CN1275646C - Nose drops of recombined human interferon alpha 2b and preparing method - Google Patents
Nose drops of recombined human interferon alpha 2b and preparing method Download PDFInfo
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- CN1275646C CN1275646C CN 200410036734 CN200410036734A CN1275646C CN 1275646 C CN1275646 C CN 1275646C CN 200410036734 CN200410036734 CN 200410036734 CN 200410036734 A CN200410036734 A CN 200410036734A CN 1275646 C CN1275646 C CN 1275646C
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- interferon alpha
- human interferon
- recombinant human
- nasal drop
- protective liquid
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- 102100040018 Interferon alpha-2 Human genes 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims description 5
- 108010079944 Interferon-alpha2b Proteins 0.000 title abstract description 6
- 229940100662 nasal drops Drugs 0.000 title description 2
- 239000007788 liquid Substances 0.000 claims abstract description 22
- 102000008100 Human Serum Albumin Human genes 0.000 claims abstract description 14
- 108091006905 Human Serum Albumin Proteins 0.000 claims abstract description 14
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims abstract description 14
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 101000959794 Homo sapiens Interferon alpha-2 Proteins 0.000 claims description 47
- 239000007923 nasal drop Substances 0.000 claims description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 12
- 238000005374 membrane filtration Methods 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 18
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 206010022000 influenza Diseases 0.000 abstract description 2
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 2
- 206010047470 viral myocarditis Diseases 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract 6
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 abstract 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 abstract 2
- 208000006454 hepatitis Diseases 0.000 abstract 2
- 231100000283 hepatitis Toxicity 0.000 abstract 2
- 230000001154 acute effect Effects 0.000 abstract 1
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- 230000037396 body weight Effects 0.000 description 6
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- 238000012360 testing method Methods 0.000 description 5
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- 241000699670 Mus sp. Species 0.000 description 3
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a nose drop of recombined human interferon alpha 2b and a preparation method thereof. The nose drop contains 100 to 3000 thousand IU/ml of medical recombined human interferon alpha 2b, 0.5% to 2 wt% of human serum albumin in protective liquid and 0.01% to 0.05 wt% of ethylparaben. The components are prepared into ethylparaben and human serum albumin protective liquid by physiological saline, and then the recombined human interferon alpha 2b is dissolved in the protective liquid to regulate the concentration of the protective liquid to 100 to 3000 thousand IU/ml; a filter film of 0.22 um is used for filtering and sterilizing the protective liquid, and finally, the protective liquid is packed separately. The nose drop can effectively treat and prevent serious acute respiratory tract syndromes (SARS), influenza, hepatitis b, hepatitis c, viral myocarditis, multiple sclerosis and other diseases.
Description
Affiliated technical field the present invention relates to have medicinal antiviral, regulates the interferon of the effect of immunologic function, relates in particular to recombinant human interferon alpha 2 b nasal drop and preparation method thereof.
Background technology is disturbed and is have the inhibition virus replication, various biological effects such as cell proliferation and adjusting immunne response.Be widely used in treatment and diseases such as prophylaxis of viral infections, immune dysfunction.Interferon comprises α, β, γ three major types type, has found ω and Γ two interferoids recently again.Interferon-alpha can be divided into many hypotypes, respectively called after α 1, α 2, α 3 ..., wherein α 2 comprises α 2a and two kinds of hypotypes of α 2b again.The sequence structure feature of interferon alpha 2 b and recombination and preparation thereof are seen " European Pharmacopoeia " (version in 2000).
Divide from its preparation method, interferon can be divided into natural interferon and recombinant interferon.Natural interferon is by the leukocyte of cultivating the people and utilizes suitable stimulation former (as fowl plague virus, Sendai virus) that it is stimulated and induce, and makes it produce interferon, utilizes biochemical method to carry out purification again and obtains.Recombinant interferon then is the method by gene recombinaton, and interferon gene is incorporated into (as escherichia coli) in the suitable expression system, makes interferon obtain great expression in the method by fermentation or cell culture, obtains by separation and purification then.Recombinant human interferon alpha 2 b utilizes the method exactly, with people's interferon alpha 2 b gene integration in escherichia coli, by fermentation, purification and obtain the recombinant human interferon alpha 2 b of high-purity, high yield.Recombinant human interferon alpha 2 is compared with natural interferon, has purity height, big, the low cost and other advantages of output.
Natural interferon is mostly adopted in existing interferon-alpha research, discloses a kind of compound interferon buccal tablet and preparation method thereof as Chinese patent application 98105384.x, but employing is the mixture of natural interferon-alpha and interleukin II.Chinese patent application 95111433.6 discloses a kind of buccal tablet of human leucocyte interferon and preparation method thereof, but the human leukocyte interferon that adopts is to be induced, purify by Sendai virus by healthy human leukocyte, and makes through special inactivation of viruses processing.Chinese patent application 98105383.1 discloses a kind of interferon-buccal tablet and preparation method thereof, but employing is interferon-.The also implicit recombinant human alpha interferon compositions that discloses a kind of oral administration of Chinese patent application 95101216.9, but component complexity, cost height.Chinese patent application 0213242.2 also discloses a kind of recombinant human interferon alpha nose drops and production technology thereof, but component complexity, cost height, curative effect are still to be tested.These natural interferon-alpha buccal tablets have antiviral, regulate the effect of immunologic function, are low dose as resisiting influenza virus, SARS coronary virus resistant, hepatitis B virus, hepatitis C virus, the dosage that uses, and are below 10000IU, more with 100IU～500IU.The disclosed technical scheme of above-mentioned document all exists weak points such as component complexity, cost of material height.
Recombinant human interferon alpha 2 b has injection, eye drop, suppository, gel, ointment etc. at present.Injection commonly used has the patient of increasing misery, big, the expensive deficiency of side effect.The research report of recombinant human interferon alpha 2 nasal drop dosage form is very few.Therefore, research and development nasal drop dosage form, give full play to this dosage form bioavailability height (interferon obtains good absorption by nasal mucosa), medication convenient (, being particularly suitable for children), patient's better tolerance, advantage such as cheap, become people and expect because of there not being hypopharynx.The inventor through a large amount of experimentatioies, has finished the present invention according to the requirement of SFDA finally.
Summary of the invention the object of the present invention is to provide a kind of bioavailability height, simple, the safe and effective dosage of component, good effect, side effect recombinant human interferon alpha 2 b nasal drop little, easy to use.
The present invention also aims to provide recombinant human interferon alpha 2 b nasal drop preparation method, make that recombinant human interferon alpha 2 b inactivation in preparation process is few.
In order to reach above purpose, the invention provides a kind of recombinant human interferon alpha 2 b nasal drop, wherein comprise recombinant human interferon alpha 2 b as active ingredient, and the protection liquid of pharmaceutically approving, protection liquid is selected from human albumin, ethyl hydroxybenzoate etc.
The recombinant human interferon alpha 2 b content of above-mentioned nasal drop is 100,000 IU～3,000,000 IU/ml, protection liquid human albumin percentage by weight 0.5%～2%, ethyl hydroxybenzoate percentage by weight 0.01%～0.05%.
Preparation technology of the present invention is; elder generation is mixed with 0.01%～0.05% ethyl hydroxybenzoate with normal saline and 0.5%～2% human albumin is a protection liquid; recombinant human interferon alpha 2 b being dissolved in protection, to make its concentration in the liquid be 100,000 IU～3,000,000 IU/ml again; then through the degerming of 0.22um membrane filtration, last packing.
The present invention also can use other suitable additive such as antiseptic and correctives.
Recombinant human interferon alpha 2 b nasal drop of the present invention shows safe and effective through series of experiment research, have antiviral, regulates effects such as immunologic function.Can be used for treatment and prevention severe acute respiratory syndrome (SARS), influenza, hepatitis B, hepatitis C, viral myocarditis, multiple sclerosis and other disease.
The present invention is because the protection fluid component is selected simply, rationally, and nasal drop is pollution-free, impurity few, no latent factor, thus the present invention to have a bioavailability height, simple, the safe and effective dosage of component, good effect, side effect little, easy to use.Human interferon-alpha-2 b inactivation in preparation process is few.
Mode below by embodiment further specifies the present invention, does not therefore limit the present invention among the described scope of embodiments.
The specific embodiment
Embodiment 1 recombinant human interferon alpha 2 b nasal drop (100,000 IU/ml) preparation
Component:
Recombinant human interferon alpha 2 b 100,000 IU
The human albumin 0.5%
Ethyl hydroxybenzoate 0.01%
Preparation method:
Earlier be mixed with 0.01% ethyl hydroxybenzoate and 0.5% human albumin is a protection liquid, again recombinant human interferon alpha 2 b be dissolved in that to make its concentration in the protection liquid be 100,000 IU/ml with normal saline, then through the degerming of 0.22um membrane filtration, last packing.
Embodiment 2 recombinant human interferon alpha 2 b nasal drop (1,000,000 IU/ml) preparation
Component:
Recombinant human interferon alpha 2 b 1,000,000 IU
The human albumin 1%
Ethyl hydroxybenzoate 0.03%
Preparation method:
Earlier be mixed with 0.03% ethyl hydroxybenzoate and 1% human albumin is a protection liquid, again recombinant human interferon alpha 2 b be dissolved in that to make its concentration in the protection liquid be 1,000,000 IU/ml with normal saline, then through the degerming of 0.22um membrane filtration, last packing.
Embodiment 3 recombinant human interferon alpha 2 b nasal drop (3,000,000 IU/ml) preparation
Component:
Recombinant human interferon alpha 2 b 3,000,000 IU
The human albumin 2%
Ethyl hydroxybenzoate 0.05%
Preparation method:
Earlier be mixed with 0.05% ethyl hydroxybenzoate and 2% human albumin is a protection liquid, again recombinant human interferon alpha 2 b be dissolved in that to make its concentration in the protection liquid be 3,000,000 IU/ml with normal saline, then through the degerming of 0.22um membrane filtration, last packing.
Experimental example 1 recombinant human interferon alpha 2 b nasal drop acute toxicity test
Experiment purpose: it is disposable behind nasal administration to observe the recombinant human interferon alpha 2 b nasal drop, because toxic reaction and death condition that mucosa absorption produced.
Experiment material:
1, medicine: the recombinant human interferon alpha 2 b nasal drop, 500,000 IU/ml, king Ying Telong biotech firm provides by sea, Shenzhen.
2 animals: 20 male and female half and half of Wistar rat, body weight 250-300g, animal housing provides by the institute for drug control, Jilin Province, quality certification numbering 10--1009.
Experimental technique:
1, dosage is selected: recombinant human interferon alpha 2 b nasal drop clinical every day of plan is 500,000 IU/ people with dosage, and on the basis of prerun, choosing is higher than 100 times of amounts of clinical dosage.
2, grouping, administration and observation: above-mentioned rat is divided into normal saline group and recombinant human interferon alpha 2 b nasal drop group.Nasal drop is dropped in the nasal cavity, and 5,000 ten thousand IU/, animal state, hair, appetite, extremity activity, the mental status, death condition and body weight change are observed in 1 administration at once, continuous 14 days.
Experimental result:
1, within the administration 7 days, normal saline group and recombinant human interferon alpha 2 b nasal drop treated animal hair, appetite, extremity activity, the mental status are all no abnormal, none death, and body weight does not also have significant difference, sees the following form.
The anxious poison test of table recombinant human interferon alpha 2 b nasal drop and normal saline group body weight change (x ± s, n=5)
| Group | Before the administration (g) | After the administration 7 days (g) | After the administration 14 days (g) |
| The normal saline group | 270.2±13.78 | 290.0±14.96 | 310.2±14.19 |
| α 2b nasal drop group | 271.7±14.45 | 292.0±14.95 | 311.3±15.93 |
2, the clinical plan consumption of recombinant human interferon alpha 2 b nasal drop is IU/ people's every days 500,000, calculates if body weight for humans is pressed 60kg, i.e. 8333IU/kg; And anxious malicious evidence, dosage 5,000 ten thousand IU/ only toxic reaction do not occur, if rat body weight press 0.27kg calculating, promptly 18,518 ten thousand IU/kg are equivalent to 22000 times of clinical dosage, so clinical application is as safe as a house.
Experimental example 2 rat immunity of organisms IgG (g/L) detect
Experiment purpose: detect the recombinant human interferon alpha 2 b nasal drop to the effect of rat immunity power, for clinical application effect property provides foundation.
Experiment material:
1, medicine: the recombinant human interferon alpha 2 b nasal drop, 500,000 IU/ml are provided by Haiwang Yingtelong Biological Technology Co., Ltd., Shenzhen City.
2, animal: 40 of Wistar rats, male and female half and half, body weight 200-300g, animal housing provides by the institute for drug control, Jilin Province.
Experimental technique:
1, animal grouping, dosage: rat is divided into two groups of A, B at random, and the A group is collunarium normal saline matched group, 20; The B group is collunarium recombinant human interferon alpha 2 b nasal drop test group, 20, and continuous collunarium 7 time-of-weeks, 3 days 1 time, each 500,000 IU/kg.
2, detect rat IgG (g/L)
Experimental result:
| Grouping | Experimental program | Number of animals | IgG(g/L) |
| A | The normal saline matched group | 20 | 12.13 |
| B | Recombinant human interferon alpha 2 b nasal drop test group | 20 | 41.87 |
A, B organize relatively: P＜0.01
Conclusion: learn index determining and statistical analysis through the recombinant human interferon alpha 2 b nasal drop being used for rat immunity, significant difference is arranged, expression has improved immunity of organisms.
Experimental example 3 mice immunity of organisms IgM (g/L) detect
Experiment purpose: detect the recombinant human interferon alpha 2 b nasal drop to the effect of mouse immune power, for clinical application effect property provides foundation.
Experiment material:
1, medicine: the recombinant human interferon alpha 2 b nasal drop, 500,000 IU/ml are provided by Haiwang Yingtelong Biological Technology Co., Ltd., Shenzhen City.
2, animal: 40 of mices, male and female half and half, body weight 25-40g, animal housing provides by the institute for drug control, Jilin Province.
Experimental technique:
1, animal grouping, dosage: rat is divided into two groups of A, B at random, and the A group is collunarium normal saline matched group, 20; The B group is collunarium recombinant human interferon alpha 2 b nasal drop test group, 20, and continuous collunarium 3 time-of-weeks, 2 days 1 time, each 500,000 IU/kg.
2, detect mice IgM (g/L)
Experimental result:
| Grouping | Experimental program | Number of animals | IgM(g/L) |
| A | The normal saline matched group | 20 | 4.07 |
| B | Recombinant human interferon alpha 2 b nasal drop test group | 20 | 14.76 |
A, B organize relatively: P＜0.01
Conclusion: learn index determining and statistical analysis through the recombinant human interferon alpha 2 b nasal drop being used for mouse immune, significant difference is arranged, expression has improved immunity of organisms.
Claims (3)
1. a recombinant human interferon alpha 2 b nasal drop wherein comprises the recombinant human interferon alpha 2 b as active ingredient, and the protection liquid of pharmaceutically approving; Protection liquid is mixed with normal saline, wherein comprises human albumin and ethyl hydroxybenzoate as active ingredient.
2, nasal drop according to claim 1; recombinant human interferon alpha 2 b content as active ingredient is 100,000 IU/ml-300, ten thousand IU/ml; in the described protection liquid, human albumin's percentage by weight 0.5%～2%, ethyl hydroxybenzoate percentage by weight 0.01%～0.05%.
3. the method for making of nasal drop according to claim 1; elder generation is mixed with 0.01%～0.05% ethyl hydroxybenzoate with normal saline and 0.5%～2% human albumin is a protection liquid; recombinant human interferon alpha 2 b being dissolved in protection, to make its concentration in the liquid be 100,000 IU～3,000,000 IU/ml again; then through the degerming of 0.22um membrane filtration, last packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410036734 CN1275646C (en) | 2003-04-28 | 2004-04-28 | Nose drops of recombined human interferon alpha 2b and preparing method |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03114322 CN1443573A (en) | 2003-04-28 | 2003-04-28 | Recombinant human interferon alpha 2 b nose drops and its production method |
| CN03114322.9 | 2003-04-28 | ||
| CN 200410036734 CN1275646C (en) | 2003-04-28 | 2004-04-28 | Nose drops of recombined human interferon alpha 2b and preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1539500A CN1539500A (en) | 2004-10-27 |
| CN1275646C true CN1275646C (en) | 2006-09-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200410036734 Expired - Lifetime CN1275646C (en) | 2003-04-28 | 2004-04-28 | Nose drops of recombined human interferon alpha 2b and preparing method |
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| Country | Link |
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| CN (1) | CN1275646C (en) |
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- 2004-04-28 CN CN 200410036734 patent/CN1275646C/en not_active Expired - Lifetime
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| Publication number | Publication date |
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| CN1539500A (en) | 2004-10-27 |
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