CN112494489B - Apixaban-containing compound sustained-release preparation and preparation method thereof - Google Patents
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Abstract
The invention discloses a compound sustained-release preparation containing apixaban and a preparation method thereof, the preparation consists of apixaban particles, edoxaban sustained-release pellets and other pharmaceutically acceptable auxiliary materials thereof, the edoxaban sustained-release pellets are sequentially provided with a blank pellet core, an isolation coating layer and a drug-containing layer from inside to outside, the drug-containing layer consists of edoxaban, hydroxypropyl cellulose and a filling agent, and the compound sustained-release preparation is obtained by spraying a drug-containing dispersion solution onto a coated pellet core by a bottom spray coating method to obtain a drug-loaded quick-release pellet and then coating the drug-loaded quick-release pellet with a sustained-release coating layer; the apixaban granules are prepared by granulating apixaban, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium. The compound sustained-release preparation can take effect quickly, release medicine stably for a long time, reduce the medicine taking times of patients, improve the compliance and improve the medicine taking safety of the patients, thereby meeting the treatment requirement and meeting the requirement of clinical medicine taking.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of an epixaban compound sustained-release tablet.
Background
Apixaban is a novel oral direct factor Xa inhibitor with the chemical formula of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl]-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c]Pyridine-3-carboxamide. Molecular formula C25H25N5O4And the molecular weight is 459.50. The structural formula is as follows:
activation of factor Xa, the main actual role of which is the production of thrombin by limited proteolysis of prothrombin, is important in the final common pathway of coagulation linking endogenous and exogenous activation mechanisms. The production of thrombin (the final serine protease in the pathway of producing a fibrin clot from its precursors) is amplified by the formation of the prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipids). Since one molecule of factor Xa was calculated to produce 138 thrombin inhibiting molecules, factor Xa may be more effective in disrupting the coagulation system than in the inactivation of thrombin. Thus, factor Xa inhibitors are a class of compounds effective in the treatment of thromboembolic disorders.
Apixaban (apixaban) is an anticoagulant co-developed by Behcet Massachusetts and Perey, and acts directly on coagulation factor Xa, and is used for treating venous thrombotic diseases including Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE). In 5 months 2011, the european union approved the oral factor Xa direct inhibitor apixaban (trade name Eliquis) for marketing to adult patients in elective hip or knee replacement surgery to prevent Venous Thrombosis (VTE). The Apixaban in the existing anticoagulant has obvious treatment effect and can quickly and effectively achieve the treatment effect after being taken, and the Apixaban and a corresponding anticoagulant sustained-release preparation form a compound to form a composition which can quickly release a drug in the early stage of taking the drug and can play a role in releasing the drug stably, thereby having important significance for preventing and treating venous thrombosis.
Edoxaban, chemical name: n- (5-Chloropyridin-2-yl) -N' - [ (1S, 2R, 4S) -4- (dimethylcarbamoyl) -2- (5-methyl-4, 5, 6, 7-tetrahydro [1, 3 ]]Thiazolo [5, 4-c ]]Pyridine-2-carboxamide) cyclohexyl]Acetamide mono (4-methylbenzenesulfonic acid) -hydrate,CAS number: 1229194-11-9, formula: c24H30ClN7O4S.C7H8O3S.H2O, molecular weight: 738.27, having the following chemical formula:
edoxaban (active ingredient: edoxaban p-toluenesulfonate hydrate), a small molecule oral anticoagulant developed by the first three co-company, japan, is a factor Xa blocker, is marketed in japan in 2017 and is listed in the basic drug list (dosage form: tablet, 15, 30 mg). The edoxaban achieves an oral anticoagulant drug for inhibiting thrombosis through selective, reversible and direct inhibition of Fxa, and has 104 times higher selectivity on FXa than FLLa. Japanese foreign clinical trials prove that the product can effectively inhibit the concurrent VTE of patients who receive lower limb plastic surgery, and is safe and reliable. Exoxaban is readily soluble in dimethyl sulfoxide, N-dimethylamide, sparingly soluble in methanol, water, acetonitrile, slightly soluble in ethanol, very slightly soluble in acetone, ethyl acetate, and practically insoluble in isopropanol. After oral Izodan administration, Tmax is about 1-2h, and the absolute bioavailability is 62%. The edoxaban after absorption is in a two-phase distribution, and the steady blood concentration can be reached within 3 d. The main factor influencing the instability of the prepared preparation is that the water absorption is easy due to the self molecular structure. The solution is not ideal when placed at room temperature for a certain time; meanwhile, the preparation is difficult to operate due to strong hygroscopicity and poor fluidity. In addition, the problem that the edoxaban sustained-release tablet prepared in the prior art is unstable in sustained release, large in fluctuation, difficult in auxiliary material selection, unstable in preparation, easy in moisture absorption and the like needs to be solved.
In chinese patent application publication No. CN107773547A, a method for preparing edoxaban sustained-release tablets is disclosed, which contains edoxaban, high-viscosity hypromellose, medium-viscosity hypromellose, water-soluble filler, and other pharmaceutical excipients. But the effect of quick release cannot be achieved, and the release rate is unstable.
In the chinese patent application with publication number CN103919746A, a method for preparing an edoxaban sustained-release matrix tablet is disclosed, the formulation composition (g/g): 14 to 21 percent of Edoxaban p-benzene mesylate hydrate; 0-36% of hydroxypropyl methylcellulose; 0-28% of carbomer; 10 to 28 percent of lactose; 29 to 38 percent of diluent; 0-3% of polyvidone; 0.6-4% of a lubricant. When the prescription does not contain povidone adhesive, the preparation method is to mix the raw materials and the auxiliary materials evenly and then directly tabletting the whole powder, or only use the wetting agent to prepare wet granules, dry and granulate the granules and then tabletting the granules. When the prescription contains povidone as adhesive, the preparation method comprises sieving the raw materials with 120 mesh sieve; uniformly mixing the raw material medicines, hydroxypropyl methylcellulose, carbomer, lactose and a diluent, adding a proper amount of adhesive solution, granulating by a wet method, and drying; and thirdly, granulating, adding a lubricant according to the prescription amount, uniformly mixing and tabletting. The cumulative release amount of the drugs in 1h, 4h and 8h is 15-40%, 40-70% and more than 80%.
Therefore, the development of the compound slow-release tablet of the Idoxaban and the apixaban with good dissolution rate, quick release and stable quality has great significance.
Disclosure of Invention
In order to overcome the problems of unstable blood solubility and slow early-stage drug release rate of the conventional edoxaban tablets after administration, the invention aims to provide the compound sustained-release preparation containing apixaban and the preparation method thereof.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a compound sustained-release preparation containing apixaban is characterized in that firstly, low-substituted hydroxypropyl cellulose is used as a carrier to prepare an edoxaban solid dispersion, so that the solubility of the edoxaban is improved, the solubility of a medicament can be better improved, the stability in the storage process is ensured, and the aim of releasing the medicament stably is fulfilled. And secondly, the slow release coating layer takes ethyl cellulose as a slow release coating material and takes sodium stearyl fumarate as a lubricant, so that the release rate of the drug is better controlled.
The Idoxaban sustained-release pellet is obtained by coating a drug-loaded quick-release pellet with a sustained-release coating layer.
The slow release coating layer material consists of ethyl cellulose, hydroxypropyl cellulose and sodium stearyl fumarate, and the weight ratio of the hydroxypropyl cellulose to the ethyl cellulose to the sodium stearyl fumarate is 1: 5: 1. The weight of the coating is increased by 8 to 12.5 percent based on the ethyl cellulose.
If sodium stearyl fumarate is not added, the obtained sustained-release tablet is relatively slow in initial release, but finally, the viscosity of the sustained-release coating layer is too high, so that the release of the drug in the later period is influenced, the overall release degree is relatively low, and the difference of the release degrees is relatively large.
The drug-loaded quick-release pellet is obtained by carrying a edoxaban dispersion solution on a blank coated pellet core; the edoxaban dispersion solution is obtained by adding edoxaban into a mixed aqueous solution of low-substituted hydroxypropyl cellulose and copovidone; the low-substituted hydroxypropyl cellulose is used as a disintegrant to ensure that the slow-release of the edoxaban is complete; the mass ratio of the edoxaban to the low-substituted hydroxypropyl cellulose to the copovidone is 1 to (1.5-1.8) to (0.15-0.18). Preferably, the ratio is 1: 1.67: 0.167. The copovidone plays a role in preventing the solid dispersion from aging, and if the copovidone is not added, the early-stage drug release is less, and the final release degree is low.
The blank pellet core is made of cross-linked polyvinylpyrrolidone, the isolation coating layer is gastric-soluble film coating powder (purchased from Carlekang, and specifically comprises titanium dioxide, talcum powder, red ferric oxide, polyethylene glycol, polyvinyl alcohol and yellow ferric oxide), and the weight of the isolation coating layer is increased by 15-20% relative to the blank pellet core.
The pharmaceutically acceptable auxiliary materials are filler, disintegrant and lubricant; wherein the filler is selected from one or more of pregelatinized starch, mannitol, and lactose; the disintegrant is selected from crospovidone or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate or calcium stearate.
The preparation method of the compound sustained-release preparation containing apixaban comprises the following specific steps:
(1) preparing isolation coating liquid for later use, sieving the cross-linked polyvinylpyrrolidone with a forty-mesh sieve to remove fine powder, adding into a fluidized bed, and spraying the isolation coating liquid onto the cross-linked polyvinylpyrrolidone by a bottom-spraying coating method for coating to obtain a coated pellet core; the coating material is gastric soluble film coating powder (purchased from Carlekang, and specifically comprises titanium dioxide, talcum powder, red ferric oxide, polyethylene glycol, polyvinyl alcohol and yellow ferric oxide).
(2) Adding the low-substituted hydroxypropyl cellulose and the copovidone into water, stirring until the low-substituted hydroxypropyl cellulose and the copovidone are completely dissolved, adding the edoxaban, and stirring until the edoxaban is dissolved to obtain an edoxaban dispersion solution.
(3) Adding the coated pellet core prepared in the step (1) into a fluidized bed, and spraying the edoxaban dispersion solution prepared in the step (2) onto the coated pellet core by adopting a bottom spraying coating method to obtain the drug-loaded quick-release pellet.
(4) Preparing a sustained-release coating solution for later use, adding the drug-loaded quick-release pellets prepared in the step (3) into a fluidized bed, and spraying the sustained-release coating solution at the bottom for coating to obtain the sustained-release pellets.
(5) Apixaban is mixed with microcrystalline cellulose and croscarmellose sodium, and granulated with hydroxypropyl cellulose solution to obtain granules.
(6) Mixing the Idoxaban sustained-release pellets and the Apixaban particles according to the mixing mass ratio of 27: 80, mixing with other pharmaceutically acceptable adjuvants, and tabletting.
The beneficial effects are as follows:
(1) the compound sustained-release preparation containing apixaban prepared by the invention is prepared by mixing apixaban particles and edoxaban sustained-release pellets coated with sustained-release coatings according to the mixing mass ratio of 27: 80 and tabletting. After the Apixaban granule is orally taken in the stomach, the Apixaban granule can be rapidly disintegrated, rapidly released and rapidly taken. The edoxaban slow-release coating layer slowly and stably releases to achieve the aim of long-acting drug release. Overall, the medicament is quickly released in the early stage, takes effect quickly, is stably released in the later stage, and can obtain better treatment effect. The frequency of taking the medicine by the patient is reduced, the compliance is improved, the safety of taking the medicine by the patient is improved, and the requirement of clinical medication is met.
(2) At the final stage of drug release, water permeates into the pill core, and the blank pill core absorbs moisture and expands to promote complete drug release.
Detailed Description
The technical solution of the present invention will now be further described by examples 1 to 3 shown in table 1.
TABLE 1
The preparation method comprises the following steps:
a) sieving cross-linked polyvinylpyrrolidone with a forty-mesh sieve to remove fine powder, adding into a fluidized bed, and coating by spraying the cross-linked polyvinylpyrrolidone with an isolation coating solution by a bottom-spraying coating method to obtain a coated pellet core; the isolating coating liquid is gastric soluble coating powder, specifically a mixture of titanium dioxide, talcum powder, red ferric oxide, polyethylene glycol, polyvinyl alcohol, yellow ferric oxide and the like, and the coating weight gain is 15%.
b) Adding low-substituted hydroxypropyl cellulose and copovidone into water, stirring until the low-substituted hydroxypropyl cellulose and the copovidone are completely dissolved, adding edoxaban, and stirring until the edoxaban is dissolved to obtain a dispersion solution of the low-substituted hydroxypropyl cellulose and the copovidone; the mass ratio of the low-substituted hydroxypropyl cellulose to the copovidone is 10: 1, the mass ratio of the edoxaban to the low-substituted hydroxypropyl cellulose is 3: 5.
c) Adding the coated pellet core prepared in the step a) into a fluidized bed, and spraying the edoxaban dispersion solution prepared in the step b) onto the coated pellet core by adopting a bottom spraying coating method to obtain the quick-release pellet.
d) Adding part of the quick-release pellets prepared in the step c) into a fluidized bed, spraying a slow-release coating solution at the bottom for coating, wherein the air inlet temperature is 35-40 ℃, the atomization pressure is 0.1-0.2Mpa, the rotating speed of a liquid inlet pump is 5-10rpm, and the weight of the coating is increased by about 25 percent to obtain the slow-release pellets.
e) The sustained-release coating layer takes ethyl cellulose as a sustained-release coating material, takes sodium stearyl fumarate as an anti-sticking agent, takes hydroxypropyl cellulose as a disintegrating agent, wherein the hydroxypropyl cellulose and the sodium stearyl fumarate are mixed by mass, and the mass ratio of the ethyl cellulose to the hydroxypropyl cellulose is 5: 1.
f) Apixaban is mixed with microcrystalline cellulose and croscarmellose sodium, and then added with hydroxypropyl cellulose solution to granulate to obtain granules.
g) Mixing the Idoxaban sustained-release pellets with the Apixaban granules in equal mass, uniformly mixing with other pharmaceutically acceptable auxiliary materials, and tabletting to obtain the drug.
In the embodiments 1 to 3, other pharmaceutically acceptable excipients are hydroxypropyl cellulose, mannitol, microcrystalline cellulose, magnesium stearate as a lubricant, crospovidone as a disintegrant, low-substituted hydroxypropyl cellulose, and croscarmellose sodium.
Comparative example 1
The formulation and process were the same as in examples 1-3, except that copovidone was not added to the formulation of the immediate release pellet.
Comparative example 2
The formulation and process are the same as in examples 1-3 except that sodium stearyl fumarate is not added to the formulation of the sustained release pellets.
Example 4 evaluation of Release degree
And (3) measuring the release degree: 10 samples of the compound slow-release epixaban tablets prepared in each example were sampled, accelerated at 40 ℃ and 75% RH for 6 months, and then measured according to the method of release rate measurement, using a device of a first dissolution rate measurement method, using purified water as a solvent and a rotation speed of 100 rpm, and operated according to the method, measured by ultraviolet spectrophotometry, and absorbance was measured at a wavelength of 237 nm; taking a proper amount of the Izodan and Apixaban reference substances respectively, adding the solvent to dissolve and quantitatively dilute into about 20ug of solution in each 1ml, measuring the absorbance by the same method, calculating the release degree according to an external standard method, and taking the mean value of all the release degrees of each group. The results are as follows:
TABLE 2
The examination conditions of table 3 are: accelerated at 40 deg.C and 75% RH for 6 months.
TABLE 3
The examination conditions of table 3 are: accelerated at 40 deg.C and 75% RH for 6 months.
According to the test results of the above table, the apixaban particles in examples 1-3 can release drug rapidly, and the edaxaban sustained-release pellets take effect slowly in 15 min; the release is stable within 4-16h, the release rate RSD of each tablet is small, and the release is almost complete within 16 h.
In contrast, in comparative example 1, since copovidone functions as a binder, without adding copovidone, the drug concentration in the solid dispersion vehicle exceeds the solubility of the drug in the solid dispersion vehicle at the storage temperature, resulting in aging of the solid dispersion, the final release degree is low, and the difference in the release degrees is large.
Comparative example 2, no sodium stearyl fumarate was added, and although release was faster at the beginning, the final release was lower and the difference in release was greater. It is estimated that sodium stearyl fumarate acts as a lubricant, which can act to improve drug disintegration and promote drug dissolution.
TABLE 4 stability test
Note: table 4 below shows the stability conditions of 40 ℃ and 75% for different storage times.
TABLE 5
Note: table 5 below shows the stability conditions of 40 ℃ and 75% for different storage times.
And (4) conclusion: the experimental results show that the apixaban can play a role in quick drug release in the early stage after the drug is taken, the action of the epixaban is slow in the early stage, and the drug can be released stably in the later stage, so that the epixaban can quickly take effect in the early stage and stably release the drug in the later stage in the epixaban compound sustained-release tablet, the rapid action can be achieved in the early stage, the drug can be released stably in the later stage, and the compliance of a patient is improved.
Claims (6)
1. A compound sustained-release preparation containing apixaban is characterized by comprising apixaban particles, edoxaban sustained-release pellets and pharmaceutically acceptable auxiliary materials; the edoxaban sustained-release pellet comprises a blank pellet core, an isolation coating layer, a drug-containing layer and a sustained-release coating layer from inside to outside in sequence, wherein the drug-containing layer consists of edoxaban, low-substituted hydroxypropyl cellulose and filler copovidone; the mass ratio of the edoxaban, the low-substituted hydroxypropyl cellulose and the copovidone in the medicine-containing layer is 1: (1.5-1.8): (0.15-0.18); the slow release coating layer is composed of ethyl cellulose, hydroxypropyl cellulose and sodium stearyl fumarate, and the weight ratio of the hydroxypropyl cellulose to the ethyl cellulose to the sodium stearyl fumarate is 1: 5: 1; the weight of the coating is increased by 8 to 12.5 percent based on the ethyl cellulose; the Apixaban granule is prepared by mixing Apixaban, microcrystalline cellulose and croscarmellose sodium, and granulating with hydroxypropyl cellulose solution.
2. The compound sustained-release preparation containing apixaban according to claim 1, characterized in that the mass ratio of the epixaban, the low-substituted hydroxypropylcellulose and the copovidone in the drug-containing layer is 1: 1.67: 0.167.
3. the compound sustained-release preparation containing apixaban according to claim 1, characterized in that the blank pellet core material is crosslinked polyvinylpyrrolidone, the isolation coating layer is gastric-soluble film coating powder, and the weight of the isolation coating layer is 15-20% relative to the blank pellet core.
4. The compound sustained-release preparation containing apixaban according to claim 1, characterized in that the pharmaceutically acceptable excipients are filler, disintegrant, lubricant; wherein the filler is selected from one or more of pregelatinized starch, mannitol, and lactose; the disintegrant is selected from crospovidone or low-substituted hydroxypropyl cellulose; the lubricant is selected from magnesium stearate or calcium stearate.
5. The compound sustained-release preparation containing apixaban according to claim 4, characterized in that the apixaban granules are obtained by wet granulation of apixaban, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium, wherein the mass ratio of apixaban, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium is 1-4:40-160:1-4: 2-8.
6. The preparation method of the compound sustained-release preparation containing apixaban according to claim 1, which is characterized by comprising the following steps:
(1) preparing isolation coating liquid for later use, sieving the cross-linked polyvinylpyrrolidone to remove fine powder, adding into a fluidized bed, and spraying the isolation coating liquid onto the cross-linked polyvinylpyrrolidone by a bottom-spraying coating method to obtain coated pellet cores for later use;
(2) adding low-substituted hydroxypropyl cellulose and copovidone into water, stirring until the low-substituted hydroxypropyl cellulose and the copovidone are completely dissolved, adding edoxaban, and stirring until the edoxaban is dissolved to obtain an edoxaban dispersion solution;
(3) adding the coated pellet core prepared in the step (1) into a fluidized bed, and spraying the edoxaban dispersion solution prepared in the step (2) onto the coated pellet core by adopting a bottom spraying coating method to form a drug-containing layer to obtain a quick-release pellet;
(4) preparing a sustained-release coating solution for later use, adding the quick-release pellets prepared in the step (3) into a fluidized bed, and spraying the sustained-release coating solution at the bottom for coating to form a sustained-release coating layer to obtain sustained-release pellets;
(5) mixing apixaban, microcrystalline cellulose and croscarmellose sodium, and granulating with hydroxypropyl cellulose solution to obtain apixaban granule;
(6) mixing the Idoxaban sustained-release pellets and the Apixaban particles according to the mixing mass ratio of 27: 80, mixing with other pharmaceutically acceptable adjuvants, and tabletting.
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| CN103919746A (en) * | 2014-04-17 | 2014-07-16 | 山东省医药工业研究所 | Edoxaban sustained release tablet and preparation method thereof |
| WO2015097090A1 (en) * | 2013-12-23 | 2015-07-02 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical composition |
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| CN107773547A (en) * | 2016-08-24 | 2018-03-09 | 天津市汉康医药生物技术有限公司 | A kind of Yi Dushaban sustained releases tablet medicament composition and preparation method thereof |
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| WO2013022924A1 (en) * | 2011-08-08 | 2013-02-14 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical formulations |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015097090A1 (en) * | 2013-12-23 | 2015-07-02 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical composition |
| CN103919746A (en) * | 2014-04-17 | 2014-07-16 | 山东省医药工业研究所 | Edoxaban sustained release tablet and preparation method thereof |
| CN106860868A (en) * | 2015-12-11 | 2017-06-20 | 北京百奥药业有限责任公司 | The pharmaceutical composition of husky class's class medicine and Lumbrokinase, preparation and its application |
| CN107773547A (en) * | 2016-08-24 | 2018-03-09 | 天津市汉康医药生物技术有限公司 | A kind of Yi Dushaban sustained releases tablet medicament composition and preparation method thereof |
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