CN102552177A - Freeze-dried recombinant human brain natriuretic peptide (rhBNP) preparation and preparation method thereof - Google Patents
Freeze-dried recombinant human brain natriuretic peptide (rhBNP) preparation and preparation method thereof Download PDFInfo
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- CN102552177A CN102552177A CN2011104534324A CN201110453432A CN102552177A CN 102552177 A CN102552177 A CN 102552177A CN 2011104534324 A CN2011104534324 A CN 2011104534324A CN 201110453432 A CN201110453432 A CN 201110453432A CN 102552177 A CN102552177 A CN 102552177A
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- natriuretic peptide
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Abstract
The invention discloses a freeze-dried recombinant human brain natriuretic peptide (rhBNP) preparation. The preparation is prepared from the following Chinese herbal medicines and auxiliary materials in part by weight: 0.5 part of rhBNP, 0.2 to 20 parts of buffer solution system, 1 to 20 parts of excipient and 1 to 20 parts of NaC1. The invention also discloses a preparation method for the freeze-dried rhBNP preparation. By optimization of the auxiliary materials, rhBNP has high stability, and effectiveness and safety of medicines are ensured.
Description
Technical field
The present invention relates to lyophilized formulations of recombined human brain natriuretic peptide and preparation method thereof, belong to drug world.
Background technology
Recombined human brain natriuretic peptide (rhBNP) is succeeded in developing by the U.S.; And be used to treat the medicine of new generation of congestive heart failure clinically; Mechanism of its treatment heart failure be it to a certain extent can the antagonism epinephrine, the activity of Re-A-A element and endothelin system, lax vascular smooth muscle and expand the peripheral artery vein blood vessel, the drainage of increase sodium and sharp sodium, diuresis; Alleviate the front and back load of heart, be of value to the alleviation of the heart failure state of an illness.
The lyophilizing recombinant human brain natriuretic peptide of domestic clinical practice, trade name are newly lived plain, every 0.5mg.For acute heart failure patient's treatment, detailed directions: the plain 0.5mg that newly lives is dissolved in 100ml liquid, gives loading dose 1.5 μ g/kg, intravenous injection, and the time of injecting must not be less than 90 seconds, the surplus vena axillaris 0.01 μ g (kgmin) that instils
-1, persistent instillation, SM 48～72 hours.For example, be the patient of 60kg for body weight, with extracting the quiet notes of 18～20ml in the 100ml liquid, surplus liquid 7～8ml/h continuous intravenous is dripped.For the treatment of chronic heart failure, detailed directions is: give (0.0075～0.01) μ g (kgmin)
-1Intravenous drip, 1～2 outpatient service vein treatment weekly, be 12 weeks the course of treatment.Yet; Because rhBNP is a polypeptide drug; It in vivo and in vitro environment possibly stand down chemical degradation and physical change and the inactivation of multiple complicacy; Therefore, the method that research improves the stability of this pharmaceutical preparation just seems particularly necessary, at present also not about improving the pertinent literature report of the plain lyophilized formulations stability of new work.
Summary of the invention
Technical scheme of the present invention has provided a kind of recombined human brain natriuretic peptide lyophilized formulations of good stability.This bright method for preparing that this lyophilized formulations also is provided.
The invention provides a kind of recombined human brain natriuretic peptide lyophilized formulations, it is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, buffer solution system 0.2-20 part, excipient 1-20 part, NaCl 1-20 part.
Wherein, described buffer solution system is phosphate, citric acid and acetate; Be preferably phosphate or citric acid.
Wherein, described buffer solution system is a phosphate.
Wherein, described excipient is human serum albumin, mannitol, glycine, hetastarch; Be preferably human serum albumin or mannitol.
Wherein, described excipient is the human serum albumin.
Recombined human brain natriuretic peptide lyophilized formulations of the present invention is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, human serum albumin 1-20 part, Na
2HPO
40.1-10 part, NaH
2PO
40.1-10 part, NaCl 1-20 part.
Further preferably, it is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, 10 parts of human serum albumins, Na
2HPO
41.73 part, NaH
2PO
40.93 part, 9 parts of NaCl.
The present invention also provides the method for preparing of this recombined human brain natriuretic peptide lyophilized formulations, and it comprises the steps:
(1) gets recombined human brain natriuretic peptide, buffer solution system, excipient, the NaCl of recipe quantity, with water for injection dissolving, solution for standby; Or
(2) get buffer solution system, excipient, the NaCl of recipe quantity, be dissolved in the solution of the recombined human brain natriuretic peptide that contains recipe quantity the gained solution for standby;
(3) behind the solution impurity removal and purification with step (1) or (2) gained, with the refined liquid packing, lyophilization gets product.
The present invention preferred through to adjuvant makes the recombined human brain natriuretic peptide have good stable property, guaranteed the effectiveness and the safety of medicine.
Below, foregoing of the present invention is done further detailed description again through the specific embodiment of embodiment form.But should not be construed as is the restriction to protection domain of the present invention, all based on above-mentioned technological thought, and the modification, replacement, the change that utilize ordinary skill knowledge and customary means to make all belong to scope of the present invention.
Description of drawings
Fig. 1 example schematic
The specific embodiment
The selection of embodiment 1 recombined human brain natriuretic peptide bottling dosage
The bibliographical information of the clinical trial that external rhBNP is relevant: external clinical present RD is that intravenous drip is 0.015ug/kg.min and 0.03ug/kg.min; Continuous drip 6 hours; By American-European average man body weight is 80kg, and therefore every dosage specification should be 432ug and 864ug.We, tentatively confirm with 0.015 μ g/kg.min as dosage in conjunction with the document of abroad having delivered through the pharmacological effect test to animal; By Chinese's average weight in 60kg, continuously quiet 6 hours, then every dosage should be 324 μ g, so the bottling amount is increased to 500 μ g/ dosage.
Embodiment 2 recombined human brain natriuretic peptide 0.5mg
Na
2HPO
4?1.73mg
NaH
2PO
4?0.93mg
Human serum albumin 10mg
NaCl9mg
Method for making: after the dissolving, add proper amount of active carbon, mixing, after suitably leaving standstill, through coarse filtration, fine straining, refined liquid, prop up packing by 1ml/ after, lid is rolled in lyophilization, gets product, and contains recombined human brain natriuretic peptide 500RU (0.5mg) in every finished product.
Embodiment 3 recombined human brain natriuretic peptide 0.5mg
Na
2HPO
4?1.73mg
NaH
2PO
4?0.93mg
Mannitol 8mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 4 recombined human brain natriuretic peptide 0.5mg
Na
2HPO
4?1.73mg
NaH
2PO
4?0.93mg
Glycine 6mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 5 recombined human brain natriuretic peptide 0.5mg
Na
2HPO
4?1.73mg
NaH
2PO
4?0.93mg
Hetastarch 6mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 6 recombined human brain natriuretic peptide 0.5mg
Sodium citrate 5.9mg
Citric acid 0.11mg
Human serum albumin 10mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 7 recombined human brain natriuretic peptide 0.5mg
Sodium citrate 5.9mg
Citric acid 0.11mg
Mannitol 8mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 8 recombined human brain natriuretic peptide 0.5mg
Sodium citrate 5.9mg
Citric acid 0.11mg
Glycine 6mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 9 recombined human brain natriuretic peptide 0.5mg
Sodium citrate 5.9mg
Citric acid 0.11mg
Hetastarch 6mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 10 recombined human brain natriuretic peptide 0.5mg
Sodium acetate 1.64mg
Acetic acid 0.002mg
Human serum albumin 10mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 11 recombined human brain natriuretic peptide 0.5mg
Sodium acetate 1.64mg
Acetic acid 0.002mg
Mannitol 8mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 12 recombined human brain natriuretic peptide 0.5mg
Sodium acetate 1.64mg
Acetic acid 0.002mg
Glycine 6mg
NaCl?9mg
Method for making is with embodiment 2
Embodiment 13 recombined human brain natriuretic peptide 0.5mg
Sodium acetate 1.64mg
Acetic acid 0.002mg
Hetastarch 6mg
NaCl?9mg
Method for making is with embodiment 2
Below be the long-term stable experiment and the activity test of prescription screening test and preparation.
Test Example 1 recombined human brain natriuretic peptide lyophilized formulations prescription optimization test
One. test method:
The preparation prescription optimization test is mainly confirmed through the stability that detects rhBNP under the different pharmaceutical formulation conditions, is specially with the RP-HPLC method content of the rhBNP in the finished product is measured.
Chromatographic column: Source 5RPC 4.6/150 prepacked column (Pharmacia Biotech)
Instrument: AKTA explorer100
The RP-HPLC condition is: mobile phase A is the water that contains 0.1%TFA, 5%Acetonitrile; Mobile phase B is the Acetonitrile that contains 0.1%TFA, 10% water; Gradient is: 0% → 20%B, 2CV, and 20% → 30%B, 3CV, 30% → 80%B, 1CV, applied sample amount are 500 μ l, flow velocity is 0.5ml/min, detects wavelength 215nm.
Two. the pharmaceutical formulation adjuvant
Table 1: pharmaceutical formulation adjuvant
| Adjuvant | Manufacturer |
| Na 2HPO 4 | Chengdu chemical reagent factory |
| NaH 2PO 4 | Chengdu chemical reagent factory |
| Citric acid | Chengdu chemical reagent factory |
| Sodium citrate | Chengdu chemical reagent factory |
| Acetic acid | Chengdu chemical reagent factory |
| Sodium acetate | Chengdu chemical reagent factory |
| NaCl | Chengdu chemical reagent factory |
| Mannitol | Chengdu chemical reagent factory |
| Glycine | Chengdu chemical reagent factory |
| Hetastarch | Chengdu chemical reagent factory |
| The human serum albumin | Chengdu Inst. of Biological Products |
Three. the preparation prescription optimization test
Biological product will keep its biological activity as much as possible, and dosage form must be stablized, and is easy and simple to handle, is easy to repetition, and the management that can strictly regulate.Lyophilized formulations is a kind of dosage form that present biological product extensively adopt.
1. the selection of dosage
The bibliographical information of the clinical trial that external rhBNP is relevant: external clinical present RD is that intravenous drip is 0.015ug/kg.min and 0.03ug/kg.min; Continuous drip 6 hours; By American-European average man body weight is 80kg, and therefore every dosage specification should be 432ug and 864ug.We, tentatively confirm with 0.015 μ g/kg.min as dosage in conjunction with the document of abroad having delivered through the pharmacological effect test to animal; By Chinese's average weight in 60kg, continuously quiet 6 hours, then every dosage should be 324 μ g, considers the report that does not still have Chinese's clinical trial at present, so the bottling amount is increased to 500 μ g/ dosage.
2. the selection of buffer system
500 μ grhBNP are dissolved in the 1ml buffer, and buffer system adopts phosphate, citric acid and acetate respectively, and concentration does not wait from 5mM-100mM; PH remains between the 5-8, and temperature is 2-8 ℃, and the time is one month; Investigate stability of sample, result of the test is (μ g) as follows:
Table 2: buffer system and PH are to the influence (concentration) of rhBNP stability
| Buffer PH | 5 | 5.5 | 6 | 6.5 | 7 | 7.5 | 8 |
| Phosphate | 387 | 396 | 413 | 422 | 468 | 486 | 416 |
| Citric acid | 346 | 398 | 394 | 415 | 435 | 457 | 392 |
| Acetate | 322 | 372 | 388 | 398 | 416 | 421 | 386 |
It is following to be converted into percentage result:
Table 3: buffer system and PH are to the influence (percentage ratio) of rhBNP stability
| Buffer PH | 5 | 5.5 | 6 | 6.5 | 7 | 7.5 | 8 |
| Phosphate | 77.4 | 79.2 | 82.6 | 84.4 | 93.6 | 97.2 | 83.2 |
| Citric acid | 69.2 | 79.6 | 78.8 | 83.0 | 87.0 | 91.4 | 78.4 |
| Acetate | 64.4 | 74.4 | 77.6 | 79.6 | 83.2 | 84.2 | 77.2 |
The result shows that buffer system adopts phosphate 20mM, PH7.5 (corresponding Na
2HPO
41.7mg, NaH
2PO
40.93mg), sample stability is best.
3. the selection of excipient
500 μ grhBNP are dissolved in phosphate buffer, and (20mM PH7.5), distinguishes end user's serum albumin, mannitol, glycine, hetastarch excipient, and temperature is 2-8 ℃, and the time is one month, investigates stability of sample.
(1) human serum albumin
Table 4: the different amounts human serum albumin is to the influence of rhBNP stability
| The human serum albumin | 0 | 2.5mg | 5mg | 10mg | 20mg | 40mg |
| RhBNP content | 481 | 489 | 497 | 499 | 493 | 486 |
| Percentage ratio | 96.2 | 97.8 | 99.4 | 99.8 | 98.6 | 97.2 |
(2) mannitol
Table 5: different amounts mannitol is to the influence of rhBNP stability
| Mannitol | 0 | 2mg | 4mg | 8mg | 16mg | 32mg |
| RhBNP content | 483 | 487 | 497 | 498 | 489 | 487 |
| Percentage ratio | 96.6 | 97.4 | 99.4 | 99.6 | 97.8 | 97.4 |
(3) glycine
Table 6: the different amounts glycine is to the influence of rhBNP stability
| Glycine | 0 | 2mg | 4mg | 8mg | 16mg | 32mg |
| RhBNP content | 482 | 486 | 493 | 489 | 487 | 487 |
| Percentage ratio | 96.4 | 97.2 | 98.6 | 97.8 | 97.4 | 97.4 |
(4) hetastarch
Table 7: the different amounts hetastarch is to the influence of rhBNP stability
| Hetastarch | 0 | 2mg | 4mg | 8mg | 16mg | 32mg |
| RhBNP content | 483 | 487 | 494 | 491 | 488 | 486 |
| Percentage ratio | 96.6 | 97.4 | 98.8 | 98.2 | 97.6 | 97.2 |
The result shows human serum albumin or mannitol better effects if, and the human serum albumin has better effect.In the biological product manufacture process, adding the human serum albumin has good protective effect to the stability of albumen or polypeptide usually, thereby often is used as excipient.
Select the human serum albumin as excipient in front on the basis of test, and select the human serum albumin of 1% and 0.5% concentration under different temperatures, to carry out the stability of sample investigation.The result shows that the human serum albumin of two kinds of concentration all has good protective effect to rhBNP, but it is better to add 1% human serum albumin (being that human albumin's consumption is 10mg) molding effect.Therefore select 1% human serum albumin as formulation concentrations.
Table 8: variable concentrations human serum albumin condition of different temperatures is to the influence of rhBNP stability
The selection of NaCl
In the manufacturing process, contain NaCl in the rhBNP solution that obtains, consider that human body needs 150mM NaCl to keep etc. and oozes, so contain NaCl in the goods.And freeze dried the time, the goods that contain 150mM NaCl are under identical freeze dried condition, and its moisture is lower, so more help the preservation of rhBNP lyophilized formulations.
The test of Test Example 2 lyophilized formulations prescription screenings
The difference of lyophilized formulations on outward appearance, dissolution time, clarity and stability that different formulations makes investigated in the prescription screening test.Outward appearance should be the loose body of white shelly, and dissolubility will be got well (planted agent was dissolved fully in 5 minutes), should be clear liquid after the dissolving, and especially the stability of recombined human brain natriuretic peptide will be got well.
The stability employing RP-HPLC method of rhBNP is measured the content of the rhBNP in the lyophilized formulations and is reflected.Concrete detection method is following:
Chromatographic column: Source 5RPC 4.6/150 prepacked column (Pharmacia Biotech)
Instrument: AKTA explorer100
The RP-HPLC condition is: mobile phase A is the water that contains 0.1%TFA, 5%Acetonitrile; Mobile phase B is the Acetonitrile that contains 0.1%TFA, 10% water; Gradient is: 0% → 20%B, 2CV, and 20% → 30%B, 3CV, 30% → 80%B, 1CV, applied sample amount are 500 l, flow velocity is 0.5ml/min, detects wavelength 215nm.
By the lyophilized formulations that above-mentioned prescription makes, temperature is 2-8 ℃, and the time is one month, the stability of coming judgement sample through the content of measuring rhBNP.
Lyophilized formulations prescription screening result of the test is following:
The test of table 9 lyophilized formulations prescription screening
Result of the test shows, adopts embodiment 2 (recombined human brain natriuretic peptide 0.5mg, Na
2HPO
41.73mg, NaH
2PO
40.93mg, human serum albumin 10mg, NaCl 9mg) said preparation prescription the lyophilized formulations dissolubility, clarity, the best stability that obtain.
The long-term stable experiment and the activity test of Test Example 3 lyophilized formulations prescription
Investigate the long-time stability and the activity of embodiment 2 said pharmaceutical formulations.The quality of the pharmaceutical preparations requires like following table:
Table 10 formulation samples prescription
| Index | Quality of the pharmaceutical preparations requirement |
| Outward appearance | Should be the loose body of white shelly. |
| Dissolution time | With the water for injection dissolving, the planted agent was dissolved fully in 5 minutes under the room temperature. |
| Clarity | Littlely be with opalescent clear liquid, should be muddy, contain foreign body or shake the deposition of not loosing. |
| PH value | 6.5～8.0 |
| Active | 500RU |
| Moisture | ≤3.0% (g/g) |
Content of the test:
1.2～8 ℃ of investigations that keep sample: these article are placed 2～8 ℃ of refrigerators, be set in respectively and measure above index respectively in March, June, JIUYUE, December, 18 months, 24 months, 30 months, 36 months etc.
2. the room temperature investigation that keeps sample: these article are placed 25 ℃ of calorstats, be set in respectively and measure above index respectively in March, June, JIUYUE, December, 18 months, 24 months, 30 months etc.
The investigation 3.37 ℃ keep sample: these article are placed 37 ℃ of calorstats, be set in respectively and measure above index respectively in March, June, JIUYUE, December, 18 months, 24 months, 30 months etc.
3. biological activity test assay method (tremulous pulse bar method)
Material: the rhBNP sample, specification: 0.5mg/ props up,
Phenylephrine, Shanghai Hefeng Pharmaceutical Co., Ltd. produces, lot number: 981101
RhBNP work is with reference to article, and specification is that 0.1mg/ props up, and activity is 100U, is provided by this laboratory.
Principle: at first utilize Phenylephrine and its receptors bind on blood vessel; The generation vascular effect that contracts the resting tension of blood vessel is improved, and stable maintenance is at certain level; Utilize rhBNP to combine then with its natriuretic peptide receptor on blood vessel; Generation through the variation of antiotasis, is measured the biological activity of rhBNP to the expansion vascular effect of rabbit thoracic aorta bar.
3.1 the compound method of solution:
The preparation of tissue fluid: the prescription of tyrode ' s liquid (with 1 liter of solution note):
NaCl?8g；KCl?0.2g；MgSO
4.7H2O?0.26g；NaH
2PO
4?0.065g；NaHCO
3?1g；Glucose?1g；CaCl
2?0.2g
Earlier will be except that CaCl
2Other component in addition adds in the 600ml distilled water to dissolving fully, again with CaCl
2Add in the 40ml distilled water to dissolving fully, again with CaCl
2Solution slowly adds when stirring in the 600ml solution, and is at last that the solution dilution that mixes is subsequent use to 1000ml.
With normal saline the concentration of Phenylephrine is formulated as 1.25 * 10
-2Mg/ml;
Respectively rhBNP work is dissolved in the 1ml normal saline with reference to article and testing sample earlier, and then is diluted to 0.1mg/ml concentration,, and compile and upward manage number as follows again by 1: 10 dilution proportion standard sample and testing sample:
The pipe number: No.1 No.2 No.3
RhBNP work is with reference to article---→ 0.1mg/ml---→ 0.01mg/ml---→ 0.001mg/ml
The rhBNP testing sample---→ 0.1mg/ml---→ 0.01mg/ml---→ 0.001mg/ml
3.2 the preparation of tremulous pulse bar
Get one of 1.5-2.0kg new zealand rabbit,, put to death with dislocation method then, get branches of descending thoracic aorta with pentobarbital sodium anesthesia.The artery bar is cut into long, the wide tremulous pulse spiral bar of 2.5mm about 1.5cm, and hangs in the Magnus' bath that contains 20ml tyrode's solution (37 ℃), logical oxygen; PH value remains on 7.4; Blood vessel is added the 1g preload, stablized 2 hours, changed 1 time tyrode's solution therebetween in per 20 minutes; The monitor chart drive speed is adjusted to 2.5mm/min, sensitivity * 0.02.The tension variation of record blood vessel.
After treating baseline stability, the 0.05ml Phenylephrine that adding prepares is in Magnus' bath, and making its final concentration in Magnus' bath is 1.56 * 10
-4Mg/ml, curve rise to peak and stable after, begin to add the rhBNP standard sample, and the record tension variation by the cumulative concentration dose regimen.
3.3 accumulation dosage regimen: following steps; From No. three pipe beginning of work with reference to QC; In Magnus' bath, add 6.25,6.25,12.5,25,50 respectively at every turn, 100ul, and then get second pipe, add 20,40 respectively, 80ul at every turn; Get first pipe again, add 16,32 respectively, the 64ul sample at every turn.Each add sample after, wait until that tension curve is reduced to steady position after, enter into next step dosing program again, till tension curve is near baseline.
Step is following:
3.4 after accomplishing above-mentioned administration, eluting was also stablized 1 hour, changed 1 time tyrode's solution in per 20 minutes therebetween, treat baseline stability after, add Phenylephrine solution that 0.05ml prepares again in Magnus' bath, then its final concentration in Magnus' bath is 1.56 * 10
-4Mg/ml, curve rise to peak and stable after, begin to add the rhBNP testing sample by the cumulative concentration dose regimen, the accumulation medication with reference to article, and writes down tension variation with work.
3.5 the record of data and processing
The record format of according to the form below; Data are write down and handle; Final concentration value after wherein the Conc. representative sample adds in the Magnus' bath; LogC represents the common logarithm value of this final concentration; A representative in each adding work with reference to article and the tension force amplitude that begins from baseline after treating tension stability; On behalf of each adding work, OA produces the tension variation value that the stable tension force platform that raises begins from adding Phenylephrine with reference to article and after treating tension stability, and OA% represent OA with respect to the tensile relative value who adds Phenylephrine and produce the stable tension force platform of rising, and B represents the tension force amplitude that begins from baseline at adding testing sample at every turn and after treating tension stability; OB representative is each after adding testing sample and treating tension stability produces the tension variation value that the stable tension force platform that raises begins from adding Phenylephrine, and on behalf of OB, OB% produce the relative value of tension force amplitude of the stable tension force platform of rising with respect to adding Phenylephrine.
Example schematic is seen Fig. 1: i.e. OA=K-A, OB=K-B, OA%=(K-A)/K, OB%=(K-B)/K
OA% and OB% have represented the reaction percentage rate of the work of rhBNP with reference to article and vasodilator effect that testing sample produces respectively; Respectively LogC value and OA%, the input of OB% value are rolled up in the software of the DR Analytical Computer Program establishment of delivering on the 5th phase 347-349 page or leaf at " the Shanghai first medical college journal " the 12nd with reference to the Xu Duan full professor, obtain ED50 separately.
3.6 the active calculating of testing sample
Active computing formula is:
Sample activity=standard substance activity * (standard substance ED
50* diluted sample multiple)/(sample ED
50* standard substance extension rate)
The result is following for the formulation samples stability test:
4～8 ℃ of investigation specification: 500RU that keep sample of table 11 recombinant human brain natriuretic peptide lyophilized injectable powder
The result: recombinant human brain natriuretic peptide lyophilized injectable powder (specification: 500RU/ props up) sample is at 2～8 ℃ of reserved sample observings, and sampling detects each item index at the appointed time, with before the test relatively, no change almost, activity stabilized (more than 97%), each item index meets the requirements.
Table 12 recombinant human brain natriuretic peptide lyophilized injectable powder room temperature investigation specification: the 500RU that keeps sample
The result: recombinant human brain natriuretic peptide lyophilized injectable powder (specification: 500RU/ props up) sample is at the room temperature reserved sample observing, and sampling detects each item index at the appointed time, with before the test relatively, no change almost, activity stabilized (more than 93%), each item index meets the requirements.
37 ℃ of investigation specification: 500RU that keep sample of table 13 recombinant human brain natriuretic peptide lyophilized injectable powder
The result: recombinant human brain natriuretic peptide lyophilized injectable powder (specification: 500RU/ props up) sample is at 37 ℃ of reserved sample observings; And sampling detects each item index at the appointed time, and is relatively preceding with test, almost no change; Activity stabilized (more than 85%), each item index meet clinical preceding prescription.
Recombined human brain natriuretic peptide lyophilized formulations was preserved 12 months under higher temperature, and its pharmaceutically active still can reach more than 85%; Under nearly room temperature, preserved 12 months; Its pharmaceutically active remains on more than 93%, stored refrigerated 12 months, and its pharmaceutically active remains on more than 97%.Preferred through to pharmaceutical formulation makes the recombined human brain natriuretic peptide have good stable property, guaranteed the effectiveness and the safety of medicine.
Claims (8)
1. recombined human brain natriuretic peptide lyophilized formulations, it is characterized in that: it is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, buffer solution system 0.2-20 part, excipient 1-20 part, NaCl 1-20 part.
2. recombined human brain natriuretic peptide lyophilized formulations according to claim 1 is characterized in that: described buffer solution system is phosphate, citric acid and acetate; Be preferably phosphate or citric acid.
3. recombined human brain natriuretic peptide lyophilized formulations according to claim 2 is characterized in that: described buffer solution system is a phosphate.
4. recombined human brain natriuretic peptide lyophilized formulations according to claim 1 is characterized in that: described excipient is human serum albumin, mannitol, glycine, hetastarch; Be preferably human serum albumin or mannitol.
5. recombined human brain natriuretic peptide lyophilized formulations according to claim 4 is characterized in that: described excipient is the human serum albumin.
6. according to any described recombined human brain natriuretic peptide lyophilized formulations of claim 1-5, it is characterized in that: it is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, human serum albumin 1-20 part, Na
2HPO
40.1-10 part, NaH
2PO
40.1-10 part, NaCl 1-20 part.
7. recombined human brain natriuretic peptide lyophilized formulations according to claim 6 is characterized in that: it is to be prepared from following materials of weight proportions medicine and adjuvant:
0.5 part of recombined human brain natriuretic peptide, 10 parts of human serum albumins, Na
2HPO
41.73 part, NaH
2PO
40.93 part, 9 parts of NaCl.
8. the method for preparing of any described recombined human brain natriuretic peptide lyophilized formulations of claim 1-7, it is characterized in that: it comprises the steps:
(1) gets recombined human brain natriuretic peptide, buffer solution system, excipient, the NaCl of recipe quantity, with water for injection dissolving, solution for standby; Or
(2) get buffer solution system, excipient, the NaCl of recipe quantity, be dissolved in the solution of the recombined human brain natriuretic peptide that contains recipe quantity the gained solution for standby;
(3) behind the solution impurity removal and purification with step (1) or (2) gained, with the refined liquid packing, lyophilization gets product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103990115A (en) * | 2014-05-09 | 2014-08-20 | 深圳翰宇药业股份有限公司 | Nesiritide pharmaceutical composition, preparing method thereof and preparations thereof |
| CN104825403A (en) * | 2015-04-30 | 2015-08-12 | 上海景泽生物技术有限公司 | Freeze-dried B type natriuretic peptide preparation and preparation method thereof |
| CN104861075A (en) * | 2015-05-08 | 2015-08-26 | 成都金凯生物技术有限公司 | Long-acting recombinant human brain natriuretic peptide fusion protein and preparation method and thereof and application |
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| US20060008415A1 (en) * | 2004-06-25 | 2006-01-12 | Protein Design Labs, Inc. | Stable liquid and lyophilized formulation of proteins |
| US20090163421A1 (en) * | 2007-12-19 | 2009-06-25 | Ekr Therapeutics, Inc. | Room Temperature Stable, Lyophilized Natriuretic Peptide Formulations |
| JP2009180527A (en) * | 2008-01-29 | 2009-08-13 | Sanyo Chem Ind Ltd | Antigen-containing aqueous solution |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060008415A1 (en) * | 2004-06-25 | 2006-01-12 | Protein Design Labs, Inc. | Stable liquid and lyophilized formulation of proteins |
| US20090163421A1 (en) * | 2007-12-19 | 2009-06-25 | Ekr Therapeutics, Inc. | Room Temperature Stable, Lyophilized Natriuretic Peptide Formulations |
| JP2009180527A (en) * | 2008-01-29 | 2009-08-13 | Sanyo Chem Ind Ltd | Antigen-containing aqueous solution |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103990115A (en) * | 2014-05-09 | 2014-08-20 | 深圳翰宇药业股份有限公司 | Nesiritide pharmaceutical composition, preparing method thereof and preparations thereof |
| CN103990115B (en) * | 2014-05-09 | 2016-06-15 | 深圳翰宇药业股份有限公司 | A kind of Nesiritide pharmaceutical composition and preparation method thereof, preparation |
| CN104825403A (en) * | 2015-04-30 | 2015-08-12 | 上海景泽生物技术有限公司 | Freeze-dried B type natriuretic peptide preparation and preparation method thereof |
| CN104825403B (en) * | 2015-04-30 | 2019-06-04 | 上海景泽生物技术有限公司 | A kind of freeze-drying B-typeNatriuretic Peptide preparation and preparation method thereof |
| CN104861075A (en) * | 2015-05-08 | 2015-08-26 | 成都金凯生物技术有限公司 | Long-acting recombinant human brain natriuretic peptide fusion protein and preparation method and thereof and application |
| CN104861075B (en) * | 2015-05-08 | 2018-06-08 | 成都金凯生物技术有限公司 | A kind of long-acting recombinant human brain natriuretic peptide fusion protein and preparation method thereof and purposes |
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| CN102552177B (en) | 2013-04-10 |
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Effective date of registration: 20170816 Address after: 850000 Beijing Middle Road, Tibet, No. 93 Middle Road, Lhasa Patentee after: Nuodikang Pharmaceutical Industry Co., Ltd., Tibet Address before: 610023 Jinjiang Industrial Development Zone, Sichuan, Chengdu Patentee before: Chengdu Nuodikang Biological Pharmaceutical Co., Ltd. |