CN104888196A - Stable interferon alpha multi-dose pen injection - Google Patents
Stable interferon alpha multi-dose pen injection Download PDFInfo
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- CN104888196A CN104888196A CN201510357975.4A CN201510357975A CN104888196A CN 104888196 A CN104888196 A CN 104888196A CN 201510357975 A CN201510357975 A CN 201510357975A CN 104888196 A CN104888196 A CN 104888196A
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Abstract
The invention belongs to the field of protein medicine preparation and relates to stable interferon alpha multi-dose pen injection. The stable interferon alpha multi-dose pen injection comprises treatment effective amount of interferon alpha and an appropriate amount of injection pharmaceutic adjuvant. The injection pharmaceutic adjuvant comprises albumin and phenolic preservatives. The stable interferon alpha multi-dose pen injection can keep safe, effective and stable in repeated use.
Description
Technical field
What the present invention was general relates to stable interferon-ALPHA injection, relates to a stable interferon-ALPHA multiple dose injection especially.
Background technology
Interferon (Interferon, IFN) be that one is produced by animal body at first, there is the cytokine class pharmaceutical grade protein of broad-spectrum antiviral, antiproliferative and immunoregulation effect, can be divided into from the different of the mechanism of action type that α, β, γ, λ etc. are large according to its generating unit, and often kind of large type can be divided into some little hypotypes, between hypotypes different in same large type, on primary structure, difference is very little, on the above higher structure of secondary closely.In several large type, α type is most widely used one, and this kind of interferon of current clinical practice mainly comprises Interferon a2a, interferon alpha 2 b, Interferon α1 b, Interferon Alfacon-1 etc.
Alpha-interferon is at present at the dosage form mainly injection of Clinical practice, the indication of its approval application comprises hepatitis B, hepatitis C, hairy cell leukemia, sharp-pointed wet tumor and kinds of tumors etc., wherein the treatment of a course for the treatment of of most indications needs the time of more than 16 weeks, medication more than 3 times weekly.Because administration time is long, need frequently to carry out injection for curing to hospital, this just uses alpha-interferon injection for treating target indication to bring very large inconvenience to patient, and even painful, also hinders alpha-interferon injection applying clinically to a great extent.
Multiple dose pen, that a kind of patient that development in recent years is got up can not by the help of hospital, doctor, nurse, and the independent new medical apparatus and instruments repeatedly using drug injection liquid product, it has been widely used on injection of insulin liquid product (comprise the Silver Norfloxacin of Novo Nordisk, excellent companion's pen that gift comes, Bayer visit woods pen), interferon injection products has also had involved (Schering Plough company applies it to Intron A
on product).
In addition, compared with traditional drug injection liquid product, the multiple dose injection products of medicine also has a following points advantage: one is without the need to carrying out destructive opening process to the medicine bottle of depot injections when using, thus can prevent the broken glass chip produced from entering into the liquid, enter human body in company with medicinal liquid and human body is damaged; Two be can avoid the disposable syringe of the violation occurred in a large number in practical clinical repeatedly use brought unsafe injection problem; Three is medical wastes that the consumption that can reduce disposable syringe product brings, thus is conducive to environmental conservation.
But from traditional drug injection liquid product, behind Kaifeng, mostly be disposable feature different, the nonexpondable feature of a multiple dose injection products of medicine adds medicine and is in use exposed to number of times in surrounding and time, thus also just has higher requirement to its safety and stability.Therefore to need in the multiple links comprising drug injection formula of liquid comparatively traditional drug injection products to make further Optimal improvements, the requirement of a multiple dose injection products Clinical practice of medicine could be met.
Report the formula composition of some traditional interferon-ALPHA injection, preparation method and result of use in prior art, they can as the reference basis optimizing an interferon-ALPHA multiple dose injection formula composition.
Such as Chinese patent application CN95195600.0 discloses with a kind of stable aqueous alpha interferon solution formulations, and it does not contain blood of human body derivative products (comprising human serum albumin) but comprises: (a) 0.1 × 10
6-100 × 10
6the α-type interferon of IU/ml; B () keeps the buffer system of pH within the scope of 4.5-7.1; The chelating agen of (c) effective dose; D () is enough to poly-(oxygen-1,2-second two base) ester derivant of dehydration mountain pears alcohol list – 9-octadecenoic acid that stable α-type interferon tackles the some of α-type interferon loss; The tonicity agents of (e) effective dose; The antibiotic antiseptic of (f) effective dose; (g) be enough to prepare the above-mentioned water for injection listing the some of the solution of component.This aqueous solution preparation is claimed in the Long-term Storage timeliness of at least 24 months, to be kept the height of α-type interferon chemistry, high physics and high biological stability.
And for example Chinese patent application CN00815919.X discloses a kind of aqueous solution formulation of alpha-interferon, this aqueous solution formulation comprises alpha-interferon, stabilizing agent, osmotic pressure regulator, antibiotic antiseptic and buffer system, do not comprise human serum albumin and chelating agen, pH is 4.5-6.0, and described antibiotic antiseptic is selected from the phenol of 0.1-0.3w/v%, the metacresol of 0.1-0.15w/v% or the mixture of described phenol and metacresol.This aqueous solution formulation claims the activity that can keep alpha-interferon for a long time, by the amount of antiseptic being reduced the potential danger eliminated human body, and very stable.
Summary of the invention
The object of this invention is to provide an a kind of stable interferon-ALPHA multiple dose injection, to solve multiple injection, stability problem, biocidal property problem that the more common interferon-ALPHA injection that the use procedure being repeatedly exposed to surrounding brings to an interferon-ALPHA multiple dose injection is more outstanding, and even the safety issue brought by stability and biocidal property problem.
For realizing this object, in the embodiment on basis, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, it contains the treatment interferon-ALPHA of effective dose and the injection pharmaceutically acceptable auxiliaries of Sq, and described injection pharmaceutically acceptable auxiliaries comprises albumin and antiseptic phenols.
Albumin is also known as albumin; be that in human or animal's blood plasma, content is the highest, can play and maintain plasma colloid osmotic pressure, combination and transhipment material, coordinate the integrity of endothelium, protection hemocyte regulates blood coagulation, do not activate a kind of native protein of the effects such as inflammatory reaction, Organoprotective, antioxidation, injury repairing.Albumin is applied in pharmaceutical preparation, especially in biotech drug injection formulation, role mainly helps the biologic activity maintaining biotech drug, reduce container wall to the absorption of biotech drug, and regulate the osmotic pressure of biotech drug.
Albumin of the present invention can select animal serum albumin, such as bovine serum albumin, or human serum albumin, but in order to reduce immunogenicity, preferred human serum albumin.
Albuminous total concentration of the present invention should between 5-50mg/ml, preferably between 10-20mg/ml.
Pharmaceutical preservative with no toxicity is that a class is added in medicine, growth of microorganism is suppressed in the production of medicine, transport, storage and use procedure, especially harmful microorganism growth, and prevent microorganism and metabolite thereof from destroying the material of ingredient, particularly active component.Antiseptic phenols is the antiseptic that chemical constitution belongs to phenolic compound, and phenolic compound is the quasi-aromatic compound that on aromatic ring, hydrogen is optionally substituted by a hydroxyl group.
Antiseptic phenols of the present invention is including, but not limited to phenol, cresol (comprising again orthoresol, metacresol, paracresol), Nipagin ester (i.e. p-Hydroxybenzoate, comprise methyl parahydroxybenzoate, ethyl ester, propyl ester, butyl ester etc.) in the combination of one or more, preferred cresol, Nipagin ester or their combination, and more preferably metacresol.
The total concentration of antiseptic phenols of the present invention should between 0.2-3mg/ml, preferably between 0.5-2mg/ml.
Except albumin and antiseptic phenols, injection pharmaceutically acceptable auxiliaries of the present invention also preferably comprises the agent of pH stable regulation, a greater variety of osmotic pressure regulator, a greater variety of interferon-ALPHA activity protecting agent and/or a greater variety of adsorption inhibitor.
The effect pH of an interferon-ALPHA multiple dose injection being stabilized in physiology appropriate pH (5.0-8.0) is played in the agent of pH stable regulation, and require physiological safety, selectable scope including, but not limited to phosphate buffered solution system, citrate buffer solution system, Ascorbate buffer solution system, preferably phosphate buffer solution system.The total concentration of such pH stable regulation agent should between 0.1-500mmol/L, preferably between 1-100mmol/L, and more preferably between 5-20mmol/L.
Osmotic pressure regulator plays and the osmotic pressure of an interferon-ALPHA multiple dose injection is adjusted to the effect isotonic with blood of human body, in addition to albumin, and the combination of one or more in the materials such as all right selective chlorination sodium, mannitol, glucose.
Interferon-ALPHA activity protecting agent play protection interferon-ALPHA the preparation of multiple dose injection, transport, storage and in using activity do not lose or the effect of less forfeiture; in addition to albumin, the combination of one or more in aminoacid, polyhydric alcohol, cyclodextrin, lecithin matter can also be selected.
Adsorption inhibitor plays and suppresses or reduce the effect to the absorption of interferon-ALPHA and other adjuvants of the container that contains a multiple dose injection of interferon-ALPHA, in addition to albumin, and can also option table surface-active agent, and preferred Tweens non-ionic surface active agent.
It should be pointed out that an a kind of or class material may play the effect of above-mentioned multiple pharmaceutically acceptable auxiliaries function in an interferon-ALPHA multiple dose injection of the present invention simultaneously.Except the effect that albumin plays osmotic pressure regulator, activity protecting agent, adsorption inhibitor simultaneously; if such as containing mannitol, then it can play the effect of osmotic pressure regulator and activity protecting agent in an interferon-ALPHA multiple dose injection of the present invention simultaneously.
First an interferon-ALPHA multiple dose injection of the present invention should dissolve each pharmaceutically acceptable auxiliaries by preparation aequum in process for preparation, after mixing homogeneously with the stock solution of interferon-ALPHA, then regulate the volume of solution to targeted injection liquid dose volume.The dissolving of each pharmaceutically acceptable auxiliaries can be carried out simultaneously, also can carry out respectively, but the preparation of slightly solubility pharmaceutically acceptable auxiliaries should be carried out separately, and optionally heats and/or add certain cosolvent.At least the injection of reply mixing gained carries out bacteria removing, the method mainly membrane filtration of process; Preferably after each pharmaceutically acceptable auxiliaries dissolves, all carry out bacteria removing, and then mix with interferon-ALPHA stock solution prepared by aseptic processing, the method of each pharmaceutically acceptable auxiliaries bacteria removing can be membrane filtration and/or high pressure moist heat sterilization, but thermal instability pharmaceutically acceptable auxiliaries is unsuitable for high pressure moist heat sterilization.Water needed for preparation processes preferably through the process of ion exchange deionization and distillation.Injection after bacteria removing is aseptically sub-packed in special container by subpackage volume requirement, such as, in clamped bottle, obtains a final interferon-ALPHA multiple dose injection products.
The interferon-ALPHA multiple dose injection products prepared is evaluated except stability, biocidal property except sampling method, detection method and the test item that conveniently injection products requires, the also preferred preservation condition at actual requirement, stability, biocidal property is evaluated at the nonexpondable point in time sampling of reality, and more preferably in the preservation condition poorer than actual requirement condition, and/or evaluate stability, biocidal property than the actual point in time sampling frequently that uses.
One or more including, but not limited in the following of the project of Detection of Stability: outward appearance detects, pH detects, interferon-ALPHA biologic activity detects, and preferred outward appearance detects and detects with interferon-ALPHA biologic activity.
Outward appearance detects and adopts observation method of naked eye, sees color and the turbidity of solution.
PH detects " the pH value algoscopy " that preferably adopt " Pharmacopoeia of People's Republic of China version (three) in 2010 " annex V A to specify.
" the interferon biological activity algoscopy " of annex X C regulation that interferon-ALPHA Activity determination preferably adopts " Pharmacopoeia of People's Republic of China version (three) in 2010 ".
One or more including, but not limited in the following of the project that biocidal property detects: detections of antibacterial effect, antibacterial content detection, sterility test detect, preferred sterility test detection.
Antibacterial effect detects " antibacterial (antiseptic) the effect inspection technique guideline " that preferably specify with reference to " Pharmacopoeia of People's Republic of China version (three) in 2010 " annex XVII and carries out.
" the metacresol algoscopy " of annex VI N regulation that antibacterial content detection preferably adopts " Pharmacopoeia of People's Republic of China version (three) in 2010 ".
Sterility test detects " Sterility Test " that preferably adopt " Pharmacopoeia of People's Republic of China version (three) in 2010 " annex XIIA to specify.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, it contains the interferon-ALPHA of 0.1-1000 μ g/ml.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, it contains the interferon-ALPHA of 1-100 μ g/ml.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said interferon-ALPHA is selected from the combination of one or more in Interferon a2a, interferon alpha 2 b, Interferon α1 b, Interferon Alfacon-1.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said interferon-ALPHA is Interferon α1 b.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said albuminous total concentration is 5-50mg/ml.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said albuminous total concentration is 10-20mg/ml.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, the total concentration of wherein said antiseptic phenols is 0.2-3mg/ml.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, the total concentration of wherein said antiseptic phenols is 0.5-2mg/ml.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said antiseptic phenols is selected from the combination of one or more in phenol, cresol, Nipagin ester.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said antiseptic phenols is metacresol.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said injection pharmaceutically acceptable auxiliaries comprises the agent of pH stable regulation, is selected from the combination of one or more in phosphate buffered solution system, citrate buffer solution system, Ascorbate buffer solution system.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said injection pharmaceutically acceptable auxiliaries comprises osmotic pressure regulator in addition to albumin, is selected from the combination of one or more in sodium chloride, mannitol, glucose.
In a preferred embodiment; the invention provides an a kind of stable interferon-ALPHA multiple dose injection; wherein said injection pharmaceutically acceptable auxiliaries comprises interferon-ALPHA activity protecting agent in addition to albumin, is selected from the combination of one or more in aminoacid, polyhydric alcohol, cyclodextrin, lecithin matter.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, wherein said injection pharmaceutically acceptable auxiliaries comprises adsorption inhibitor in addition to albumin, is selected from the combination of one or more in Tweens non-ionic surface active agent.
In a preferred embodiment, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, it contains the interferon-ALPHA of 0.1-1000 μ g/ml, the human serum albumin of 5-50mg/ml, the metacresol of 0.2-3mg/ml, 1-100mmol/L sodium hydrogen phosphate-sodium dihydrogen phosphate, pH7.0 solution, and regulate osmotic pressure to the NaCl isotonic with blood of human body.
In a kind of embodiment be more preferably, the invention provides an a kind of stable interferon-ALPHA multiple dose injection, it contains the interferon-ALPHA of 1-100 μ g/ml, the human serum albumin of 10-20mg/ml, the metacresol of 0.5-2mg/ml, 5-20mmol/L sodium hydrogen phosphate-sodium dihydrogen phosphate, pH7.0 solution, and regulate osmotic pressure to the NaCl isotonic with blood of human body.
The term " interferon-ALPHA " used in the present invention comprises the antiviral active substance of the native sequences that human body is produced by leukocyte under extraneous pathogenic agent stimulates, also the recombinant molecule identical with above-mentioned native sequences selecting suitable expression vector to express by gene engineering method is comprised, also comprise the molecule being integrated with the engineer of above-mentioned natural interferon alpha conserved sequence selecting suitable expression vector to express by gene engineering method, i.e. Interferon Alfacon-1 molecule.Therefore, Interferon Alfacon-1 refers to the interferon-ALPHA molecule of an interferoid alpha molecule instead of a kind of specific amino acid sequence, but in an embodiment of the present invention representational to refer in particular in Chinese patent application CN02159950.5 in the open sequence of sequence table 3 and in description embodiment the Interferon Alfacon-1 of open preparation method.
The term " treatment effective dose " used in the present invention represents when drug administration active component is used for the treatment of or prevents disease, and the amount of active constituents of medicine is enough to realize the treatment to disease or prevention.Treatment effective dose by according to active constituents of medicine, disease and its seriousness and treat the age, body weight etc. of patient and different.
The term " injection pharmaceutically acceptable auxiliaries " used in the present invention refers to when injection formula designs, for solving the problem such as dissolubility, effectiveness, stability, safety of injection, join in injection formula except active constituents of medicine self to other auxiliary elements of human body or animal body safety.
The term " total concentration " used in the present invention refers to the summation of the concentration of such materials all, and such as albuminous total concentration refers to the summation of the concentration of various albumin class material (such as human serum albumin, bovine serum albumin); The total concentration of antiseptic phenols refers to the summation of the concentration of various antiseptic phenols (such as phenol, cresol, Nipagin ester).
The term " isotonic with blood of human body " used in the present invention refer to the osmotic pressure of solution blood of human body Standard physiological osmotic pressure (300mOsm/L) ± scope of 10% in (270-330mOsm/L).
It should be pointed out that the implication of other term used in the implication of some terms used in the present invention of above-mentioned explanation and above-mentioned unaccounted the present invention all well known to a person skilled in the art.Why the implication of these terms used in the present invention is made explanations, for the ease of auditor, and technical staff, market sale personnel, legal staff that the present invention is correlated with understand the present invention, therefore these not should be understood to limitation of the present invention to the explanation of the implication of the term used in the present invention.
Detailed description of the invention
By following embodiment, enforcement of the present invention is described further, but embodiments of the present invention are not limited to following embodiment.
Embodiment 1: the preparation of a different formulations interferon-ALPHA multiple dose injection
According to an interferon-ALPHA multiple dose injection of the formula composition preparation different formulations of such as following table 1.
The formula composition of an interferon-ALPHA multiple dose injection of table 1 different formulations
By 3 milliliters of transparent mode clamped bottle (product codes: 1406096) that amount subpackage SCHOTT Glass Technology (Suzhou) Co., Ltd. that an interferon-ALPHA multiple dose injection of each formula prepared aseptically props up with 3.3ml/ respectively manufactures.
Embodiment 2: stability and the biocidal property of a different formulations interferon-ALPHA multiple dose injection are tested
An interferon-ALPHA multiple dose injection of each formula of the method subpackage clamped bottle by previous embodiment 1 is placed in after subpackage cold compartment of refrigerator (2-8 DEG C, lower same) immediately to preserve.1 clamped bottle packaging is respectively got at the 0th day each formula preserved, jolting observes outward appearance after mixing, and then loads onto after Ou Man Ford medical apparatus and instruments (Shanghai) Co., Ltd. manufactures the matching used syringe needle sold and loads in the pen-type injector being all the said firm's manufacture sale.The multiple dose of an each formula injection is propelled 500 μ l to carrying out blank through autoclaved EP pipe under daily atmospheric environment, and what EP pipe was collected propel, and liquid is placed in immediately that cold compartment of refrigerator preserves and carry out interferon-ALPHA biologic activity as early as possible respectively and detect and detect with sterility test.By carry out blank propel after the multiple dose injection of each formula under daily atmospheric environment, continue to deposit 1 hour after, each clamped bottle packaging is taken out from pen-type injector, put back to cold compartment of refrigerator to preserve, and carry out the operation same with the 0th day after again taking out at the 2nd, 4,6,8,10 day respectively.
Outward appearance detects and adopts observation method of naked eye, and see color and the turbidity of solution, concrete testing result is as shown in table 2 below.
The stability outward appearance testing result of a table 2 different formulations interferon-ALPHA multiple dose injection
| Formula number | Sampling in 0 day | Sampling in 2 days | Sampling in 4 days | Sampling in 6 days | Sampling in 8 days | Sampling in 10 days |
| Formula 1 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 2 | Clear | Clear | Clear | White opacity | White opacity | White opacity |
| Formula 3 | Clear | Clear | Clear | Clear | White opacity | White opacity |
| Formula 4 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 5 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
| Formula 6 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
| Formula 7 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 8 | Clear | Clear | Clear | White opacity | White opacity | White opacity |
| Formula 9 | Clear | Clear | Clear | Clear | White opacity | White opacity |
| Formula 10 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 11 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
| Formula 12 | Clear | Clear | White opacity | White opacity | White opacity | White opacity |
| Formula 13 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 14 | Clear | Clear | Clear | White opacity | White opacity | White opacity |
| Formula 15 | Clear | Clear | Clear | Clear | White opacity | White opacity |
| Formula 16 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 17 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
| Formula 18 | Clear | Clear | White opacity | White opacity | White opacity | White opacity |
| Formula 19 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 20 | Clear | Clear | Clear | White opacity | White opacity | White opacity |
| Formula 21 | Clear | Clear | Clear | Clear | White opacity | White opacity |
| Formula 22 | Clear | Clear | Clear | Clear | Clear | Clear |
| Formula 23 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
| Formula 24 | Clear | White opacity | White opacity | White opacity | White opacity | White opacity |
Interferon-ALPHA biologic activity detects " the interferon biological activity algoscopy " that adopt " Pharmacopoeia of People's Republic of China version (three) in 2010 " annex X C to specify, and concrete testing result is as shown in table 3 below.
The stability biologic activity testing result of a table 3 different formulations interferon-ALPHA multiple dose injection
Sterility test detects " Sterility Test " that adopt " Pharmacopoeia of People's Republic of China version (three) in 2010 " annex XII A to specify, and strain, bacterium solution preparation and test sample process all adopt membrane-filter procedure.Concrete testing result is as shown in table 4 below.
The Bacteriostatic Sterile testing inspection result of a table 4 different formulations interferon-ALPHA multiple dose injection
| Formula number | Sampling in 0 day | Sampling in 2 days | Sampling in 4 days | Sampling in 6 days | Sampling in 8 days | Sampling in 10 days |
| Formula 1 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 2 | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Formula 3 | Qualified | Qualified | Qualified | Qualified | Defective | Defective |
| Formula 4 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 5 | Qualified | Qualified | Defective | Defective | Defective | Defective |
| Formula 6 | Qualified | Defective | Defective | Defective | Defective | Defective |
| Formula 7 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 8 | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Formula 9 | Qualified | Qualified | Qualified | Qualified | Defective | Defective |
| Formula 10 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 11 | Qualified | Qualified | Defective | Defective | Defective | Defective |
| Formula 12 | Qualified | Qualified | Defective | Defective | Defective | Defective |
| Formula 13 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 14 | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Formula 15 | Qualified | Qualified | Qualified | Qualified | Defective | Defective |
| Formula 16 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 17 | Qualified | Defective | Defective | Defective | Defective | Defective |
| Formula 18 | Qualified | Qualified | Defective | Defective | Defective | Defective |
| Formula 19 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 20 | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Formula 21 | Qualified | Qualified | Qualified | Qualified | Defective | Defective |
| Formula 22 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Formula 23 | Qualified | Defective | Defective | Defective | Defective | Defective |
| Formula 24 | Qualified | Defective | Defective | Defective | Defective | Defective |
Claims (10)
1. a stable interferon-ALPHA multiple dose injection, is characterized in that described injection pharmaceutically acceptable auxiliaries comprises albumin and antiseptic phenols containing the treatment interferon-ALPHA of effective dose and the injection pharmaceutically acceptable auxiliaries of Sq.
2. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that the interferon-ALPHA containing 0.1-1000 μ g/ml.
3. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that described interferon-ALPHA is selected from the combination of one or more in Interferon a2a, interferon alpha 2 b, Interferon α1 b, Interferon Alfacon-1.
4. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that described albuminous total concentration is 5-50mg/ml.
5. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that the total concentration of described antiseptic phenols is 0.2-3mg/ml.
6. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that described antiseptic phenols is selected from the combination of one or more in phenol, cresol, Nipagin ester.
7. an interferon-ALPHA multiple dose injection according to claim 1, it is characterized in that described injection pharmaceutically acceptable auxiliaries comprises the agent of pH stable regulation, be selected from the combination of one or more in phosphate buffered solution system, citrate buffer solution system, Ascorbate buffer solution system.
8. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that described injection pharmaceutically acceptable auxiliaries comprises osmotic pressure regulator in addition to albumin, is selected from the combination of one or more in sodium chloride, mannitol, glucose.
9. an interferon-ALPHA multiple dose injection according to claim 1; it is characterized in that described injection pharmaceutically acceptable auxiliaries comprises interferon-ALPHA activity protecting agent in addition to albumin, be selected from the combination of one or more in aminoacid, polyhydric alcohol, cyclodextrin, lecithin matter.
10. an interferon-ALPHA multiple dose injection according to claim 1, is characterized in that described injection pharmaceutically acceptable auxiliaries comprises adsorption inhibitor in addition to albumin, is selected from the combination of one or more in Tweens non-ionic surface active agent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105816857A (en) * | 2016-04-22 | 2016-08-03 | 北京三元基因药业股份有限公司 | Aqueous solution preparation of interferon (IFN) |
| CN109602705A (en) * | 2018-12-26 | 2019-04-12 | 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 spray |
| CN111494611A (en) * | 2020-06-08 | 2020-08-07 | 长春生物制品研究所有限责任公司 | Interferon injection liquid packaged by cartridge bottle multi-dose pen type injection combination |
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| CN1391478A (en) * | 1999-11-19 | 2003-01-15 | 株式会社Lgci | Aqueous solution formulation of alpha-interferon |
| CN1724567A (en) * | 2004-07-22 | 2006-01-25 | 北京三元基因工程有限公司 | Stable recombination human interferon alpha 1b water solution |
| CN102000324A (en) * | 2009-09-01 | 2011-04-06 | 天津瑞普生物技术股份有限公司 | Long-efficiency and stable animal interferon solution preparation and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105816857A (en) * | 2016-04-22 | 2016-08-03 | 北京三元基因药业股份有限公司 | Aqueous solution preparation of interferon (IFN) |
| CN109602705A (en) * | 2018-12-26 | 2019-04-12 | 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 spray |
| CN111494611A (en) * | 2020-06-08 | 2020-08-07 | 长春生物制品研究所有限责任公司 | Interferon injection liquid packaged by cartridge bottle multi-dose pen type injection combination |
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