not described in detail in the present invention are all known techniques.
Example 1
The preparation process comprises the following steps:
granulating copovidone and poloxamer by using a hot-melt extruder, uniformly mixing with dronedarone hydrochloride and crospovidone, adding a proper amount of pure water, granulating, adding magnesium stearate in a prescription amount into the dried granules, uniformly mixing, and tabletting to obtain the compound.
Example 2
The preparation process comprises the following steps:
granulating acrylic resin E and poloxamer by using a hot-melt extruder, uniformly mixing with dronedarone hydrochloride and crospovidone, adding a proper amount of pure water, granulating, adding magnesium stearate in a formula amount into dried granules, uniformly mixing, and tabletting to obtain the finished product.
Example 3
The preparation process comprises the following steps:
granulating acrylic resin E and poloxamer by using a hot-melt extruder, uniformly mixing with dronedarone hydrochloride and crospovidone, adding a proper amount of pure water, granulating, adding magnesium stearate in a formula amount into dried granules, uniformly mixing, and tabletting to obtain the finished product.
Example 4
The preparation process comprises the following steps:
granulating acrylic resin E and poloxamer by using a hot-melt extruder, uniformly mixing with dronedarone hydrochloride and sodium carboxymethyl starch, adding a proper amount of pure water, granulating, adding magnesium stearate in a prescription amount into dried granules, uniformly mixing, and tabletting to obtain the tablet.
Comparative example 1:
the preparation process comprises the following steps:
mixing acrylic resin E, poloxamer, dronedarone hydrochloride and crospovidone uniformly, adding a proper amount of pure water, granulating, adding magnesium stearate in a prescribed amount into the dried granules, mixing uniformly, and tabletting.
Comparative example 2:
the preparation process comprises the following steps:
mixing acrylic resin E, poloxamer, dronedarone hydrochloride and crospovidone uniformly, adding a proper amount of pure water, granulating, adding magnesium stearate in a prescribed amount into the dried granules, mixing uniformly, and tabletting. (duojia resin uniform sticking)
Comparative example 3:
the preparation process comprises the following steps:
mixing acrylic resin E, dronedarone hydrochloride and crospovidone uniformly, adding a proper amount of pure water, granulating, adding magnesium stearate in a prescribed amount into the dried granules, mixing uniformly, and tabletting to obtain the tablet. (poor solubility without Poloxamer)
Verification of the examples:
1. dronedarone hydrochloride in a solution at ph6.7 was kept for the experiment. First, a micronized solid dispersion solution containing 2mg/ml dronedarone hydrochloride and hydroxypropyl methylcellulose was prepared in phosphate buffer at pH4.5 at 37 ℃ for 2 hours, then the solution was diluted 10-fold in neutral phosphate buffer at pH 7 to a final pH of 6.7, after 2 hours at 37 ℃, the solution was filtered and the active ingredient in the solution was measured with an ultraviolet spectrophotometer, and the results are shown in table 1.
TABLE 1 amount of principal drug in neutral solution
As seen from Table 1, examples 1-4 greatly improved the solubility of the drug in a neutral pH environment; the solubility was also good in comparative examples 1 and 2; comparative example 3 was less effective because no poloxamer was added.
2. Dissolution was measured in phosphate buffer at pH 4.5.
Dissolution conditions: 75 r/min, volume 1000ml, and measuring wavelength 290nm by spectrophotometry. The measurement time was 90min, and the results are shown in Table 2.
Table 2 dissolution in phosphate buffer ph4.5
| Examples | Dissolution rate |
| Example 1 | 98.5% |
| Example 2 | 97.4% |
| Example 3 | 96.9% |
| Example 4 | 96.8% |
| Comparative example 1 | 95.7% |
| Comparative example 2 | 96.7% |
| Comparative example 3 | 80.6% |
As seen from Table 2, the phosphate buffer solution at pH4.5 was poor in dissolution except that poloxamer was not added to comparative example 3.
3. Visual inspection of tablets
TABLE 3 tablet appearance examination
| Examples | Appearance of the product |
| Example 1 | Has good surface |
| Example 2 | Has good surface |
| Example 3 | Has good surface |
| Example 4 | Has good surface |
| Comparative example 1 | Rough surface and obvious sticking phenomenon |
| Comparative example 2 | Rough surface and obvious sticking phenomenon |
| Comparative example 3 | Has good surface |
As seen from Table 3, the comparative examples employ the hot-melt extrusion technique, and the tablets were compressed, and the tablet surface was good; comparative example 3 with no poloxamer added, the sheeting was good; comparative examples poloxamers were added, but were not encapsulated in a polymeric material using hot melt extrusion, all sticking.
In conclusion, the superiority of the invention is further verified. In the process of melting and granulating the poloxamer and the molten skeleton material, the poloxamer and the molten skeleton material can form a co-melt body, and the co-melt body and the molten skeleton material are uniformly mixed, so that the sticking can be effectively prevented in the later-stage tabletting process, and the dissolution rate of the tablet can be improved.
Claims (10)
1. A dronedarone hydrochloride tablet comprises dronedarone hydrochloride, a molten framework material and poloxamer, and the preparation method comprises the following steps: firstly, melting and granulating poloxamer and a molten framework material, mixing with dronedarone hydrochloride and other auxiliary materials, granulating, and preparing tablets;
the molten skeleton material is a medicinal polymer material;
the other auxiliary materials comprise a disintegrating agent and a lubricating agent;
the melting framework material is one or more of copovidone, acrylic resin E and hydroxypropyl cellulose;
the mass ratio of the dronedarone hydrochloride, the molten skeleton material, the poloxamer, the disintegrating agent and the lubricating agent is 400:20-400:20-200:10-100: 2-10;
the disintegrating agent is one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone and sodium carboxymethyl starch.
2. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the disintegrant is crospovidone.
3. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the lubricant is one or more of magnesium stearate, calcium stearate and superfine silica gel powder.
4. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the lubricant is magnesium stearate.
5. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the dosage of the melting framework material is 30-200 parts.
6. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the dosage of the melting framework material is 80 parts.
7. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the dosage of the poloxamer is 20-100 parts.
8. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the dosage of the poloxamer is 40 parts.
9. A dronedarone hydrochloride tablet as claimed in claim 1, wherein: the other auxiliary materials also contain a bonding agent and a diluting agent; the binder is cellulose derivative, and the diluent is at least one of lactose, mannitol, and starch.
10. The dronedarone hydrochloride tablet of claim 9 wherein: the binder is at least one of methylcellulose, hydroxyethyl cellulose, methyl hydroxypropyl cellulose, and polyethylene glycol.
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| CN201410016892.4A CN104771376B (en) | 2014-01-15 | 2014-01-15 | Dronedarone hydrochloride tablet and preparation method thereof |
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| CN201410016892.4A CN104771376B (en) | 2014-01-15 | 2014-01-15 | Dronedarone hydrochloride tablet and preparation method thereof |
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| CN104771376B true CN104771376B (en) | 2021-01-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105412027B (en) * | 2015-11-13 | 2018-10-26 | 青岛市海慈医疗集团 | A kind of preparation method of Dronedarone hydrochloride tablet |
| CN108042501A (en) * | 2017-12-28 | 2018-05-18 | 广东伊茗药业有限公司 | A kind of Dronedarone hydrochloride tablet without surfactant |
| US20240148693A1 (en) * | 2021-03-17 | 2024-05-09 | Changsha Jingyi Pharmaceutical Technology Co., Ltd | Composition, preparation method therefor, and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1267217A (en) * | 1997-06-23 | 2000-09-20 | 萨诺菲-合成实验室公司 | Solid pharmaceutical composition contg. benzofurane derivs. |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1267217A (en) * | 1997-06-23 | 2000-09-20 | 萨诺菲-合成实验室公司 | Solid pharmaceutical composition contg. benzofurane derivs. |
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