CN1318087C - Removing albumin nerve growth factor agent - Google Patents
Removing albumin nerve growth factor agent Download PDFInfo
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- CN1318087C CN1318087C CNB031407323A CN03140732A CN1318087C CN 1318087 C CN1318087 C CN 1318087C CN B031407323 A CNB031407323 A CN B031407323A CN 03140732 A CN03140732 A CN 03140732A CN 1318087 C CN1318087 C CN 1318087C
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- Prior art keywords
- growth factor
- nerve growth
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- injection
- stabilizing agent
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- 108010025020 Nerve Growth Factor Proteins 0.000 title claims abstract description 106
- 102000015336 Nerve Growth Factor Human genes 0.000 title claims abstract description 102
- 229940053128 nerve growth factor Drugs 0.000 title claims abstract description 102
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- 108010088751 Albumins Proteins 0.000 title claims abstract description 27
- 239000003795 chemical substances by application Substances 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 69
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 21
- 239000000843 powder Substances 0.000 claims description 19
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 18
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
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- 235000010355 mannitol Nutrition 0.000 claims description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 6
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- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- JZDHUJAFXGNDSB-UHFFFAOYSA-N glutamylalanine Chemical compound OC(=O)C(C)NC(=O)C(N)CCC(O)=O JZDHUJAFXGNDSB-UHFFFAOYSA-N 0.000 claims description 3
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- Medicinal Preparation (AREA)
Abstract
The present invention discloses a removing albumin nerve growth factor agent which basically comprises the following components: a, effective dose of nerve growth factors (NGF), b, isotonic agents, c, buffer solutions maintaining the pH value of the preparation at 5.0 to 8.5, d, stabilizing agents of amino acid or the mixture of the amino acid and non-ionic surface active agents, and e, water for injection. The present invention uses the amino acid or the mixture of the amino acid and the non-ionic surface active agents as stabilizing agents, which makes the NGF preparation capable of being made into freeze-drying agents and aqueous agents with convenient operation, effectively avoids blood product pollution caused by human serum albumin, solves the problem of NGF quantification and reduces production cost. The contrast experiment with the existing product proves that the stabilizing agents selected by the present invention can reach the same stabilizing effect with the prior art and replace the human serum albumin.
Description
Technical field
The present invention relates to albumin nerve growth factor preparation, belong to field of biological pharmacy.
Background technology
Nerve growth factor (NGF) is one of topmost active component of nervous system; it can keep the existence of sympathetic nerve and sensory neurone; influence the survival of axoneuron, promote the differentiation of neurocyte, the normal function of neuroprotective system is had important function.
At present, the various NGF preparations of producing and selling are the freeze-dried powder dosage form both at home and abroad, and end user's serum albumin is as stabilizing agent.The human serum albumin obtains by extracting in human blood, the placental blood, and the people is not had interindividual variation, can not cause allergic immune reaction between individuality, is applied to biological product production.Yet, in production and use, exist more following problems:
At first; the human serum albumin can affine virus have immunogenic glycoprotein part; make it leave host cell or virion and be cracked into sheet and have no progeny and further do not degraded, thereby kept viral immunogenicity, therefore be widely used as the protective agent of virus for a long time in virus.Because this specific character, some human serum albumins that carry the virus that derives from the difficult detection in blood donor's blood bring pollution can for the preparation of producing, and cause serious infectious disease in patient's medication, as acquired immune deficiency syndrome (AIDS), hepatitis etc.Given this kind problem happens occasionally, and the insider generally recognizes real necessity that the stabilizing agent of seeking a kind of alternative human serum albumin is arranged.
Secondly, because the content lower (4～30 μ g/ml) of NGF in the preparation, and human serum albumin and NGF are protein, and its concentration in preparation is difficult to accurately determine the content of effective ingredient NGF apparently higher than NGF when causing the product calibrating, be unfavorable for control of product quality; Be usually used in the method for protein content determination in the biological product such as Lowry method, ultraviolet absorption method, Bradford method etc. at present and all can not effectively get rid of this interference.
Three, the human serum albumin source is very limited, generally only is used for clinical raising critical patient nutrition mechanism, keeps colloidal osmotic pressure, shock, transportation and Detoxication, uses this kind stabilizing agent will increase production cost.
Summary of the invention
The purpose of this invention is to provide a kind of nerve growth factor preparation that does not contain human serum albumin's stabilizing agent.
For achieving the above object, the present invention is by the following technical solutions:
Remove albumin nerve growth factor preparation, it consists essentially of following composition:
A. the nerve growth factor of effective dose (NGF);
B. isotonic agent;
C. keep the preparation pH value and be 5.0～8.5 buffer;
D. as the aminoacid of stabilizing agent or the mixture of aminoacid and non-ionic surface active agent;
E. water for injection.
Described isotonic agent is a sodium chloride, is used to keep fluid tension, keeps the isotonicity of preparation, and its dosage is 8.5mg/ml most preferably.
Be applicable to that buffer of the present invention is any buffer of 5.0～8.5 for keeping preparation pH value under aqueous solution state, as phosphate buffer and citrate buffer solution.The preferred buffer of the present invention is a phosphate buffer, and pH value is preferred 6.5～7.5, most preferably 6.8～7.2, because the pH value scope is consistent with the pH value of human body fluid, can effectively avoid the medication zest.
The mixture that innovation part of the present invention is to use aminoacid or aminoacid and non-ionic surface active agent substitutes the human serum albumin as stabilizing agent.Aminoacid in the stabilizing agent can strengthen the tension force between protein and the water, improves the protein hydration level, alleviates machine circle shearing force to proteinic damage, impels effective ingredient to form crystallization in freeze-drying process, reduces proteinic polymerization in freeze-drying process; Prevent that freeze dried substance from distillation and dry run disintegrate taking place, make lyophilized protein form bigger surface area, quicken dry run.Non-ionic surface active agent in the stabilizing agent can be kept proteinic helical structure, prevents protein polymerization in solution, stop the adhesion at vessel surface of protein and peptide material.
Described aminoacid as stabilizing agent is selected from several in alanine, aspartic acid, arginine, glycine, NSC 334200, lysine and the histidine, and the parts by weight of each seed amino acid in mixture are identical.The preferred mixture of being made up of alanine, glycine and arginine, alanine, glycine and the arginine ratio of weight and number in mixture is 1: 1: 0.5～1: 1: 3.
Described non-ionic surface active agent as stabilizing agent is selected from Tween-20 (tween 20), Tween-80 (tween 80) and F-68, preferred tween 80, and its dosage is 0.001～0.1%, and is preferred 0.005～0.05%, most preferably 0.008～0.03%.
The present invention can obtain optimum efficiency with the mixture of alanine, glycine, arginine and tween 80 as stabilizing agent, and the dosage of stabilizing agent is 1～20mg/ml, preferred 8～13mg/ml.
Preparation of the present invention can be made aqueous injection, comprises following composition:
A.4～500 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.0～8.0 phosphate buffer;
D.1～the 20mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Preparation of the present invention can be lyophilized injectable powder, and it also contains the biological acceptable extender of, and it comprises following composition:
A.4～500 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.0～8.0 phosphate buffer;
D.1～the 20mg/ml stabilizing agent;
E.6% mannitol;
F. the preceding solution total amount of lyophilizing adds to the water for injection of 0.66ml.
Beneficial effect of the present invention is: the present invention selects for use aminoacid or aminoacid and non-ionic surface active agent as stabilizing agent, make the NGF preparation can not only make lyophilized preparation and can also be prepared into water preparation easy to use, the blood product pollution of effectively having avoided the human serum albumin to cause, solve the quantitative difficult problem of NGF, and reduced production cost; Experiment showed, that by comparing the stabilizing agent that the present invention selects for use can reach stablizing effect same as the prior art, can replace the human serum albumin fully with existing product.
Being described further below in conjunction with preferred embodiment, is not the qualification to embodiment of the present invention.
The specific embodiment
Embodiment 1, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.4 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.8 phosphate buffer;
D.1.0mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of weight and number is 1: 1: 0.5.
Solution is behind 0.22 μ m membrane filtration, and is aseptic subpackaged.With aqueous injection place that humidity is 92%, temperature is incubator preserve separately 0 day, 5 days, 15 days, 20 days, January, February of 40 ℃, adopt then chicken dorsal ganglion method detect NGF biological activity, use pH meter to detect the injection pH value, detect aseptic situation and observe the transparency of solution according to method described in " Chinese biological goods rules 2000 editions ".As a result, the specific activity of the NGF of each time point be 4545,4545,3000,3000,1500,1500BU/ml (labelled amount: 3000BU/ml).The pH value of injection does not change during this period, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 2, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.10 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.5 phosphate buffer;
D.5.0mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of component is 1: 1: 1.
Injection storage condition and time are with embodiment 1.NGF is respectively 4545,4545,4545,3000,3000 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 3, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.15 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.10mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of weight and number is 1: 1: 1.
Injection storage condition and time are with embodiment 1.NGF is respectively 4545,4545,4545,4545,3000 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 4, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.20 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.10mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of weight and number is 1: 1: 1.
Injection storage condition and time are with embodiment 1.NGF is respectively 4545,4545,4545,4545,3000 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 5, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.10mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and non-ionic surface active agent (tween 80), and the ratio of weight and number of three seed amino acids is 1: 1: 1; The concentration of tween 80 is 0.03%.
Injection storage condition and time are with embodiment 1.NGF is respectively 13636,4545,4545,4545,4545 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 6, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.20mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and non-ionic surface active agent (tween 80), and the ratio of weight and number of three seed amino acids is 1: 1: 1; The concentration of tween 80 is 0.01%.
Injection storage condition and time are with embodiment 1.NGF is respectively 13636,13636,4545,4545,4545 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 7, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.20mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine, histidine, lysine, NSC 334200 and non-ionic surface active agent (tween 80), and each amino acid whose parts by weight is identical; The concentration of tween 80 is 0.01%.
Injection storage condition and time are with embodiment 1.NGF is respectively 13636,13636,4545,4545,4545 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 8, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.20mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80, and the ratio of weight and number of three seed amino acids is 1: 1: 1; The concentration of tween 80 is 0.005%.
Injection storage condition and time are with embodiment 1.NGF is respectively 13636,4545,4545,4545,4545 in the specific activity of each time point, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 9, remove albumin nerve growth factor aqueous injection
Pharmaceutical formulation:
A.100 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.20mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80, and the ratio of weight and number of three seed amino acids is 1: 1: 1; The concentration of tween 80 is 0.01%.
Injection storage condition and time are with embodiment 1.NGF is respectively 13636,13636,13636,4545,4545 in the specific activity of each time point, 3000BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative, and it is transparent that liquid keeps.
Embodiment 10, remove albumin nerve growth factor lyophilized injectable powder
A.4 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keeping the preparation pH value is 6.0 phosphate buffers;
D.1.0mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine, and three seed amino acid ratios of weight and number are 1: 1: 2.
Solution adopts the lyophilizing of frozen drying method behind 0.22 μ m membrane filtration.Earlier freeze dryer, freeze drying box temperature are reduced to-45 ℃, sample were put into pre-freeze 2 hours again, start vacuum pump, treat that vacuum reaches certain numerical value after, slowly open valve, close fridge, slowly be warming up to-25 ℃, treat water evaporates intact back intensification, in the time of 25 ℃, change drying again over to, capping then.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 4545,4545,4545,4545,4545 in the specific activity of each time point NGF, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 11, remove albumin nerve growth factor lyophilized injectable powder
A.10 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.5 phosphate buffer;
D.5.0mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of weight and number is 1: 1: 1.
Injection storage condition and time and preparation technology are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting the described method of EXAMPLE l to detect the activity of NGF, the result is respectively 4545,4545,4545,4545,4545 in the specific activity of each time point NGF, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 12, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.15 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.10mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of weight and number is 1: 1: 1.
Injection storage condition and time and preparation technology are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 4545,4545,4545,4545,4545 in the specific activity of each time point NGF, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 13, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.20 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.10mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine and glycine, and three's ratio of component is 1: 1: 1.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 4545,4545,4545,4545,4545 in the specific activity of each time point NGF, 1500BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 14, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.20mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80, and the ratio of component of three seed amino acids is 1: 1: 1; The concentration of tween 80 is 0.03%.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 13636,13636,13636,4545,4545 in the specific activity of each time point NGF, 3000BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 15, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.0 phosphate buffer;
D.20mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80 for stabilizing agent wherein, and the ratio of component of three seed amino acids is 1: 1: 2; The concentration of tween 80 is 0.01%.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 13636,13636,4545,4545,4545 in the specific activity of each time point NGF, 3000BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 16, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.30 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.20mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80, and the ratio of component of three seed amino acids is 1: 1: 2; The concentration of tween 80 is 0.005%.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 13636,13636,4545,4545,4545 in the specific activity of each time point NGF, 3000BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 17, remove albumin nerve growth factor lyophilized injectable powder
Pharmaceutical formulation:
A.100 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 7.4 phosphate buffer;
D.20mg/ml stabilizing agent;
E.60mg/ml mannitol;
F. the solution total amount adds to the water for injection of 0.66ml.
Wherein stabilizing agent is alanine, arginine, glycine and tween 80, and the ratio of component of three seed amino acids is 1: 1: 1; The concentration of non-ionic surface active agent is 0.01%.
Injection storage condition and time are with embodiment 1.Dissolve the powder pin in each time point with 0.66ml water for injection, and adopting embodiment 1 described method to detect the activity of NGF, the result is respectively 13636,13636,13636,4545,4545 in the specific activity of each time point NGF, 3000BU/ml (labelled amount: 3000BU/ml).PH value of injection does not change during this, and Bacteria Detection is negative.
Embodiment 18, embodiment 7 and embodiment 14 pharmaceutical formulations and existing albumin NGF prescription biological activity are relatively
By the foregoing description as can be known, the dosage performance of the stabilizing agent that embodiment 7 and embodiment 14 are selected is than best, so select for use itself and the existing albumin preparation that contains to make stability and compare (injection storage condition and time are with embodiment 1), result such as following table:
Table 1. embodiment 7,14 preparations contain albumin preparation stability relatively with existing
| The prescription title | Different time points is surveyed slip-knot fruit (BU/ml) | |||||
| 0 day | 5 days | 15 days | 20 days | January | February | |
| Embodiment 7 | 13636 | 4545 | 4545 | 4545 | 4545 | 3000 |
| Embodiment 14 | 13636 | 13636 | 4545 | 4545 | 4545 | 3000 |
| Existing preparation | 13636 | 13636 | 4545 | 4545 | 4545 | 3000 |
The present invention selects for use aminoacid or aminoacid and non-ionic surface active agent as stabilizing agent, make the NGF preparation can not only make lyophilized preparation and can also be prepared into water preparation easy to use, the blood product pollution of effectively having avoided the human serum albumin to cause, solve the quantitative difficult problem of NGF, and reduced production cost; Experiment showed, that by comparing the stabilizing agent that the present invention selects for use can reach stablizing effect same as the prior art, can replace the human serum albumin fully with existing product.
Claims (17)
1, remove albumin nerve growth factor preparation, it is characterized in that it consists essentially of following composition:
A.4～500 μ g/ml nerve growth factor;
B. isotonic agent;
C. keep the preparation pH value and be 5.0～8.5 buffer;
D. as the aminoacid of stabilizing agent or the mixture of aminoacid and non-ionic surface active agent;
E. water for injection;
Wherein be selected from alanine, arginine, glycine, NSC 334200, lysine and the histidine three kinds or six kinds as the aminoacid of stabilizing agent.
2, nerve growth factor preparation according to claim 1 is characterized in that: described isotonic agent is a sodium chloride.
3, nerve growth factor preparation according to claim 2 is characterized in that: the dosage of described sodium chloride is 8.5mg/ml.
4, nerve growth factor preparation according to claim 1 is characterized in that: described buffer is that to keep the preparation pH value be 5.0～8.5 phosphate buffer.
5, nerve growth factor preparation according to claim 4 is characterized in that: described pH value preferred 6.5～7.5.
6, nerve growth factor preparation according to claim 5 is characterized in that: described pH value most preferably 6.8～7.2.
7, nerve growth factor preparation according to claim 1 is characterized in that: described aminoacid as stabilizing agent is alanine, glycine and arginic mixture.
8, nerve growth factor preparation according to claim 7 is characterized in that: described alanine, glycine and the arginine ratio of weight and number in mixture is 1: 1: 0.5～1: 1: 3.
9, nerve growth factor preparation according to claim 1 is characterized in that: described non-ionic surface active agent as stabilizing agent is selected from Tween-20 (tween 20), Tween-80 (tween 80) and F-68.
10, nerve growth factor preparation according to claim 9 is characterized in that: the dosage of described non-ionic surface active agent is 0.001～0.1%.
11, according to the described nerve growth factor preparation of claim 10, it is characterized in that: the dosage of described non-ionic surface active agent preferred 0.005～0.05%.
12, according to the described nerve growth factor preparation of claim 11, it is characterized in that: the dosage of described non-ionic surface active agent most preferably 0.008～0.03%.
13, nerve growth factor preparation according to claim 1 is characterized in that: the dosage of described stabilizing agent is 1～20mg/ml.
14, nerve growth factor preparation according to claim 13 is characterized in that: the preferred 8～13mg/ml of the dosage of described stabilizing agent.
15, according to any one described nerve growth factor preparation in the claim 1 to 14, it is characterized in that said preparation is an aqueous injection, comprises following composition:
A.4～500 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.8～7.2 phosphate buffer;
D.8～the 13mg/ml stabilizing agent;
E. the solution total amount adds to the water for injection of 0.66ml.
16, any one described nerve growth factor preparation of claim 1 to 14 is made lyophilized injectable powder, it is characterized in that: described preparation also contains the biological acceptable extender of.
17, nerve growth factor preparation according to claim 16 is characterized in that it comprises following composition:
A.4～500 the nerve growth factor of μ g/ml;
B.8.5mg/ml sodium chloride;
C. keep the preparation pH value and be 6.8～7.2 phosphate buffer;
D.8～the 13mg/ml stabilizing agent;
E.6% mannitol;
F. the preceding solution total amount of lyophilizing adds to the water for injection of 0.66ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031407323A CN1318087C (en) | 2003-06-06 | 2003-06-06 | Removing albumin nerve growth factor agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031407323A CN1318087C (en) | 2003-06-06 | 2003-06-06 | Removing albumin nerve growth factor agent |
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| CN1552440A CN1552440A (en) | 2004-12-08 |
| CN1318087C true CN1318087C (en) | 2007-05-30 |
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|---|---|---|---|
| CNB031407323A Expired - Lifetime CN1318087C (en) | 2003-06-06 | 2003-06-06 | Removing albumin nerve growth factor agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105521483A (en) * | 2014-09-30 | 2016-04-27 | 陕西艾美雅生物科技有限公司 | Composite bioactive factor freeze-drying method and composite bioactive factor freeze-dried powder |
| EP3287140B1 (en) * | 2015-04-21 | 2021-06-02 | Staidson (Beijing) Biopharmaceuticals Co., Ltd. | Nerve growth factor composition and powder injection |
| WO2016169453A1 (en) * | 2015-04-21 | 2016-10-27 | 舒泰神（北京）生物制药股份有限公司 | Nerve growth factor composition and powder injection |
| WO2016169455A1 (en) * | 2015-04-21 | 2016-10-27 | 舒泰神（北京）生物制药股份有限公司 | Nerve growth factor composition and powder injection |
| CN109260147B (en) * | 2018-10-15 | 2019-09-13 | 珠海亿胜生物制药有限公司 | It is a kind of for treating or preventing the recombination human basic fibroblast growth factor injection of neurotrosis |
| CN114177273B (en) * | 2021-11-29 | 2024-05-28 | 苏州人本药业有限公司 | Liquid preparation containing neurotoxin and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0551325A (en) * | 1991-04-19 | 1993-03-02 | Morinaga Milk Ind Co Ltd | Agent for promoting production of nerve growth factor |
| CN1133012A (en) * | 1993-08-20 | 1996-10-09 | 辛泰克斯（美国）公司 | Pharmaceutical formulations of nerve growth factor |
| CN1201394A (en) * | 1995-11-07 | 1998-12-09 | 基因技术股份有限公司 | Stabilized formulation of NGF |
| CN1245434A (en) * | 1996-12-24 | 2000-02-23 | 拜奥根有限公司 | Stable liquid interferon formulations |
-
2003
- 2003-06-06 CN CNB031407323A patent/CN1318087C/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0551325A (en) * | 1991-04-19 | 1993-03-02 | Morinaga Milk Ind Co Ltd | Agent for promoting production of nerve growth factor |
| CN1133012A (en) * | 1993-08-20 | 1996-10-09 | 辛泰克斯（美国）公司 | Pharmaceutical formulations of nerve growth factor |
| CN1201394A (en) * | 1995-11-07 | 1998-12-09 | 基因技术股份有限公司 | Stabilized formulation of NGF |
| CN1245434A (en) * | 1996-12-24 | 2000-02-23 | 拜奥根有限公司 | Stable liquid interferon formulations |
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| CN1552440A (en) | 2004-12-08 |
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