CN102579421A - Antiarrhythmic medicinal composition and preparation method thereof - Google Patents
Antiarrhythmic medicinal composition and preparation method thereof Download PDFInfo
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- CN102579421A CN102579421A CN2012100765574A CN201210076557A CN102579421A CN 102579421 A CN102579421 A CN 102579421A CN 2012100765574 A CN2012100765574 A CN 2012100765574A CN 201210076557 A CN201210076557 A CN 201210076557A CN 102579421 A CN102579421 A CN 102579421A
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Abstract
The invention relates to an antiarrhythmic medicinal composition and a preparation method thereof. According to the composition, active ingredients comprise dronedarone or pharmaceutically-acceptable salt thereof, and non-active ingredients comprise one or more of polymers and multiple common additives of preparations. The preparation process for the composition comprises the key step of preparing solid dispersoid by a hot-melting extrusion method, so that tablets, capsules and granules can be prepared. The invention has the advantages that: a preparation with a high dissolution rate can be prepared according to a proper formula by a simple and pollution-free process, and the preparation can be absorbed well in bodies; and samples are stable under the condition of accelerated tests.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of anti-arrhythmic composition and method of making the same.
Background technology
In treatment arrhythmia field, amiodarone is one of active drug, but the untoward reaction of prolonged application amiodarone is more, is main with thyroid, retinal damage and pulmonary's toxicity wherein, and the iodine in above-mentioned untoward reaction and its structure is in close relations.Dronedarone is a benzofuran derivatives; Chemical constitution with the similar amiodarone that does not contain iodine, atomic to the influence of thyroxin, its lipotropy than amiodarone a little less than; Take back phospholipid and can not be deposited on pulmonary, so the outer untoward reaction of cardiovascular system is lacked than amiodarone.And dronedarone all has retardation to calcium, potassium, sodium channel, and has antiadrenergic drug and can act on, and toleration is good.Clinical trial proves: dronedarone is present unique antiarrhythmic drug that can significantly reduce atrial fibrillation/atrial flutter patient M & M that demonstrates.
Hydrochloric acid dronedarone chemistry is by name: N-[2-butyl-3-[4-[3-(dibutylamino) propoxyl group] phenyl]-5-benzofuranyl]-sulfonyl methane amine hydrochlorate, molecular weight 593.22.Dissolubility is a pH dependent form, between pH3-5, and the solvable 2g medicine of terminating an agreement in every 1000mL medium, soluble,very slightly in the water; And it is almost insoluble in the pH1.0 hydrochloric acid solution, pH6.8 buffer.Therefore though medicine in gastric environment dissolving after the meal better gets into that will separate out fast behind the intestinal about pH6.8 can't be by the crystal that directly absorbs, first pass effect of hepar in addition, the dronedarone absolute bioavailability is lower.
Chinese patent 98808158.X discloses a kind of solid composite medicament that contains benzofuran derivatives; Comprise non-ionic surface active agent and dronedarone or its hydrochlorate, the non-ionic hydrophilic surfactant poloxamer 407 in the compositions can make medicine when getting into the pH6.7 environment by the pH4.5 environment, keep more dissolved state.This patent drugs shows for the dynamic test result: administration under the fasted conditions, and the prescription Cmax and the AUC that contain poloxamer 407 are all obvious greater than the prescription that does not contain poloxamer 407; For administration after the meal, the influence that whether contains 407 couples of Cmax of poloxamer and AUC is not obvious; Administration Cmax and AUC all are starkly lower than the feed condition under the prescription fasted conditions of poloxamer 407 but contain.
Chinese patent CN 100560067C discloses a kind of hydrochloric acid dronedarone medicinal compositions for oral use and preparation method thereof, unites and uses polyvinylpyrrolidone and sodium lauryl sulphate to improve drug dissolution.But with regard to practical application, the sodium lauryl sulphate consumption might produce acute toxicities such as zest to body in this patent.
Therefore, be necessary to develop a kind of new dronedarone medicinal compositions for oral use.
Summary of the invention
The present invention relates to a kind of pharmaceutical composition, it comprise dronedarone or its pharmaceutically acceptable salt as active component, and the acceptable polymer of pharmacy.
Dronedarone pharmaceutically acceptable salt described in the present invention can be selected from but be not limited to hydrochlorate, citrate, maleate, tartrate, sulfate, nitrate, mesylate, hydrobromate, wherein the preferred salt hydrochlorate.
It is 200～400mg that each administration unit of pharmaceutical composition of the present invention contains with the dronedarone active ingredient calculated, and promptly to contain with the dronedarone active ingredient calculated be 200～400mg for each tablet, each capsule or every bag of granule.
Described in the present invention, pharmaceutically acceptable polymers include, but are not limited to polyethylene glycol 6000 - Vinyl caprolactam - vinyl acetate copolymers, polyvinyl pyrrolidone - vinyl acetate copolymers, polyvinylpyrrolidone ketones, acrylic resin , cellulose derivatives such as one or more, in which polyethylene glycol 6000 - Vinyl caprolactam - vinyl acetate copolymer is
Polyvinylpyrrolidone - vinyl acetate copolymers selected from
VA64,
S-630 etc.; povidone ketone selected from povidone K30, Povidone K90, etc.; acrylic resin selected from
EPO,
E100,
MAE? 100P, etc.; cellulose derivatives selected from hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropylmethyl cellulose phthalate and the like.The part by weight of acceptable polymer of said pharmacy and dronedarone is 0.2: 1～10: 1, preferred 0.5: 1～2: 1.
Except that the acceptable polymer of pharmacy, pharmaceutical composition of the present invention also can contain the pharmacy acceptable additive, comprises adhesive, disintegrating agent, filler, lubricant, fluidizer etc.Adhesive can link together material separate, can select hypromellose, polyvinylpyrrolidone etc., and the part by weight of adhesive and dronedarone is 0.05: 1～1: 1, preferred 0.1: 1～0.4: 1.Disintegrating agent has good water absorption and dilatancy; Make preparation split the material that is broken into fine particle in vivo rapidly; Thereby make rapidly dissolving and being absorbed of medicine; Optional choosing friends joins sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, low-substituted hydroxypropyl cellulose etc., and the part by weight of disintegrating agent and dronedarone is 0.05: 1～1: 1, preferred 0.1: 1～0.4: 1.Filler can be beneficial to the solid preparation molding, and can prevent effectively that solid dispersion from assembling agglomeratingly in process in leaching, can select starch, lactose, microcrystalline Cellulose etc., and the part by weight of filler and dronedarone is 0.1: 1～5: 1, preferred 0.1: 1～1: 1.Fluidizer, lubricant can improve mobility of particle, alleviate the frictional force between storeroom and material and mould; Can be selected from Pulvis Talci, silicon dioxide, magnesium stearate, polyethylene glycol 6000 etc.; The part by weight of fluidizer, lubricant and dronedarone is 0.005: 1～0.2: 1, preferred 0.01: 1～0.1: 1.
Composition process of the present invention is: at first prepares solid dispersion, again solid dispersion formed preparation, specific as follows:
A. prepare solid dispersion:
With dronedarone or its pharmaceutically acceptable salt and the acceptable polymer mixed of pharmacy, add the hot melt extruder, the extrudate that obtains is through cooling off, pulverize, sieving.
The temperature that hot melt is extruded is: 80～250 ℃, and preferred 110～170 ℃.The extruder rotating speed is 5～100rpm, preferred 20～40rpm.
B. the current techique through this area forms appropriate formulation with solid dispersion and pharmacy acceptable additive.
Compositions of the present invention is used to treat arrhythmia, is applicable to paroxysmal or permanent atrial fibrillation or atrial flutter patient.
The invention has the advantages that: for the poorly water soluble drugs as dronedarone and salt thereof; Through choose suitable carrier, employing hot melt extrusion molding prepares solid dispersion; Behind softening, melting, shearing, dispersion, remix; Raw material farthest is scattered in the hydrophilic polymer, and process advantage and carrier character can significantly be improved drug dissolution and degree of absorption.And raw material need not micronization, does not introduce organic solvent in the production process, can not cause environmental pollution.
Be embodied in:
1. compare with crude drug, polymer can significantly improve drug dissolution;
2. compare with traditional mixing, granulation, tablet forming technique, process preparation again behind the preparation solid dispersion, external stripping of medicine and area under the drug-time curve significantly improve;
3. technology proposed by the invention for just mix, hot melt is extruded, crushing screening, always mix, process preparation, need not to add water, drying-free in the process, thereby effectively avoid drug hydrolysis; This technology also need not micronization, need not to add organic solvent, the simple environmental protection of technology.
Description of drawings:
Accompanying drawing 1 dronedarone raw material, comparative example tablet, embodiment 4 physical mixtures, embodiment 4 solid dispersion, embodiment 4 tablets stripping curve in the pH1.0 hydrochloric acid solution
Accompanying drawing 2 hydrochloric acid dronedarone sheets (embodiment 4 tablets and comparative example tablet) curve when the intravital medicine of beasle dog
The specific embodiment
Following embodiment is used to further specify the present invention, but is not the restriction to protection domain of the present invention.The hydrochloric acid dronedarone is that Jiangsu Simcere Pharmaceutical Research Co., Ltd is from grinding.
Embodiment 1
Table 1 embodiment 1 prescription is formed
The preparation solid dispersion:
With
(polyethylene glycol 6000-caprolactam-vinyl acetate co-polymer) and hydrochloric acid dronedarone (in base) according to the prescription mixed, physical mixture.Set hot melt extruder temperature and rotating speed, physical mixture is added the feedstuff device, extrude, pulverize, sieve, subsequent use.
The solid dispersion post processing:
According to prescription ratio in the last table hydrochloric acid dronedarone solid dispersion, microcrystalline Cellulose, hypromellose, polyvinylpolypyrrolidone are mixed, add recipe quantity magnesium stearate and silicon dioxide again, mixing.
Said mixture can direct compression, also can load capsule or directly be packaged into granule.Other embodiment also together.
Embodiment 2
Table 2 embodiment 2 prescriptions are formed
Preparation technology is with embodiment 1.
Embodiment 3
Table 3 embodiment 3 prescriptions are formed
Preparation technology is with embodiment 1.
Table 4 embodiment 4 prescriptions are formed
Preparation technology is with embodiment 1.
Comparative example
Use wet granulation technology to prepare hydrochloric acid dronedarone sheet, prescription is formed with reference to embodiment 4
Table 5 comparative example 1 prescription is formed
| The hydrochloric acid dronedarone | 213mg |
| Kollidon?VA?64 | 400mg |
| Partially pregelatinized starch PC-10 | 139mg |
| Polyvinylpolypyrrolidone | 40mg |
| Magnesium stearate | 4mg |
| Silicon dioxide | 4mg |
| Sheet is heavy | 800mg |
Technology:
Recipe quantity hydrochloric acid dronedarone, Kollidon VA 64, partially pregelatinized starch, 1/2 recipe quantity polyvinylpolypyrrolidone are mixed; With the purified water is the wetting agent wet granulation; Dry back granulate adds residue polyvinylpolypyrrolidone, magnesium stearate, silicon dioxide, mixing, tabletting.
Invention effect one: the solubilization of solid dispersion
Test method: adopt dissolution slurry method to measure.Get a tablet and drop into 1000mL, pH1.0 hydrochloric acid towards liquid (hydrochloric 9ml, polyoxyethylene sorbitan monoleate 2g among every 1000mL); Keep 37 ± 5 ℃; 75rpm, respectively at 10,20,30,45,60, the 90min sampling, and additional equal volume dissolution medium; 0.8 μ m filtering with microporous membrane is got subsequent filtrate as need testing solution.Other gets the about 21mg of reference substance, puts in the 50ml measuring bottle, adds ethanol and makes dissolving in right amount and be diluted to scale, shakes up, as reference substance solution.Precision is measured need testing solution and each 1ml of reference substance solution; Put respectively in the 20ml measuring bottle; Add the stripping medium to scale, shake up, according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2010 A); Wavelength at 290nm is measured absorbance respectively, calculates every accumulation dissolution at above-mentioned time point.The result sees accompanying drawing 1.
Accompanying drawing is 1 result show:
1. the physical mixture dissolution is higher than crude drug, and promptly Kollidon VA 64 has certain solubilization;
2. though the dissolution of solid dispersion is higher than physical mixture, solubilising power is limited, and dissolution increases not obvious behind the 10min.Reason possibly assembled agglomeratingly in medium for the solid dispersion powder, suppresses the medicine stripping.Need pay close attention to preparation disintegrate situation during the post processing of prompting solid dispersion;
3. embodiment 4 formulation and technologies promote dissolution and have remarkable contribution.
Invention effect two: solid dispersion promotes drug absorption
Research beasle dog oral before the meal embodiment 4 tablets, oral embodiment 4 tablets and comparative example tablet medicine be for dynamic behavior after the meal, relatively under three kinds of situation medicine in the intravital absorption difference of dog.The result sees accompanying drawing 2.
Accompanying drawing is 2 results show:
1. in beasle dog pharmacokinetics test after the meal; Peak reaching time of blood concentration is almost consistent in two kinds of preparation bodies; But the highest blood drug level and the area under the drug-time curve of embodiment 4 tablets all are significantly higher than the comparative example tablet, and this result and dissolution in vitro result are consistent.Explain that using the hot melt extrusion molding to prepare solid dispersion in the preparation process can promote drug absorption.
2. embodiment 4 tablets are taken peak reaching time of blood concentration before the meal and are lagged behind after the meal slightly and take medicine; And maximum plasma concentration is lower than after the meal slightly; But both area under the drug-time curve are roughly suitable; Explain that the possibility onset of taking medicine before the meal is slow slightly, but with regard to whole structure, the influence of the absorption unable to take food thing of gained preparation of the present invention.
Invention effect three: the prepared tablet of solid dispersion gets study on the stability
To put the stability test case according to the tablet aluminium-plastic bubble plate packing of embodiment 4 preparations, the condition that keeps sample is 40 ℃/75%RH.Respectively at 1,2,3,6 month sampling and measuring content, related substance, dissolution, and with 0 o'clock relatively.
Table 7 embodiment 4 sample stabilities (40 ℃/75%RH)
Table 7 is the result show, composition stable property of the present invention is better.
Claims (10)
1. pharmaceutical composition; It is characterized in that comprising dronedarone or its pharmaceutically acceptable salt, the acceptable polymer of pharmacy, said polymer is selected from one or more of polyethylene glycol 6000-caprolactam-vinyl acetate co-polymer, polyvinylpyrrolidone-vinyl acetate co-polymer class, polyvidone class, crylic acid resin, cellulose derivative apoplexy due to endogenous wind.
2. pharmaceutical composition according to claim 1 is characterized in that said pharmaceutically acceptable salt is selected from hydrochlorate, citrate, maleate, tartrate, sulfate, nitrate, mesylate or hydrobromate.
3. pharmaceutical composition according to claim 1 is characterized in that each administration unit contains with dronedarone active ingredient calculated 200 ~ 400mg.
4. according to the said pharmaceutical composition of claim 1, it is characterized in that said polymer is selected from polyvinylpyrrolidone-vinyl acetate co-polymer class and is selected from Kollidon
VA64 or Plasdone
S-630; The polyvidone class is selected from 30 POVIDONE K 30 BP/USP 30 or 30 POVIDONE K 30 BP/USP 90; Crylic acid resin is selected from Eudragit
EPO, Eudragit
E100 or Kollicoat
MAE 100P; The cellulose derivative class is selected from hypromellose, hydroxyethyl-cellulose or HPMCP.
5. pharmaceutical composition according to claim 1 is characterized in that the part by weight of acceptable polymer of said pharmacy and dronedarone is 0.2:1 ~ 10:1.
6. pharmaceutical composition according to claim 5 is characterized in that the part by weight of acceptable polymer of said pharmacy and dronedarone is 0.5:1 ~ 2:1.
7. pharmaceutical composition according to claim 1 is characterized in that said compositions can also comprise the pharmacy acceptable additive.
8. described preparation of drug combination method of claim 1 is characterized in that dronedarone or its pharmaceutically acceptable salt and the acceptable polymer mixed of pharmacy are added the hot melt extruder, and the extrudate that obtains is through cooling off, pulverize, sieving.
9. method for preparing according to claim 8, the hot melting temperature that it is characterized in that said hot melt extruder is 80 ~ 250 ℃, the rotating speed of hot melt extruder is 5 ~ 100rpm.
10. method for preparing according to claim 9, the hot melting temperature that it is characterized in that said hot melt extruder is 110 ~ 170 ℃, hot melt extruder rotating speed is 20 ~ 40rpm.
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| CN2012100765574A CN102579421A (en) | 2012-03-22 | 2012-03-22 | Antiarrhythmic medicinal composition and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565763A (en) * | 2012-07-26 | 2014-02-12 | 山东新时代药业有限公司 | Dronedarone hydrochloride tablet and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102342907A (en) * | 2010-07-30 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | Dronedarone solid dispersoid and preparation method thereof |
-
2012
- 2012-03-22 CN CN2012100765574A patent/CN102579421A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102342907A (en) * | 2010-07-30 | 2012-02-08 | 江苏恒瑞医药股份有限公司 | Dronedarone solid dispersoid and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄健，等: "热熔挤出技术制备普罗布考固体分散体及其大鼠体内药动学研究", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565763A (en) * | 2012-07-26 | 2014-02-12 | 山东新时代药业有限公司 | Dronedarone hydrochloride tablet and preparation method thereof |
| CN103565763B (en) * | 2012-07-26 | 2016-09-07 | 山东新时代药业有限公司 | A kind of Dronedarone hydrochloride tablet and preparation method thereof |
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Application publication date: 20120718 |