CN1181888C - Stable recombination human alpha interferon liquid preparation and productive process thereof - Google Patents
Stable recombination human alpha interferon liquid preparation and productive process thereof Download PDFInfo
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- CN1181888C CN1181888C CNB031270271A CN03127027A CN1181888C CN 1181888 C CN1181888 C CN 1181888C CN B031270271 A CNB031270271 A CN B031270271A CN 03127027 A CN03127027 A CN 03127027A CN 1181888 C CN1181888 C CN 1181888C
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Abstract
The present invention provides a stable recombination human alpha interferon liquid preparation and a preparation process thereof. The liquid preparation is prepared from interferon, human serum albumin, a moisture retention lubricant, a thickening agent, an isotonic regulator sodium chloride, 0 to 0.05% of EDTA-Na and 0.1 to 1% of tween-80 according to the proportion. The period of validity of the liquid interferon can be prolonged to be more than two years so that the problem of the shortness of the period of validity of interferon liquid preparations is solved; the liquid preparation can be made into eye drops, nasal drops and spraying agents. The liquid preparation of the present invention has the advantages that the bio-compatibility and the stability are good, and the liquid preparation has the functions of lubrication and moisture retention; the stimulation to skin mucosa is reduced, and the attach time of interferon in the medication positions is prolonged; the quick clearance of the medicine from the medication positions, particularly from nasopharynx, is prevented, and the administration times are reduced so that the aims of the synergism and the sustained release of the liquid preparation are achieved, and thus, the therapeutic effect is improved. The liquid preparation has the characteristics of simple preparation process, short practical production period, convenient operation, fast absorption, reliable therapeutic effect, etc., and has very high clinical application value.
Description
Technical field:
The invention provides a kind of stable recombinant human alpha 2a interferon liquid formulations and production technology; this stable liquid preparation is except that containing recombinant human alpha 2a interferon; also contain the lubricant of preserving moisture, protective agent, thickening agent, antiseptic, stabilizing agent, belong to interferon dosage form production technical field.
Background technology:
α 2a interferon liquid formulations has preventive effect to SARS virus, influenza virus and rhinovirus, can be used for nasal membrane, eye mucosa, oral mucosa and sublingual spraying or splashes into administration.Though liquid preparations such as existing α 2a interferon nasal drop and eye drop appear on the market, its protective agent, thickening agent are undesirable, all exist short problem of effect phase, storage life only one year about, be unfavorable for preservation, influenced the use of this medicine.
Summary of the invention:
The invention provides a kind of stable recombinant human alpha 2a interferon liquid formulations, the raising effect phase reached more than 2 years.
The present invention also provides its production technology, is applicable to suitability for industrialized production.
Liquid preparation of the present invention can be made into eye drop, nasal drop, spray.
Technical solution of the present invention is as follows: according to the requirement and the interferon biological characteristic of nasal drop, eye drop, spray, add suitable wetting agent, protective agent, thickening agent, antiseptic, stabilizing agent and make aqueous solution preparation.
Basic recipe of the present invention is as follows: (by weight percentage)
α 2a interferon alpha-2 0～1,000 ten thousand IU/ml, human albumin 0.1～1%, the lubricant 0～1% of preserving moisture, thickening agent 0.1～1%, isoosmotic adjusting agent sodium chloride 0.4～0.9%, stabilizing agent EDTA-Na 0～0.05%, tween 80 0.1～1%, surplus are water for injection.
Above-mentioned thickening agent comprises: gelatin, polyvinyl alcohol, described reagent can be respectively united use with the human albumin and can be prolonged interferon liquid formulations and imitate more than phase to 2 year.
The above-mentioned lubricant of preserving moisture comprises: chitosan, hyaluronic acid sodium, they also have thickening power simultaneously.
Protective agent: human albumin and thickening protective agent are united use also can add stabilizing agent EDTA-Na, tween 80
Container: optional eye drop bottle is used for eye drip, intranasal administration; Aerosol container is a spray delivery.
Described α 2a interferon or (IFN-α) can be the recombined human alpha-interferons with the gene engineering method preparation, also can be that alpha-interferon is meant α, α with the people source LeIF of human leukocyte preparation
2a, α
2b... the serial alpha-interferon of 23 hypotypes under waiting.
Concrete preparing process may further comprise the steps to be finished:
1. preparation
Preparation A liquid: antiseptic (as thimerosal, methyl parahydroxybenzoate/propyl ester/ethyl ester), sodium chloride, EDTA-Na are added an amount of water for injection, 121 ℃ of autoclavings 30 minutes, standby.
Preparation B liquid: the lubricant of will preserving moisture slowly adds in an amount of refrigerative water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
Preparation C liquid: the thickening protective agent is added scale accurately in the container, add the abundant swelling of proper amount of water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filters to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to full dose.
Divide to install in the respective liquid container, as: eye-drop liquid bottle or aerosol container, make different dosage forms.
Good effect of the present invention is: said preparation can obviously prolong liquid interferon and imitate more than phase to 2 year, solved a short difficult problem of interferon liquid formulations effect phase, bio-compatibility of the present invention and good stability, has lubricated moisture-keeping function simultaneously, minimizing is to the stimulation of nasal mucosa, increased the viscosity of interferon liquid formulations, prolonging interferon adheres to the time around nasal membrane, and prevent that medicine from removing especially nasopharynx part from agents area fast and removing, increase medicine and absorption surface time of contact, reduce administration number of times, thereby make it to reach potentiation and slow releasing function raising curative effect.Characteristics such as and it is simple to have preparation technology, practical with short production cycle, easy to use, that absorption is fast, curative effect is reliable have very high clinical value.This liquid preparation can be made into eye drop, nasal drop, spray.
The specific embodiment:
Embodiment 1
Prescription:
Recombinant human alpha 2a interferon 3,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 0.5g
Hyaluronate sodium 0.02g
EDTA-Na 0.005g
Tween 80 1ml
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben, EDTA-Na, tween 80 by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio hyaluronate sodium is slowly added in the refrigerative 10ml water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
C liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 15ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 2
Prescription:
Recombinant human alpha 2a interferon 300IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 0.5g
EDTA-Na 0.005g
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben, EDTA-Na by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 15ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
With mixing in the A liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation, filter to B liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 3
Prescription:
Recombinant human alpha 2a interferon 100IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 0.5g
Hyaluronate sodium 0.02g
Human albumin 20% 5ml
Add the injection water to 100ml
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio hyaluronate sodium is slowly added in the refrigerative 10ml water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
C liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 15ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 4
Prescription:
Recombinant human alpha 2a interferon 1,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 0.5g
Hyaluronate sodium 0.02g
EDTA-Na 0.005g
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben, EDTA-Na by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio hyaluronate sodium is slowly added in the refrigerative 10ml water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
C liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 15ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 5
Prescription:
Recombinant human alpha 2a interferon 1,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 1g
Hyaluronate sodium 0.02g
EDTA-Na 0.005g
Tween 80 1ml
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben, EDTA-Na, tween 80 by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: slow the overflowing of formula ratio hyaluronate sodium added in the refrigerative 5ml water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
C liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 20ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 6
Prescription:
Recombinant human alpha 2a interferon 1,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 0.5g
Chitosan 0.05g
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio chitosan is slowly added in the refrigerative 10ml water for injection, and the limit edged shakes container, and placing spends the night makes abundant dissolving.
C liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 15ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
The B liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation is added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 7
Prescription:
Recombinant human alpha 2a interferon 1,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Gelatin 1g
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
B liquid: the formula ratio gelatin is added scale accurately in the container, add the abundant swelling of 20ml water for injection after, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
α 2a interferon stock solution, human albumin are added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, the sterile working be sub-packed in the plastic bottle or aerosol container in, 2-8 ℃ of preservation.
Embodiment 8
Prescription:
Recombinant human alpha 2a interferon 1,000,000 IU/ml.
Sodium chloride 0.85g
Methyl hydroxybenzoate 0.03g
Propylparaben 0.02g
Human albumin 20% 5ml
Add the injection water to 100ml
Preparation technology:
1, preparation:
A liquid: get sodium chloride, methyl hydroxybenzoate, propylparaben by prescription and put in the container, add 70ml water for injection, 121 ℃ of autoclavings 30 minutes, standby.
2. α 2a interferon liquid formulations preparation:
Mixing in the A liquid of α 2a interferon stock solution, human albumin and above-mentioned preparation, filter to the dry heat sterilization container with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to 100ml, aseptic subpackaged in plastic bottle or in the aerosol container, 2-8 ℃ of preservation.
The foregoing description prescription difference sees the following form:
| Hyaluronate sodium (g) | 0.02 | --- | 0.02 | 0.02 | 0.02 | --- | --- | --- |
| Chitosan (g) | --- | --- | --- | --- | --- | 0.05 | --- | --- |
| EDTA-Na(g) | 0.005 | 0.005 | --- | 0.005 | 0.005 | --- | --- | --- |
| Tween 80 (ml) | 1 | --- | --- | --- | 1 | --- | --- | --- |
| Human albumin's (20%) | 5ml | 5ml | 5ml | 5ml | 2.5ml | 5ml | --- | 5ml |
| Interferon-alpha (IU/ml) | 3,000,000 | 3,000,000 | 1,000,000 | 1,000,000 | 1,000,000 | 1,000,000 | 1,000,000 | 1,000,000 |
| Add the injection water to cumulative volume | 100ml | |||||||
According to the temperature and the requirement of humidity associating accelerated test method of 2000 editions appendix XIX of Pharmacopoeia of the People's Republic of China C medicine stability guideline and U.S. FDA recommendation, the study on the stability report does not see the following form under equality of temperature, the damp condition:
40 ± 2 ℃ of relative humitures of table 1 (RH), 75 ± 5% active units: 10
6IU/ml
25 ± 2 ℃ of relative humitures of table 2 (RH), 20 ± 2% active units: 10
6IU/ml
2 ℃～8 ℃ active units of table 3: 10
6IU/ml
Embodiment 1,2,3,4,5,6 is an optimization formula, under 40 ± 2 ℃ of relative humiditys of temperature (RH), 75 ± 5% conditions, store three months, store six months under 25 ± 2 ℃ of relative humiditys (RH), 20 ± 2% conditions, every index such as store 25 months limit test of microbe, outward appearance, pH value under 2 ℃～8 ℃ conditions, tire is still in claimed range, this product stores under 2 ℃～8 ℃ conditions, and effect duration can be decided to be 2 years.Above-mentioned prescription has all carried out animal acute toxicity test and irritation test, and the result shows that this interferon liquid formulations collunarium, spray delivery toxic reaction are low, to mucocutaneous nonirritant, clinical drug safety.
Claims (3)
1, a kind of stable recombinant human alpha 2a interferon liquid formulations is characterized in that the liquid preparation of being made by following substance weight percentage ratio:
α 2a interferon 100～3,000,000 IU/ml, human albumin 0.1～1%, preserve moisture lubricant chitosan 0～0.05% or hyaluronate sodium 0～0.02%, thickening agent gelatin 0.1～1%, isoosmotic adjusting agent sodium chloride 0.85%, stabilizing agent EDTA-Na 0～0.005%, tween 80 0～1%, antiseptic methyl hydroxybenzoate 0.03% and propylparaben 0.02%.
2, a kind of stable recombinant human alpha 2a interferon liquid formulations production technology is characterized in that may further comprise the steps and finishes:
A liquid: in the described ratio of claim 1 antiseptic methyl hydroxybenzoate and propylparaben, sodium chloride, EDTA-Na, tween 80 are added an amount of water for injection, 121 ℃ of autoclavings 30 minutes, standby;
B liquid: slowly add in the refrigerative water for injection in will preserve moisture lubricant chitosan or hyaluronate sodium of the described ratio of claim 1, the limit edged shakes container, and placing spends the night makes abundant dissolving;
C liquid: in the described ratio of claim 1 the thickening agent gelatin is added scale accurately in the container, add the abundant swelling of proper amount of water for injection after, 121 ℃ of autoclavings 30 minutes, standby;
The preparation interferon liquid formulations:
In the described ratio of claim 1 with α 2a interferon stock solution, human albumin, and the B liquid of above-mentioned preparation be added to mixing in the above-mentioned preparation A liquid, filter to C liquid with 0.22 μ m filter membrane degerming then, add sterilized water for injection at last to full dose, get product of the present invention.
3, liquid preparation according to claim 1, dosage form comprises eye drop, nasal drop, spray.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031270271A CN1181888C (en) | 2003-05-16 | 2003-05-16 | Stable recombination human alpha interferon liquid preparation and productive process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031270271A CN1181888C (en) | 2003-05-16 | 2003-05-16 | Stable recombination human alpha interferon liquid preparation and productive process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1449821A CN1449821A (en) | 2003-10-22 |
| CN1181888C true CN1181888C (en) | 2004-12-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031270271A Expired - Fee Related CN1181888C (en) | 2003-05-16 | 2003-05-16 | Stable recombination human alpha interferon liquid preparation and productive process thereof |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100465642C (en) * | 2007-07-18 | 2009-03-04 | 清华大学 | Method for increasing anti matrix effect in immunity detection for environmental sample, and dedicated buffer solution |
| CN103463623B (en) * | 2013-09-03 | 2015-09-09 | 长春海伯尔生物技术有限责任公司 | A kind of Peg-IFN alpha-2b injection and preparation method thereof |
| CN105031621B (en) * | 2015-08-18 | 2018-07-03 | 安徽安科生物工程（集团）股份有限公司 | Recombinant human interferon alpha 2 b gel and preparation method thereof |
| CN109010803A (en) * | 2018-10-26 | 2018-12-18 | 安徽安科生物工程（集团）股份有限公司 | A kind of recombinant human interferon alpha 2 b eye drops and preparation method thereof |
| CN112717123A (en) * | 2020-12-29 | 2021-04-30 | 泰州博莱得利生物科技有限公司 | Cat nose drops and application thereof |
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2003
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