CN103142509B - A kind of injection bortezomib pharmaceutical composition - Google Patents
A kind of injection bortezomib pharmaceutical composition Download PDFInfo
- Publication number
- CN103142509B CN103142509B CN201310070127.6A CN201310070127A CN103142509B CN 103142509 B CN103142509 B CN 103142509B CN 201310070127 A CN201310070127 A CN 201310070127A CN 103142509 B CN103142509 B CN 103142509B
- Authority
- CN
- China
- Prior art keywords
- bortezomib
- amino acid
- composition
- freeze
- fillers
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
To solve the technical problem of bortezomib stability difference and dissolubility difference, the present invention provides a kind of bortezomib pharmaceutical composition, and it is 1 that described pharmaceutical composition, which includes mass ratio,:2 100 bortezomib and amino acid.The present invention can effectively improve bortezomib solubility, and effect is suitable or more excellent with commercialized product, and the bortezomib pharmaceutical composition provided is safe and non-stimulating, prescription cost is cheap, preparation method is simple, and stability is better than existing bortezomib preparation, is advantageous to industrialized production.
Description
Technical field
The invention belongs to field of medicaments, in particular belongs to field of pharmaceutical preparations, the present invention relates to a kind of injection boron for assistant
Rice pharmaceutical composition.
Background technology
Bortezomib (Bortezomib) is a kind of dipeptides ylboronic acid compound, and FDA approval is obtained May 19 in 2003
List marketing, trade name " Bortezomib（velcade）", it is injection freeze-dried powder.For treating recurrent and intractable multiple
Property myeloma.Solubility of the bortezomib raw material in water only has 0.076mg/ml, and the solubility of bulk drug is relatively low, directly prepares
It is unable to reach suitable concentration.Need to use suitable hydrotropy technology.
Commercialized product " Bortezomib " employs the technology of patent WO02059130, WO2002059131.The patent is replaced using boron
The complex compound that rice and carbohydrate are formed is helped, the sugar includes condensation sugared such as mannitol and sorbierite.The patent by bortezomib and
Mannitol is mixed and made into lyophilized formulations, and wherein bortezomib and mannitol exists with complex form, and the patent claims to carry significantly
The dissolubility of high bortezomib.But found in commercialized product application, bortezomib less stable, for environment such as soda acid
Degree and temperature change are especially sensitive, and relevant material increase, harm is brought to human body in placement process.
Freeze-dried, wherein amino fourth three is made of bortezomib and tromethamine in CN201080004118.1 inventions
Alcohol proppant, while there is certain hydrotropy to act on, tests prove that solute effect is preferable.But use tromethamine to be used as and help
Solvent has the following disadvantages：First, tromethamine sheet as alkalescence, it is necessary to again with acid regulation to the acceptable PH models of human body
Enclose, bortezomib in aqueous, in acid, easily occurs degraded under the conditions of alkali and increases relevant thing；Secondly, if be adjusted
Generation then has bortezomib precipitation when exceeding pH value 7.6-8.4 scopes, and this precipitation is irreversible；Again, amino fourth three
Side effect of the alcohol as parenteral solution in itself be：This product can cause hypoglycemia, low blood pressure, Nausea and vomiting, can also suppress to breathe, very
To make breathing stop etc. side effect；It may cause local tissue necrosis outside liquid medicine spill blood vessel.
WO2010114982, which discloses a kind of lyophilized formulations, includes bortezomib or pharmaceutically acceptable salt or ester, inclusion
Thing, at least one conditioner and surfactant.The invention is molten to increase medicine by adding inclusion compound and surfactant
Solution property, certain effect is played for improving drug solubility, but a large amount of auxiliary materials are added, considerably increase redissolution liquid
Amount, cause infusion inconvenience, surfactant has certain toxicity and excitant in addition.
Some preparation of prior art is that bortezomib is made into liquid form, administered by infusion, due to well-known
Bortezomib is extremely unstable, unstable to acid, alkali, oxidizable, facile hydrolysis, therefore liquid forms and lyophilized solid preparation shape
Formula, which is compared, does not substantially have advantage.
To sum up, lack in the prior art a kind of on the basis of improvement bortezomib is deliquescent, additionally it is possible to improve boron for assistant
The freeze-drying medicinal composition of rice preparation stability.
The content of the invention
To solve the technical problem of bortezomib stability difference and dissolubility difference, the present invention provides a kind of bortezomib medicine
Composition.Technical solution of the present invention can effectively improve bortezomib solubility, and effect is suitable or more excellent with commercialized product, is provided
Bortezomib pharmaceutical composition it is safe and non-stimulating, prescription cost is cheap, and preparation method is simple, it is most important that improves existing
The defects of preparation stability difference, be advantageous to industrialized production.
The present invention provides a kind of bortezomib pharmaceutical composition, it is characterised in that it is 1 that the composition, which includes mass ratio,:2-
100 bortezomib and amino acid.
Wherein, amino acid of the present invention, for the amino acid with hydroxyl or sulfydryl.
Preferably, the amino acid is l-amino acid.
Hydroxyl of the present invention refers to the hydroxyl in addition to the hydroxyl in the basic group carboxyl of amino acid.
Preferably, amino acid of the present invention, one kind or more in serine, threonine and cysteine
Kind.
Further, each component ratio is that the mass ratio of bortezomib and amino acid is 1 in composition of the present invention:2-
50。
Further, the mass ratio of bortezomib and amino acid is 1 in composition of the present invention:5-20.
Further, the mass ratio of bortezomib and amino acid is 1 in composition of the present invention:10.
Pharmaceutical composition of the present invention also can further include other fillers, bortezomib, amino acid and filler
Mass ratio be 1:2-50:2-50, wherein the amino acid is the amino acid with hydroxyl or sulfydryl, other filler choosings
From one or both of mannitol, sorbierite.Preferably, wherein amino acid is in serine, threonine and cysteine
One or more.
Preferably, the present invention provides a kind of bortezomib pharmaceutical composition, it is characterised in that the composition is by boron for assistant
Rice, amino acid and other fillers composition, the wherein mass ratio of bortezomib, amino acid and filler are 1:2-8:2-8, its
In, one or more of the amino acid in serine, threonine and cysteine；Other fillers are selected from mannitol, sorb
One or both of alcohol.
It is further preferred that the present invention provides a kind of bortezomib pharmaceutical composition, it is characterised in that the composition by
Bortezomib, cysteine and mannitol composition, the wherein mass ratio of each component are 1:5:5.
In the present invention, the bortezomib pharmaceutical composition of other fillers is added compared with not adding other fillers,
Product appearance is more preferable, and freeze-drying prods color is white, loose, is not easy to collapse.
The present invention also provides a kind of method for preparing above-mentioned bortezomib pharmaceutical composition, it is characterised in that includes following step
Suddenly：
1）, take bortezomib raw material to add 40 ~ 100% tert-butyl alcohol room temperature ultrasound to make dissolving；
2）, take amino acid and filler to add suitable quantity of water to dissolve；
3）, step 1 resulting solution is added to step 2）Mix, filter in resulting solution, packing；
4）, freeze-drying, produce.
Pharmaceutical composition prepared by this preparation technology, at 40 DEG C, 75% relative humidity is its freeze-drying prods in lower 6 months
Stable.Show that total impurities is less than 0.2%, and when reconstruct, the composition of solution form keeps at least 24 hours steady
It is fixed.
It is the elaboration to the innovative point of the present invention below：Research finds that solubility of the bortezomib raw material in water only has
0.076mg/ml, solubility is low in water, directly prepares and is unable to reach suitable concentration, and therefore, prior art is using different
Solubilization technique improves bortezomib solubility, can just make bortezomib that formulation application be made in clinic, has in the prior art more
Kind scheme, wherein effect are most preferably added using mannitol and sorbierite as the condensation carbohydrate of representative, and such auxiliary material can be with boron
Bortezomib is complexed so as to improve solubility.But the technical scheme and other solubilization technique schemes are difficult to overcome bortezomib
Another shortcoming, i.e. stability is poor, and research shows that bortezomib is unstable in acid, alkali, the environment that aoxidizes and have water, easily
Degraded, drug effect reduction is not only resulted in, also result in relevant material substantial increase, harm is brought to human body.Therefore, how to solve simultaneously
Bortezomib solubility problem and stability problem, turn into a technical barrier.
The present inventor is under study for action it was unexpectedly observed that contain hydroxyl or mercapto in partial amino-acid, especially structure
The amino acid of base, the solubility of bortezomib can be significantly improved, its effect is suitable with commercialized product or better than commercialized product, and
And these amino acid also have another excellent results, that is, product stability raising is made after adding prescription, hence it is evident that produce better than listing
Product, wherein cysteine best results.
Embodiment
The purpose of embodiments described below is to better illustrate the present invention, but the scope of the present invention should not be formed
Limit.
Embodiment 1
Using following prescription：Bortezomib 35mg；Cysteine 175mg；Mannitol 175mg.
Preparation method：
Bortezomib raw material adds tert-butyl alcohol 2ml, and ultrasonic dissolution makes to be completely dissolved for 5 minutes at room temperature, takes auxiliary material to add 9ml
Water dissolves, and merges with the solution of above-mentioned bortezomib, and 0.22 μm of membrane filtration packing, every 1ml to 5ml neutral boron silica glass freezes
It is freeze-dried in dry bottle, nitrogen charging gland outlet.
Embodiment 2
Using following prescription：Bortezomib 35mg；Cysteine 175mg.
Preparation method is the same as embodiment 1.
Embodiment 3
Using following prescription：Bortezomib 35mg；Cysteine 350mg.
Preparation method is the same as embodiment 1.
Embodiment 4
Using following prescription：Bortezomib 35mg；Serine 350mg.
Preparation method is the same as embodiment 1.
Embodiment 5
Using following prescription：Bortezomib 35mg；Threonine 350mg.
Preparation method is the same as embodiment 1.
Embodiment 6
Using following prescription：Bortezomib 35mg；Cysteine 700mg.
Preparation method：
Bortezomib raw material adds tert-butyl alcohol 2ml, and ultrasonic dissolution makes to be completely dissolved for 5 minutes at room temperature, takes auxiliary material to add
18ml water dissolves, and merges with the solution of above-mentioned bortezomib, 0.22 μm of membrane filtration packing, every 1ml to 5ml neutrality borosilicate glass
Glass freezes to be freeze-dried in bottle, nitrogen charging gland outlet.
Embodiment 7
Using following prescription：Bortezomib 35mg；Serine 700mg.
Preparation method is the same as embodiment 6.
Embodiment 8
Using following prescription：Bortezomib 35mg；Serine 175mg；Sorbierite 175mg.
Preparation method is the same as embodiment 1.
Embodiment 9
Using following prescription：Bortezomib 35mg；Threonine 175mg；Mannitol 175mg.
Preparation method is the same as embodiment 1.
Embodiment 10
Using following prescription：Bortezomib 35mg；Cysteine 70mg；Mannitol 70mg.
Preparation method is the same as embodiment 1.
Embodiment 11
Using following prescription：Bortezomib 35mg；Threonine 70mg；Sorbierite 70mg.
Preparation method is the same as embodiment 1.
Embodiment 12
Using following prescription：Bortezomib 35mg；Threonine 280mg；Sorbierite 280mg.
Preparation method：
Bortezomib raw material adds tert-butyl alcohol 2ml, and ultrasonic dissolution makes to be completely dissolved for 5 minutes at room temperature, takes auxiliary material to add
15ml water dissolves, and merges with the solution of above-mentioned bortezomib, 0.22 μm of membrane filtration packing, every 1ml to 5ml neutrality borosilicate glass
Glass freezes to be freeze-dried in bottle, nitrogen charging gland outlet.
Embodiment 13
Using following prescription：Bortezomib 35mg；Cys2 80mg；Mannitol 280mg.
Preparation method is the same as embodiment 12.
Embodiment 14
Using following prescription：Bortezomib 35mg；Serine 70mg；Mannitol 280mg.
Preparation method is the same as embodiment 12.
For investigate commercialized product prescription and use other amino acid for auxiliary material products obtained therefrom with it is of the invention in dissolubility, stably
Difference in terms of property, special standby comparative example 1-4.
Comparative example 1
Using with the identical prescription of commercialized product：Bortezomib 35mg；Mannitol 350mg.
Preparation method is the same as embodiment 1.
Comparative example 2
Using following prescription：Bortezomib 35mg；Glycine 350mg.
Preparation method is with embodiment 1, as a result：Solvent can not form homogeneous settled solution after merging, and have Precipitation.
Comparative example 3
Using following prescription：Bortezomib 35mg；Phenylalanine-3,4-quinone 50mg.
Preparation method is with embodiment 1, as a result：Solvent can not form homogeneous settled solution after merging, and have Precipitation.
Comparative example 4
Using following prescription：Bortezomib 35mg；Tyrosine 350mg.
Preparation method is the same as embodiment 1.
Embodiment 15
To investigate the solubilizing effect of each prescription, spy carries out tests below.
Dissolving（Redissolve）Experiment：Example 1-14, comparative example 1, the lyophilized sample of commercialized product, and bortezomib are former
Material, add 0.9% sodium chloride solution that the solution of the 1mg/ml containing bortezomib is made according to Clinical practice amount, determine dissolving（Redissolve）When
Between, it is as a result as follows：
。
It these results suggest that, the embodiment of the present invention, comparative example 1 and commercialized product prescription can increase to be dissolved in bortezomib water
Degree, makes product easily prepared, and can smoothly be redissolved in 20s.But the tyrosine prescription of comparative example 4 does not reach same effect.
Embodiment 16
Stability test contrast is carried out with commercialized product and embodiment 1：Investigation condition：40 DEG C ± 2 DEG C, relative humidity 75%
±5%。
。
Conclusion：As a result show, injection bortezomib shelf-stability prepared by embodiment 1 is substantially better than commercialized product.
Embodiment 17
The stability test result of embodiment 3,4,9：Investigation condition：40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.
。
Conclusion：As a result show, injection bortezomib shelf-stability prepared by embodiment 3,4,9 meets quality standard will
Ask, shelf-stability is better than or substantially suitable with commercialized product.
Claims (7)
1. a kind of bortezomib freeze-drying medicinal composition, it is characterised in that the composition includes bortezomib and amino acid, boron
The mass ratio of Bortezomib and amino acid is 1:2-20, wherein, the amino acid is one in serine, threonine and cysteine
Kind is a variety of.
2. bortezomib freeze-drying medicinal composition as claimed in claim 1, it is characterised in that the matter of bortezomib and amino acid
Amount is than being 1:5-20.
3. bortezomib freeze-drying medicinal composition as claimed in claim 2, it is characterised in that the matter of bortezomib and amino acid
Amount is than being 1:10.
4. bortezomib freeze-drying medicinal composition as claimed in claim 1, it is characterised in that described pharmaceutical composition is further
Comprising other fillers, the mass ratio of bortezomib, amino acid and other fillers is 1:2-20:2-50, wherein, the amino
Acid is the one or more in serine, threonine and cysteine；The one kind of other fillers in mannitol, sorbierite
Or two kinds.
5. bortezomib freeze-drying medicinal composition as claimed in claim 1, it is characterised in that the composition by bortezomib,
Amino acid and other fillers composition, the mass ratio of bortezomib, amino acid and other fillers is 1:2-8:2-8, wherein, institute
State one or more of the amino acid in serine, threonine and cysteine；Other fillers are selected from mannitol, sorbierite
One or both of.
6. bortezomib freeze-drying medicinal composition as claimed in claim 5, it is characterised in that the composition by bortezomib,
Cysteine and mannitol composition, the mass ratio of bortezomib, cysteine and mannitol is 1:5:5.
7. a kind of method for preparing the bortezomib freeze-drying medicinal composition as any one of claim 1-6, its feature exist
In comprising the following steps：
1) bortezomib raw material, is taken to add 40~100% tert-butyl alcohol room temperature ultrasound to make dissolving；
2) amino acid and filler, is taken to add suitable quantity of water to dissolve；
3), step 1) resulting solution is added in step 2) resulting solution and mixed, is filtered, packing；
4), it is freeze-dried, produces.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310070127.6A CN103142509B (en) | 2013-03-06 | 2013-03-06 | A kind of injection bortezomib pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310070127.6A CN103142509B (en) | 2013-03-06 | 2013-03-06 | A kind of injection bortezomib pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103142509A CN103142509A (en) | 2013-06-12 |
| CN103142509B true CN103142509B (en) | 2018-01-02 |
Family
ID=48541026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310070127.6A Active CN103142509B (en) | 2013-03-06 | 2013-03-06 | A kind of injection bortezomib pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103142509B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Citations (2)
| 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 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8962572B2 (en) * | 2010-10-05 | 2015-02-24 | Fresenius Kabi Usa, Llc | Bortezomib formulations |
-
2013
- 2013-03-06 CN CN201310070127.6A patent/CN103142509B/en active Active
Patent Citations (2)
| 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103142509A (en) | 2013-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI580443B (en) | Manufacture of degarelix | |
| CN110464846B (en) | Meloxicam composition, preparation method and application thereof | |
| CN103142509B (en) | A kind of injection bortezomib pharmaceutical composition | |
| CN102525963B (en) | Netilmicin sulfate lyophiled powder injection and preparation method thereof | |
| JP7538802B2 (en) | Carbetocin drug and its manufacturing process | |
| CN102784382B (en) | Argatroban drug composition and preparation method and application of argatroban drug composition | |
| CN114886848A (en) | Preparation method of nano-micelle composition and prepared nano-micelle composition | |
| CN101791315B (en) | Compound monoammonium glycyrrhizinate S pharmaceutical composition and preparation method of large-capacity injection thereof | |
| CN104840418A (en) | Fasudil hydrochloride injection composition and preparation method thereof | |
| CA3157999A1 (en) | Injectable compositions of ursodeoxycholic acid | |
| WO2018133009A1 (en) | Vonoprazan fumarate composition and preparation method thereof | |
| WO2007143895A1 (en) | Supersaturated solution of gemcitabine hydrochloride and prepraration method thereof | |
| CA3000634C (en) | Novel ophthalmic composition comprising rebamipide and method for preparing the same | |
| CN102688183A (en) | Stable moxifloxacin hydrochloride injection | |
| CN102895178B (en) | Strong solution-type moxifloxacin hydrochloride injection and preparation method thereof | |
| CN102210686A (en) | Pharmaceutical composition containing ganciclovir compound, and preparation method thereof | |
| CN102233130B (en) | Stable pharmaceutical preparation containing thymosin 1 derivatives | |
| CN100336508C (en) | Stable palonosetron injection | |
| CN103494779A (en) | Andrographolide powder preparation for injection and preparation method thereof | |
| EP3054924B1 (en) | Stable pharmaceutical formulations of caspofungin | |
| JP4475405B2 (en) | Pharmaceutical composition | |
| CN106389359A (en) | Belinostat medicine composition for injection and preparation method thereof | |
| CN103877578B (en) | Pharmaceutical naloxone hydrochloride composition for injection and preparation method of pharmaceutical naloxone hydrochloride composition | |
| CN103432067A (en) | Ketoprofen solution and preparation method thereof | |
| CN110314132B (en) | Ornithine aspartate injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
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 |
|
| COR | Change of bibliographic data |
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 |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
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 |