CN103142509A - Bortezomib pharmaceutic composition for injection - Google Patents
Bortezomib pharmaceutic composition for injection Download PDFInfo
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- CN103142509A CN103142509A CN2013100701276A CN201310070127A CN103142509A CN 103142509 A CN103142509 A CN 103142509A CN 2013100701276 A CN2013100701276 A CN 2013100701276A CN 201310070127 A CN201310070127 A CN 201310070127A CN 103142509 A CN103142509 A CN 103142509A
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Abstract
The invention provides a bortezomib pharmaceutic composition, and aims to solve the technical problem that the stability and dissolubility of the bortezomib are poor. The pharmaceutic composition contains bortezomib and amino acid in the mass ratio of 1:(2-100). By using the bortezomib pharmaceutic composition for injection, the dissolubility of the bortezomib can be effectively improved, and the effect is equivalent or superior to that of the products in the market. The bortezomib pharmaceutic composition is safe and non-irritant, the preparation cost is low, the preparation method is simple, and the stability is superior to that of the existing bortezomib preparation. The bortezomib pharmaceutic composition is favorable for industrial production.
Description
Technical field
The invention belongs to field of medicaments, the concrete field of pharmaceutical preparations that belongs to the present invention relates to a kind of injection bortezomib pharmaceutical composition.
Background technology
Bortezomib (Bortezomib) was a kind of dipeptides ylboronic acid compound, obtained the approval list marketing of FDA May 19 in 2003, and commodity are called " Bortezomib (velcade) ", are the injection freeze-dried powder.Be used for the treatment of recurrent and Refractory Multiple Myeloma.The dissolubility of bortezomib raw material in water only has 0.076mg/ml, and the dissolubility of crude drug is lower, and directly preparation can't reach suitable concentration.Need to adopt suitable hydrotropy technology.
Listing product " Bortezomib " has adopted the technology of patent WO02059130, WO2002059131.The complex that this patent adopts bortezomib and saccharide to form, described sugar comprises condensation sugar for example mannitol and sorbitol.This patent is mixed and made into lyophilized formulations with bortezomib and mannitol, and wherein bortezomib and mannitol exist with complex form, and this patent claims greatly to improve the dissolubility of bortezomib.But in using, the listing product finds, the bortezomib less stable, and responsive especially for environment such as acid-base value and variations in temperature, in put procedure, related substance increases, and human body is brought harm.
Adopt bortezomib and tromethane to make lyophilized preparation in the CN201080004118.1 invention, wherein the tromethane proppant, have certain hydrotropy effect simultaneously, and is better through the evidence solute effect.But adopt tromethane to have following shortcoming as cosolvent: at first, tromethane is originally as alkalescence, need again to be adjusted to the acceptable PH scope of human body with acid, degraded easily occurs relevant thing is increased in aqueous solution in bortezomib under acid, alkali condition; Secondly, if when exceeding pH value 7.6-8.4 scope when regulating have bortezomib and separate out, and this to separate out be irreversible; Again, tromethane as the side effect of injection itself is: this product can cause hypoglycemia, hypotension, feels sick, vomit, and also can suppress to breathe, and even makes the side effect such as respiratory arrest; The liquid medicine spill blood vessel is outer may cause local tissue necrosis.
WO2010114982 discloses a kind of lyophilized formulations and has comprised bortezomib or pharmaceutically acceptable salt or ester, clathrate, at least a conditioner and surfactant.This invention is by adding clathrate and surfactant to increase drug solubility, play certain effect for improving drug solubility, but added a large amount of adjuvants, greatly increased the redissolution amount of liquid, cause infusion inconvenience, surfactant has certain toxicity and zest in addition.
Some preparation of prior art is that bortezomib is made liquid form, and the infusion administration is because well-known bortezomib is extremely unstable, to acid, alkali is unstable, easily oxidation, facile hydrolysis, so the liquid preparation form is compared with the lyophilized solid dosage form and is not obviously had advantage.
To sum up, lack a kind of the improvement on bortezomib deliquescent basis in prior art, can also improve the freeze-drying medicinal composition of bortezomib preparation stability.
Summary of the invention
For solving bortezomib poor stability and poorly soluble technical problem, the invention provides a kind of bortezomib pharmaceutical composition.Technical solution of the present invention can effectively improve the bortezomib dissolubility, effect and listing product are quite or more excellent, the bortezomib pharmaceutical composition that provides is safe and non-stimulating, write out a prescription with low cost, preparation method is simple, the most important thing is to improve the poor defective of existing preparation stability, be conducive to suitability for industrialized production.
The invention provides a kind of bortezomib pharmaceutical composition, it is characterized in that described compositions comprises bortezomib and the aminoacid that mass ratio is 1:2-100.
Wherein, aminoacid of the present invention is for having the aminoacid of hydroxyl or sulfydryl.
Preferably, described aminoacid is L-aminoacid.
Hydroxyl of the present invention refers to the hydroxyl hydroxyl in the basic group carboxyl of aminoacid.
Preferably, aminoacid of the present invention is selected from one or more in serine, threonine and cysteine.
Further, in compositions of the present invention, each component ratio is that bortezomib and amino acid whose mass ratio are 1:2-50.
Further, in compositions of the present invention, bortezomib and amino acid whose mass ratio are 1:5-20.
Further, in compositions of the present invention, bortezomib and amino acid whose mass ratio are 1:10.
Pharmaceutical composition of the present invention also can further comprise other filler, the mass ratio of bortezomib, aminoacid and filler is 1:2-50:2-50, wherein said aminoacid is the aminoacid with hydroxyl or sulfydryl, and described other filler is selected from one or both in mannitol, sorbitol.Preferably, wherein aminoacid is selected from one or more in serine, threonine and cysteine.
Preferably, the invention provides a kind of bortezomib pharmaceutical composition, it is characterized in that described compositions is comprised of bortezomib, aminoacid and other filler, wherein the mass ratio of bortezomib, aminoacid and filler is 1:2-8:2-8, wherein, aminoacid is selected from one or more in serine, threonine and cysteine; Other filler is selected from one or both in mannitol, sorbitol.
Further preferably, the invention provides a kind of bortezomib pharmaceutical composition, it is characterized in that described compositions is comprised of bortezomib, cysteine and mannitol, wherein the mass ratio of each component is 1:5:5.
In the present invention, the bortezomib pharmaceutical composition that adds other filler with do not add comparing of other filler, product appearance is better, the freeze-drying prods color is white, and is loose, is difficult for subsiding.
The present invention also provides a kind of method for preparing above-mentioned bortezomib pharmaceutical composition, it is characterized in that comprising following steps:
1), get the bortezomib raw material and add that 40 ~ 100% tert-butyl alcohol room temperature is ultrasonic makes dissolving;
2), get aminoacid and filler and add the suitable quantity of water dissolving;
3), step 1 gained solution is joined step 2) mixing in gained solution, filter packing;
4), lyophilization, and get final product.
The pharmaceutical composition of this preparation technology preparation, its freeze-drying prods is at 40 ℃, and 75% relative humidity is stable in lower 6 months.Show total impurities lower than 0.2%, and when reconstruct, the described compositions of solution form keeps at least 24 hours stablizing.
Be below the elaboration to innovative point of the present invention: research finds that the dissolubility of bortezomib raw material in water only has 0.076mg/ml, in water, dissolubility is low, directly preparation can't reach suitable concentration, therefore, prior art all adopts different solubilising technology to improve the bortezomib dissolubility, just can make bortezomib make formulation application in clinical, kinds of schemes is arranged in prior art, wherein effect is best is the condensation saccharide that adds take mannitol and sorbitol as representative, thereby this type of adjuvant can improve dissolubility with the bortezomib complexation.But this technical scheme and other solubilising technical schemes all are difficult to overcome another shortcoming of bortezomib, it is poor stability, studies show that bortezomib in acid, alkali, oxidation and have the environment of water all unstable, easily degraded, not only cause drug effect to reduce, also cause related substance to roll up, bring harm to human body.Therefore, how to solve simultaneously bortezomib solubility problem and stability problem, become a technical barrier.
The present inventor is surprised to find that under study for action, partial amino-acid, especially contain the aminoacid of hydroxyl or sulfydryl in structure, can obviously improve the dissolubility of bortezomib, its effect and listing product quite or be better than the product that goes on the market, and, these aminoacid also have another excellent results, make the product stability raising after namely adding prescription, obviously be better than the product that goes on the market, wherein the cysteine best results.
The specific embodiment
Below the purpose of described embodiment be for better explanation the present invention, limit but should not consist of scope of the present invention.
Embodiment 1
Adopt following prescription: bortezomib 35mg; Cysteine 175mg; Mannitol 175mg.
Preparation method:
The bortezomib raw material adds tert-butyl alcohol 2ml, and at room temperature ultrasonic dissolution made dissolving fully in 5 minutes, got adjuvant and added the 9ml water dissolution, merge with the solution of above-mentioned bortezomib, 0.22 the packing of μ m membrane filtration, nitrogen gland outlet is filled in lyophilization in every 1ml to 5ml neutral boron silica glass lyophilizing bottle.
Embodiment 2
Adopt following prescription: bortezomib 35mg; Cysteine 175mg.
Preparation method is with embodiment 1.
Embodiment 3
Adopt following prescription: bortezomib 35mg; Cysteine 350mg.
Preparation method is with embodiment 1.
Embodiment 4
Adopt following prescription: bortezomib 35mg; Serine 350mg.
Preparation method is with embodiment 1.
Embodiment 5
Adopt following prescription: bortezomib 35mg; Threonine 350mg.
Preparation method is with embodiment 1.
Embodiment 6
Adopt following prescription: bortezomib 35mg; Cysteine 700mg.
Preparation method:
The bortezomib raw material adds tert-butyl alcohol 2ml, and at room temperature ultrasonic dissolution made dissolving fully in 5 minutes, got adjuvant and added the 18ml water dissolution, merge with the solution of above-mentioned bortezomib, 0.22 the packing of μ m membrane filtration, nitrogen gland outlet is filled in lyophilization in every 1ml to 5ml neutral boron silica glass lyophilizing bottle.
Embodiment 7
Adopt following prescription: bortezomib 35mg; Serine 700mg.
Preparation method is with embodiment 6.
Embodiment 8
Adopt following prescription: bortezomib 35mg; Serine 175mg; Sorbitol 175mg.
Preparation method is with embodiment 1.
Embodiment 9
Adopt following prescription: bortezomib 35mg; Threonine 175mg; Mannitol 175mg.
Preparation method is with embodiment 1.
Embodiment 10
Adopt following prescription: bortezomib 35mg; Cysteine 70mg; Mannitol 70mg.
Preparation method is with embodiment 1.
Embodiment 11
Adopt following prescription: bortezomib 35mg; Threonine 70mg; Sorbitol 70mg.
Preparation method is with embodiment 1.
Embodiment 12
Adopt following prescription: bortezomib 35mg; Threonine 280mg; Sorbitol 280mg.
Preparation method:
The bortezomib raw material adds tert-butyl alcohol 2ml, and at room temperature ultrasonic dissolution made dissolving fully in 5 minutes, got adjuvant and added the 15ml water dissolution, merge with the solution of above-mentioned bortezomib, 0.22 the packing of μ m membrane filtration, nitrogen gland outlet is filled in lyophilization in every 1ml to 5ml neutral boron silica glass lyophilizing bottle.
Embodiment 13
Adopt following prescription: bortezomib 35mg; Cys2 80mg; Mannitol 280mg.
Preparation method is with embodiment 12.
Embodiment 14
Adopt following prescription: bortezomib 35mg; Serine 70mg; Mannitol 280mg.
Preparation method is with embodiment 12.
Be the adjuvant products obtained therefrom with the present invention dissolubility, different, special for Comparative Examples 1-4 aspect stable for investigating listing product prescription and adopting other aminoacid.
Comparative Examples 1
Adopt and the identical prescription of listing product: bortezomib 35mg; Mannitol 350mg.
Preparation method is with embodiment 1.
Comparative Examples 2
Adopt following prescription: bortezomib 35mg; Glycine 350mg.
Preparation method is with embodiment 1, and result: solvent can't form the homogeneous settled solution after merging, and Precipitation is arranged.
Comparative Examples 3
Adopt following prescription: bortezomib 35mg; Phenylalanine-3,4-quinone 50mg.
Preparation method is with embodiment 1, and result: solvent can't form the homogeneous settled solution after merging, and Precipitation is arranged.
Comparative Examples 4
Adopt following prescription: bortezomib 35mg; Tyrosine 350mg.
Preparation method is with embodiment 1.
Embodiment 15
For investigating the solubilizing effect of each prescription, the spy carries out following test.
Dissolving (redissolution) test: the lyophilizing sample of getting embodiment 1-14, Comparative Examples 1, listing product, and bortezomib raw material, add 0.9% sodium chloride solution according to clinical use amount and make the solution that contains bortezomib 1mg/ml, measure dissolving (redissolution) time, result is as follows:
These results suggest that, the embodiment of the present invention, Comparative Examples 1 and listing product prescription can increase dissolubility in bortezomib water, make product be easy to preparation, and can redissolve smoothly in 20s.But the tyrosine of Comparative Examples 4 prescription does not reach same effect.
Embodiment 16
Carry out the stability test contrast with listing product and embodiment 1: the investigation condition: 40 ℃ ± 2 ℃, relative humidity 75% ± 5%.
Conclusion: result shows, the injection bortezomib shelf-stability of embodiment 1 preparation obviously is better than the product that goes on the market.
Embodiment 17
Embodiment 3,4,9 stability test result: investigation condition: 40 ℃ ± 2 ℃, relative humidity 75% ± 5%.
。
Conclusion: result shows, the injection bortezomib shelf-stabilities of embodiment 3,4,9 preparations meet the quality standard requirement, and shelf-stability is better than or is substantially suitable with the listing product.
Claims (11)
1. a bortezomib pharmaceutical composition, is characterized in that described compositions comprises bortezomib and aminoacid, and bortezomib and amino acid whose mass ratio are 1:2-100.
2. bortezomib pharmaceutical composition as claimed in claim 1, is characterized in that described aminoacid is the aminoacid with hydroxyl or sulfydryl.
3. bortezomib pharmaceutical composition as claimed in claim 1, is characterized in that described aminoacid is selected from one or more in serine, threonine and cysteine.
4. bortezomib pharmaceutical composition as described in any one in claim 1-3, is characterized in that bortezomib and amino acid whose mass ratio are 1:2-50.
5. bortezomib pharmaceutical composition as claimed in claim 4, is characterized in that bortezomib and amino acid whose mass ratio are 1:5-20.
6. bortezomib pharmaceutical composition as claimed in claim 5, is characterized in that bortezomib and amino acid whose mass ratio are 1:10.
7. bortezomib pharmaceutical composition as described in any one in claim 1, it is characterized in that described pharmaceutical composition further comprises other filler, the mass ratio of bortezomib, aminoacid and other filler is 1:2-50:2-50, wherein, described aminoacid is the aminoacid with hydroxyl or sulfydryl; Other filler is selected from one or both in mannitol, sorbitol.
8. bortezomib pharmaceutical composition as claimed in claim 7, is characterized in that described aminoacid is selected from one or more in serine, threonine and cysteine.
9. bortezomib pharmaceutical composition as claimed in claim 1, it is characterized in that described compositions is comprised of bortezomib, aminoacid and other filler, the mass ratio of bortezomib, aminoacid and other filler is 1:2-8:2-8, wherein, described aminoacid is selected from one or more in serine, threonine and cysteine; Other filler is selected from one or both in mannitol, sorbitol.
10. bortezomib pharmaceutical composition as claimed in claim 9, is characterized in that described compositions is comprised of bortezomib, cysteine and mannitol, and the mass ratio of bortezomib, cysteine and mannitol is 1:5:5.
11. a method for preparing as bortezomib pharmaceutical composition as described in any one in claim 1-10 is characterized in that comprising following steps:
1), get the bortezomib raw material and add that 40 ~ 100% tert-butyl alcohol room temperature is ultrasonic makes dissolving;
2), get aminoacid and filler and add the suitable quantity of water dissolving;
3), step 1) gained solution is joined step 2) mixing in gained solution, filter packing;
4), lyophilization, and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310070127.6A CN103142509B (en) | 2013-03-06 | 2013-03-06 | A kind of injection bortezomib pharmaceutical composition |
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| CN201310070127.6A CN103142509B (en) | 2013-03-06 | 2013-03-06 | A kind of injection bortezomib pharmaceutical composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720666A (en) * | 2013-12-16 | 2014-04-16 | 亿腾药业（泰州）有限公司 | Preparation method for bortezomib freeze-dried preparation for injection |
| CN104414982A (en) * | 2013-08-28 | 2015-03-18 | 山东新时代药业有限公司 | Freeze-dried bortezomib powder injection and preparation method thereof |
| CN107224569A (en) * | 2016-03-26 | 2017-10-03 | 复旦大学 | Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use |
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| CN101795671A (en) * | 2007-08-21 | 2010-08-04 | 阿尔扎公司 | Liposome compositions for in vivo administration of boronic acid compounds |
| WO2012047845A1 (en) * | 2010-10-05 | 2012-04-12 | App Pharmaceuticals | Bortezomib formulations stabilised with boric |
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
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2013
- 2013-03-06 CN CN201310070127.6A patent/CN103142509B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101795671A (en) * | 2007-08-21 | 2010-08-04 | 阿尔扎公司 | Liposome compositions for in vivo administration of boronic acid compounds |
| WO2012047845A1 (en) * | 2010-10-05 | 2012-04-12 | App Pharmaceuticals | Bortezomib formulations stabilised with boric |
| CN102784114A (en) * | 2011-05-14 | 2012-11-21 | 山东新时代药业有限公司 | Bortezomib freeze-dried powder injection and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104414982A (en) * | 2013-08-28 | 2015-03-18 | 山东新时代药业有限公司 | Freeze-dried bortezomib powder injection and preparation method thereof |
| CN104414982B (en) * | 2013-08-28 | 2018-06-22 | 山东新时代药业有限公司 | A kind of bortezomib freeze drying powder injection and preparation method thereof |
| CN103720666A (en) * | 2013-12-16 | 2014-04-16 | 亿腾药业（泰州）有限公司 | Preparation method for bortezomib freeze-dried preparation for injection |
| CN103720666B (en) * | 2013-12-16 | 2015-11-25 | 亿腾药业（泰州）有限公司 | A kind of preparation method of injection bortezomib lyophilized formulations |
| CN107224569A (en) * | 2016-03-26 | 2017-10-03 | 复旦大学 | Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use |
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Inventor after: Liu Cuiyan Inventor after: Fan Yuntao Inventor after: Wang Yanjiao Inventor after: Liu Na Inventor after: Ji Dehua Inventor after: An Yinhua Inventor after: Guo Xiaofeng Inventor after: Zhao Qian Inventor after: Zhuang Honglin Inventor after: Wang Yan Inventor after: Bo Lichao Inventor after: Geng Jia Inventor after: Guo Wenmin Inventor after: Yang Hanyu Inventor after: Wang Binglin Inventor after: Hua Mingli Inventor before: Liu Cuiyan Inventor before: Fan Yunchou Inventor before: Wang Yanjiao Inventor before: Liu Na Inventor before: Ji Dehua Inventor before: An Yinhua Inventor before: Guo Xiaofeng Inventor before: Zhao Qian Inventor before: Zhuang Honglin Inventor before: Wang Yan Inventor before: Bo Lichao Inventor before: Geng Jia Inventor before: Guo Wenmin Inventor before: Yang Hanyu Inventor before: Wang Binglin Inventor before: Hua Mingli |
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Free format text: CORRECT: INVENTOR; FROM: LIU CUIYAN ZHUANG HONGLIN WANG YAN BU LICHAO GENG JIA GUO WENMIN YANG HANYU WANG BINGLIN HUA MINGLI FAN YUNCHOU WANG YANJIAO LIU NA JI DEHUA AN YINHUA GUO XIAOFENG ZHAO QIAN TO: LIU CUIYAN ZHUANG HONGLIN WANG YAN BU LICHAO GENG JIA GUO WENMIN YANG HANYU WANG BINGLIN HUA MINGLI FAN YUNTAO WANG YANJIAO LIU NA JI DEHUA AN YINHUA GUO XIAOFENG ZHAO QIAN |
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Effective date of registration: 20171220 Address after: 050035 No. 226, the Yellow River Avenue, hi tech Industrial Development Zone, Hebei, Shijiazhuang Co-patentee after: Shijiazhuang Pharmaceutical Group Ouyi Pharma Co., Ltd. Patentee after: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group Address before: 050035 the Yellow River Road, Hebei, Shijiazhuang, No. 226 Patentee before: Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. of CSPC Group |
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