CN100402060C - Heart beneficial keton dispersion tablet and its preparation method - Google Patents
Heart beneficial keton dispersion tablet and its preparation method Download PDFInfo
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- CN100402060C CN100402060C CNB2005100425178A CN200510042517A CN100402060C CN 100402060 C CN100402060 C CN 100402060C CN B2005100425178 A CNB2005100425178 A CN B2005100425178A CN 200510042517 A CN200510042517 A CN 200510042517A CN 100402060 C CN100402060 C CN 100402060C
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- carboxymethyl starch
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- yixintong
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Abstract
The present invention relates to a crataemone dispersive tablet. The present invention is prepared by that crataemone micronized to have less than 300 meshes, lactose, microcrystalline cellulose, polyvinylpyrrolidone, sodium dodecyl sulfate and a part of sodium carboxymethyl starch are made into disintegration granules whose granule diameter is less than 0.5mm, and magnesium stearate and the residual sodium carboxymethyl starch are added and are pressed into the dispersive tablet. After being taken, the dispersive tablet is quickly disintegrated into the disintegration granules with the granule diameter of about 0.5mm, and consequently, the disintegration granules are rapidly disintegrated twice into minute crataemone miropowder; accordingly, the disintegration speed of the tablet is improved; the disintegration time limit is less than 2 minutes, and the present invention has the advantages of high medicine dissolution speed and high bioavailability; the dissolution degree in five minutes reaches more than 87%.
Description
Affiliated technical field:
The present invention relates to contain the pharmaceutical composition of Yixintong, is the improvement technology about a kind of Crataegutt oral preparation.
Background technology:
Following definition is applicable to whole description and claims:
Yixintong: be the common name of the Fructus Crataegi total flavones that extracts by Folium Crataegi, be recorded in one one 563 pages of Chinese Pharmacopoeia versions in 2000.
In add carboxymethyl starch sodium: be meant that the carboxymethyl starch sodium that is added is contained among every disintegrate microgranule when preparation Yixintong disintegrate microgranule.
Add carboxymethyl starch sodium: be meant the Yixintong disintegrate microgranule of making, when being prepared into Yixin ketone dispersing tablets, the carboxymethyl starch sodium of Jia Ruing once more, it is in outside every Yixintong disintegrate microgranule, is distributed between each disintegrate microgranule.
Yixintong is by the total flavones that extracts in the Folium Crataegi.Folium Crataegi is the dried leaves of rosaceous plant Fructus Pyri Pashiae (CrataegusPinnatifida Bge.Var.majqr N.E.Br.) or Fructus Crataegi (C.Pinnatifida Bge.).Folium Crataegi just has the record of being used as medicine and curing the disease as far back as Eastern Jin Dynasty's epoch, and Compendium of Material Medica is carried " the hawthorn stem and leaf liquor is controlled dermatitis rhus ", " Chinese medicine voluminous dictionary " record " leaf and flower are made tea to obey and can be treated hypertension ".
The Fructus Crataegi The Chemical Constituents beginning sees nineteen twenty-one Anon, and is less until the research fifties, focuses mostly at compositions such as contained vitamin, tannin and triterpeness.After the fifties, find that contained flavones ingredient has tangible pharmacologically active to cardiovascular system in the Fructus Crataegi.On the basis of this research and application, begin the sixties chemical constituent in the Folium Crataegi is studied, flavones ingredient especially, up to the present, kind surplus the flavones ingredient of report has 40.
Folium Crataegi is used as medicine and cures the disease early on the booksly, and modern pharmacological research shows that Fructus Crataegi flavone has many-sided effect to cardiovascular system: 1. blood pressure lowering; 2. increase coronary flow; 3. cholesterol reducing; 4. anoxia enduring; 5. heart tonifying etc.Therefore the preparation of haw berry, leaf and flower extract constantly occurs, and is used for clinical.There have the fifties report West Germany Kavlstuhe schwabe pharmaceutical factory development and production injection Crataegutt and coated tablet Crataegutt to be used for abroad to be clinical, treatment coronary heart disease, myocardial infarction etc.The injection Esbertcdrd of West Germany Salzgitter Schapty Brummer chemical pharmaceutical factory development is used for clinical, treatment coronary circulation disease and angina pectoris etc.Report diseases such as the tablet Hawthorn of Britain development and injection Esbericard are used for clinical treatment hypertension, senilely have a weak heart, coronary heart disease, hyperlipidemia the sixties.Bulgaria also developed similar formulations Crataemon and was used for clinical treatment coronary heart disease the seventies, and in many national applications patent.The similar formulations that Japan three Co., Ltd. produce has the myocardial contraction of enhancing, strengthens coronary flow and effects such as blood pressure regulation, diuresis are arranged, and is applicable to slight heart failure, is characterized in there is not cumulative action.External these preparations are used so far clinically, go through not waning.Japan and more American-European countries also use Folium Crataegi extract as food additive and health product, welcome by consumers in general.
Domestic the mid-80 begins to have the Folium Crataegi extract preparation diseases such as capsule, clinical treatment hypertension, angina pectoris, coronary heart disease, hyperlipidemia of promptly feeling at ease.The Taiyuan, Shanxi pharmacy nineties two factories have developed the Yixintong sheet, have the effect of blood circulation promoting and blood stasis dispelling, the logical heart arteries and veins of a surname, the easypro network of regulating the flow of vital energy.Be used for diseases such as chest distress, palpitation and amnesia, vertigo and tinnitus and coronary heart disease, angina pectoris, hyperlipidemia and cerebral arterial insufficiency.
Tablet in the existing dosage form, according to " Chinese pharmacopoeia version regulation in 2000, its dissolution be 45min reach 70% of labelled amount be qualified.Disintegrate and dissolution rate are slow, have influenced the abundant absorption and the bioavailability of this medicine.Though liquid preparation absorbs soon, uses inconvenience, and poor stability, packing, transportation, storage be inconvenience all.Therefore be necessary to develop easy to use, absorb soon, the novel 'Yixintong ' that bioavailability is high meets clinical needs better.
Summary of the invention:
The object of the present invention is to provide a kind of taking convenience, absorb soon Crataegutt oral dispersible tablet formulation and process technology thereof that bioavailability is high.
The present invention improves absorption and the bioavailability of human body to Yixintong to shorten the disintegration of tablet time, to improve its dissolution and start with.Solution of the present invention is that Yixintong is mixed with a kind of Yixin ketone dispersing tablets of disintegrate rapidly.Because the difference of principal agent character has very big influence for the disintegration rate of dispersible tablet, therefore to design the component of every kind of dispersible tablet according to the characteristic of principal agent.The disintegration rate of tablet and dispersible tablet is measured all according to the regulation in the Chinese Pharmacopoeia version in 2000 and is carried out.
Dispersible tablet of the present invention is made up of components such as Yixintong, disintegrating agent carboxymethyl base Starch Sodium, suspending agent microcrystalline Cellulose, polyvinyl pyrrolidone, magnesium stearate lubricant and surfactant sodium lauryl sulphates.Its constituent content, be by weight percentage: the Yixintong of 5.0～30.0wt%, 3.0 the carboxymethyl starch sodium of～7.0wt%, 15.0 the microcrystalline Cellulose of～30.0wt%, 40.0 the lactose of～75.0wt%, 0.5 the magnesium stearate of～1.0wt%, the sodium lauryl sulphate of 0.3～1.5wt%, the polyvinylpyrrolidone of 1.0～3.0wt%.
The present invention is a disintegrating agent with the carboxymethyl starch sodium, and its degree of exchange of the carboxymethyl starch sodium of selecting for use is generally about 0.3-0.5, and swellbility is 5ml/g.Test shows that the carboxymethyl starch sodium addition is less than 3.0wt%, and is not obvious to the influence of disintegration rate; And addition can prolong disintegration time on the contrary greater than 8%, may be because produce due to the colloid substance after the carboxymethyl starch sodium partial hydrolysis.So the carboxymethyl starch sodium addition that the present invention selects for use is 3.0-7.0wt%.
The present invention is suspensoid with the microcrystalline Cellulose.Microcrystalline Cellulose is the straight-chain polysaccharide that is made of pyranoid ring D-glucose, and its degree of polymerization is 200, and swellbility is 3.4ml/g.It has good flowability and disintegration microcrystalline Cellulose, and chance water disintegrate rapidly forms uniform viscosity suspension, has disintegrating agent and suspensoid dual function.Yet experiment shows that the disintegration time of tablet is also relevant with the addition of microcrystalline Cellulose, and result of the test sees Table 1.
The relation of table 1 disintegrating agent ratio and disintegration time
As can be seen from Table 1, the addition of carboxymethyl starch and microcrystalline Cellulose is excessive, can prolong disintegration time, may be because carboxymethyl starch sodium and microcrystalline Cellulose are met the reason of water retrogradation.The carboxymethyl starch sodium consumption that adds is bigger to the disintegration time influence, and the consumption of microcrystalline Cellulose is little to the influence of disintegration time than carboxymethyl starch sodium.
Further the additional proportion of carboxymethyl starch sodium and microcrystalline Cellulose is done the optimization Test selection, the results are shown in Table 2
The part of table 2 disintegrating agent ratio is optimized the result
So it is 15-30wt% that the present invention selects the content of microcrystalline Cellulose for use, and the optimum weight ratio of carboxymethyl starch sodium and microcrystalline Cellulose is 1: 4-1: 5.Screening determines that the interior dosage of carboxymethyl starch sodium is 1.5-4.5wt% by experiment, and outer dosage is that 2.0-3.6wt% is advisable.The Yixin ketone dispersing tablets of so making can disintegrate fully in 2 minutes.
The molecular weight of the polyvinylpyrrolidone that the present invention selects for use is 25000-40000.The polyvinylpyrrolidone hydrophilic is strong, uses this binding agent that disintegration of tablet is accelerated, and helps the stripping of medicine.The surfactant sodium lauryl sulphate has solubilization, and it and polyvinylpyrrolidone use simultaneously, can promote the disintegrate of tablet and the stripping of medicine.
The compound method of dispersible tablet of the present invention is: at first Yixintong is micronized to below 300 orders, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are all crossed 100 mesh sieves; Polyvinylpyrrolidone is dissolved in 70% ethanol, is mixed with 5% polyvinylpyrrolidone alcoholic solution, add sodium lauryl sulphate again, make that its concentration is 1%, make both mixed solutions, preserve standby.
Then with Yixintong elder generation successively and part of sodium carboxymethyl starch, with the equivalent method mixing that progressively increases,,, make the abundant mixing of Yixintong and disintegrating agent to eliminate the Electrostatic Absorption between the Yixintong micropowder again with the microcrystalline cellulose mixing, add the lactose ground and mixed at last and sieve mixing.
Then, add the mixed solution of a certain amount of polyvinylpyrrolidone, sodium lauryl sulphate, make soft material.Granulate with 30 mesh sieves, 40 ℃ of oven dry, reuse 30 mesh sieve granulate are made the Yixintong disintegrate microgranule of particle diameter less than 0.5mm.Thereafter, in these exsiccant disintegrate microgranules, the magnesium stearate of additional proportion amount and remaining carboxymethyl starch sodium mix homogeneously again, under 5-8kg pressure, tabletting makes Yixin ketone dispersing tablets.
Before an important feature of the present invention was film-making, the component in the dispersible tablet was all carried out micronization processes, and Yixintong is micronized to below 300 orders.Can improve particulate specific surface area after the micronization, make after the dispersible tablet disintegrate medicine can be faster, dissolve in the body fluid more fully.
Another characteristics of the present invention are that Yixintong is at first made the disintegrate microgranule of particle diameter less than 0.5mm, and then are pressed into the dispersible tablet that is easy to disintegrate.Include components such as part of sodium carboxymethyl starch, microcrystalline Cellulose, lactose, polyvinylpyrrolidone, sodium lauryl sulphate in the said disintegrate microgranule; Except that above-mentioned disintegrate microgranule, also add another part carboxymethyl starch sodium and magnesium stearate in the dispersible tablet.The disintegrating agent carboxymethyl base Starch Sodium here is that branch two parts add, and a part is to be added among the disintegrate microgranule, adds in the title; Another part then adds when tabletting, is included in outside the disintegrate microgranule, is distributed between these microgranules, claims to add.In add with the preferred relative scale that adds carboxymethyl starch sodium be 1: 1-1: 2.
Can certainly will be pressed into dispersible tablet behind the disposable in proportion mixing of each component.But the Yixin ketone dispersing tablets that constitutes by mode of the present invention, after taking, the very fast disintegrate of tablet becomes the disintegrate microgranule about particle diameter 0.5mm, then these disintegrate microgranules again secondary disintegrate promptly be tiny Yixintong micropowder, thereby improved the disintegration rate of tablet, shortened the disintegration time of tablet.And because the solubilization of microcrystalline Cellulose in the disintegrate microgranule and auxiliary agent such as surfactant sodium lauryl sulphate, improved the dissolution of principal agent Yixintong.
For showing progressive of the present invention, we have done the disintegration time and the dissolution test of Yixin ketone dispersing tablets of the present invention, and contrast with the Yixintong tablet.Tablet is chosen the Yixintong sheet that Shanxi Jinjia Pharmaceutical Co., Ltd. produces.Dissolution determination method adopts two appendix xc second methods of Chinese Pharmacopoeia version in 2000, and rotating speed is 75 rev/mins.Result of the test sees Table 3 and table 4.
Table 3 Yixin ketone dispersing tablets and disintegration of tablet velocity ratio are
Table 4 Yixin ketone dispersing tablets and tablet dissolution are relatively
As can be seen from Table 3, the disintegration rate of Yixin ketone dispersing tablets of the present invention has improved 5-6 doubly than Yixintong tablet.
As can be seen from Table 4,5 minutes dissolutions of Yixin ketone dispersing tablets of the present invention promptly reach more than 87%, are about 17.5 times of tablet.
We have also done the stability test of Yixin ketone dispersing tablets of the present invention, three batches of test specimens are got in test, put under the condition of illumination (4500LX), high temperature (60 ℃), high humidity (RH92.5%) and placed 10 days, respectively at 5 days, 10 days its dispersing uniformities of sampling and measuring, dissolution.Result of the test sees Table 5.
Table 5 Yixin ketone dispersing tablets stability test result
Result of the test shows that sample was placed 10 days under illumination, high temperature, super-humid conditions, its disintegration rate and dissolution there are no significant difference.
In a word, advantage of the present invention is clearly, Yixin ketone dispersing tablets disintegration rate of the present invention is fast, and its disintegration, the medicine dissolution rate was fast less than 2 minutes, the bioavailability height, its dissolution of 5 minutes reaches more than 87%, is 17.5 times of tablet, this better stability of preparation, transportation, storage and easy to use can be satisfied the needs of clinical application better.
The specific embodiment
The invention will be further described with by way of example more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Earlier Yixintong is micronized to below 300 orders, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 100 mesh sieves;
Take by weighing 3.1 gram polyvinylpyrrolidones and 1.4 gram sodium lauryl sulphates are dissolved in 70% ethanol and are mixed with mixed solution, standby.Wherein contain 5% polyvinylpyrrolidone and 1% sodium lauryl sulphate.
Take by weighing through micronized Yixintong 32.0 grams, earlier with 3.0 gram carboxymethyl starch sodium with the equivalent method mixing that progressively increases, then add the abundant mixing of 31 gram microcrystalline Cellulose after, add 129 gram lactose and mix, sieve, add above-mentioned mixed solution and make soft material.Granulate with 30 mesh sieves, and, make the disintegrate microgranule of particle diameter with 30 mesh sieve granulate again less than 0.5mm 40 ℃ of oven dry down.Add 1.4 gram magnesium stearate and 4.1 gram carboxymethyl starch sodium mixings then.After the percentage composition of Yixintong calculating sheet weighs in measuring granule, under 5-8kg pressure, be pressed into sheet.So can suppress 1000 Yixin ketone dispersing tablets.Its disintegration time is 1.4 minutes, and dissolution was 87%. in 5 minutes
The several examples of following reuse further specify the present invention, and following example is to produce the Formulation Example of 1000 Yixin ketone dispersing tablets.
Claims (6)
1. Yixin ketone dispersing tablets, contain binding agent, filler, lubricant, solubilizing agent and disintegrating agent component, the composition content that it is characterized in that said dispersible tablet, be by weight percentage: the Yixintong of 5.0～30.0wt%, the carboxymethyl starch sodium of 3.0～7.0wt%, the microcrystalline Cellulose of 15.0～30.0wt%, 40.0 the lactose of～75.0wt%, 0.5 the magnesium stearate of～1.0wt%, the sodium lauryl sulphate of 0.3～1.5wt%, the polyvinylpyrrolidone of 1.0～3.0wt%.
2. according to the described dispersible tablet of claim 1, it is characterized in that the said carboxymethyl starch sodium and the relative weight ratio of microcrystalline Cellulose are 1: 4-1: 5.
3. according to the compound method of the described dispersible tablet of claim 1, it is characterized in that comprising following main preparation steps:
(1) Yixintong is micronized to below 300 orders, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are all crossed 100 mesh sieves;
(2) preparation disintegrate microgranule:
I) with the carboxymethyl starch sodium of Yixintong and interior dosage with the equivalent method mixing that progressively increases, add microcrystalline Cellulose and lactose more successively, mix, sieve, standby;
Ii) polyvinylpyrrolidone and surfactant sodium lauryl sulphate are dissolved in 70% ethanol, make mixed solution, wherein contain 5% polyvinylpyrrolidone and 1% sodium lauryl sulphate;
Iii) above-mentioned mixed solution is added i) mixture in, make soft material, granulate, dry with 30 eye mesh screens; With 30 mesh sieve granulate, make the Yixintong disintegrate microgranule of particle diameter again less than 0.5mm;
(3) preparation Yixin ketone dispersing tablets: with the carboxymethyl starch sodium and the exsiccant Yixintong disintegrate microgranule mix homogeneously of magnesium stearate and outer dosage, tabletting is made Yixin ketone dispersing tablets of the present invention.
4. according to claim 1 or 2 described dispersible tablets, it is characterized in that said carboxymethyl starch sodium adds at preparation disintegrate microgranule and dispersible tablet time-division two parts respectively, adding carboxymethyl starch sodium in wherein is 1 with the relative scale that adds carboxymethyl starch sodium: 1-1: 2.
5. according to claim 1 or 2 described dispersible tablets, add the content of carboxymethyl starch sodium in it is characterized in that wherein, be by weight percentage: 1.5～4.5wt%.
6. according to claim 1 or 2 described dispersible tablets, it is characterized in that wherein adding the content of carboxymethyl starch sodium, be by weight percentage: 2.0～3.6wt%.
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| CN1565448A (en) * | 2003-06-16 | 2005-01-19 | 河北赛克药业有限公司 | Nitrendipine dispersion tablet and method for making same |
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