CN103356495A - Letrozole tablet and preparation method thereof - Google Patents
Letrozole tablet and preparation method thereof Download PDFInfo
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- CN103356495A CN103356495A CN2013101595363A CN201310159536A CN103356495A CN 103356495 A CN103356495 A CN 103356495A CN 2013101595363 A CN2013101595363 A CN 2013101595363A CN 201310159536 A CN201310159536 A CN 201310159536A CN 103356495 A CN103356495 A CN 103356495A
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- letrozole
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Abstract
The invention relates to a letrozole tablet and a preparation method thereof. The letrozole tablet comprises the following main auxiliary materials: microcrystalline cellulose, lactose, sodium starch glycolate, L-HPC (low-substituted hydroxypropyl cellulose), sodium lauryl sulfate, Tween 80, magnesium stearate and starch; the preferable sodium lauryl sulfate:Tween 80 ratio is 2:1, and the sodium starch glycolate:L-HPC ratio is 5:1. The tablet has stable product quality, obviously enhances the letrozole dissolution, and effectively enhances the bioavailability; and the tablet preparation technique is simple, does not need special equipment, and is convenient to operate and suitable for industrial production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of letrozole tablet and preparation method thereof.
Background technology
Letrozole (Letrozole) chemistry 1-[two (4-cyano-phenyl) methyl by name]-1,2, the 4-triazole, be artificial synthesize benzyl triazole derivative, be a kind of oral, nonsteroidal third generation arimedex with high degree of specificity, having jumped at present becomes the first-line treatment of Postmenopausal Breast Cancer medicine.Letrozole was used for the first-line treatment advanced breast cancer more than 30 countries and regions listings, and is widely used as the two wires medication of breast carcinoma in U.S.'s listing first in Britain's listing by the research and development of Switzerland Ciba drugmaker in 1996 in 1997 at present.Domestic Hengrui Medicine Co., Ltd., Jiangsu Prov. obtained production certification, trade name " Fu Rui " in 1999.The also at home listing in 2003 of the letrozole of Novartis Co.,Ltd, trade name " furlong ".
Letrozole has been got permission at present more than 70 country's listings; Third generation arimedex all is higher than the medicine tamoxifen (tamoxifen) of the most frequently used breast carcinoma endocrine therapy in the curative effect of breast cancer treatment stages.In first-line treatment, letrozole all is better than tamoxifen at effective percentage, clinical Benefit rate, progression of disease, treatment Time To Failure and 1 year, the 2 years aspects such as existence, toleration is better than tamoxifen, and effective to the patient of tamoxifen failure, and might overcome the tamoxifen drug resistance.After the treatment menopause, estrogen receptor and/or the progesterone receptor positive or the not clear advanced breast cancer patient of receptor situation, these patients need be in nature or the menopausal state due to the artificial induction.In August, 2004 Switzerland's approval " furlong " is as the subsequent reinforced auxiliary treatment of the early-stage breast cancer of receptor positive after the menopause.The breast carcinoma of early stage patient of receptor positive continues to use " furlong " to carry out the subsequent reinforced auxiliary treatment after tamoxifen treatment in 5 years after in October, the 2004 FDA approval menopause.
The oral rear absorption of letrozole is complete rapidly, and is distributed in fast, widely tissue.This product metabolism is slow, presents obvious terminal the elimination, and plasma half-life is about 2 days.2.5mg dosage on the one, 2~6 weeks can reach stable state.Letrozole has the specificity of height, does not reduce level of adrenocortical hormone, therefore, need not to replenish sugar and mineralocorticoid during application.
Chinese patent CN101467971 discloses a kind of dispersible tablet that contains letrozole, makes tablet with other adjuvants again after letrozole and carrier are made solid dispersion.But solid dispersion preparation technology is difficult to amplify, the suitability for industrialized production difficulty.
The letrozole poorly water-soluble, the letrozole dosage form of listing is conventional tablet at present.For oral solid formulation, dissolution is an important quality investigation index, because the bioavailability of dissolution and oral solid formulation is closely related, also directly affects the curative effect of medicine.Because the relatively poor water solublity of letrozole needs to solve the poor problem of dissolution by preparation technique during the preparation solid preparation.Chinese patent CN101099724 discloses a kind of micronization femara and compositions thereof, the method becomes particle diameter to be combined with carrier behind the 10-100 micron letrozole micronization to be prepared into the preparation with suitable dissolution again, but micronized process need expends large energy, the risk that particle aggregation is arranged, and particle diameter is too little, preparation process powder is floating seriously can be lost material and cause dust pollution, is unfavorable for industry's enlarging production.
Summary of the invention
The purpose of this invention is to provide a kind of letrozole piece preparation method, the tablet constant product quality of the method preparation significantly improves the dissolution of letrozole, the Effective Raise bioavailability, and this tablet producing technology is simple, does not need special installation, easy to operate, be fit to suitability for industrialized production.
For dissolution and the stability that improves tablet, reduce the impurity in the tablet, kind and the consumption of solubilizing agent in the tablet formulation and disintegrating agent carried out preferably.
To achieve these goals, the invention provides following technical scheme:
A kind of letrozole sheet, it major auxiliary burden that comprises is: microcrystalline Cellulose, lactose, carboxymethylstach sodium, L-HPC, sodium laurylsulfate, Tween 80, magnesium stearate, starch.
Inventive point of the present invention is unexpected discovery when selecting specific solubilizing agent and disintegrating agent, and the letrozole tablet quality that makes is stable, and dissolution significantly improves, and bioavailability is improved significantly.Be specially: (1) adds surfactant as solubilizing agent, and by test of many times, unexpected discovery is sodium laurylsulfate in writing out a prescription: when the content ratio of Tween 80 was 2:1, the letrozole sheet solubilizing effect that makes was best; (2) select disintegrating agent to make up to realize best disintegrate effect, the disintegrate best results of letrozole sheet when unexpected discovery is 5:1 when the content ratio of carboxymethylstach sodium: L-HPC in the prescription.
The letrozole sheet of the different prescriptions of table 1 prepares sample
Conclusion: sodium laurylsulfate in writing out a prescription: when the content ratio of Tween 80 is 2:1, when the content ratio of and carboxymethylstach sodium: L-HPC is 5:1 (R1), the effect duration of letrozole sheet reaches 5 years, and the 10min dissolution reaches 82%, the 45min dissolution reaches 99.2%, show best quality, obviously be better than other prescription (R2-R4).In addition, the content of letrozole content (%) behind 6 months accelerated stability tests, R1 prescription 99.6% obviously is better than other prescription (R2-R4).
Therefore, letrozole tablet of the present invention has the following advantages: stability greatly improves, and dissolution significantly increases.
The specific embodiment
(1) preparation of letrozole tablet
Embodiment 1: the preparation of letrozole tablet
The letrozole tablet recipe:
Letrozole 2.5g
Microcrystalline Cellulose 12.5g
Lactose 90g
Carboxymethylstach sodium 2.5g
L-HPC 0.5g
Sodium laurylsulfate 1.0g
Tween 80 0.5g
Magnesium stearate 1.5g
Starch is an amount of
Make altogether 1000
Preparation method:
The binding agent preparation: get starch, add suitable quantity of water, stir evenly, add water boil, namely getting concentration is 2.5% left and right sides starch slurry, adds the tween 80 mixing;
Pulverize, sieve: get the letrozole crude drug, micronizing is crossed respectively 80 mesh sieves with microcrystalline cellulose excipients, lactose, carboxymethylstach sodium, L-HPC, sodium laurylsulfate;
Mix, granulate: the letrozole of getting after the pulverizing mixed afterwards mistake 80 mesh sieves, triplicate by the equivalent incremental method with lactose; Again with microcrystalline Cellulose, residue lactose, carboxymethylstach sodium, L-HPC and sodium laurylsulfate mixing, put and add above-mentioned starch slurry granulation in the granulator, 50~55 ℃ are dried in the pellet moisture 2%, 40 mesh sieve granulate, put in total mixed machine, add magnesium stearate, mixed sampling and measuring content and moisture 20 minutes;
Tabletting: contain letrozole 2.5mg by every and calculate average sheet heavily, tabletting is controlled tablet weight variation in ± 5%, and is adjusted to suitable hardness;
The packing: tablet after testing the projects such as friability, dissolution and uniformity of dosage units qualified after, aluminum-plastic packaged, again through outer package, and get final product.
Control Example 1: the preparation of letrozole tablet
The letrozole tablet recipe:
Letrozole 2.5g
PVP K30 4.375g
Tween 80 1.875g
Mannitol 3.75g
Lactose 62.5g
Microcrystalline Cellulose 56.25g
Crosslinked polyethylene polypyrrole alkane ketone 5g
Magnesium stearate 0.625g makes 1000.
Preparation method:
The PVP K30 (PVP K30) of recipe quantity, Tween 80, mannitol are added in the 400ml water, stir into homogeneous solution, letrozole is added in this solution, it was uniformly dispersed in ultrasonic 5 minutes and obtains suspension; Lactose, microcrystalline Cellulose, crosslinked polyethylene polypyrrole alkane ketone (PVPP) mix homogeneously with above-mentioned recipe quantity, above-mentioned suspension is sprayed into mixed accessories with peristaltic pump by spray gun, stir while spraying, soft material processed, 20 orders are granulated, 50 ℃ of oven dry add magnesium stearate mix homogeneously, tabletting behind the granulate.
Control Example 2: the preparation of letrozole tablet
Letrozole 2.5g
Sorbitol 12 g
Dextrin 57.4g
Aspartame 1.7 g
Crospolyvinylpyrrolidone 7.5 g
Polyoxyethylene sorbitan monoleate 0.1 g
Hypromellose 0.6 g
Flavoring orange essence 1.0 g make 1000.
Preparation method:
(1) letrozole was pulverized 170 mesh sieves, for subsequent use;
(2) all adjuvants are crossed 80 mesh sieves, for subsequent use;
(3) take by weighing sorbitol, dextrin, aspartame, the crospolyvinylpyrrolidone mix homogeneously of recipe quantity, get material I, get the letrozole of recipe quantity, equivalent adding material I, mix homogeneously gets 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) add flavoring orange essence in dried granule, mix homogeneously is packed and be get final product.
(2) stability test of letrozole tablet
Adopt above-described embodiment 1 and control Example 1(to make with reference to CN102485217A), control Example 2(makes with reference to CN101669942A), the stability of the letrozole tablet that the three is made is measured.
Accelerated stability test,Carry out with reference to 2010 editions appendix XC of Chinese Pharmacopoeia crude drug pharmaceutical preparation stability test guideline.
Each sample is got three batches, is 40 ℃ ± 2 ℃ in temperature, and relative humidity is to place under 75% ± 5% condition 6 months, respectively at 1,2,3, the sampling in June investigates character, letrozole content of isomer, pH value, microbial limit, the drug content of sample.The result is as follows:
Character: up to specification,White or off-white color tablet.
Microbial limit: up to specification,According to giving birth to speck limit test method (appendix XI J) inspection, up to specification.
Disintegration: up to specification,Check according to inspection technique disintegration (pharmacopeia 2010 appendix X A), up to specification.
Assay:
Instrument and reagent
The Agilent1100 high performance liquid chromatograph
Chromatographic column (Erie is special, C18, and 4.6 μ m * 250mm)
Acetonitrile (chromatograph alcohol), methanol (chromatograph alcohol), sodium dihydrogen phosphate (A.R.), phosphoric acid (A.R.)
The letrozole reference substance (lot number: 070701-1, content: 99.6%, provided by Hainan ten thousand special medicine company limiteies)
Letrozole isomer reference substance (lot number: 20071015, content: 100%, provided by Hainan ten thousand special medicine company limiteies)
Chromatographic condition
Be filler with octadecylsilane chemically bonded silica, with sodium dihydrogen phosphate [ get sodium dihydrogen phosphate 7.8g, add water 1000ml dissolving, regulate pH 3.0 with phosphoric acid,diluted (1 → 10) ]-methanol-acetonitrile (50:45:5) is mobile phase, the detection wavelength is 230nm.Get the letrozole reference substance and letrozole isomer reference substance is an amount of, add the mobile phase dissolving and make the solution that contains letrozole and each 0.05mg of letrozole isomer among every 1ml, as the system suitability test solution, get 20ul injection liquid chromatography, the record chromatogram, the separating degree at letrozole peak and letrozole isomer peak must not be less than 1.5, and number of theoretical plate calculates by the letrozole peak should be not less than 3000.
The preparation of solution
Need testing solution: get 10 in letrozole tablet, porphyrize, precision takes by weighing approximately 0.11g, puts in the measuring bottle of 10ml, with mobile phase dissolving and be diluted to scale, shakes up, and filters, as need testing solution.
Contrast solution: precision weighing letrozole reference substance is 15mg approximately, puts in the 100ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up (as stock solution), and precision measures 0.5ml and puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale.
Letrozole isomer reference substance solution: precision weighing letrozole isomer reference substance is 15mg approximately, put in the 100ml measuring bottle, add the mobile phase dissolving and be diluted to scale, shake up (as stock solution), precision measures 0.5ml and puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale.
Blank adjuvant solution: more an amount of than taking by weighing the mixed powder of this product adjuvant by prescription, prepare according to the need testing solution compound method.
Assay method:According to 2010 editions appendix VI of Chinese Pharmacopoeia D high effective liquid chromatography for measuring.
Result of the test:
Table 2 accelerated stability test result (0 month)
Table 3 accelerated stability test result (January)
Table 4 accelerated stability test result (February)
Table 5 accelerated stability test result (March)
Table 6 accelerated stability test result (June)
Can find out from above-mentioned experimental result, letrozole tablet of the present invention is in accelerated test, highly stable (letrozole tablet drug content after 6 months of corresponding controlled trial example 1 is down to 95%) about 99%, the good stability of letrozole tablet maintenance of the embodiment of the invention 1 of maintaining of the content of principal agent letrozole.As seen compare with control Example 1 and 2, the stability of the letrozole tablet of embodiments of the invention 1 greatly improves, and shows as
6 months accelerated stability testThe letrozole content of isomer of tablet few (0.19%) and letrozole content more stable (99.93%).As seen letrozole tablet of the present invention has improved the safety of clinical use greatly, and more convenient in clinical use.
(3) dissolution determination of letrozole tablet
Adopt above-described embodiment 1 and control Example 1(to make with reference to CN102485217A), control Example 2(makes with reference to CN101669942A), the dissolution of the letrozole tablet that the three is made is measured.
Adopt the second method in two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method, take 0.1mol/L hydrochloric acid 500mL as dissolution medium, rotating speed is 100 to turn/min, respectively at 3,5,10,15,30,45 and the 60min sampling and measuring.
Table 7 Dissolution Rate Testing result
Can find out from above-mentioned experimental result, embodiment 1(is letrozole tablet of the present invention) (corresponding controlled trial example 1 only is 62.5% about 82% for the dissolution of 10min, control experiment example 2 only is 59.7%%), the dissolution of 45min only is 88.6% in the corresponding controlled trial example 1 of 99.2%(, and control experiment example 2 only is 86.5%).As seen the dissolution of letrozole tablet of the present invention greatly improves, Effective Raise the bioavailability of letrozole tablet, more be conducive to clinical use.
According to above preferred embodiment the present invention has been made description.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (5)
1. letrozole tablet, it major auxiliary burden that comprises is: microcrystalline Cellulose, lactose, carboxymethylstach sodium, L-HPC, sodium laurylsulfate, Tween 80, magnesium stearate, starch.
2. letrozole tablet claimed in claim 1 is characterized in that: the content of carboxymethylstach sodium in the adjuvant: L-HPC is than being 5:1.
3. letrozole tablet claimed in claim 1 is characterized in that: sodium laurylsulfate in the adjuvant: the content of Tween 80 is than being 2:1.
4. letrozole tablet claimed in claim 1 is characterized in that its concrete prescription comprises:
Letrozole 2.5g
Microcrystalline Cellulose 12.5g
Lactose 90g
Carboxymethylstach sodium 2.5g
L-HPC 0.5g
Sodium laurylsulfate 1.0g
Tween 80 0.5g
Magnesium stearate 1.5g
Starch is an amount of
Make altogether 1000.
5. the preparation method of the described letrozole tablet of claim 4:
The binding agent preparation: get starch, add suitable quantity of water, stir evenly, add water boil, namely getting concentration is 2.5% left and right sides starch slurry, adds the tween 80 mixing;
Pulverize, sieve: get the letrozole crude drug, micronizing is crossed respectively 80 mesh sieves with microcrystalline cellulose excipients, lactose, carboxymethylstach sodium, L-HPC, sodium laurylsulfate;
Mix, granulate: the letrozole of getting after the pulverizing mixed afterwards mistake 80 mesh sieves, triplicate by the equivalent incremental method with lactose; Again with microcrystalline Cellulose, residue lactose, carboxymethylstach sodium, L-HPC and sodium laurylsulfate mixing, put and add above-mentioned starch slurry granulation in the granulator, 50~55 ℃ are dried in the pellet moisture 2%, 40 mesh sieve granulate, put in total mixed machine, add magnesium stearate, mixed sampling and measuring content and moisture 20 minutes;
Tabletting: contain letrozole 2.5mg by every and calculate average sheet heavily, tabletting is controlled tablet weight variation in ± 5%, and is adjusted to suitable hardness;
The packing: tablet after testing the projects such as friability, dissolution and uniformity of dosage units qualified after, aluminum-plastic packaged, again through outer package, and get final product.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107737112A (en) * | 2017-11-07 | 2018-02-27 | 海南锦瑞制药有限公司 | A kind of Letrozole piece and preparation method thereof |
CN106983727B (en) * | 2017-05-27 | 2020-04-14 | 江苏苏南药业实业有限公司 | Letrozole tablet and preparation method thereof |
US20210283144A1 (en) * | 2020-03-11 | 2021-09-16 | Northwestern University | Modulation of sex steroid hormone production and activity for treating and preventing hernias |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101669942A (en) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | Insoluble pharmaceutical composition |
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- 2013-05-03 CN CN201310159536.3A patent/CN103356495B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101669942A (en) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | Insoluble pharmaceutical composition |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106983727B (en) * | 2017-05-27 | 2020-04-14 | 江苏苏南药业实业有限公司 | Letrozole tablet and preparation method thereof |
CN107737112A (en) * | 2017-11-07 | 2018-02-27 | 海南锦瑞制药有限公司 | A kind of Letrozole piece and preparation method thereof |
CN107737112B (en) * | 2017-11-07 | 2020-05-19 | 海南锦瑞制药有限公司 | Letrozole tablet and preparation method thereof |
US20210283144A1 (en) * | 2020-03-11 | 2021-09-16 | Northwestern University | Modulation of sex steroid hormone production and activity for treating and preventing hernias |
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Address after: 570216 Hainan province Haikou city Jinpan Development Zone Industrial Village No. 2-5 Patentee after: Hainan Heng Heng pharmaceutical Limited by Share Ltd Address before: 570216 Hainan province Haikou city Jinpan Development Zone Industrial Village No. 2-5 Patentee before: Hainan Linheng Pharmaceutical Co., Ltd. |
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