CN104771375A - Dronedarone hydrochloride tablet and preparation method thereof - Google Patents
Dronedarone hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN104771375A CN104771375A CN201410016812.5A CN201410016812A CN104771375A CN 104771375 A CN104771375 A CN 104771375A CN 201410016812 A CN201410016812 A CN 201410016812A CN 104771375 A CN104771375 A CN 104771375A
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- dronedarone hydrochloride
- citric acid
- dronedarone
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- hydrochloride tablet
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Abstract
The invention discloses a dronedarone hydrochloride tablet and a preparation method thereof; the tablet contains citric acid and is prepared by the following method: mixing dronedarone hydrochloride, citric acid and pharmaceutically common auxiliary materials evenly, adding an aqueous solution, granulating, drying, adding a lubricant, mixing, and tabletting to obtain the product. Compared with the prior art, the dronedarone hydrochloride tablet has the dissolution rate of dronedarone hydrochloride in tap water significantly improved, and the in-vivo environment is better simulated; micronization, dispersion preparation and other complex operations are not needed, the preparation process is relatively simple, operations are convenient, addition of poloxamer and other surfactants are not needed, and the tablet is rapidly dissolved in a gastric juice.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, in particular to a kind of Dronedarone hydrochloride tablet and preparation method thereof.
Background technology
Dronedarone chemistry 2-normal-butyl-3-[4-(3-di-n-butyl-amino propoxyl group) benzoyl]-5-methyl sulfonamide benzofuran by name is the treatment antiarrhythmic medicament having Sai Nuofei-first De Nabao company recent development.
Dronedarone hydrochloride dissolubility in water-bearing media is very low, particularly its dissolubility at room temperature presents pH dependency, in the scope of pH3 to 5, have maxima solubility, is about 1-2mg/ml, become very low at pH about 6 to 7 times dissolubility, under pH=7, dissolubility only has 10 μ g/ml.
Just because of it dissolves feature, so the process raised gradually at this pH of the process from stomach to intestinal, the dissolubility of dronedarone hydrochloride reduces gradually, by to cause under the intestinal environment of higher pH cannot from solid preparation stripping or dissolution very low, cause the bioavailability of dronedarone hydrochloride gastrointestinal administration low, therefore the method that can improve dronedarone hydrochloride dissolution must be found, to improve its bioavailability
WO9858643 discloses a kind of solid composite medicament containing benzofuran derivatives, it finds to add poloxamer class nonionic surfactant in preparation, dronedarone hydrochloride can be made under pH6-7 condition can not to separate out precipitation, improve the bioavailability of dronedarone hydrochloride.But poloxamer fusing point is low, at about 60 DEG C, easy sticking during tabletting.
CN102078307A discloses a kind of Dronedarone hydrochloride pharmaceutical composition, the tablet made with adjuvant again after dronedarone hydrochloride being utilized solid dispersion technology micronization processes, improves the dissolubility of principal agent.Employ solvent deposition technology, by drug deposition in inert carrier surface, to increase surface area, thus improve dissolution rate, but technique is comparatively complicated.
CN100560067C provides a kind of solid composite medicament, wherein containing micronized dronedarone hydrochloride, surfactant and the hydrophilic polymer as cosolvent.
Inventor considers that prior art is using pH4.5 phosphate buffer as dissolution medium, fully can not simulate human body environment, because dronedarone hydrochloride is in the medium of pH4.5, dissolubility is best, therefore inventor intends selecting water as dissolution medium, preparation can in water the Dronedarone hydrochloride tablet of Fast Stripping.For improving Dronedarone hydrochloride tablet dissolution, carry out great many of experiments, unexpected discovery is when carrying out stripping and measuring, if residual a small amount of tap water in stripping rotor, medicinal liquid will be muddy rapidly, for confirming this phenomenon further, inventor adds a small amount of tap water by the solution of dronedarone hydrochloride, medicinal liquid becomes mixed, and absorbance obviously reduces, and does not all propose solution in prior art.
In prior art, adopt phosphatic purification of aqueous solutions as dissolution medium, fail fully to simulate human gastrointestinal tract environment, consider that human body drinking water is tap water, therefore can better human body environment be simulated with tap water.The object of the present invention is to provide a kind of Dronedarone hydrochloride tablet, adopt polymer solution in water as dissolution medium, also can stripping completely.
For reaching the object of the invention, inventor considers that reason that medicine is separated out may be that ion in tap water is combined with medicine, forms slightly solubility complex, if add complexing of metal ion agent, likely solves the problem.
In prior art, for above-mentioned situation, first it is envisioned that chelating agent is added, no doubt, adding chelating agent can solve the problem, but for dronedarone hydrochloride, not not merely solve its problem separated out, because its dissolubility and pH have dependency, even if therefore solve run into tap water separate out problem, also cannot avoid the problem that medicine is separated out in the Stomach in Patients that gastric acid secretion is few.
For solving the problem, inventors performed a large amount of creative experiments, finding unexpectedly, when adding citric acid in Dronedarone hydrochloride tablet, when stripping measures, preferably resolving the problems referred to above, achieving beyond thought effect.
Particularly, inventor is screened by lot of experiments, and finally obtains the technical scheme realizing the object of the invention as follows:
The invention provides a kind of Dronedarone hydrochloride tablet, containing citric acid in tablet, and prepare by the following method: dronedarone hydrochloride, citric acid are mixed homogeneously with pharmaceutically conventional adjuvant, add aqueous solution to granulate, drying, adds mix lubricant, and tabletting forms.
Dronedarone hydrochloride tablet of the present invention, the weight ratio of dronedarone hydrochloride and citric acid is 1:0.2-0.4.
Further preferably, the weight ratio of dronedarone hydrochloride and citric acid is 1:0.3.
Dronedarone hydrochloride tablet of the present invention, pharmaceutically conventional adjuvant comprises disintegrating agent, filler.
Described disintegrating agent is one or more in polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium.
Described filler is one or more in microcrystalline Cellulose, lactose, starch, mannitol.
Dronedarone hydrochloride tablet of the present invention, prepare by the following method:
Dronedarone hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, citric acid all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
The technology of the present invention effect is:
(1) a kind of Dronedarone hydrochloride tablet of the present invention, significantly improves the dissolution of dronedarone hydrochloride in tap water, simulates internal milieu preferably.
(2) a kind of Dronedarone hydrochloride tablet of the present invention, without the need to complex operations such as micronization, preparation dispersions, preparation process is fairly simple, easy to operate.
(3) a kind of Dronedarone hydrochloride tablet of the present invention, does not need to add the surfactants such as poloxamer, i.e. rapid stripping in gastric juice.
Summary of the invention
Detailed description of the invention
Now further describe beneficial effect of the present invention by following examples, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
Embodiment 1
Dronedarone hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, citric acid all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
Embodiment 2
Dronedarone hydrochloride, lactose, cross-linking sodium carboxymethyl cellulose, citric acid all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
Embodiment 3
Dronedarone hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, citric acid all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
Comparative example 1
Dronedarone hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
Comparative example 2
Dronedarone hydrochloride comminution by gas stream, obtains the micronize dronedarone hydrochloride that particle diameter is less than 15nm; Sodium lauryl sulfate and PVP K30 are dissolved in water, are suspended wherein by micronize dronedarone hydrochloride, obtain suspension; Lactose is suspended in fluidized bed pelletizer, is sprayed in lactose by suspension and granulates, made granule, additional enter microcrystalline Cellulose PH101 and magnesium stearate, mixing, tabletting.
Comparative example 3
(1) dronedarone hydrochloride solid dispersion: take dronedarone hydrochloride, microcrystalline Cellulose respectively, adds alcoholic solution stirring and dissolving, reduction vaporization removing dehydrated alcohol, vacuum drying, ground No. 6 sieves.
(2) take adjuvant used respectively to dry in advance, cross No. 6 sieves, recipe quantity takes.
(3) by after (1) and (2) mix homogeneously, adopt 1% hydroxypropyl emthylcellulose alcoholic solution to granulate, 55 DEG C are dried to moisture lower than 3%.
(4) always mix, granule (3) is added magnesium stearate, partial cross-linked sodium carboxymethyl cellulose, tabletting after mixing.
Comparative example 4
Above-mentioned material was pulverized 80 mesh sieves respectively, after abundant to dronedarone hydrochloride, lactose, microcrystalline Cellulose, citric acid and PVP S630 mix homogeneously, add water soft material processed, 18 mesh sieves are granulated, 60 DEG C of drying about 2h, 16 mesh sieve granulate, add magnesium stearate outward, mixing, tabletting, film coating.
Comparative example 5
Get dronedarone hydrochloride 42.6g, soybean phospholipid 4g is scattered in 500ml70% ethanol, adopt spraying dry to obtain powder, powder and pregelatinized Starch 5g, crospolyvinylpyrrolidone 5g, castor oil hydrogenated 0.6g are mixed tabletting afterwards.
Checking embodiment:
Dissolution is measured in polymer solution in water.Dissolution conditions: 75 turns/min, volume 1000ml, according to spectrophotometry, measures wavelength 290nm.Minute 15min, 45min.
Table 1 is dissolution in tap water
| Embodiment | 15min dissolution (%) | 45min dissolution (%) | Dissolution fluid state |
| Embodiment 1 | 85.6 | 99.9 | Comparatively clarify |
| Embodiment 2 | 87.4 | 98.9 | Comparatively clarify |
| Embodiment 3 | 86.8 | 100.2 | Comparatively clarify |
| Comparative example 1 | 10.2 | 23.5 | Turbid solution |
| Comparative example 2 | 34.5 | 75.1 | Turbid solution |
| Comparative example 3 | 46.2 | 70.3 | Turbid solution |
| Comparative example 4 | 20.1 | 64.1 | Turbid solution |
| Comparative example 5 | 36.5 | 71.3 | Turbid solution |
As seen from Table 1, the embodiment of the present invention all energy Fast Strippings completely in polymer solution in water, dissolution fluid is comparatively clarified; Comparative example 1, do not add citric acid, and drug-eluting is slow, and dissolution fluid becomes turbid solution; Comparative example 2,3,4,5, adopt prior art, and in tap water medium, stripping is slow, and medicinal liquid becomes muddy, reason be all do not add citric acid in the present invention or addition few.
2, directly in pH4.5 phosphate buffer (pure water preparation), dissolution is measured.
Dissolution conditions: 75 turns/min, volume 1000ml, according to spectrophotometry, measures wavelength 290nm.Minute 15min, 45min
| Embodiment | 15min dissolution (%) | 45min dissolution (%) | Dissolution fluid state |
| Embodiment 1 | 90.3 | 100.2 | Comparatively clarify |
| Embodiment 2 | 91.2 | 100.7 | Comparatively clarify |
| Embodiment 3 | 92.6 | 99.8 | Comparatively clarify |
| Comparative example 1 | 86.2 | 96.4 | Comparatively clarify |
| Comparative example 2 | 87.4 | 97.6 | Comparatively clarify |
| Comparative example 3 | 83.4 | 96.8 | Comparatively clarify |
| Comparative example 4 | 51.2 | 93.6 | Comparatively clarify |
| Comparative example 5 | 62.4 | 94.5 | Slightly muddy |
As seen from Table 2, in pH4.5 phosphate buffer (pure water preparation), embodiment is smaller with comparative example's drug-eluting result difference.
3, in pH4.5 phosphate buffer (tap water preparation), dissolution is measured.
Dissolution conditions: 75 turns/min, volume 1000ml, according to spectrophotometry, measures wavelength 290nm.Minute 15min, 45min
| Embodiment | 15min dissolution (%) | 45min dissolution (%) | Dissolution fluid state |
| Embodiment 1 | 90.2 | 99.8 | Comparatively clarify |
| Embodiment 2 | 89.7 | 99.7 | Comparatively clarify |
| Embodiment 3 | 91.3 | 100.2 | Comparatively clarify |
| Comparative example 1 | 56.2 | 78.4 | Turbid solution |
| Comparative example 2 | 62.1 | 80.3 | Turbid solution |
| Comparative example 3 | 63.6 | 82.5 | Turbid solution |
| Comparative example 4 | 25.6 | 68.5 | Turbid solution |
| Comparative example 5 | 38.4 | 73.5 | Turbid solution |
As seen from Table 3, embodiment of the present invention 1-3, drug-eluting is rapid, and medicinal liquid is comparatively clarified; Comparative example 1, and medicinal liquid is muddy, and dissolution is obviously slack-off, and final stripping is incomplete; Comparative example 2,3,4,5, and medicinal liquid is muddy equally, and stripping is slack-off, and stripping is incomplete.
Comprehensive described result, although (pure water preparation) all energy strippings completely in pH4.5 phosphate buffer of all embodiments, in tap water, dissolution has notable difference, demonstrates superiority of the present invention.
Claims (8)
1. a Dronedarone hydrochloride tablet, is characterized in that, containing citric acid in tablet, and prepare by the following method: dronedarone hydrochloride, citric acid are mixed homogeneously with pharmaceutically conventional adjuvant, add aqueous solution and granulate, dry, add mix lubricant, tabletting forms.
2. Dronedarone hydrochloride tablet according to claim 1, is characterized in that, the weight ratio of dronedarone hydrochloride and citric acid is 1:0.2-0.4.
3. Dronedarone hydrochloride tablet according to claim 1, is characterized in that, the weight ratio of dronedarone hydrochloride and citric acid is 1:0.3.
4. Dronedarone hydrochloride tablet according to claim 1, is characterized in that, pharmaceutically conventional adjuvant comprises disintegrating agent, filler.
5. Dronedarone hydrochloride tablet according to claim 4, is characterized in that, disintegrating agent is one or more in polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium.
6. Dronedarone hydrochloride tablet according to claim 4, is characterized in that, filler is one or more in microcrystalline Cellulose, lactose, starch, mannitol.
7. Dronedarone hydrochloride tablet according to claim 1, is characterized in that, prepares by the following method:
Dronedarone hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, citric acid all cross 100 mesh sieves, and recipe quantity takes, mix homogeneously, adds aqueous solution, granulate, by made granule and magnesium stearate mixing, and tabletting.
8. a preparation method for Dronedarone hydrochloride tablet, is characterized in that, it comprises the steps: that dronedarone hydrochloride, citric acid are mixed homogeneously with pharmaceutically conventional adjuvant, and add aqueous solution and granulate, dry, add mix lubricant, tabletting forms.
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| CN201410016812.5A CN104771375B (en) | 2014-01-15 | 2014-01-15 | A kind of Dronedarone hydrochloride tablet and preparation method thereof |
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| CN201410016812.5A CN104771375B (en) | 2014-01-15 | 2014-01-15 | A kind of Dronedarone hydrochloride tablet and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108042499A (en) * | 2017-12-19 | 2018-05-18 | 佛山市弘泰药物研发有限公司 | A kind of dronedarone hydrochloride dispersible tablet and preparation method thereof |
| CN108042489A (en) * | 2017-12-19 | 2018-05-18 | 佛山市弘泰药物研发有限公司 | A kind of dronedarone hydrochloride self-micro emulsion formulation and preparation method thereof |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614139A (en) * | 2011-01-28 | 2012-08-01 | 杭州容立医药科技有限公司 | Solid pharmaceutical composition containing benzofuran derivative |
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- 2014-01-15 CN CN201410016812.5A patent/CN104771375B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614139A (en) * | 2011-01-28 | 2012-08-01 | 杭州容立医药科技有限公司 | Solid pharmaceutical composition containing benzofuran derivative |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108042499A (en) * | 2017-12-19 | 2018-05-18 | 佛山市弘泰药物研发有限公司 | A kind of dronedarone hydrochloride dispersible tablet and preparation method thereof |
| CN108042489A (en) * | 2017-12-19 | 2018-05-18 | 佛山市弘泰药物研发有限公司 | A kind of dronedarone hydrochloride self-micro emulsion formulation and preparation method thereof |
| 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 |
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