CN105944084B - Nerve growth factor composition and preparation method thereof - Google Patents
Nerve growth factor composition and preparation method thereof Download PDFInfo
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- 108010025020 Nerve Growth Factor Proteins 0.000 title claims abstract description 59
- 102000015336 Nerve Growth Factor Human genes 0.000 title claims abstract description 56
- 229940053128 nerve growth factor Drugs 0.000 title claims abstract description 56
- 239000000203 mixture Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims description 9
- 238000004108 freeze drying Methods 0.000 claims abstract description 40
- 229940119744 dextran 40 Drugs 0.000 claims abstract description 26
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims abstract description 26
- 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 abstract description 22
- 229930195725 Mannitol Natural products 0.000 claims abstract description 22
- 239000000594 mannitol Substances 0.000 claims abstract description 22
- 235000010355 mannitol Nutrition 0.000 claims abstract description 22
- 102000008100 Human Serum Albumin Human genes 0.000 claims abstract description 18
- 108091006905 Human Serum Albumin Proteins 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000011049 filling Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000005070 sampling Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 241001529936 Murinae Species 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 3
- 239000003998 snake venom Substances 0.000 claims description 3
- 108050009271 Venom nerve growth factor Proteins 0.000 claims description 2
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- 239000000463 material Substances 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 238000000465 moulding Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 102000007072 Nerve Growth Factors Human genes 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
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- 238000003908 quality control method Methods 0.000 description 2
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- 238000013112 stability test Methods 0.000 description 2
- 210000001913 submandibular gland Anatomy 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101001111439 Homo sapiens Beta-nerve growth factor Proteins 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
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- 239000002158 endotoxin Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 230000006870 function Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 102000046917 human NGF Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 230000005709 nerve cell growth Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Neurosurgery (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Psychology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a nerve growth factor composition, which is characterized by comprising nerve growth factor, mannitol, human serum albumin and dextran 40; the nerve growth factor composition provided by the invention has the advantages that the freeze-drying time is shortened, the freeze-drying volume is large, the medicine adsorptivity is good, the nerve growth factor composition can be adsorbed on the bottle wall, and the nerve growth factor composition is not easy to break in the transportation process; on the other hand, the freeze-dried bulk and loose medicine has beautiful appearance, is popular in clinical use, and is beneficial to promoting sales.
Description
Technical Field
The present invention relates to nerve growth factor compositions and methods of making the same.
Background
Nerve Growth Factor (NGF) is the earliest found among neurotrophic factors, and is the most thoroughly studied at present, and has a nerve cell growth regulating factor with the double biological functions of neuronal nutrition and protrusion growth promotion, and has important regulation and control functions on development, differentiation, growth, regeneration and expression of functional characteristics of central and peripheral neurons. Nerve growth factors are mainly distributed in human body in brain, ganglion, iris, heart, spleen, placenta and other tissues, fibroblast, smooth muscle, skeletal muscle, glial cell, schwann cell and the like, other preparation sources are male mouse submandibular gland, bovine seminal plasma, snake venom, guinea pig prostate and the like, wherein the mouse nerve growth factors from the mouse submandibular gland have 90% homology with human NGF.
At present, most nerve growth factor preparations produced and sold at home and abroad are freeze-dried powder, and albumin is used as a stabilizer. The content of albumin in the freeze-dried preparation even exceeds the content of nerve growth factor, and the high albumin content ensures that the freeze-drying step time is long, but simple reduction of the albumin content or improvement of parameter setting of a freeze-drying production machine can lead to unstable product quality and influence on clinical medication safety. In the production process, the nerve growth factor freeze-drying step is found to take a long time, becomes a speed limiting step, reduces the production efficiency, and increases the time cost and the labor cost of production.
Chinese patent ZL 03140732.3 provides a nerve growth factor injection, human serum albumin is removed, and after careful analysis, tween 80 is added as a stabilizer auxiliary material, and an amino acid mixture cannot play a role of a stabilizer. Human serum albumin and tween 80 are common stabilizer auxiliary materials, but the use of tween 80 in injection is limited in China at present due to the high toxicity of tween 80. And disclosed in chinese patent ZL 03140732.3 is an injection rather than a lyophilized formulation.
Therefore, there is a need to develop new nerve growth factor compositions characterized by reduced lyophilization step time and further characterized by reduced amounts of human serum albumin.
Disclosure of Invention
The invention aims to provide a nerve growth factor composition, which is characterized in that the time of a freeze-drying step is shortened.
The invention is realized by using the following technical scheme. The invention provides a nerve growth factor composition, which is characterized by adding dextran 40.
Preferably, a nerve growth factor composition comprises nerve growth factor, mannitol, human serum albumin and dextran 40.
Preferably, the weight ratio of mannitol to dextran 40 is 4:1-1:9.
Preferably, the weight ratio of mannitol to dextran 40 is 4:1-1:1.
Preferably, the weight ratio of mannitol to dextran 40 is 4:1.
A nerve growth factor composition, which comprises 0.3 part of mouse nerve growth factor, 112 parts of mannitol, 28 parts of dextran 40, 7 parts of human serum albumin and a proper amount of pH regulator (by weight).
A nerve growth factor composition is prepared by the following steps: (1) Adding nerve growth factor raw material into mixed solution of human serum albumin, mannitol, dextran 40 and phosphate, adding injectable water to the total amount, and stirring;
(2) Sampling to measure the pH value to be 6.0-8.0;
(3) Sterilizing and filtering the prepared liquid medicine by a microporous filter membrane with the diameter of 0.2 mu m, and then entering a filling room;
(4) And (5) filling by half adding a plug, and freeze-drying.
Preferably, the nerve growth factor composition preparation process step (2) uses 1mol/L HCl solution or 1mol/L NaOH solution to adjust the pH value.
Preferably, the nerve growth factor is selected from the group consisting of murine nerve growth factor, human nerve growth factor, bovine nerve growth factor, snake venom nerve growth factor.
Preferably murine nerve growth factor.
Although there is no provision in the relevant pharmaceutical quality standards for the shaping effect of lyophilized formulations, we have found that for lyophilized formulations the volume size and the degree of bulking after lyophilization can have a significant impact on the pharmaceutical product. On one hand, the freeze-dried medicine has large volume and good loose medicine adsorptivity, can be adsorbed on the bottle wall, and is not easy to break in the transportation process; on the other hand, the freeze-dried bulk and loose medicine has beautiful appearance, is popular in clinical use, and is beneficial to promoting sales.
During the research and development process, the addition of the dextran 40 not only shortens the freeze-drying time, but also reduces the usage amount of human serum albumin on the premise of not affecting the quality of the medicine. The reduction of the amount of human serum albumin is a surprising experimental effect, since the price of dextran 40 is relatively low, which on the one hand reduces the production costs and on the other hand reduces the occurrence of potential adverse reactions caused by human serum albumin. And the addition of dextran 40 does not affect the freeze-drying formation.
Detailed Description
Example 1
(1) Taking mouse nerve growth factor raw material, adding into human serum albumin, excipient and phosphate mixed solution, adding water for injection to the total amount, and stirring uniformly.
(2) The pH value measured by sampling is 6.0-8.0, otherwise, 1mol/L HCl solution or 1mol/L NaOH solution is used for adjusting.
(3) The prepared liquid medicine is sterilized and filtered by a microporous filter membrane with the diameter of 0.2 mu m and enters a filling room.
(4) And (5) filling by half adding a plug, and freeze-drying.
The amounts of the components added, as well as the excipient compositions, were as in table 1.
Table 1: prescription of prescription
Table 2: lyophilization results
| Reconstitution time (seconds) | Freeze drying time hr | Product formability | Clarity of the product | |
| Component 1 | 3 | 20 | Minimum volume, block | Clarifying |
| Component 2 | 1 | 22 | Large and very loose | Clarifying |
| Component 3 | 15 | 28 | The volume is slightly smaller and loose, and the block has cracks | Clarifying |
| Component 4 | 1 | 20 | Small and loose volume | Clarifying |
| Component 5 | 15 | 28 | The volume is slightly smaller and loose, and the block has cracks | Clarifying |
| Component 6 | 15 | 28 | The volume is slightly smaller and loose, and the block has cracks | Clarifying |
As can be seen from table 2, when lactose, mannitol and dextran 40 are used as the freeze-drying auxiliary materials alone, the freeze-drying time of lactose is longest, and the molding effect of the product obtained after freeze-drying is also poor; although the freeze-drying time of the dextran 40 is the shortest, the molding effect of the product obtained after freeze-drying is poor; mannitol has a good molding effect, but the freeze-drying time is longer than that of dextran 40. Based on the result that the three are independently used as the freeze-drying auxiliary materials, the three are mixed two by two, and as can be seen from the table 2, the freeze-drying time can be prolonged by adding lactose, and the defects that the freeze-drying time of mannitol is long and the freeze-drying forming effect of the dextran 40 is poor can be overcome by combining mannitol and the dextran 40. Preferably mannitol and dextran 40 are combined as components of the nerve growth factor composition.
Besides lactose, mannitol and dextran 40, other auxiliary materials such as low endotoxin sorbitol, glycine, tertiary butanol, absolute ethyl alcohol, isopropanol, sucrose and the like are also selected, but the lyophilized preparation has poor stability, long lyophilization time, incapability of being molded and the like, and cannot be used in the nerve growth factor lyophilized preparation.
The above product has a large volume, a slightly smaller volume and a minimum volume in the evaluation of moldability as defined below:
The volume is large: the edge of the nerve growth factor composition obtained after freeze-drying is tightly attached to the bottle wall;
The volume is slightly smaller: most of the edges of the nerve growth factor composition obtained after freeze-drying are adhered to the bottle wall, and macroscopic gaps are formed between the edges of the small parts and the bottle wall;
The volume is the smallest: the nerve growth factor composition obtained after lyophilization had a margin away from the bottle wall or a small amount of contact between the margin of the nerve growth factor composition and the bottle wall.
Example 2
(1) Taking mouse nerve growth factor raw material, adding into human serum albumin, excipient and phosphate mixed solution, adding water for injection to the total amount, and stirring uniformly.
(2) The pH value measured by sampling is 6.0-8.0, otherwise, 1mol/L HCl solution or 1mol/L NaOH solution is used for adjusting.
(3) The prepared liquid medicine is sterilized and filtered by a microporous filter membrane with the diameter of 0.2 mu m and enters a filling room.
(4) And (5) filling by half adding a plug, and freeze-drying.
The amounts of the components added, as well as the excipient compositions, were as per table 3.
Table 3: prescription of prescription
Table 4: lyophilization results
| Reconstitution time (seconds) | Freeze drying time hr | Product formability | Clarity of the product | |
| Component 7 | 1 | 18 | Large and very loose | Clarifying |
| Component 8 | 1 | 18 | Small and loose volume | Clarifying |
| Component 9 | 3 | 18 | Minimum volume, block | Clarifying |
| Component 10 | 1 | 20 | Large and very loose | Clarifying |
As can be seen from table 4, the combination of mannitol and dextran 40 has better lyophilization effect than mannitol alone, specifically, the lyophilization time is shortened, but the lyophilization molding is good. And, when the weight ratio of mannitol and dextran 40 is 4:1, the lyophilization effect is best.
And we have surprisingly found that when the amount of human serum albumin used in example 1 is 1% and the weight ratio of mannitol and dextran 40 in this example is 4:1, the lyophilization effect of nerve growth factor is not affected as compared with the result in example 1 when the amount of human serum albumin used is reduced to 0.1%.
Example 3
(1) Taking mouse nerve growth factor raw material, adding into human serum albumin, mannitol, dextran-40 and phosphate mixed solution, adding water for injection to the total amount, and stirring uniformly.
(2) The pH value measured by sampling is 6.0-8.0, otherwise, 1mol/L HCl solution or 1mol/L NaOH solution is used for adjusting.
(3) The prepared liquid medicine is sterilized and filtered by a microporous filter membrane with the diameter of 0.2 mu m and enters a filling room.
(4) And (5) filling by half adding a plug, and freeze-drying.
(5) Pressing, discharging from the box, capping, checking with eyes, labeling, and packaging to obtain the nerve growth factor composition.
The addition amounts of the respective components were carried out in accordance with table 5.
Table 5: prescription of prescription
Example 4
The nerve growth factor composition in example 3 was prepared as lot numbers S20100101, S20100102, and S20100103, respectively.
The stability test is carried out according to the Chinese pharmacopoeia, the experimental conditions are referred to the requirements of the Chinese pharmacopoeia, the test results (the conditions are 25+/-2 ℃ and 60+/-5% RH) of the mouse nerve growth factor for injection are accelerated, and the experimental results are as follows.
Table 6: stability investigation experiment results
From the stability test examination result table 6, it is seen that the ratio of mannitol to dextran 40 is 4:1, and the stability of the nerve growth factor composition obtained by freeze-drying after reducing the usage amount of human serum albumin meets the requirement of quality control. When the proportion of mannitol and dextran 40 is 4:1, the freeze-drying time is shortened, but the quality of the obtained product can still meet the quality control requirement, and the method has obvious progress.
Claims (5)
1. A nerve growth factor composition, comprising the following components: 0.3 part of nerve growth factor, 112 parts of mannitol, 28 parts of dextran 40, 7 parts of human serum albumin and a proper amount of pH regulator (by weight), and the water for injection is added to 7000 parts.
2. The nerve growth factor composition of claim 1, wherein the process for preparing the same comprises the steps of:
(1) Adding nerve growth factor raw material into mixed solution of human serum albumin, mannitol, dextran 40 and phosphate, adding injectable water to the total amount, and stirring;
(2) Sampling to measure the pH value to be 6.0-8.0;
(3) Sterilizing and filtering the prepared liquid medicine by a microporous filter membrane with the diameter of 0.2 mu m, and then entering a filling room;
(4) And (5) filling by half adding a plug, and freeze-drying.
3. The nerve growth factor composition of claim 2, wherein the preparation process step (2) uses 1mol/L HCl solution or 1mol/L NaOH solution to adjust the pH.
4. The nerve growth factor composition of claim 1, wherein the nerve growth factor is selected from the group consisting of murine nerve growth factor, human nerve growth factor, bovine nerve growth factor, snake venom nerve growth factor.
5. The nerve growth factor composition of claim 4, wherein the nerve growth factor is a murine nerve growth factor.
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| CN105944084B true CN105944084B (en) | 2024-05-03 |
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| CN1394648A (en) * | 2002-04-30 | 2003-02-05 | 长春长生基因药业股份有限公司 | Recombinant basic fibroblast growth factor protection agent |
| CN1878794A (en) * | 2002-10-08 | 2006-12-13 | 里纳特神经系统学公司 | NGF antagonist and opioid analgesic use in pain treatment |
| CN101613394A (en) * | 2008-06-27 | 2009-12-30 | 熊玲媛 | The preparation method of the preparation method of mouse nerve growth factor and injection mouse nerve growth factor |
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1394648A (en) * | 2002-04-30 | 2003-02-05 | 长春长生基因药业股份有限公司 | Recombinant basic fibroblast growth factor protection agent |
| CN1878794A (en) * | 2002-10-08 | 2006-12-13 | 里纳特神经系统学公司 | NGF antagonist and opioid analgesic use in pain treatment |
| CN101613394A (en) * | 2008-06-27 | 2009-12-30 | 熊玲媛 | The preparation method of the preparation method of mouse nerve growth factor and injection mouse nerve growth factor |
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