CN105944084A - Nerve growth factor composition and preparation method thereof - Google Patents
Nerve growth factor composition and preparation method thereof Download PDFInfo
- Publication number
- CN105944084A CN105944084A CN201610349227.6A CN201610349227A CN105944084A CN 105944084 A CN105944084 A CN 105944084A CN 201610349227 A CN201610349227 A CN 201610349227A CN 105944084 A CN105944084 A CN 105944084A
- Authority
- CN
- China
- Prior art keywords
- growth factor
- nerve growth
- dextran
- composition
- mannitol
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
Abstract
The invention provides a nerve growth factor composition. The nerve growth factor composition is characterized by comprising a nerve growth factor, mannitol, human serum albumin and dextran. The time of the freeze-drying step of the nerve growth factor composition provided by the invention is shortened, freeze-drying size is large, and loose medicines are good in adsorptivity, can be adsorbed on a bottle wall, and cannot be broken easily in a transformation process; and on the other hand, the freeze-drying size is large, the loose medicines are attractive in appearance, and are welcome when used clinically, and sale is promoted.
Description
Technical field
The present invention relates to nerve growth factor composition and preparation method thereof.
Background technology
Nerve growth factor (NGF) is to be found the earliest in neurotrophic factor, and research is the most thorough at present, has neurotrophic and promotees projection
Growth double biological function a kind of nerve growth regulatory factor, it to maincenter and peripheral nerve unit growth, break up, grow, regenerate and
The expression of functional characteristic is respectively provided with important regulating and controlling effect.Nerve growth factor be distributed mainly in human body brain, neuroganglion, iris, heart, spleen,
Placenta Hominis etc. tissue and fibroblast, smooth muscle, skeletal muscle, glial cell, Schwann cell etc., other prepare source have male mice submaxillary gland,
Cattle refining, snake venom, Cavia porcellus prostate etc., wherein the mouse nerve growth factor of derived mice submaxillary gland and mankind NGF have 90% homology.
At present, the nerve growth factor preparation major part produced and sold both at home and abroad is lyophilized powder, and many use albumin are as stabilizer.Albumin exists
Content in lyophilized formulations has been even more than the content of nerve growth factor, and high albumin content makes the step of freeze drying time long, but simply reduces
Albumin content or improvement lyophilizing produce the parameter of machine and arrange, and can cause unstable product quality, affect clinical drug safety.In production process
In, it has been found that it is long that nerve growth factor step of freeze drying expends the time, becomes rate-limiting step, reduces production efficiency, increases the time cost produced
And human cost.
Chinese patent ZL 03140732.3 provides a kind of nerve growth factor injection, removes human albumin, through carefully analyzing, and Qi Zhongjia
Entered Tween 80 as stabilizer adjuvant, ispol can not play the effect of stabilizer.Human albumin and Tween 80 are all conventional
Stabilizer adjuvant, but owing to the toxicity of Tween 80 is relatively big, present China has limited Tween 80 use in injection.And China
Disclosed in patent ZL 03140732.3 is injection rather than lyophilized formulations.
Accordingly, it would be desirable to the new a kind of nerve growth factor composition of research and development, it is characterised in that the step of freeze drying time shortens, and further it is characterized in that
Reduce the usage amount of human albumin.
Summary of the invention
It is an object of the invention to, it is provided that a kind of nerve growth factor composition, it is characterised in that the step of freeze drying time shortens.
The present invention uses techniques below scheme to realize.The present invention provides a kind of nerve growth factor composition, it is characterised in that add dextran
40。
Preferably, a kind of nerve growth factor composition, its component includes nerve growth factor, mannitol, human albumin and Dextran 40.
Preferably, described mannitol is 4: 1-1: 9 with the part by weight of Dextran 40.
Preferably, described mannitol is 4: 1-1: 1 with the part by weight of Dextran 40.
Preferably, described mannitol is 4: 1 with the part by weight of Dextran 40.
A kind of nerve growth factor composition, its component include 0.3 part of mouse nerve growth factor, 112 portions of mannitol, 28 parts of Dextran 40s, 7
Divide human albumin and qs pH adjuster (by weight).
A kind of nerve growth factor composition, preparation technology is: (1) takes nerve growth factor raw material, joins human albumin, mannitol, the right side
In rotation sugar acid anhydride 40 and phosphate mixed liquor, mend and inject water to prepare total amount, stir；
(2) sampling is surveyed pH value and be should be 6.0～8.0；
(3) medicinal liquid prepared enters bottling department through 0.2 μm microporous filter membrane aseptic filtration；
(4) partly jump a queue fill, lyophilizing.
Preferably, described nerve growth factor composition step of preparation process (2), regulate by 1mol/L HCl solution or 1mol/L NaOH solution
PH value.
Preferably, described nerve growth factor is selected from mouse nerve growth factor, growth factor of human nerve, cattle nerve growth factor, snake venom nerve growth
The factor.
It is preferably mouse nerve growth factor.
Although not about the regulation of lyophilized formulations molding effect in relevant drug standard, but it have been found that for lyophilized formulations, after lyophilizing
Medicine can be caused important impact by volume size and porousness.On the one hand, the medicine excellent adsorption that lyophilizing volume is big and loose, can adsorb
On bottle wall, transportation is not easy crush；On the other hand, the medicine profile that lyophilizing volume is big and loose is beautiful, compares by joyous during Clinical practice
Meet, may advantageously facilitate sale.
We find in R&D process, and the addition of Dextran 40 is possible not only to shorten freeze-drying time, and is not affecting the premise of drug quality
Under, reduce the usage amount of human albumin.The reduction of human albumin's usage amount, because the price comparison of Dextran 40 is cheap, on the one hand can
To reduce production cost, on the other hand can also reduce the incidence rate of the potential adverse effect that human albumin causes, be surprising experiment effect.And
And the addition of Dextran 40 can't affect lyophilizing molding effect.
Detailed description of the invention
Embodiment 1
(1) take mouse nerve growth factor raw material, join in human albumin, excipient and phosphate mixed liquor, mend and inject water to preparation
Total amount, stirs.
(2) sampling is surveyed pH value and be should be 6.0～8.0, otherwise with 1mol/L HCl solution or the regulation of 1mol/L NaOH solution.
(3) medicinal liquid prepared enters bottling department through 0.2 μm microporous filter membrane aseptic filtration.
(4) partly jump a queue fill, lyophilizing.
The addition of each component, and excipient composition carry out according to form 1.
Form 1: prescription
Form 2: lyophilizing result
| The redissolution time (second) | Freeze-drying time hr | Formed product | Clarity | |
| Component 1 | 3 | 20 | Volume is minimum, block | Clarification |
| Component 2 | 1 | 22 | Volume greatly, the most loose | Clarification |
| Component 3 | 15 | 28 | Volume is smaller, loose, and block has slight crack | Clarification |
| Component 4 | 1 | 20 | Volume is smaller, loose | Clarification |
| Component 5 | 15 | 28 | Volume is smaller, loose, and block has slight crack | Clarification |
| Component 6 | 15 | 28 | Volume is smaller, loose, and block has slight crack | Clarification |
During by form 2 it can be seen that lactose, mannitol and Dextran 40 are separately as lyophilizing adjuvant, the freeze-drying time of lactose is the longest, and
The formed product effect obtained after lyophilizing is the most bad；Although the freeze-drying time of Dextran 40 is the shortest, but the formed product effect obtained after lyophilizing
Bad；Though the molding effect of mannitol is good, but freeze-drying time is longer than Dextran 40.Based on three separately as the result of lyophilizing adjuvant, I
Three is mixed two-by-two, it will be seen that the addition of lactose all can lengthen freeze-drying time from form 2, and mannitol and Dextran 40 combination
The freeze-drying time that can overcome mannitol is long, and the defect that Dextran 40 lyophilizing molding effect is bad.Preferably mannitol and Dextran 40 group
Cooperation is the component of nerve growth factor composition.
In addition to lactose, mannitol and Dextran 40, we have also screened other adjuvant such as low endotoxin sorbitol, glycine, tertiary fourth
Alcohol, dehydrated alcohol, isopropanol, sucrose etc., but due to lyophilized formulations poor stability, freeze-drying time are long and cannot the problem such as molding, all cannot
In nerve growth factor lyophilized formulations.
Volume in the evaluation of above formed product is big, volume is smaller, volume minimal definition is as follows:
Volume is big: a bottle wall is close at the nerve growth factor composition edge obtained after lyophilizing；
Volume is smaller: the nerve growth factor composition edge major part patch bottle wall obtained after lyophilizing, has naked eyes visible between fraction edge and bottle wall
Gap；
Volume is minimum: the nerve growth factor composition edge obtained after lyophilizing is away from bottle wall, or the most least a portion of nerve growth factor composition limit
Have between rim edge with bottle wall and contact on a small quantity.
Embodiment 2
(1) take mouse nerve growth factor raw material, join in human albumin, excipient and phosphate mixed liquor, mend and inject water to preparation
Total amount, stirs.
(2) sampling is surveyed pH value and be should be 6.0～8.0, otherwise with 1mol/L HCl solution or the regulation of 1mol/L NaOH solution.
(3) medicinal liquid prepared enters bottling department through 0.2 μm microporous filter membrane aseptic filtration.
(4) partly jump a queue fill, lyophilizing.
The addition of each component, and excipient composition carry out according to form 3.
Form 3: prescription
Form 4: lyophilizing result
| The redissolution time (second) | Freeze-drying time hr | Formed product | Clarity | |
| Component 7 | 1 | 18 | Volume greatly, the most loose | Clarification |
| Component 8 | 1 | 18 | Volume is smaller, loose | Clarification |
| Component 9 | 3 | 18 | Volume is minimum, block | Clarification |
| Component 10 | 1 | 20 | Volume greatly, the most loose | Clarification |
As can be seen from Table 4, the combination of mannitol and Dextran 40 is better than the effect that mannitol is used alone, specially freeze-drying time quilt
Shorten, but lyophilizing forming.Further, when the part by weight of mannitol and Dextran 40 is 4: 1, effect is best.
And the discovery that we are pleasantly surprised, the usage amount of human albumin is 1% in embodiment 1, and mannitol and dextran in the present embodiment
When the part by weight of 40 is 4: 1, when the usage amount of human albumin is reduced to 0.1%, compared with the result in embodiment 1, nerve growth factor
The effect of son is unaffected.
Embodiment 3
(1) take mouse nerve growth factor raw material, join in human albumin, mannitol, dextran-40 and phosphate mixed liquor, add
Water for injection, to preparing total amount, stirs.
(2) sampling is surveyed pH value and be should be 6.0～8.0, otherwise with 1mol/L HCl solution or the regulation of 1mol/L NaOH solution.
(3) medicinal liquid prepared enters bottling department through 0.2 μm microporous filter membrane aseptic filtration.
(4) partly jump a queue fill, lyophilizing.
(5) tamponade, outlet, roll lid, visual inspection, labeling, packaging, prepare nerve growth factor composition.
The addition of each component is carried out according to form 5.
Form 5: prescription
Embodiment 4
Nerve growth factor composition in Example 3, lot number is respectively S20100101, S20100102, S20100103.
Carrying out steady testing according to Chinese Pharmacopoeia, experiment condition sees Chinese Pharmacopoeia requirement, injection mouse nerve growth factor accelerated test result (bar
Part: 25 ± 2 DEG C, RH60% ± 5%), experimental result is as follows.
Form 6: study on the stability experimental result
Investigating result form 6 from stability test to see, the ratio of mannitol and Dextran 40 is 4: 1, after reducing the usage amount of human albumin,
The nerve growth factor composition stability that lyophilizing obtains meets the requirement of quality control.When the ratio of mannitol and Dextran 40 is 4: 1, freeze
The dry time shortens, but the product quality obtained remains able to meet quality control requirement, possesses marked improvement.
Claims (10)
1. a nerve growth factor composition, it is characterised in that add Dextran 40.
2. nerve growth factor composition as claimed in claim 1, it is characterised in that it includes nerve growth factor, mannitol, human albumin
And Dextran 40.
3. nerve growth factor composition as claimed in claim 2, it is characterised in that described mannitol with the part by weight of Dextran 40 is
4∶1-1∶9。
4. nerve growth factor composition as claimed in claim 3, it is characterised in that described mannitol with the part by weight of Dextran 40 is
4∶1-1∶1。
5. nerve growth factor composition as claimed in claim 4, it is characterised in that described mannitol is 4: 1 with the part by weight of Dextran 40.
6. nerve growth factor composition as claimed in claim 2, it is characterised in that it includes 0.3 part of mouse nerve growth factor, 112 parts of manna
Alcohol, 28 parts of Dextran 40s, 7 points of human albumin and qs pH adjuster (by weight).
7. nerve growth factor composition as claimed in claim 2, it is characterised in that its preparation technology is following steps:
(1) take nerve growth factor raw material, join in human albumin, mannitol, Dextran 40 and phosphate mixed liquor, add injection
With water to preparing total amount, stir；
(2) sampling is surveyed pH value and be should be 6.0～8.0；
(3) medicinal liquid prepared enters bottling department through 0.2 μm microporous filter membrane aseptic filtration；
(4) partly jump a queue fill, lyophilizing.
8. nerve growth factor composition as claimed in claim 7, it is characterised in that described step of preparation process (2), molten with 1mol/L HCl
Liquid or 1mol/L NaOH solution regulation pH value.
9. nerve growth factor composition as claimed in claim 2, it is characterised in that described nerve growth factor selected from mouse nerve growth factor,
Growth factor of human nerve, cattle nerve growth factor, snake venom nerve growth factor.
10. nerve growth factor composition as claimed in claim 9, it is characterised in that described nerve growth factor is mouse nerve growth factor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610349227.6A CN105944084A (en) | 2016-05-19 | 2016-05-19 | Nerve growth factor composition and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610349227.6A CN105944084A (en) | 2016-05-19 | 2016-05-19 | Nerve growth factor composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
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| CN105944084A true CN105944084A (en) | 2016-09-21 |
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ID=56909696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610349227.6A Pending CN105944084A (en) | 2016-05-19 | 2016-05-19 | Nerve growth factor composition and preparation method thereof |
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| Country | Link |
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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 |
-
2016
- 2016-05-19 CN CN201610349227.6A patent/CN105944084A/en active Pending
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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