CN106309384A - Injection-use carperitide freeze-dried composition and preparation method thereof - Google Patents
Injection-use carperitide freeze-dried composition and preparation method thereof Download PDFInfo
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- CN106309384A CN106309384A CN201510357639.XA CN201510357639A CN106309384A CN 106309384 A CN106309384 A CN 106309384A CN 201510357639 A CN201510357639 A CN 201510357639A CN 106309384 A CN106309384 A CN 106309384A
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- carperitide
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- dried composition
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Abstract
The invention relates to the field of medicine preparations and discloses an injection-use carperitide freeze-dried composition and a preparation method thereof. The freeze-dried composition is composed of a main medicine carperitide, an excipient and a protective agent. The excipient is one or more than two selected from lactose, saccharose, glucose, sodium chloride and sorbitol; and the protective agent is one or more than two selected from glycine, arginine, glucan, PVP and xylitol. Through regulation of the auxiliary materials in the carperitide freeze-dried composition, the carperitide is synergistically protected by selecting the components having framework shaping and protecting effects, so that the composition has excellent stability at room temperature and even at an extreme environment being higher than 25 DEG C. The freeze-dried composition, compared with a commercial carperitide powder injection, has significant advantages.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to a kind of injection carperitide freeze-dried composition and
Its preparation method.
Background technology
Carperitide is identical with the ANP produced in human body, initially passes through gene recombinaton mode and obtains,
It is ring-type 28 amino acid polypeptides.
The ANP produced in human body is a kind of circulation regulation hormone, by stimulating cardiac muscle to stretch, by ventricular muscles
Cell synthesis release, then by hat vein distribution whole body, in the tissue such as vasoactive smooth muscle and kidney
Be combined with GC-A receptor, activation of guanylate cyclase, make cyclic guanosine monophosphate increase, and cause blood vessel to expand
Open and diuresis.After carperitide enters blood of human body by intravenous injection, play and endogenous hormone
The physiological action that ANP is similar, it is mainly used in treating acute heart failure and (includes that chronic heart failure is acute to add
Weight).
Carperitide is Suntory Ltd in 1984 (now: Asubio Pharma company) and palace
Rugged medical university joint research synthesis, by gene recombination method produce by the α of 28 Amino acid profiles
Type atrial natriuretic peptide.Pharmaceutical research result shows that this medical instrument has and expands blood vessel, diuresis, 1986
Proceed by its clinical trial for acute heart failure.Result shows, before this medicine can alleviate heart,
Afterload, increases cardiac output but does not affect heart rate, it is believed that acute heart failure is had good by it
Therapeutical effect.Nineteen ninety-five Astellas, Pharma company was by the first company (being now the one or three common company)
List in Japan, trade name "INJECTION 1000 ", it is to be applied to acute mental and physical efforts the earliest
The polypeptide formulations of exhaustion treatment.
At present, the carperitide preparation of clinical practice only has injection freeze-dried powder one dosage form.Both at home and abroad
Preparation method about injection carperitide is also little, and the hygroscopicity of carperitide raw material own is strong, at height
Instability under gentle light conditions, the existing preparation stored temperature listed is 2～8 DEG C, and the shelf-life is 2
Year.Preserving by this condition, cost is greatly increased, and hospital and patient are also not easy to store.Meanwhile,
Under conditions of higher than 25 DEG C, its hydrolysis rate is accelerated, and affects the use safety of product.The most severe
The use condition carved is unfavorable for its using and promoting clinically.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of injection carperitide freeze-dried composition and
Preparation method so that described carperitide freeze-dried composition can have higher under conditions of higher than 25 DEG C
Stability.
For achieving the above object, the present invention provides following technical scheme:
A kind of injection carperitide freeze-dried composition, by principal agent carperitide, excipient and protective agent group
Become；
Described excipient be in lactose, sucrose, glucose, sodium chloride, sorbitol one or both with
On；Described protective agent be glycine, arginine, glucosan, PVP, xylitol one or more.
In existing technology, injection carperitide lyophilized injectable powder use mannitol as adjuvant, but
The mannitol solution of high concentration may occur at low tempertaure storage or during the use of other liquid preparation compatibilities
Salting-out phenomenon, has a strong impact on the safety and stability of product.For not enough in prior art, the present invention changes card
The auxiliary material combination of the vertical peptide of training, ensures the stability of carperitide freeze-drying prods by suitable component.
In several excipient that the present invention is limited, its in lyophilized injectable powder as skeleton excipient,
In the lyophilizing of protein medicaments, to particle excipient.Further, since their space steric effect can be more
Effectively carperitide is carried out cryoprotection, help to maintain particle size and lyophilizing block is formed.
And in several protective agents that the present invention is limited, it can improve the glass transition temperature of excipient, and lead to
Cross the glassy structure of stabilizing sugar, protein and amino acid whose stability in common raising freezing dry process.
It should be noted that the excipient described in instant component and protective agent, simply according to being limited
The effect played in this freeze-dried composition of the fixed component and the summary name that carries out, its with this area in often
The excipient of rule and protectant concept differing, it is equivalent to the first component and the second component both
Describing mode.
Wherein, as preferably, each components by weight is as follows:
Carperitide: excipient: protective agent=0.1:(17.5～70): (3～5).It is highly preferred that each group
Divide weight ratio as follows:
Carperitide: excipient: protective agent=0.1:(30～60): (3～5).
As preferably, described excipient is one or both in lactose, sucrose, more preferably lactose or
Sucrose.
As preferably, described protective agent is one or both in glycine, arginine, the sweetest
Propylhomoserin or arginine.
Meanwhile, present invention also offers the preparation method of above-mentioned freeze-dried composition, including:
Take water for injection excipient dissolving, protective agent and carperitide, be subsequently adding water for injection and adjust card
The vertical peptide concentration of training is required drug level, sterilization treatment, lyophilizing, it is thus achieved that freeze-dried composition.
As preferably, described preparation method includes:
Measure the water for injection being cooled to 45 ± 5 DEG C, put in appropriate containers, weigh protective agent stirring and dissolving,
Adding excipient, stirring, to dissolving, is subsequently adding carperitide stirring and extremely dissolves, add water for injection
Adjusting carperitide concentration is required drug level, stirs, then the microporous filter membrane by 0.22 μm
Filtration sterilization, filtrate lyophilizing, it is thus achieved that freeze-dried composition.
As preferably, described step of freeze drying is:
Step A, solution is cooled to-10 DEG C ± 1 DEG C, then in 1h, conduction oil temperature is reduced to-45
DEG C, keep 7h；
Step B, it is evacuated to 10～15pa by freeze drying box body, with the speed of 1～1.5 DEG C/h to conduction oil
Carrying out hyperthermic treatment, be incubated after conduction oil temperature rises to-30 DEG C, temperature retention time is 42h～55h,
The temperature difference of sample and conduction oil is less than 8～12 DEG C；
Conduction oil is heated up by step C, speed with 1 DEG C/5～10min, and products temperature rises to 20 DEG C ± 2
DEG C, it is incubated 4～6h.
The present invention of pH value to(for) solution in preparation process there are certain requirements and needs to reach 4.5～6.5, mistake
Low or too high pH can accelerate the hydrolysis rate of raw material, so that the amount of maximum single contaminant increases, reduction is frozen
The stability of dry composition.In preparation, preparing according to the inventive method, the pH value of general solution can be straight
Connect and meet the requirements, it is not necessary to regulation.If pH value meets the requirements after solution dissolves, need not regulation, if
Undesirable, preferably regulated by 0.1M hydrochloric acid and/or 0.1M sodium hydroxide solution.
Carperitide freeze-dried composition of the present invention and commercially available carperitide lyophilized injectable powder are at initial phase
Under homogenous quantities degree premise, respectively at 30 DEG C, 75%RH and 40 DEG C, it is accelerated under the conditions of 75%RH
Test, carries out the test and appraisal of stability.Result shows, product of the present invention remained able to control after 3 months
Product is in qualified scope, and commercially available prod has been melted at about 1 month, it is impossible to use.
From above technical scheme, the present invention by adjusting the adjuvant in carperitide freeze-dried composition,
Select the component coordinating protection carperitide with skeleton figuration and protective effect so that it is can be at room temperature
Even at the extreme environment higher than 25 DEG C, there is good stability, compare commercially available carperitide powder pin
Agent has significant advantage.
Detailed description of the invention
The invention discloses a kind of injection carperitide freeze-dried composition and preparation method thereof, this area skill
Art personnel can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, institute
Having similar replacement and change apparent to those skilled in the art, they are considered as bag
Include in the present invention.Product and the preparation method of the present invention are described by preferred embodiment, phase
Pass personnel substantially can in without departing from present invention, spirit and scope to compound as herein described and
Preparation method is modified or suitably changes and combine, and realizes and applies the technology of the present invention.
In certain specific embodiments of the invention, the weight ratio of described each component can also be:
Carperitide: excipient: protective agent=0.1:45:4, carperitide: excipient: protective agent=0.1:60:5, card
The vertical peptide of training: excipient: protective agent=0.1:51:3 or carperitide: excipient: protective agent=0.1:30:5.Tie below
Close embodiment, the present invention is expanded on further.
Embodiment 1: the preparation of freeze-dried composition of the present invention
1, component
Table 1
| Component | Weight |
| Carperitide | 0.1g |
| Sucrose | 45g |
| Glycine | 4g |
| Water for injection | 600ml(600g) |
2, preparation method
Measure the water for injection 480ml being cooled to 45 ± 5 DEG C, put in appropriate containers, weigh glycine 4g,
Stirring while adding making it dissolve, add sucrose 45g, stirring, to dissolving, is subsequently adding 0.1g Ka Peili
Peptide stirring is extremely dissolved, and sampling detection medicinal liquid pH value (should be in the range of 4.5～6.5, such as undesirable use
0.1M hydrochloric acid and/or the regulation of 0.1M sodium hydroxide solution), inject water to 600ml；Stir,
Filtering with microporous membrane by 0.22 μm is degerming again, and filtrate collection is in the sterile chamber sealed.
Then, by filtrate fill in the tubular injection bottle of 10ml (every bottle of 5ml), send into after partly jumping a queue
Freeze drying box, lyophilizing program is as follows:
A, pre-freeze: first composition solution is cooled to-10 DEG C ± 1 DEG C, then by heat conduction oil temperature in 1h
Degree is reduced to-45 DEG C, keeps 7h.
B, sublimation drying: be evacuated to 10～15pa by freeze drying box body, with the speed pair of 1～1.5 DEG C/h
Conduction oil carries out hyperthermic treatment, is incubated after conduction oil temperature rises to-30 DEG C, and temperature retention time is
The temperature difference of 42h～55h, sample and conduction oil is less than 8～12 DEG C
C, parsing-desiccation: conduction oil is heated up by the speed with every 1 DEG C/5～10min, is risen to by products temperature
20 DEG C ± 2 DEG C, it is incubated 4～6h.
After freeze-drying process completes, tamponade, outlet, roll and obtain freeze-dried composition after lid, labeling, packaging.
Embodiment 2: the preparation of freeze-dried composition of the present invention
1, component
Table 2
| Component | Weight |
| Carperitide | 0.1g |
| Sucrose | 60g |
| Arginine | 5g |
| Water for injection | 600ml(600g) |
2, preparation method: with embodiment 1.
Embodiment 3: the preparation of freeze-dried composition of the present invention
1, component
Table 3
| Component | Weight |
| Carperitide | 0.1g |
| Lactose | 51g |
| Glycine | 3g |
| Water for injection | 600ml(600g) |
2, preparation method: with embodiment 1
Embodiment 4: the preparation of freeze-dried composition of the present invention
1, component
Table 4
| Component | Weight |
| Carperitide | 0.1g |
| Lactose | 30g |
| Arginine | 5g |
| Water for injection | 600ml(600g) |
2, preparation method: with embodiment 1.
Embodiment 5: accelerated test
Be divided into 30 DEG C, 75%RH and 40 DEG C, 75%RH two set condition setting-out, in 0 month, January, 3
Moon sampling.The results are shown in Table 5-table 9.Subjects is embodiment 1-4 sample and commercial samples.
5 30 DEG C of table, 75%RH and 40 DEG C, lower 0 month test data of 75%RH
6 30 DEG C of table, 75%RH test data in lower January
7 30 DEG C of table, 75%RH test data in lower March
8 40 DEG C of table, 75%RH test data in lower January
9 40 DEG C of table, 75%RH test data in lower March
The result of consolidated statement 5-table 9 it can be seen that under the extreme condition higher than 25 DEG C, commercial samples with
The increase of temperature, the time that can maintain solid-state is the shortest, and the amplitude that impurity etc. increase is higher than this
The sample of invention.And the sample of the present invention is under two extreme conditions, the property of products application all can be kept
Shape, impurity increases in tolerance interval, still conforms to product quality requirement.
Embodiment 6: the contrast test of different component weight ratio
Lyophilizing group is carried out for subjects with the formula of table 10 and 11 two non-invention components by weight of table
The preparation of compound, investigates the components by weight impact on product quality, the results are shown in Table 12.
Table 10
| Component | Weight |
| Carperitide | 0.1g |
| Sucrose | 12g |
| Arginine | 1.8g |
| Water for injection | 600ml(600g) |
Table 11
| Component | Weight |
| Carperitide | 0.1g |
| Sucrose | 84g |
| Arginine | 7.2g |
| Water for injection | 600ml(600g) |
Table 12
From table 12 result, the formula of non-invention components by weight can cause carperitide lyophilizing to combine
The decline of article matter, makes freeze-dried composition atrophy and melting phenomenon occur.
The above is only the preferred embodiment of the present invention, it is noted that general for the art
For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to make some improvement and profit
Decorations, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (9)
1. an injection carperitide freeze-dried composition, it is characterised in that by principal agent carperitide, tax
Shape agent and protective agent composition；
Described excipient be in lactose, sucrose, glucose, sodium chloride, sorbitol one or both with
On；Described protective agent be glycine, arginine, glucosan, PVP, xylitol one or more.
Freeze-dried composition the most according to claim 1, it is characterised in that each components by weight is as follows:
Carperitide: excipient: protective agent=0.1:(17.5～70): (3～5).
The most according to claim 2 freeze-dried composition, it is characterized in that, each components by weight is as follows:
Carperitide: excipient: protective agent=0.1:(30～60): (3～5).
4. according to freeze-dried composition described in claim 1-3 any one, it is characterised in that described figuration
Agent is one or both in lactose, sucrose.
5. according to freeze-dried composition described in claim 1-3 any one, it is characterised in that described protection
Agent is one or both in glycine, arginine.
6. the preparation method of freeze-dried composition described in claim 1, it is characterised in that including:
Take water for injection excipient dissolving, protective agent and carperitide, be subsequently adding water for injection and adjust card
The vertical peptide concentration of training is required drug level, sterilization treatment, lyophilizing, it is thus achieved that freeze-dried composition.
Preparation method the most according to claim 6, it is characterised in that including:
Measure the water for injection being cooled to 45 ± 5 DEG C, put in appropriate containers, weigh protective agent stirring and dissolving,
Adding excipient, stirring, to dissolving, is subsequently adding carperitide stirring and extremely dissolves, add water for injection
Adjusting carperitide concentration is required drug level, stirs, then the microporous filter membrane by 0.22 μm
Filtration sterilization, filtrate lyophilizing, it is thus achieved that freeze-dried composition.
8. according to preparation method described in claim 6 or 7, it is characterised in that described step of freeze drying is:
Step A, solution is cooled to-10 DEG C ± 1 DEG C, then in 1h, conduction oil temperature is reduced to-45
DEG C, keep 7h；
Step B, it is evacuated to 10～15pa by freeze drying box body, with the speed of 1～1.5 DEG C/h to conduction oil
Carrying out hyperthermic treatment, be incubated after conduction oil temperature rises to-30 DEG C, temperature retention time is 42h～55h,
The temperature difference of sample and conduction oil is less than 8～12 DEG C；
Conduction oil is heated up by step C, speed with 1 DEG C/5～10min, and products temperature rises to 20 DEG C ± 2
DEG C, it is incubated 4～6h.
9. according to preparation method described in claim 6 or 7, it is characterised in that be additionally included in described injection
After water dissolution excipient, protective agent and carperitide, by 0.1M hydrochloric acid and/or 0.1M sodium hydroxide
Solution maintains solution ph to be 4.5～6.5.
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Citations (4)
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| CN103142489A (en) * | 2012-11-28 | 2013-06-12 | 深圳市健元医药科技有限公司 | Human alpha-atrial natriuretic peptide sustained release microsphere preparation and preparation method thereof |
| CN103784403A (en) * | 2013-12-26 | 2014-05-14 | 深圳市健元医药科技有限公司 | Long-acting liposome preparation for pulmonary drug delivery and preparation method thereof |
| JP2015078177A (en) * | 2013-09-11 | 2015-04-23 | 第一三共株式会社 | Lyophilized products for room temperature preservation |
| CN104546702A (en) * | 2015-02-06 | 2015-04-29 | 石家庄沃泰生物科技有限公司 | Recombinant human brain natriuretic peptide injection and preparation method thereof |
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2015
- 2015-06-25 CN CN201510357639.XA patent/CN106309384B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142489A (en) * | 2012-11-28 | 2013-06-12 | 深圳市健元医药科技有限公司 | Human alpha-atrial natriuretic peptide sustained release microsphere preparation and preparation method thereof |
| JP2015078177A (en) * | 2013-09-11 | 2015-04-23 | 第一三共株式会社 | Lyophilized products for room temperature preservation |
| CN103784403A (en) * | 2013-12-26 | 2014-05-14 | 深圳市健元医药科技有限公司 | Long-acting liposome preparation for pulmonary drug delivery and preparation method thereof |
| CN104546702A (en) * | 2015-02-06 | 2015-04-29 | 石家庄沃泰生物科技有限公司 | Recombinant human brain natriuretic peptide injection and preparation method thereof |
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| 元英进主编: "《现代制药工艺学》", 31 July 2004, 化学工艺出版社 * |
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