CN101011572A - Medicinal composition of recombinant human parathormone(1-84) and its preparing process - Google Patents
Medicinal composition of recombinant human parathormone(1-84) and its preparing process Download PDFInfo
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- CN101011572A CN101011572A CN 200710078166 CN200710078166A CN101011572A CN 101011572 A CN101011572 A CN 101011572A CN 200710078166 CN200710078166 CN 200710078166 CN 200710078166 A CN200710078166 A CN 200710078166A CN 101011572 A CN101011572 A CN 101011572A
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- parathyroid hormone
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- human parathyroid
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- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 80
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000000203 mixture Substances 0.000 title claims abstract description 10
- 102000003982 Parathyroid hormone Human genes 0.000 title abstract description 24
- 108090000445 Parathyroid hormone Proteins 0.000 title abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 51
- 239000010413 mother solution Substances 0.000 claims abstract description 26
- 239000000872 buffer Substances 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- 239000003223 protective agent Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 5
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 5
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims description 62
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims description 62
- 102000058004 human PTH Human genes 0.000 claims description 62
- 239000000243 solution Substances 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 229930006000 Sucrose Natural products 0.000 claims description 16
- 239000005720 sucrose Substances 0.000 claims description 16
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012482 calibration solution Substances 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000001508 potassium citrate Substances 0.000 claims description 3
- 229960002635 potassium citrate Drugs 0.000 claims description 3
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 3
- 235000011082 potassium citrates Nutrition 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 125000000185 sucrose group Chemical group 0.000 claims description 2
- 239000000890 drug combination Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000007710 freezing Methods 0.000 abstract description 3
- 230000008014 freezing Effects 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 238000007493 shaping process Methods 0.000 abstract 1
- 238000004458 analytical method Methods 0.000 description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 14
- 230000004071 biological effect Effects 0.000 description 11
- 229960001319 parathyroid hormone Drugs 0.000 description 10
- 239000000843 powder Substances 0.000 description 8
- 238000004321 preservation Methods 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NJYFRQQXXXRJHK-UHFFFAOYSA-N (4-aminophenyl) thiocyanate Chemical compound NC1=CC=C(SC#N)C=C1 NJYFRQQXXXRJHK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 108010001394 Disaccharidases Proteins 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 210000004409 osteocyte Anatomy 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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Abstract
The invention relates to a method for preparing recombined parathormone (1-84) drug composite, which comprises parathormone (1-84), shaping agent, and some fixity buffer for adjusting the pH value in acceptable range, protecting agent for protecting the activity of protein, and germ-free water, while the active component is parathormone. And the preparation method comprises that preparing mother solution, recombining the parathormone (1-84) mixture, making volume constant and freezing or the like. The water content of invention is lower than 3%, and the storage time of active component can reach 30 months at 2-8Deg. C, with prolonged storage time on drug purity.
Description
Technical field
The present invention relates to field of medicaments, particularly relate to a kind of recombinant human parathyroid hormone (1-84) pharmaceutical composition that improves storage stability and preparation method thereof.
Background technology
The aminoacid sequence of recombinant human parathyroid hormone (1-84) and the consensus amino acid sequence of natural parathyroid hormone, clinical confirmation, recombinant human parathyroid hormone (1-84) can apply to osteoporosis and related bone treatment of diseases.
Clinical trial confirms that interruption, low dose give parathyroid hormone (1-84) and have the bone assimilation, can increase bone amount, mechanical stress.Use parathyroid hormone (1-84) treatment can alleviate clinical symptoms to patients with osteoporosis, and the generation of control fracture, the parathyroid hormone (1-34) identical with 34 aminoacid sequences of parathyroid hormone (1-84) N end has therapeutic effect to osteoporosis equally.Greater than parathyroid hormone (1-84), this is because the segmental existence of parathyroid hormone (1-84) C terminal amino acid to toxicologic study confirmation parathyroid hormone (1-34) in the toxicity of animal before clinical.Exist and the bonded receptor of C terminal amino acid on the osteocyte, with the apoptosis that will cause osteocyte that combines of this receptor, and suppress apoptosis one of mechanism (the White and Ahmad.Curr Opin Invest Drug 2005 of parathyroid hormone performance bone assimilation effect just; 6:1057, Shraderand Raguccci.Ann Pharmacother 2005; 39:1511).Therefore, in theory, the safety that parathyroid hormone (1-84) is used is higher.
Parathyroid hormone is a kind of protein, has bigger changeableness than traditional small-molecule drug.And, different with other protein of having prepared successful medicament, parathyroid hormone is extremely responsive to Oxidation, therefore be difficult to realize commercial application, patent 94194608.8 has been reported a kind of parathyroid hormone preparation, comprise parathyroid hormone (1-84), as the mannitol of excipient with as the citric acid of buffer agent, this invention has solved bioactive ingredients stability in the preparation, but said preparation can only be preserved 9 months in 4 ℃, and the activity of the parathyroid hormone in the preparation and purity can be guaranteed.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of recombinant human parathyroid hormone (1-84) pharmaceutical composition that improves storage stability.
For achieving the above object; a kind of recombinant human parathyroid hormone (1-84) pharmaceutical composition; by the human parathyroid hormone (1-84) of medical science effective dose, excipient, its amount enough the pH value of adjusting preparation make it remain on fixedness buffer agent within the physiology tolerance interval, be used for the active protective agent of protected protein; and sterilized water, active component is recombinant human parathyroid hormone (1-84).
Further; in every ml recombinant human parathyroid hormone (1-84) pharmaceutical composition solution; the recombinant human parathyroid hormone (1-84) that comprises 50 μ g-150 μ g; the excipient of volume ratio meter meter 5%, 1-3% protective agent by weight, and in sterilized water, can make the pH value of the pharmaceutical composition solution of reprovision be buffered to the buffer agent of 5.0 ± 0.5 scopes.
Further, described recombinant human parathyroid hormone (1-84) preparation, described protective agent is a sucrose;
Further, wherein said excipient is a mannitol;
Further, wherein said fixedness buffer agent is a citrate solution;
Further, described citrate solution is selected from a kind of in sodium citrate or the potassium citrate.
Another object of the present invention is to provide a kind of preparation method for preparing aforementioned pharmaceutical compositions, may further comprise the steps:
A. prepare mother solution
Volume ratio meter by weight, compound concentration are that 20% excipient mother solution, concentration are 10% protective agent mother solution and the buffer of 1mM, and be stand-by;
B. prepare recombinant human parathyroid hormone (1-84) mixed liquor
At every 50-150 μ g recombinant human parathyroid hormone (1-84) solution, successively add 250 μ l, volume ratio meter concentration is 20% excipient mother solution and the protective agent mother solution of 100 μ l 10% by weight, regulate the pH value of mixed liquor then with the buffer agent of 1mM, the pH value scope that makes mixed liquor is between 5.0 ± 0.5;
C. standardize solution
Adopt high-performance liquid chromatogram determination recombinant human parathyroid hormone (1-84) concentration; and recombinant human parathyroid hormone (1-84) content is 50-150 μ g/ml in the calibration solution; the final concentration of excipient counts 5% for volume ratio by weight, and protectant final concentration volume ratio is by weight counted 1-3%.Above-mentioned each liquid all needs aseptic filtration before preparation;
D. lyophilizing
Under aseptic condition, above-mentioned mixed liquor with standardize solution is installed in the ampere bottle sabot lyophilizing then by dividing as required with craft or automatic packer.
The invention has the beneficial effects as follows: the invention provides the parathyroid hormone preparation that a kind of water content is no more than the powder agglomates form of 3% (weight).It is by recombinant human parathyroid hormone (1-84); excipient, protective agent and nonvolatile buffer agent mix the aseptic aqueous solution lyophilizing that obtains and form, under 2 ℃-8 ℃ condition; the storage life of its active ingredient can reach 30 months, the also corresponding prolongation of the preservation term of the purity of medicine.
What the excipient in this preparation was selected for use is mannitol; because it not only plays the activity protecting agent effect in freeze-drying process; and as the swelling agent in the freeze-drying process; form non-crystal powder agglomates; form skeleton preferably easily; moisture removes the powder agglomates of formation porosity and looseness when helping sublimation drying like this.Also help to guarantee ideal quality in the process of reprovision after the lyophilizing.
The main protective agent that adds in this preparation is a sucrose, and sucrose belongs to polyhydroxy disaccharidase, and hydrophilic is strong, and the glassy state temperature is higher, thereby after making that recombinant human parathyroid hormone (1-84) loses water in freezing dry process, its activity is kept.
The buffer agent that adds in the preparation of the present invention is a citrate buffer solution, and it is except meeting the acceptable needs of medicine, and also satisfying is nonvolatile buffering.Non-volatilely could guarantee that the variation of pH value is very little in the freeze-drying process, so not only be beneficial to the biological activity that guarantees product, and guarantee the homogeneity of product before and after reprovision.
Description of drawings
Fig. 1 is the biological activity analyses (tire) of embodiment 2 present compositions under 2-8 ℃ of storage condition.
Fig. 2 is the result that embodiment 2 present compositions adopt recombinant human parathyroid hormone (1-84) purity in the efficient liquid phase chromatographic analysis preparation.
Fig. 3 is the biological activity analysis (tire) of the present composition under 2-8 ℃ of storage condition of embodiment 3.
Fig. 4 be embodiment 3 be the result that the present composition adopts recombinant human parathyroid hormone (1-84) purity in the efficient liquid phase chromatographic analysis preparation.
Fig. 5 is the biological activity analysis (tire) of the present composition under 2-8 ℃ of storage condition of embodiment 1.
Fig. 6 be embodiment 1 be the result that the present composition adopts recombinant human parathyroid hormone (1-84) purity in the efficient liquid phase chromatographic analysis preparation.
The specific embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is described in more detail.Should be appreciated that specific embodiment described herein only in order to explanation the present invention, and be not used in qualification the present invention.
What the excipient in the preparation of the present invention was selected for use is mannitol; because it not only plays the activity protecting agent effect in freeze-drying process; and as the swelling agent in the freeze-drying process; form non-crystal powder agglomates; form skeleton preferably easily; moisture removes the powder agglomates of formation porosity and looseness when helping sublimation drying like this.Also help to guarantee ideal quality in the process of reprovision after the lyophilizing.
The main protective agent that adds in this preparation is a sucrose, and sucrose belongs to polyhydroxy disaccharidase, and hydrophilic is strong, and the glassy state temperature is higher, thereby after making that recombinant human parathyroid hormone (1-84) loses water in freezing dry process, its activity is kept.
The buffer agent that adds in the preparation of the present invention is a citrate buffer solution, and it is except meeting the acceptable needs of medicine, and also satisfying is nonvolatile buffering.Non-volatilely could guarantee that the variation of pH value is very little in the freeze-drying process, so not only be beneficial to the biological activity that guarantees product, and guarantee the homogeneity of product before and after reprovision.
In the present invention; recombinant human parathyroid hormone (1-84) preparation of stable storage is provided, and in specific embodiments, the final concentration of excipient mannitol is 5% (W/V); the pH scope that buffer agent produces is 5.0 ± 0.5, and the final concentration scope of protective agent sucrose is 1-3%.
The recombinant human parathyroid hormone (1-84) that adds in recombinant human parathyroid hormone of the present invention (1-84) preparation is the medical science effective dose.This term refers to is satisfied with the clinical treatment needs.The preparation of the present invention exploitation is to be used for the treatment of purpose, especially for the treatment of osteoporosis.Administering mode behind the preparation reprovision is a subcutaneous injection, and according to therapeutic scheme, the unit dose of the recombinant human parathyroid hormone (1-84) that uses for the people is: each 50-100 μ g, volume injected＜2.0ml often is 1.0ml.Therefore, forming recombinant human parathyroid hormone (1-84) concentration through the recombinant human parathyroid hormone (1-84) after purification and the aseptic filtration with buffer agent, protective agent and mixed with excipients is the aqueous solution of 50-100 μ g/ml.
Embodiment one:
Preparation 100ml recombinant human parathyroid hormone (1-84) pharmaceutical composition solution
A. prepare mother solution
Volume ratio meter by weight, the mannitol mother solution of preparation 20%, 10% sucrose mother solution and the sodium citrate buffer solution of 1mM, stand-by;
B. prepare recombinant human parathyroid hormone (1-84) mixed liquor
At 5mg recombinant human parathyroid hormone (1-84) solution, successively add 20% the mannitol mother solution of 25ml and the sucrose mother solution of 10ml 10%, regulate the pH value of mixed liquor then with the sodium citrate buffer agent of 1mM, the pH value scope that makes mixed liquor is between 5.0 ± 0.5
C. standardize solution
Adopt high-performance liquid chromatogram determination recombinant human parathyroid hormone (1-84) concentration, and recombinant human parathyroid hormone (1-84) content is 50 μ g/ml in the calibration solution, the final concentration of mannitol volume ratio by weight is 5%, the final concentration of sucrose is 1% (W/V), and above-mentioned each liquid all needs aseptic filtration before preparation.
D. lyophilizing
Under aseptic condition, the mixed liquor of above-mentioned standardize solution is installed in the ampere bottle of 3ml sabot lyophilizing then by 1.1ml volume branch with craft or automatic packer.
Using method
During clinical use, draw 1.0ml water for injection or normal saline with syringe and inject the ampere bottle and redissolve, extract liquid out by the using method injection.
Stability test
To be preservation under 2-8 ℃ the condition by the preparation of above-mentioned preparation method preparation in temperature.In 3,6, analyze after 9,12,15,18,21,24,27,30 months.To with the preparation reprovision in the sterilized water of 1.0ml, water be seen through rubber closure inject bottle when doing stability analysis, dissolve medicated powder in 1 minute, extract solution analysis again.
Introduce the result of various stability experiments below successively:
The biological activity analysis of recombinant human parathyroid hormone (1-84) is to analyze the generation that parathyroid hormone stimulates CAMP in UMR 106 cells.The visible Rodan et of this analytical method al (J Clin Invest1983; 72:1511) (Endocrinology 1988 with Rabbani et al; Report 123:2709).After storage 30 months, its biological activity is not seen obvious decline.See Fig. 5.
Show equally that with efficient liquid phase chromatographic analysis its purity is not seen obvious reduction after storage 30 months.See shown in Figure 6.
Can draw thus, according to group human parathyroid hormone (1-84) pharmaceutical composition of component of the present invention and method preparation, the storage life of its active ingredient obviously prolongs, the also corresponding prolongation of the preservation term of the purity of medicine.
Embodiment two:
Preparation 100ml recombinant human parathyroid hormone (1-84) pharmaceutical composition solution
A. prepare mother solution
Volume ratio meter by weight, the mannitol mother solution of preparation 20%, 10% sucrose mother solution and the buffer of 1mM, stand-by;
B. prepare recombinant human parathyroid hormone (1-84) mixed liquor
At 10mg recombinant human parathyroid hormone (1-84) solution, the volume by volume concentration by weight that successively adds 25ml be 20% mannitol mother solution and 10ml by weight volume by volume concentration be 10% sucrose mother solution, regulate the pH value of mixed liquor then with the potassium citrate buffer agent of 1mM, the pH value scope that makes mixed liquor is between 5.0 ± 0.5
C. standardize solution
Adopt high-performance liquid chromatogram determination recombinant human parathyroid hormone (1-84) concentration, and recombinant human parathyroid hormone (1-84) content is 100 μ g/ml in the calibration solution, the final concentration of mannitol volume by volume concentration by weight is 5%, and the final concentration of sucrose is that above-mentioned each liquid of 2% (W/V) all needs aseptic filtration before preparation.
D. lyophilizing
Under aseptic condition, the mixed liquor of above-mentioned standardize solution is installed in the ampere bottle of 3ml sabot lyophilizing then by 1.1ml volume branch with craft or automatic packer.
Using method
During clinical use, draw 1.0ml water for injection or normal saline with syringe and inject the ampere bottle and redissolve, extract liquid out by the using method injection.
Stability test
To be preservation under 2-8 ℃ the condition by the preparation of above-mentioned preparation method preparation in temperature.In 3,6, analyze after 9,12,15,18,21,24,27,30 months.To with the preparation reprovision in the sterilized water of 1.0ml, water be seen through rubber closure inject bottle when doing stability analysis, dissolve medicated powder in 1 minute, extract solution analysis again.
Introduce the result of various stability experiments below successively:
The biological activity analysis of recombinant human parathyroid hormone (1-84) is to analyze the generation that parathyroid hormone stimulates CAMP in the UMR106 cell.The visible Rodan et of this analytical method al (J Clin Invest1983; 72:1511) (Endocrinology 1988 with Rabbani et al; Report 123:2709).After storage 24 months, its biological activity is not seen obvious decline.See Fig. 1.
Show equally that with efficient liquid phase chromatographic analysis its purity is not seen obvious reduction after storage 30 months.
See shown in Figure 2.
Can draw thus, according to group human parathyroid hormone (1-84) pharmaceutical composition of component of the present invention and method preparation, the storage life of its active ingredient obviously prolongs, the also corresponding prolongation of the preservation term of the purity of medicine.
Embodiment three
Preparation 100ml recombinant human parathyroid hormone (1-84) pharmaceutical composition solution
A. prepare mother solution
Volume ratio meter by weight, compound concentration are 20% mannitol mother solution, 10% sucrose mother solution and the buffer of 1mM, and be stand-by;
B. prepare recombinant human parathyroid hormone (1-84) mixed liquor
At 15 mg recombinant human parathyroid hormone (1-84) solution, successively add 25ml concentration and be 20% mannitol mother solution and 10mL concentration and be 10% sucrose mother solution, regulate the pH value of mixed liquor then with the citric acid buffer agent of 1mM, the pH value scope that makes mixed liquor is between 5.0 ± 0.5
C. standardize solution
Adopt high-performance liquid chromatogram determination recombinant human parathyroid hormone (1-84) concentration, and recombinant human parathyroid hormone (1-84) content is 150 μ g/ml in the calibration solution, the final concentration of excipient is 5% (W/V), and the final concentration of sucrose is that above-mentioned each liquid of 3% (W/V) all needs aseptic filtration before preparation.
D. lyophilizing
Install to by 1.1ml volume branch in the ampere bottle of 3ml with craft or the automatic packer mixed liquor with above-mentioned standardize solution under aseptic condition, the sabot lyophilizing installs in the ampere bottle sabot lyophilizing then by dividing as required then.
Using method
During clinical use, draw 1.0ml water for injection or normal saline with syringe and inject the ampere bottle and redissolve, extract liquid out by the using method injection.
Stability test
To be preservation under 2-8 ℃ the condition by the preparation of above-mentioned preparation method preparation in temperature.In 3,6, analyze after 9,12,15,18,21,24,27,30 months.To with the preparation reprovision in the sterilized water of 1.0ml, water be seen through rubber closure inject bottle when doing stability analysis, dissolve medicated powder in 1 minute, extract solution analysis again.
Introduce the result of various stability experiments below successively:
The biological activity analysis of recombinant human parathyroid hormone (1-84) is to analyze the generation that parathyroid hormone stimulates CAMP in the UMR106 cell.The visible Rodan et of this analytical method al (J Clin Invest1983; 72:1511) (Endocrinology 1988 with Rabbani et al; Report 123:2709).After storage 30 months, its biological activity is not seen obvious decline.See Fig. 3.
Show equally that with efficient liquid phase chromatographic analysis its purity is not seen obvious reduction after storage 30 months.
See shown in Figure 4.
Can draw thus, according to group human parathyroid hormone (1-84) pharmaceutical composition of component of the present invention and method preparation, the storage life of its active ingredient obviously prolongs, the also corresponding prolongation of the preservation term of the purity of medicine.
Claims (7)
1. a recombinant human parathyroid hormone (1-84) pharmaceutical composition; it is characterized in that: by the human parathyroid hormone (1-84) of medical science effective dose, excipient, its amount enough the pH value of adjusting preparation make it remain on fixedness buffer agent within the physiology tolerance interval, be used for the active protective agent of protected protein; and the sterilized water composition, active component is recombinant human parathyroid hormone (1-84).
2. a kind of recombinant human parathyroid hormone according to claim 1 (1-84) pharmaceutical composition; it is characterized in that: in every ml recombinant human parathyroid hormone (1-84) pharmaceutical composition solution; the recombinant human parathyroid hormone (1-84) that comprises 50 μ g-150 μ g; the excipient of volume ratio meter 5%, 1-3% protective agent by weight, and in sterilized water, can make the pH value of the pharmaceutical composition solution of reprovision be buffered to the buffer agent of 5.0 ± 0.5 scopes.
3. a kind of recombinant human parathyroid hormone according to claim 1 and 2 (1-84) pharmaceutical composition is characterized in that: described protective agent is a sucrose.
4. recombinant human parathyroid hormone according to claim 1 and 2 (1-84) pharmaceutical composition is characterized in that: wherein said excipient is a mannitol.
5. recombinant human parathyroid hormone according to claim 1 and 2 (1-84) pharmaceutical composition, wherein said fixedness buffer agent is a citrate solution.
6. recombinant human parathyroid hormone according to claim 5 (1-84) pharmaceutical composition, wherein said citrate solution are selected from a kind of in sodium citrate or the potassium citrate.
7. prepare the described preparation of drug combination method of claim 1, it is characterized in that: may further comprise the steps:
A. prepare mother solution
Volume ratio meter by weight, compound concentration are that 20% excipient mother solution, concentration are 10% protective agent mother solution and the buffer of 1mM, and be stand-by;
B. prepare recombinant human parathyroid hormone (1-84) mixed liquor
At every 50-150 μ g recombinant human parathyroid hormone (1-84) solution; successively add 250 μ l, volume ratio meter concentration is 20% excipient mother solution and 100 μ l by weight, volume ratio meter concentration is 10% protective agent mother solution by weight; regulate the pH value of mixed liquor then with the buffer agent of 1mM; the pH value scope that makes mixed liquor is between 5.0 ± 0.5
C. standardize solution
Adopt high-performance liquid chromatogram determination recombinant human parathyroid hormone (1-84) concentration; and recombinant human parathyroid hormone (1-84) content is 50-150 μ g/ml in the calibration solution; the final concentration of excipient volume ratio by weight counts 5%; protectant final concentration volume ratio is by weight counted above-mentioned each liquid of 1-3%, all needs aseptic filtration before preparation.
D. lyophilizing
Under aseptic condition, above-mentioned mixed liquor with standardize solution is installed in the ampere bottle sabot lyophilizing then by dividing as required with craft or automatic packer.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301058A (en) * | 2013-06-17 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Composition for teriparatide injection, and preparation method and preparation thereof |
| CN106309358A (en) * | 2015-06-29 | 2017-01-11 | 成都金凯生物技术有限公司 | Human parathyroid hormone-containing pharmaceutical composition and preparing method and use thereof |
| CN110917150A (en) * | 2019-12-31 | 2020-03-27 | 北京博康健基因科技有限公司 | PTH freeze-dried preparation and preparation method thereof |
| CN112638407A (en) * | 2018-07-30 | 2021-04-09 | 夏尔-Nps医药品有限公司 | Improved stability formulations of recombinant human parathyroid hormone |
-
2007
- 2007-02-02 CN CNB2007100781665A patent/CN100553674C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301058A (en) * | 2013-06-17 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Composition for teriparatide injection, and preparation method and preparation thereof |
| CN106309358A (en) * | 2015-06-29 | 2017-01-11 | 成都金凯生物技术有限公司 | Human parathyroid hormone-containing pharmaceutical composition and preparing method and use thereof |
| CN112638407A (en) * | 2018-07-30 | 2021-04-09 | 夏尔-Nps医药品有限公司 | Improved stability formulations of recombinant human parathyroid hormone |
| CN110917150A (en) * | 2019-12-31 | 2020-03-27 | 北京博康健基因科技有限公司 | PTH freeze-dried preparation and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN100553674C (en) | 2009-10-28 |
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