CN101669942A - Insoluble pharmaceutical composition - Google Patents
Insoluble pharmaceutical composition Download PDFInfo
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- CN101669942A CN101669942A CN200910093377A CN200910093377A CN101669942A CN 101669942 A CN101669942 A CN 101669942A CN 200910093377 A CN200910093377 A CN 200910093377A CN 200910093377 A CN200910093377 A CN 200910093377A CN 101669942 A CN101669942 A CN 101669942A
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- letrozole
- pharmaceutical composition
- insoluble pharmaceutical
- solubilizing agent
- mesh sieves
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Abstract
The invention discloses an insoluble pharmaceutical composition which contains letrozole as pharmaceutical active ingredient; the composition is added with a surfactant and reduces the particle size of the letrozole; and the joint effect of both greatly improves the dissolution of the letrozole. The insoluble pharmaceutical composition has the advantages of simple preparation process, no need forspecial equipment, convenient operation and good suitability for industrial production.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that improves insoluble drug letrozole dissolution.
Background technology
Letrozole (Letrozole) chemistry is by name 4,4 '-(1H-1,2,4-triazole-1-methine) two benzonitriles (1), be artificial synthetic benzyl triazole derivant, activity in vivo is stronger 150～250 times than first generation arimedex aminoglutethimide.Because its selectivity is higher, do not influence glucocorticoid, mineralocorticoid and thyroid function, the heavy dose of use to Adrenocorticosteroids material secretion unrestraint effect, has higher therapeutic index, compare with the estrogen antagonist medicine with other arimedexs, the antitumor action of letrozole is stronger.Letrozole is mainly used in the estrogen-dependent tumor, especially patient with breast cancer's treatment.Increasing zoopery and clinical research show, letrozole plays a significant role in many estrogen-dependent diseases such as endometriosis, leiomyoma of uterus, carcinoma of endometrium, ovarian tumor.
Letrozole is the third generation arimedex that Switzerland Novartis Vaccines ﹠ Diagnostic (Norvatis) at first develops, and goes on the market in Britain first in 1996.Be used for the first-line treatment advanced breast cancer more than 30 countries and regions listings at present, and be widely used as the two wires medication of breast carcinoma in U.S.'s listing in 1997.The letrozole of Novartis Co.,Ltd went on the market in China in 2003, the trade name furlong.Domestic Hengrui Medicine Co., Ltd., Jiangsu Prov. obtained the production certification in 1999, and the trade name cottonrose hibiscus is auspicious.The letrozole dosage form of present domestic listing has only tablet.
Letrozole is almost insoluble in water, is difficult to stripping in solid preparation, has a strong impact on its bioavailability, and then influences therapeutic effect.CN101099724 discloses a kind of micronization femara and compositions thereof, mainly the letrozole micropowder is improved the speed of stripping from preparation by comminution by gas stream, colloid mill, ball mill etc., but micronization is higher to equipment requirements, and the crude drug loss is bigger in the micropowder process.CN101467971 discloses a kind of dispersible tablet that contains letrozole, adopt solid dispersion technology to overcome the slow problem of principal agent stripping, but its technology is loaded down with trivial details, is not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of insoluble pharmaceutical composition, effectively improved the dissolution of insoluble drug letrozole.Its characteristics are to combine as solubilizing agent and two kinds of methods of particle diameter of reducing letrozole adding certain amount of surfactant in the compositions, improve the dissolution of letrozole jointly.Said composition preparation technology is simple, does not need special installation, and is easy to operate, is fit to suitability for industrialized production.
The present invention at first provide a kind of comprise the active constituents of medicine letrozole and by a certain amount of adding so that contain the compositions of the solubilizing agent that the compositions dissolution of letrozole improves.Solubilizing agent is surfactants such as sodium lauryl sulphate, polyoxyethylene sorbitan monoleate, poloxamer, preferably sodium dodecyl sulfate.The solubilizing agent consumption is 0.1～5% of a recipe quantity, and preferable amount is 0.5～2% of a recipe quantity.When preparing this pharmaceutical composition, letrozole is pulverized the processing of crossing 150 mesh sieves at least, can select for use to produce and go up 150 orders commonly used, 170 orders, 200 mesh sieves etc., preferred 200 mesh sieves.
Said composition can be granule, tablet and capsule.Crude drug letrozole consumption is 1～10% of a recipe quantity, and the amount of each unit formulation letrozole can be 2.5mg or 3.75mg or 5mg or 6.25mg or 10mg.Adjuvant also comprises disintegrating agent, filler, correctives, binding agent and lubricant etc. except that solubilizing agent, adjuvant can be according to the difference of dosage form and difference.Disintegrating agent can be microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone etc., can also mix use by different proportion separately, and total consumption is 0～30% of a recipe quantity.Filler can be starch, sucrose, lactose, pregelatinized Starch, dextrin, mannitol, sorbitol etc., can also mix use by different proportion separately, and total consumption is 20～80% of a recipe quantity.Correctives can be sweeting agent and aromatic, sweeting agent can be sucrose, glucose, lactose, mannitol, xylitol, sorbitol, sweet taste centautin, aspartame, disodium glycyrrhizinate, saccharin sodium etc., aromatic can be natural and synthetic spice, as flavoring banana essence, pineapple essence, flavoring orange essence, Cortex cinnamomi japonici (Ramulus Cinnamomi) essence, apple essence, Fructus Citri Limoniae essence, cherry essence, chocolate essence etc., can can also mix use by different proportion separately, total consumption is 0～50% of a recipe quantity.Binding agent can be starch slurry, syrup, 30 POVIDONE K 30 BP/USP 30 alcoholic solution, hypromellose etc., and total consumption is 1～10% of a recipe quantity.Lubricant is stearic acid and salt, polyethylene glycol 6000 etc., and total consumption is 0.3～5% of a recipe quantity.
The preparation method of said composition can be oral solid formulation direct powder compression commonly used/encapsulated, and wet granulation or dry granulation prepare granule, tablet and capsule.The adding mode of solubilizing agent can directly be mixed with other supplementary material, also can join in the binding agent.
Characteristics of the present invention are to combine as solubilizing agent and two kinds of methods of particle diameter of reducing letrozole adding certain amount of surfactant in the compositions, improve the dissolution of letrozole jointly.Do not add surfactant (seeing comparative example 1) and only add surfactant and do not reduce the particle diameter (seeing comparative example 2) of letrozole if only letrozole is pulverized 150 order to 200 mesh sieves in the prescription, though the stripping to letrozole has some improvement, but it is not remarkable to improve result of extraction, has only the two is combined the dissolution that could greatly improve letrozole.Letrozole was pulverized 150 order to 200 mesh sieves does not need special installation, and common pulverizer and screening machine can be realized.The invention has the advantages that preparation technology is simple, do not need special installation, easy to operate, be fit to suitability for industrialized production.
Description of drawings
Figure: letrozole compositions stripping curve comparison diagram
The specific embodiment
The present invention can be illustrated with the following examples
Embodiment 1: the letrozole granule
Prescription:
Preparation method:
(1) letrozole was pulverized 170 mesh sieves, standby;
(2) all adjuvants are crossed 80 mesh sieves, standby;
(3) take by weighing sorbitol, dextrin, aspartame, the crospolyvinylpyrrolidone mix homogeneously of recipe quantity, material I, get the letrozole of recipe quantity, equivalent adds material I, mix homogeneously, material II;
(4) polyoxyethylene sorbitan monoleate is joined in the 2% hypromellose aqueous solution and make binding agent, material II is added suitable amount of adhesive make suitable soft material, cross 24 mesh sieves and granulate, in 50 ℃ of aeration-dryings, control moisture is less than 3%, with 20 mesh sieve granulate.
(5) in dried granule, add flavoring orange essence, mix homogeneously, packing is promptly.
Embodiment 2: the letrozole tablet
Prescription:
Preparation method:
(1) letrozole was pulverized 200 mesh sieves, standby;
(2) all adjuvants are crossed 100 mesh sieves, standby;
(3) take by weighing lactose, starch, microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously of recipe quantity, material I, the letrozole and the sodium lauryl sulphate that take by weighing recipe quantity mix, equivalent adds material I, mix homogeneously, material II;
(4) material II is added 10% starch slurry and make suitable soft material in right amount, cross 20 mesh sieves and granulate, in 50 ℃ of aeration-dryings, control moisture is less than 3%, with 20 mesh sieve granulate.
(5) in dried granule, add the magnesium stearate mix homogeneously, tabletting, packing is promptly.
Embodiment 3: the letrozole capsule
Prescription:
Preparation method:
(1) letrozole was pulverized 150 mesh sieves, standby;
(2) all adjuvants are crossed 80 mesh sieves, standby;
(3) take by weighing mannitol, pregelatinized Starch, cross-linked carboxymethyl cellulose sodium, the low-substituted hydroxypropyl cellulose filler mix homogeneously of recipe quantity, get material I, get letrozole, poloxamer and the polyethylene glycol 6000 mix homogeneously of recipe quantity, equivalent adds material I, mix homogeneously gets material II;
(4) with material II fill capsule, packing promptly.
The comparative example 1: the letrozole tablet
Prescription:
Preparation method:
(1) letrozole was pulverized 200 mesh sieves, standby;
(2) all adjuvants are crossed 100 mesh sieves, standby;
(3) take by weighing sucrose, microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose mix homogeneously of recipe quantity, material I, take by weighing the letrozole of recipe quantity, equivalent adds material I, mix homogeneously, material II;
(4) material II is added 10% starch slurry and make suitable soft material in right amount, cross 20 mesh sieves and granulate, in 50 ℃ of aeration-dryings, control moisture is less than 3%, with 20 mesh sieve granulate.
(5) in dried granule, add the stearic acid mix homogeneously, tabletting, packing is promptly.
The comparative example 2: the letrozole capsule
Prescription:
Preparation method:
(1) all supplementary materials were pulverized 100 mesh sieves, standby;
(2) take by weighing letrozole, sodium lauryl sulphate, the carboxymethyl starch sodium mix homogeneously of recipe quantity, material I, take by weighing the mannitol of recipe quantity, equivalent adds material I, mix homogeneously, material II;
(3) with material II, be pressed into sheet, cross 20 mesh sieve granulate;
(4) in dried granule, add the polyethylene glycol 6000 mix homogeneously, the fill capsule, packing is promptly.
The determination of dissolution rate method:
Get commercially available letrozole sheet furlong, embodiment 1, embodiment 2, embodiment 3, comparative example 1 and comparative example 2 each 6 respectively, adopt second method in two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method, with 0.1mol/L hydrochloric acid 500mL is dissolution medium, rotating speed is 100 commentaries on classics/min, respectively at 5,10,15,30,45 and the 60min sampling and measuring, accumulation dissolution curve comparison diagram is seen accompanying drawing.
By accompanying drawing as seen, embodiment 1, embodiment 2, embodiment 3 and listing sheet furlong dissolution when 15min have all surpassed 85%, can think that embodiment 1, embodiment 2 are consistent with the former dissolution that grinds the sheet furlong that goes on the market.Only letrozole had been pulverized 200 mesh sieves and do not added surfactant in comparative example's 1 prescription, dissolution has only reached 80.2% during 15min, 2 of comparative examples have added surfactant and have not reduced the particle diameter of letrozole, and dissolution has only reached 71.8% during 15min.Can reach a conclusion thus, it is to add surfactant in the compositions and reduce the coefficient result of letrozole particle diameter that the present invention improves the letrozole method of dissolution.
Claims (12)
1. insoluble pharmaceutical composition is characterized in that: said composition comprise the active constituents of medicine letrozole and by a certain amount of adding so that contain the solubilizing agent that the compositions dissolution of letrozole improves.
2. insoluble pharmaceutical composition according to claim 1 is characterized in that: solubilizing agent is surfactants such as sodium lauryl sulphate, polyoxyethylene sorbitan monoleate, poloxamer.
3. insoluble pharmaceutical composition according to claim 1 is characterized in that: solubilizing agent is a sodium lauryl sulphate.
4. insoluble pharmaceutical composition according to claim 1 is characterized in that: solubilizing agent is a polyoxyethylene sorbitan monoleate.
5. insoluble pharmaceutical composition according to claim 1 is characterized in that: solubilizing agent is a poloxamer.
6. according to each described insoluble pharmaceutical composition among the claim 1-5, it is characterized in that: the solubilizing agent consumption is 0.1～5% of a recipe quantity.
7. according to each described insoluble pharmaceutical composition among the claim 1-5, it is characterized in that: the solubilizing agent consumption is 0.5～2% of a recipe quantity.
8. insoluble pharmaceutical composition according to claim 1 is characterized in that: letrozole is pulverized the processing of crossing 150 mesh sieves at least.
9. insoluble pharmaceutical composition according to claim 1 is characterized in that: letrozole was pulverized the processing of 150 orders or 170 orders or 200 mesh sieves.
10. insoluble pharmaceutical composition according to claim 1 is characterized in that: letrozole was pulverized the processing of 200 mesh sieves.
11. want 1 described insoluble pharmaceutical composition according to right, it is characterized in that: active component is a letrozole of pulverizing the processing of 200 mesh sieves, and solubilizing agent is the sodium lauryl sulphate of recipe quantity 0.5～2%.
12. according to each described insoluble pharmaceutical composition in claim 1 and 11, it is characterized in that: said composition is granule, tablet and capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910093377A CN101669942A (en) | 2009-09-29 | 2009-09-29 | Insoluble pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910093377A CN101669942A (en) | 2009-09-29 | 2009-09-29 | Insoluble pharmaceutical composition |
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|---|---|
| CN101669942A true CN101669942A (en) | 2010-03-17 |
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| CN200910093377A Pending CN101669942A (en) | 2009-09-29 | 2009-09-29 | Insoluble pharmaceutical composition |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485217A (en) * | 2010-12-03 | 2012-06-06 | 深圳海王药业有限公司 | Letrozole tablet with high dissolubility and preparation method thereof |
| CN103356495A (en) * | 2013-05-03 | 2013-10-23 | 海南林恒制药有限公司 | Letrozole tablet and preparation method thereof |
| CN103655513A (en) * | 2013-12-18 | 2014-03-26 | 北京科源创欣科技有限公司 | Letrozole pharmaceutical composition and preparation method thereof |
| CN105343127A (en) * | 2015-12-14 | 2016-02-24 | 武汉健民大鹏药业有限公司 | In vitro cultured calculus bovis aqueous solution and preparation method thereof |
| CN106309352A (en) * | 2015-06-29 | 2017-01-11 | 永信药品工业股份有限公司 | Method for preparing insoluble medicine solid dosage form |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101099724A (en) * | 2006-07-07 | 2008-01-09 | 上海复旦复华药业有限公司 | Micronization femara and its composition |
| CN101541316A (en) * | 2006-10-05 | 2009-09-23 | 万能药生物有限公司 | Injectable depot compositions and process of preparation of such compositions |
| CN101537184A (en) * | 2009-04-30 | 2009-09-23 | 杭州中美华东制药有限公司 | Composition containing water-insoluble high-activity drug and preparation method thereof |
-
2009
- 2009-09-29 CN CN200910093377A patent/CN101669942A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101099724A (en) * | 2006-07-07 | 2008-01-09 | 上海复旦复华药业有限公司 | Micronization femara and its composition |
| CN101541316A (en) * | 2006-10-05 | 2009-09-23 | 万能药生物有限公司 | Injectable depot compositions and process of preparation of such compositions |
| CN101537184A (en) * | 2009-04-30 | 2009-09-23 | 杭州中美华东制药有限公司 | Composition containing water-insoluble high-activity drug and preparation method thereof |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485217A (en) * | 2010-12-03 | 2012-06-06 | 深圳海王药业有限公司 | Letrozole tablet with high dissolubility and preparation method thereof |
| CN102485217B (en) * | 2010-12-03 | 2013-06-05 | 深圳海王药业有限公司 | Letrozole tablet with high dissolubility and preparation method thereof |
| CN103356495A (en) * | 2013-05-03 | 2013-10-23 | 海南林恒制药有限公司 | Letrozole tablet and preparation method thereof |
| CN103356495B (en) * | 2013-05-03 | 2015-12-02 | 海南林恒制药有限公司 | A kind of Letrozole tablet and preparation method thereof |
| CN103655513A (en) * | 2013-12-18 | 2014-03-26 | 北京科源创欣科技有限公司 | Letrozole pharmaceutical composition and preparation method thereof |
| CN106309352A (en) * | 2015-06-29 | 2017-01-11 | 永信药品工业股份有限公司 | Method for preparing insoluble medicine solid dosage form |
| US10137126B2 (en) | 2015-06-29 | 2018-11-27 | Yung Shin Pharm. Ind. Co., Ltd. | Method of preparing very slightly soluble drug with solid dosage form |
| CN105343127A (en) * | 2015-12-14 | 2016-02-24 | 武汉健民大鹏药业有限公司 | In vitro cultured calculus bovis aqueous solution and preparation method thereof |
| CN105343127B (en) * | 2015-12-14 | 2019-04-19 | 武汉健民大鹏药业有限公司 | A kind of In vitro cultured Calculus Bovis aqueous solution and preparation method thereof |
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Application publication date: 20100317 |