CN104771379A - Minodronic acid hydrate tablet preparation, and preparation method thereof - Google Patents
Minodronic acid hydrate tablet preparation, and preparation method thereof Download PDFInfo
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- CN104771379A CN104771379A CN201410010347.4A CN201410010347A CN104771379A CN 104771379 A CN104771379 A CN 104771379A CN 201410010347 A CN201410010347 A CN 201410010347A CN 104771379 A CN104771379 A CN 104771379A
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- minodronic acid
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- hydroxypropyl emthylcellulose
- minodronic
- aqueous solution
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Abstract
The invention discloses a minodronic acid hydrate tablet preparation and a preparation method thereof. According to the preparation, the minodronic acid hydrate preparation is prepared via following steps: minodronic acid hydrate and hydroxypropyl methyl cellulose are dissolved in a sodium hydroxide aqueous solution; and blank tablets are coated with an obtained solution. Compared with the prior art, preparation of a dispersion via special technology is not needed; preparation processing equipment is simple; no special equipment is needed; dissolution rate of minodronic acid hydrate is increased; and content uniformity of minodronic acid hydrate is ensured.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, in particular to a kind of minodronic acid tablet and preparation method thereof.
Background technology
A kind of systemic skeletal disease that osteoporosis (OP) is is feature with Low BMD and the regression of osseous tissue micro structure, easily causes skeleton intensity reduce and cause fracture.Osteoporosis has become modal senile disease, in addition, there is hyperthyroidism, rheumatoid arthritis, malabsorption syndrome, multiple myeloma, and the patient of excessive use glucocorticoid, GnRH promoter and antagonist etc. all easily produces osteoporosis.Therefore, the significant and application prospect widely of the medicine of the treated osteoporosis that active development is safe and effective, side effect is low, relatively inexpensive.
The medical compounds of bisphosphonates can suppress osteoclast activity, reduces bone conversion, increases bone density, have good therapeutic effect for the osteopathia that osteoporosis is relevant with tumor.This type of drug main will comprise Alendronate sodium, ibandronate, Pamidronate Disodium and minodronic acid etc., wherein, minodronic acid is the nitrogenous fragrant heterocyclic ring di-phosphonic acid salt compound of the third generation, developed by day intrinsic safety Si Tailai drugmaker, and jointly carry out market development with little Ye drugmaker, in the listing of in January, 2009 Japanese health ministry approval minodronate tablets, the hypercalcemia being used for the treatment of osteoporosis and being caused by osteoporosis and malignant tumor.The chemical name of minodronic acid: [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] two banks monohydrate, English name: minodronic acid hydrate, structural formula is as follows:
Animal experiment shows: the activity of minodronic acid is 30 ~ 100 times of Alendronate sodium and Pamidronate Disodium; Clinical trial shows: minodronic acid has significant advantage in preventing spine incidence of fracture.But minodronic acid is due to its construction features, water-soluble hardly, its dissolubility raises with PH values and raises, and in simulated gastric fluid, its dissolubility is extremely low, therefore, when adopting conventional method to prepare the solid preparation of minodronic acid, be difficult under one's belt absorb, its bioavailability will be affected.
CN200910228901.5 discloses a kind of name Minodronic acid hydrate medicine composition, a certain amount of basic auxiliary sodium carbonate is added as stabilizing agent and solubilizing agent in pharmaceutical composition disclosed in this patent of invention, to improve its dissolution, but the pH value of human normal gastric juice is 0.9 ~ 1.8, and the dissolution medium of this pharmaceutical composition is pH value be 6.86 phosphate medium, too large with the gastric juice environmental difference of human body, well can be absorbed under one's belt and be need further investigation.
CN201110078661.2 discloses a kind of minodronate tablets and preparation method thereof, comprise minodronic acid solid dispersion, diluent, disintegrating agent and lubricant, wherein minodronic acid solid dispersion is made up of minodronic acid, Polyethylene Glycol and additives, the complicated process of preparation of this invention, be difficult to control whole process conditions, thus affect the quality of product, simultaneously, the process time of preparing this minodronate tablets is long, not only consume energy, and production efficiency is affected, cause difficulty to suitability for industrialized production generally.
CN201310008298.6 discloses a kind of minodronic acid abrasive material and preparation method thereof altogether, minodronic acid and hydrophilicity condiment, the particle mean size of abrasive material is 2 μm ~ 80 μm altogether, take minodronic acid and hydrophilicity condiment and mix homogeneously, then mixture is placed in milling apparatus grinding 15 ~ 35min and obtains minodronic acid abrasive material altogether.
The specification of minodronic acid preparation is the every sheet of 1mg or less, minodronic acid raw material character is white crystal, light weight, bulk density are little, adsorptivity is large, easily be adsorbed on the metal inner surface of pharmaceutical machine, so not easily mix homogeneously with adjuvant, common tablet manufacturing technique (mixing-sieve-granulation-drying-granulate-always mixed-tabletting), easily causes the uniformity of dosage units of tablet to be difficult to ensure.In actual production, once production process controls strict, will output scrap batch, cause the very large wasting of resources.
Moreover, be generally that the solid dispersion tool of carrier is a bit sticky with Polyethylene Glycol, and solid dispersion condensation point lower (50 ~ 55 DEG C).If need tablet be prepared into, in tableting step, part Polyethylene Glycol can soften due to the heat of compression machinery motion generation, viscosity increases and sticks on drift, punch die, cannot arrange loose in time if continuous high speed tabletting produces heat, the bur of drift, punch die increases gradually, and tablet weight variation finally can be caused to increase gradually, and tablet machine can not normally be produced and tabletting even.Under existing technical conditions, to realize the production of scale, usually can only be prepared into drop pill, soft capsule or powder etc.
Meanwhile, prior art prepares minodronic acid tablet, does not fundamentally consider the little problem being difficult to mixing homogeneously brought of minodronic acid specification, and uniformity of dosage units can not get ensureing.
Therefore, we need a kind of minodronate tablets and the preparation method that can overcome above-mentioned defect, improve patient consumes's compliance, improve absorption rate, and making medicine is better extensive patients service; On the other hand, even if this prescription and technique use common machinery equipment, the quality of product can also be ensured.Make minodronate tablets reach safe and effective, quality controllable requirement, preparation technology is easy and efficient, and product yield is high.
Summary of the invention
For the defect of prior art, inventors performed great many of experiments, consider that minodronic acid specification is little, and in water, poor solubility in ethanol, but dissolubility is better in sodium hydrate aqueous solution, minodronic acid is dissolved in the sodium hydrate aqueous solution containing hydroxypropyl emthylcellulose by inventor, and by this solution coating on blank surface, the initial object of inventor is by minodronic acid, hydroxypropyl emthylcellulose is well dispersed in tablet surface, to improve the contact area of minodronic acid and dissolution medium, improve dissolution, but it is unexpected, inventor finds, by this kind of technique, the dissolution rate of minodronic acid is far away faster than the expection of inventor, obtain a kind of stripping minodronic acid tablet very rapidly.
Specifically, the present invention is realized by following technology:
The invention provides a kind of minodronic acid tablet and preparation method thereof, minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, are made by this solution coating at blank.
Minodronic acid tablet of the present invention and preparation method thereof, the weight ratio of minodronic acid and hydroxypropyl emthylcellulose is 1:1 ~ 5.
Preferably, the weight ratio of minodronic acid and hydroxypropyl emthylcellulose is 1:3.
Minodronic acid tablet of the present invention and preparation method thereof, in the aqueous solution of minodronic acid, hydroxypropyl emthylcellulose, the pH that sodium hydroxide regulates is 11 ~ 13.
Preferably, the pH of aqueous solution is 12.
Minodronic acid tablet of the present invention and preparation method thereof, prepare by the following method:
Preparation method:
Polyvinylpolypyrrolidone, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
Compared with prior art, the present invention has following advantage:
(1) do not need to prepare dispersion by special process;
(2) preparation processing equipment is simple, without the need to special installation;
(3) improve the dissolution of minodronic acid.
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
Preparation method:
Polyvinylpolypyrrolidone, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
Embodiment 2
Preparation method:
Carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
Embodiment 3
Preparation method:
Carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
Comparative example 1
1) take 25g minodronic acid and 115g Polyethylene Glycol mix homogeneously, be then placed in ball mill ball milling 35min and obtain minodronic acid abrasive material altogether, after testing, the mean diameter that minodronic acid is total to abrasive material is 45 μm;
2) in minodronic acid altogether abrasive material, add 3g hydroxypropyl cellulose, then add appropriate 70% alcoholic solution moistening soft material, cross 20 mesh sieves and granulate, dry 2h under 60 DEG C of conditions, after 20 mesh sieve granulate, finally add 6g cross-linking sodium carboxymethyl cellulose and 1.5g magnesium stearate, mix homogeneously;
3) tabletting, obtained tablet.
Comparative example 2
Preparation technology:
1), the preparation of solid dispersion: the Polyethylene Glycol of recipe quantity is heated to 80 DEG C of insulations to whole melting, add the minodronic acid of recipe quantity again, be stirred to after dissolving completely, continue stir and be cooled to 0 ~-4 DEG C, place under 0 ~-4 DEG C of condition and within 24 hours, make into crisp shape breakable object, pulverize, cross 60 mesh sieves, obtain minodronic acid solid dispersion;
2), take the microcrystalline Cellulose of recipe quantity, lactose, polyvinylpolypyrrolidone and magnesium stearate, mix homogeneously with minodronic acid solid dispersion;
3), tabletting, obtain minodronate tablets.
Comparative example 3
Preparation method:
Minodronic acid, carboxymethyl starch sodium, microcrystalline Cellulose cross 100 mesh sieves, mix homogeneously, and add pure water in right amount, granulate, magnesium stearate mix homogeneously after dry, tabletting, to obtain final product.
Comparative example 4
Preparation method:
1), the preparation of solid dispersion: the polyethylene glycol 6000 of recipe quantity is heated to 85 DEG C of insulations to whole melting, slowly add polyvinyl alcohol, be stirred to dissolving, add the bony acid of minot of recipe quantity again, be stirred to after dissolving completely, continue stir and be cooled to 0 ~-4 DEG C, place and within 20 hours, make into solid-state crisp shape breakable object, pulverize, cross 60 mesh sieves, obtain the solid prose style free from parallelism of minodronic acid;
2), take the microcrystalline Cellulose of recipe quantity, lactose, cross-linking sodium carboxymethyl cellulose and magnesium stearate, mix homogeneously with minodronic acid solid dispersion.
3), tabletting, obtain minodronate tablets.
Comparative example 5
Minodronic acid lg, soybean lecithin 60g, DOPG 15g, cholesterol 50g, tween (80) 40g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 20g, polyvidone (K30) 20g, micropowder silica gel 10g.
Preparation method:
(1) accurately take recipe quantity minodronic acid, soybean lecithin, two oily phthalein phospholipid phthalein glycerol, cholesterol, Tween 80, be dissolved in the oxolane and tert-butyl alcohol mixed solvent that 1000ml volume ratio is 2:1, stir and make it dissolve;
(2) above-mentioned solution is placed in eggplant-shape bottle, 45 DEG C of water-bath decompression removing dichloromethane and isopropyl alcohol, bottle wall forms uniformly transparent film;
(3) in eggplant-shape bottle, add the phosphonate buffer solution that 600ml pH value is 7.0, continue to rotate at 45 DEG C of water-bath normal pressures, make films swell hydration;
(4) by above-mentioned solution 0.45 μm of filtering with microporous membrane, filtrate is placed in-20 DEG C of refrigerator and cooled and freezes and spend the night, then take out thawing, multigelation three times, spraying dry obtains minodronic acid liposome powder;
(5) by bony for minot sour lipidosome solid powder and the mixing of 200g microcrystalline Cellulose, 40g shuttle methyl starch sodium and 20g PVP K30, sieve mix homogeneously, and the ethanol water adding 100m140% prepares soft material, and sieve preparation, dry;
(6) by dry granule and 10g micropowder silica gel mix homogeneously, sieve granulate;
(7) tabletting, obtained 1000 minodronic acid lipid body piece
Checking embodiment
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, with 0.075% TBAH solution of 10mM tetrasodium pyrophosphate (phosphoric acid regulates pH7.0)-acetonitrile (95: 5) for mobile phase, determined wavelength is 218nm, and theoretical cam curve calculates should be not less than 3000 by minodronic acid peak.
1. dissolution determination.According to 2010 editions two annex XC second methods, with 0.1M hydrochloric acid solution 900mL for dissolution medium (PH=0.95), rotating speed is 50 turns (slurry processes), capsule is according to Chinese Pharmacopoeia 2010 editions two annex XC first methods, with 0.1M hydrochloric acid solution 900mL for dissolution medium (PH=0.95), rotating speed is 100 turns (basket methods), respectively at sampling and measuring when 3min, 15min.
2. Determination of Content Uniformity.Get this product a slice, add suitable quantity of water, ultrasonicly make dissolving, precision measures subsequent filtrate 50 μ l injection liquid chromatography, record chromatogram; Another precision takes minodronic acid reference substance and is about 10mg, put in 100ml measuring bottle, add 0.1mol/L sodium hydroxide solution 5ml within ultrasonic 5 minutes, make minodronic acid dissolve after, be diluted with water to scale, shake up, precision measures 1ml and is placed in 100ml measuring bottle, be diluted with water to scale, shake up, product solution, is measured in the same method in contrast.
Table 1 embodiment dissolution and Determination of Content Uniformity
It can be seen from the table, embodiment of the present invention 1-3, minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, solid dispersion is prepared by packaging technique, dissolution is far faster than comparative example, and due to minodronic acid with solution state coating in tablet surface, therefore the uniformity is good, and uniformity of dosage units numerical value is little; Comparative example 1, and adopt co-rotational procedure, tablet stripping improves to some extent, but easily assembles agglomerating owing to grinding rear particle, therefore dissolution improves limited, and uniformity of dosage units numerical value is bigger than normal simultaneously; Comparative example 2, adopt solid dispersions technique, to a certain degree improve dissolution, but also need after preparation dispersion to be processed into tablet further, be not only difficult to mix homogeneously, and have impact on the result of extraction of dispersion, therefore uniformity of dosage units numerical value is bigger than normal, stripping improves limited; Comparative example 3, adopt ordinary preparation process technology, and stripping is slow, and uniformity of dosage units numerical value is large; Comparative example 4, prepare solid dispersion, to a certain degree improve dissolution, but dispersion crosses 60 mesh sieves, cause mixed effect poor, therefore uniformity of dosage units numerical value is bigger than normal; Comparative example 5, prepare liposome, increase to dissolution, but due to liposome viscosity large, mixing is difficult to mixing, have sticking phenomenon, and uniformity of dosage units numerical value is large during tabletting.
Claims (8)
1. a minodronic acid tablet, is characterized in that, it is prepared by following methods and obtains: minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, is made by this solution coating at blank.
2. minodronic acid tablet according to claim 1, is characterized in that, the weight ratio of minodronic acid and hydroxypropyl emthylcellulose is 1:1 ~ 5.
3. minodronic acid tablet according to claim 1, is characterized in that, the weight ratio of minodronic acid and hydroxypropyl emthylcellulose is 1:3.
4. minodronic acid tablet according to claim 1, is characterized in that, the pH of the aqueous solution of minodronic acid, hydroxypropyl emthylcellulose is 11 ~ 13.
5. minodronic acid tablet according to claim 1, is characterized in that, the pH of the aqueous solution of minodronic acid, hydroxypropyl emthylcellulose is 12.
6. minodronic acid tablet according to claim 1, is characterized in that, prepare by the following method and obtain:
Take above-mentioned prescription, polyvinylpolypyrrolidone, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
7. a minodronic acid tablet preparation method, is characterized in that, it comprises the steps: minodronic acid, hydroxypropyl emthylcellulose is dissolved in sodium hydrate aqueous solution, is made by this solution coating at blank.
8. minodronic acid tablet preparation method according to claim 7, it is characterized in that, it comprises the steps:
Take above-mentioned prescription, by polyvinylpolypyrrolidone, microcrystalline Cellulose, magnesium stearate mix homogeneously, tabletting; Minodronic acid, hydroxypropyl emthylcellulose are dissolved in sodium hydrate aqueous solution, by this solution coating on institute's tabletting, to obtain final product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101390843A (en) * | 2008-11-06 | 2009-03-25 | 咸阳步长医药科技发展有限公司 | Lovastatin and niacin slow-release tablet and preparation method thereof |
| CN102078323A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Minodronate-containing pharmaceutical composition |
| US20110182985A1 (en) * | 2010-01-28 | 2011-07-28 | Coughlan David C | Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof |
| CN102716132A (en) * | 2011-03-29 | 2012-10-10 | 石药集团中奇制药技术（石家庄）有限公司 | Compound amlodipine/valsartan/hydrochlorothiazide tablets and method for making the same |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390843A (en) * | 2008-11-06 | 2009-03-25 | 咸阳步长医药科技发展有限公司 | Lovastatin and niacin slow-release tablet and preparation method thereof |
| CN102078323A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Minodronate-containing pharmaceutical composition |
| US20110182985A1 (en) * | 2010-01-28 | 2011-07-28 | Coughlan David C | Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof |
| CN102716132A (en) * | 2011-03-29 | 2012-10-10 | 石药集团中奇制药技术（石家庄）有限公司 | Compound amlodipine/valsartan/hydrochlorothiazide tablets and method for making the same |
Non-Patent Citations (2)
| Title |
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| 张超云，等: "《药剂学》", 31 January 2005, 北京大学医学出版社 * |
| 潘卫三: "《工业药剂学》", 30 June 2010, 中国医药科技出版社 * |
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