CN109381695A - A kind of L-aminobutanedioic acid parritide injection and its preparation method and application - Google Patents
A kind of L-aminobutanedioic acid parritide injection and its preparation method and application Download PDFInfo
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Abstract
This application provides a kind of L-aminobutanedioic acid parritide injection, in the injection: being L-aminobutanedioic acid parritide comprising active constituent, and the concentration of parritide is 0.3-0.9mg/mL, preferably its concentration is 0.3mg/mL, 0.6mg/mL, 0.9mg/mL；Comprising buffer system, the buffer system is tartaric acid buffer, and content of the tartrate anion in the injection is 1.4mg/mL-1.6mg/mL；Comprising osmotic pressure regulator mannitol, and content of the mannitol in the injection is 47mg/mL-52mg/mL；Comprising pH adjusting agent sodium hydroxide, and the range that pH value is adjusted is 3.7-4.7.Present invention also provides the preparation methods and purposes of L-aminobutanedioic acid parritide injection.The injection quality is stablized, and preparation method is simple.
Description
Technical field
The application belongs to field of pharmaceutical preparations, more specifically, this application involves a kind of L-aminobutanedioic acid parritide injections
And its preparation method and application.
Background technique
Parritide is a kind of SMS 201-995, by playing its pharmacological action in conjunction with somatostatin receptor, in library
During glad disease complex treatment, parritide is by inhibiting ACTH secretion, to reduce the generation of cortisol, reduces and urinates free cortex
The level and serum cortisol of alcohol (UFC) improve life quality to control the state of an illness.
Parritide is a kind of ring hexapeptide SMS 201-995 of injectable, it with somatostatin receptor (ssts) by tying
It closes and plays its pharmacological activity.Known 5 people's somatostatin receptor subtypes: hsst 1,2,3,4 and 5.Under normal physiological conditions
These receptor subtypes are expressed in different tissues.From the frequent table excessively of Cushing syndrome patient's corticotropin tumour cell
Other receptor subtypes are not usually expressed up to hsst5 or in low expression level.Pasireotide is combined and hsst receptor is activated to lead
The inhibition for causing ACTH secretion, causes cortisol secretion to reduce.Its chemical structural formula is as follows:
L-aminobutanedioic acid parritide injection on April 25th, 2012 is for the first time by European EMA authorities according to the correlation method of rare disease
Rule listing, is approved to list in 48 countries successively later.The door winter of U.S. FDA on December 14 approval Novartis Co., Ltd exploitation in 2012
Propylhomoserin parritide (pasireotide diaspartate trade name Signifor) lists in the U.S..L-aminobutanedioic acid parritide note
Penetrate liquid be suitable for can not perform the operation or operative treatment failure adult Cushing disease (Cushing ' s disease) patient treatment, be
The first Orphan drug for being used to treat Cushing syndrome.
Patent US 6225284 (IN 201579) discloses the presence of parritide, especially 7476761 (IN of patent US first
204073), patent US7476761 is mentioned during preparing parritide, in solidification by addition tartaric acid come to pa
Auspicious peptide is protected.Which disclose a kind of processes for preparing parritide by patent WO2016/097962/A1, it is therefore an objective to provide
A kind of simple, stable and industrialized application method, the parritide buffer (I) and its acid group salt of this method design, by this
Method can obtain the product that HPLC detection purity is 99.0%.
Patent WO2005/046645 describes a kind of microparticle formulations of sustained release, which includes the naphthoic acid of parritide
The polymer of salt and a polylactic acid and glycolide.Patent WO2006/066868 describes a kind of containing a large amount of parritide salt
Formula, the gel systems containing parritide which is made of some high molecular materials and acetic acid or citric acid and water should
Formula can play the drug effect of parritide after being injected into body.Patent WO2008/152401 describes a kind of formula, the formula
Liquid crystal technology is used for parritide sustained release, glycerol, lecithin and organic solvent are contained in the formula, organic solvent is most
It is well ethyl alcohol.
Patent WO2013/131879 A1 the application describe the application of parritide (SOM230) and relevant parritide salt,
This application refers to that parritide can be used not only for treatment Cushing disease and can be used for treatment hypertension.This application further mentions current parritide
The treatment of clinical studies show primary treatment Cushing disease, acromegaly and neuroendocrine tumor (GEP/NETs).In this application
Referring to three phase of parritide clinic, it is indicated that parritide can quickly and persistently reduction urine free cortisol is horizontal, can produce blood pressure lowering,
Reduce total cholesterol and body-mass index.Patent WO2016/092504/A1 discloses the polypeptide drugs for treating Cushing disease
Parritide and its daily dosage.The routine dose of parritide is 300 to 600 μ g t.i.d (three times a day), but the dosage is in abdomen
Water and leural effusion do not show effective therapeutic effect when detecting.The invention proposes effective treatment of parritide or parritide salt
Daily dose is in 2000-4000 μ g, preferably 2400-3600 μ g, particularly preferred 2400-2700 μ g.
In conclusion existing patent (application) relates generally to synthesize the method for parritide raw material, the structure of parritide and control
Treat, several aspects such as the clinical application method of the formula of parritide sustained release preparation and parritide, and to parritide preparation and its
Preparation method is but not involved with.And in the prior art used in finished product L-aminobutanedioic acid parritide injection products, exist
The defects of main ingredient is unstable, and product is not easy to maintain.
Therefore, in order to overcome drawbacks described above present in the prior art, spy proposes the application.
Summary of the invention
The first purpose of the application is, provides a kind of L-aminobutanedioic acid parritide injection.
To achieve the goals above, the application adopts the following technical scheme that
A kind of L-aminobutanedioic acid parritide injection, in the injection: including active constituent L-aminobutanedioic acid parritide, and pa
The concentration of auspicious peptide is 0.3-0.9mg/mL, and preferably its concentration is 0.3mg/mL, 0.6mg/mL, 0.9mg/mL；Comprising buffer system,
The buffer system is tartaric acid buffer, and content of the tartrate anion in the injection is 1.4mg/mL-1.6mg/mL；
Comprising osmotic pressure regulator mannitol, and content of the mannitol in the injection is 47mg/mL-52mg/mL；Include pH tune
Agent sodium hydroxide is saved, and the range that pH value is adjusted is 3.7-4.7.
Preferably, the concentration of the parritide is 0.3mg/mL, 0.6mg/mL, 0.9mg/mL.
Preferably, content of the tartrate anion in the injection is 1.501mg/mL.
Preferably, content of the mannitol in the injection is 49.50mg/mL.
Preferably, the pH value for adjusting the injection is 4.2.
The second purpose of the application is, provides a kind of preparation method of L-aminobutanedioic acid parritide injection.
To achieve the goals above, the application adopts the following technical scheme that
A kind of preparation method of L-aminobutanedioic acid parritide injection, which is characterized in that the preparation method includes following step
It is rapid:
Tartrate is weighed by recipe quantity, prepares tartaric acid buffer；Mannitol is added in the tartaric acid buffer,
Stirring to mannitol dissolves, and obtains mixed solution；L-aminobutanedioic acid parritide is dissolved in the mixed solution, is stirred to molten
Solution, obtains medical fluid；By the medical fluid after filtering with microporous membrane, filtrate is obtained；Sodium hydroxide solution is added dropwise and adjusts the filtrate
PH range, stirring is to being uniformly mixed, then through filtering with microporous membrane；Water for injection is added and is settled to full dose, obtains the door
Aspartic acid parritide injection.
Ground is preferred, and the preparation method specifically includes,
(1) water for injection of batch total volume 80% is added in material-compound tank, is cooled to 20-30 DEG C, first weighs tartaric acid
Sodium is configured to EWNN solution, tartaric acid is then added dropwise, pH value is adjusted to 3.7-4.7, obtain tartaric acid buffer, incite somebody to action
It is poured into material-compound tank；
(2) mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirring is mixed to being uniformly mixed
Solution；
(3) L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in step (2) obtained mixed solution, stirring is extremely
Dissolution, obtains medical fluid；
(4) by filtering with microporous membrane of step (3) the obtained medical fluid through 0.8 μm and 0.45 μm, filtrate is obtained；
(5) sodium hydroxide solution is added dropwise into step (4) obtained filtrate, adjusting pH range is 3.7-4.7, and stirring is extremely
It is uniformly mixed, obtains the filtrate for regulating pH；
(6) the obtained filtrate for regulating pH obtains final through 2 grades 0.22 μm of filtering with microporous membrane in step (5)
Filtrate；
(7) water for injection is added in the obtained final filtrate of step (6) and is settled to full dose, obtain the door winter ammonia
Sour parritide injection.
Preferably, in step (2), the speed of stirring is 50-100r/min.
Preferably, in step (3), the speed of stirring is 50-100r/min.
It preferably, further include the process for carrying out nitrogen charging encapsulating after addition water for injection is settled to full dose.
The third purpose of the application is, provides a kind of purposes of L-aminobutanedioic acid parritide injection.
A kind of L-aminobutanedioic acid parritide injection is used to prepare the purposes in terms of the drug for the treatment of Cushing disease.
The beneficial effect that the application can generate includes:
L-aminobutanedioic acid parritide injection provided by the present application is carried out molten using the tartaric acid buffer solution containing tartrate anion
Parritide is solved, solves the case where less stable when L-aminobutanedioic acid parritide is directly dissolved in water for injection.Provided herein
L-aminobutanedioic acid parritide injection has many advantages, such as stable product quality, easy to maintain.
Present invention also provides a kind of preparation methods of parritide injection.Existing injection technology is all made of addition activity
Charcoal controls product endotoxin limit, and the application is added without active carbon during preparation, reduce active carbon in adsorbing contaminant
During endotoxin limit, lead to pollution of the active carbon to product due to filtering is incomplete.It is provided herein
L-aminobutanedioic acid parritide injection, discovery when being sterilized by the way of terminal sterilization to product under study for action, product
Related substance increase is more significant, influences product quality.Degerming is carried out to product by the way of filtration sterilization in this application,
It was found that effect is obvious, stable product quality.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
Unless otherwise instructed, the raw material in embodiments herein is bought by commercial sources, wherein
L-aminobutanedioic acid parritide produces for Wuhan Wuyao Pharmaceutical Co., Ltd；
Mannitol produces for Guangxi Nanning Chemical Pharmaceutical Ltd.；
Sodium hydroxide produces for Hu'nan Erkang Pharmaceutical Co., Ltd.；
Sodium tartrate produces for Hangzhou Lin'an Jinlong Chemical Co.Ltd；
Tartaric acid produces for Hangzhou Lin'an Jinlong Chemical Co.Ltd；
Active carbon produces for Shanghai active carbon Co., Ltd., Factory.
Following embodiment is the application to be further described, but do not limit the scope of the invention.
Embodiment 1
Table 1: the prescription of embodiment 1
Preparation method is as follows:
(1) water for injection of batch total volume 80% is added, is cooled to 20-30 DEG C, first weighs sodium tartrate, be configured to wine
Then stone acid sodium solution is added dropwise tartaric acid and pH value is adjusted to 3.7-4.7, obtains tartaric acid buffer, be poured into ingredient
In tank；
(2) mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirred with the speed of 50r/min to mixed
It closes uniformly, obtains mixed solution；
(3) L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in step (2) obtained mixed solution, with 100r/
The speed of min is stirred to dissolution, obtains medical fluid；
(4) by filtering with microporous membrane of step (3) the obtained medical fluid through 0.8 μm and 0.45 μm, filtrate is obtained；
(5) sodium hydroxide solution is added dropwise into step (4) obtained filtrate, adjusting pH range is 3.7-4.7, and stirring is extremely
It is uniformly mixed, obtains the filtrate for regulating pH；
(6) the obtained filtrate for regulating pH obtains final through 2 grades 0.22 μm of filtering with microporous membrane in step (5)
Filtrate；
(7) water for injection is added in the obtained final filtrate of step (6) and is settled to full dose, then carry out nitrogen charging encapsulating,
Obtain the L-aminobutanedioic acid parritide injection.
Comparative example 1
Table 2: the prescription of comparative example 1
Preparation method is as follows:
1, the water for injection for weighing 80% (W/V) by recipe quantity is cooled to 20-30 DEG C in material-compound tank；
2, L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in water for injection, stirring to dissolution；
3, mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirred to uniformly mixed；
4, filtering with microporous membrane of the medical fluid through 0.8 μm and 0.45 μm；
5, it is 3.7-4.7 that sodium hydroxide solution, which is added dropwise, and adjusts pH range, is stirred to uniformly mixed；
6, medical fluid is through 2 grades 0.22 μm of filtering with microporous membrane；
7, water for injection is added and is settled to full dose.
Comparative example 2:
Table 3: the prescription of comparative example 2
Preparation method is as follows:
(1) water for injection of batch total volume 80% is added, is cooled to 20-30 DEG C, first weighs sodium tartrate, be configured to wine
Then stone acid sodium solution is added dropwise tartaric acid and pH value is adjusted to 3.7-4.7, obtains tartaric acid buffer, be poured into ingredient
In tank；
(2) mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirring is mixed to being uniformly mixed
Solution；
(3) L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in step (2) obtained mixed solution, stirring is extremely
Dissolution, obtains medical fluid；
(4) active carbon of 0.1% (W/V) is added by medicine liquid volume, at 20-30 DEG C, stirs 20min；
(5) by filtering with microporous membrane of step (4) the obtained medical fluid through 0.8 μm and 0.45 μm, filtrate is obtained；
(6) sodium hydroxide solution is added dropwise into step (5) obtained filtrate, adjusting pH range is 3.7-4.7, and stirring is extremely
It is uniformly mixed, obtains the filtrate for regulating pH；
(7) the obtained filtrate for regulating pH obtains final through 2 grades 0.22 μm of filtering with microporous membrane in step (6)
Filtrate；
(8) water for injection is added in the obtained final filtrate of step (7) and is settled to full dose.
Referring to medicine stability guideline, we carry out sample preparation, system to embodiment 1, comparative example 1 and comparative example 2
Standby L-aminobutanedioic acid parritide injection out has carried out factors influencing test, and in the item of 40 DEG C of temperature and illumination 4500lx
The primary contributions factorial experiments for carrying out 5 days, 10 days under part respectively, detect sample, the results are shown in Table 4 and table 5.
Test result is shown: self-control drug items Testing index had no significant change with 0 day, and related substance is better than commercially available
Preparation shows that this product is with good stability.
1, comparative example 1 and comparative example 2 carry out sample preparation according to an embodiment of the present application, and carry out influence factor test,
Wherein in following table in relation in substance detection it is total it is miscellaneous be free of (impurity 524-03 and impurity 533-04) the result is as follows:
Table 4: factors influencing is carried out in illumination 4500lx ± 500
Table 5: in 40 DEG C of progress factors influencings of high temperature
It is shown according to result of study, tartaric acid buffer system is not added for comparative example 1, and the stability of active constituent parritide is not
It is good, lower limit of the testing result indices close to quality standard.The influence factor that tartaric acid buffer system is added in comparative example 2 is examined
It examines the results show that by sample prepared by embodiment 1, than more stable in comparative example 1 and comparative example 2, more with commercial preparation
It is close.
Embodiment 2: nitrogen is covered on the effect in stability
Prescription in embodiment 2 and embodiment 1 are consistent, but embodiment 2 the preparation method is as follows:
(1) water for injection of batch total volume 80% is added, is cooled to 20-30 DEG C, first weighs sodium tartrate, be configured to wine
Then stone acid sodium solution is added dropwise tartaric acid and pH value is adjusted to 3.7-4.7, obtains tartaric acid buffer, be poured into ingredient
In tank；
(2) mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirred with the speed of 100r/min to mixed
It closes uniformly, obtains mixed solution；
(3) L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in step (2) obtained mixed solution, with 50r/
The speed of min is stirred to dissolution, obtains medical fluid；
(4) by filtering with microporous membrane of step (3) the obtained medical fluid through 0.8 μm and 0.45 μm, filtrate is obtained；
(5) sodium hydroxide solution is added dropwise into step (4) obtained filtrate, adjusting pH range is 3.7-4.7, and stirring is extremely
It is uniformly mixed, obtains the filtrate for regulating pH；
(6) the obtained filtrate for regulating pH obtains final through 2 grades 0.22 μm of filtering with microporous membrane in step (5)
Filtrate；
(7) water for injection is added in the obtained final filtrate of step (6) and is settled to full dose, then carry out nitrogen charging encapsulating,
Obtain the L-aminobutanedioic acid parritide injection.
L-aminobutanedioic acid parritide injection liquid samples are prepared by embodiment 1 and embodiment 2 and carry out factors influencing, specifically
As a result it see the table below.
Table 6: factors influencing is carried out in illumination 4500lx ± 500
Table 7: in 40 DEG C of progress factors influencings of high temperature
Conclusion proves: the sample prepared by the formulation and technology of embodiment 2, as a result illustrates that nitrogen charging can be to the steady of product
Surely better protective effect is played.
Embodiment 3: the present embodiment is related to the L-aminobutanedioic acid parritide injection of the application and the door winter of commercially available Novartis production
Propylhomoserin parritide injection comparative study-low temperature freezing-thawing test.
According to chemicals medicine investigative technique guideline, freezing-thawing test has been carried out to this product.Reference guide principle, examination
It tests and is designed as, take 1 batch of L-aminobutanedioic acid parritide injection by sample made from embodiment 2 and the production of commercially available Novartis, do three times
Frozen-thawed cycled, cycling condition are to place 2 days under the conditions of being placed in -20 DEG C, are and then placed 2 days under the conditions of 40 DEG C, this is one
Circulation, in 3 inspections by sampling after circulation terminates.And by test result compared with 0 day.Testing result is shown in Table -1.
Table 8: L-aminobutanedioic acid parritide injection freezing-thawing test result compares
Conclusion proves: the sample prepared by the prescription and technique of embodiment 2 and commercially available L-aminobutanedioic acid parritide note
Liquid is penetrated, every quality index meets regulation.Illustrate that medical fluid prepared by the present invention has centainly under low-temperature circulating experimental condition
Shelf-stability illustrates that preparation of the invention has preferable stability in transport, storage, use process.
Embodiment 4:
The stability that the present embodiment is related to L-aminobutanedioic acid parritide injection compares:
It will be placed in stability test case by sample made from embodiment 2 and commercially available product, 40 DEG C are placed 6 months, and measurement produces
The stability of product, is as a result shown in table -9.
The accelerated test result of the L-aminobutanedioic acid parritide injection of the present invention of table 9
Conclusion: sample prepared by the embodiment of the present application 2, and study on the stability comparison is carried out with commercial preparation.As the result is shown
The L-aminobutanedioic acid parritide injection prepared by the formulation and technology of the embodiment of the present invention 2 after carrying out 6 months accelerated tests and asking,
Every quality index does not change, and the increasing degree of the related substance of product is lower than other samples.Illustrate to mention in the present invention
And preparation process, such as first prepare tartaric acid buffer, parritide be then added and prepares sample, after sample preparation comes out, into
Row nitrogen charging is filling, can preferably play the effect of stable sample quality.
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, a little variation or modification are made using the technology contents of the disclosure above and is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (10)
1. a kind of L-aminobutanedioic acid parritide injection, which is characterized in that in the injection: including active constituent L-aminobutanedioic acid pa
Auspicious peptide, and the concentration of parritide is 0.3-0.9mg/mL, preferably its concentration is 0.3mg/mL, 0.6mg/mL, 0.9mg/mL；Include
Buffer system, the buffer system is tartaric acid buffer, and content of the tartrate anion in the injection is 1.4mg/mL-
1.6mg/mL；Comprising osmotic pressure regulator mannitol, and content of the mannitol in the injection is 47mg/mL-52mg/
mL；Comprising pH adjusting agent sodium hydroxide, and the range that pH value is adjusted is 3.7-4.7.
2. L-aminobutanedioic acid parritide injection according to claim 1, which is characterized in that the injection is containing parritide
Concentration is 0.3mg/mL, 0.6mg/mL, 0.9mg/mL.
3. L-aminobutanedioic acid parritide injection according to claim 1 or 2, which is characterized in that the tartrate anion is in institute
Stating the content in injection is 1.501mg/mL.
4. L-aminobutanedioic acid parritide injection according to claim 1 or 2, which is characterized in that the mannitol is described
Content in injection is 49.50mg/mL.
5. L-aminobutanedioic acid parritide injection according to claim 1 or 2, which is characterized in that adjust the injection
PH value is 4.2.
6. a kind of preparation method of the L-aminobutanedioic acid parritide injection as described in any one of claim 1-5, feature
It is, the preparation method includes the following steps:
Tartrate is weighed by recipe quantity, prepares tartaric acid buffer；Mannitol is added in the tartaric acid buffer, stirs
It is dissolved to mannitol, obtains mixed solution；L-aminobutanedioic acid parritide is dissolved in the mixed solution, stirring is obtained to dissolving
To medical fluid；By the medical fluid after filtering with microporous membrane, filtrate is obtained；The pH model that sodium hydroxide solution adjusts the filtrate is added dropwise
It encloses, stirring is to being uniformly mixed, then through filtering with microporous membrane；Water for injection is added and is settled to full dose, obtains the L-aminobutanedioic acid
Parritide injection.
7. preparation method according to claim 6, which is characterized in that the preparation method specifically includes,
(1) water for injection of batch total volume 80% is added in material-compound tank, is cooled to 20-30 DEG C, first weighs sodium tartrate, match
EWNN solution is made, tartaric acid is then added dropwise, pH value is adjusted to 3.7-4.7, obtain tartaric acid buffer, fallen
Enter in material-compound tank；
(2) mannitol is weighed by recipe quantity, mannitol is added in material-compound tank, stirring obtains mixed solution to being uniformly mixed；
(3) L-aminobutanedioic acid parritide is weighed by recipe quantity, be added in step (2) obtained mixed solution, stirring to dissolution,
Obtain medical fluid；
(4) by filtering with microporous membrane of step (3) the obtained medical fluid through 0.8 μm and 0.45 μm, filtrate is obtained；
(5) sodium hydroxide solution is added dropwise into step (4) obtained filtrate, adjusting pH range is 3.7-4.7, stirring to mixing
Uniformly, obtain regulating the filtrate of pH；
(6) the obtained filtrate for regulating pH obtains final filtrate through 2 grades 0.22 μm of filtering with microporous membrane in step (5)；
(7) water for injection is added in the obtained final filtrate of step (6) and is settled to full dose, obtain the L-aminobutanedioic acid pa
Auspicious peptide injection.
8. preparation method according to claim 7, which is characterized in that in step (2), the speed of stirring is 50-100r/
min；In step (3), the speed of stirring is 50-100r/min.
9. preparation method according to claim 6 or 7, which is characterized in that after addition water for injection is settled to full dose, also wrap
Include the process for carrying out nitrogen charging encapsulating.
10. a kind of L-aminobutanedioic acid parritide injection as described in any one of claim 1-5, and according to claim
The L-aminobutanedioic acid parritide injection of the preparation of preparation method described in any one of 6-9, is used to prepare the medicine for the treatment of Cushing disease
The purposes in object space face.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115524407A (en) * | 2021-06-25 | 2022-12-27 | 武汉武药科技有限公司 | Separation and detection method of organic acid |
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