CN104888196B - A kind of interferon-' alpha ' multi-dose parenteral solution of stabilization - Google Patents
A kind of interferon-' alpha ' multi-dose parenteral solution of stabilization Download PDFInfo
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- CN104888196B CN104888196B CN201510357975.4A CN201510357975A CN104888196B CN 104888196 B CN104888196 B CN 104888196B CN 201510357975 A CN201510357975 A CN 201510357975A CN 104888196 B CN104888196 B CN 104888196B
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Abstract
The invention belongs to the formulation arts of pharmaceutical grade protein, it is related to a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, it contains the parenteral solution pharmaceutically acceptable auxiliaries of the interferon-' alpha ' of therapeutically effective amount and appropriate amount, and the parenteral solution pharmaceutically acceptable auxiliaries include albumin and antiseptic phenols.The multi-dose parenteral solution of the interferon-' alpha ' of the present invention can keep during be used for multiple times safely, effectively, stablize.
Description
Technical field
The present invention generally relates to stable interferon-' alpha ' parenteral solution, is noted in particular to stable interferon-' alpha ' multi-dose pen
Penetrate liquid.
Background technology
Interferon (Interferon, IFN) is that one kind is initially generated by animal body, has broad-spectrum antiviral, antiproliferative
With the cytokine class pharmaceutical grade protein of immunoregulation effect, according to the difference of its generating unit and the mechanism of action can be divided into α,
β, γ, λ etc. big type, and each big type can be divided into several small hypotypes, different hypotype in same big type
Between in primary structure difference very little, it is very close on two level more than higher structure.In several big types, α types are should
With most wide one kind, this type of interferon of clinical practice at present mainly includes Interferon a2a, interferon alpha 2 b, Interferon α1 b, answers
Close interferon etc..
Alpha-interferon is mainly at present parenteral solution in the dosage form of Clinical practice, and the indication of approval application is including B-mode
Hepatitis, hepatitis C, hairy cell leukemia, sharp wet knurl and kinds of tumors etc., wherein one course for the treatment of of most indications
Treatment needs time of 16 weeks or more, weekly medication 3 times or more.Since administration time is long, need to frequently arrive hospital carry out injection control
It treats, this just brings big inconvenience or even pain using alpha-interferon injection for treating target indication to patient, also exists
Largely hinder the popularization and application of alpha-interferon parenteral solution clinically.
Multi-dose pen is that a kind of patient developed in recent years can not be and only by hospital, the help of doctor, nurse
The vertical new medical instrument that drug injection liquid product is used for multiple times, has been widely used on injection of insulin liquid product (packet
Include the promise of Novo Nordisk and pen, gift come excellent visits woods pen with pen, Bayer), on interferon injection products also
It is related to that (Schering Plough company applies it to Intron AOn product).
In addition, compared with traditional drug injection liquid product, the multi-dose injection products of drug are also with following several
Point advantage：It is handled first, carrying out destructive opening without the medicine bottle to depot injections when using, so as to prevent broken production
Raw glass chip enters human body in company with liquid and human body is damaged into the liquid；It second is that can be to avoid actually facing
The disposable syringe of violation largely occurred in bed application repeatedly uses caused unsafe injection problem；Third,
Medical waste caused by the consumption of disposable syringe product can be reduced, so as to be conducive to environmental protection.
But the characteristics of being mostly disposable behind Kaifeng from traditional drug injection liquid product different, multi-agent of drug
Amount injection products the characteristics of being used for multiple times increase the number that drug is exposed in use in ambient enviroment and when
Between, so as to also just propose higher requirement to its safety and stability.Therefore it needs to exist including drug injection formula of liquid
Further Optimal improvements are made compared with traditional drug injection products in interior multiple links, the multi-dose pen of drug could be met
The requirement of injection products Clinical practice.
Formula composition, preparation method and the using effect of some traditional interferon-' alpha ' parenteral solutions are reported in the prior art,
They can as an optimization interferon-' alpha ' multi-dose parenteral solution formula composition reference basis.
Such as Chinese patent application CN95195600.0 is disclosed with a kind of aqueous alpha interferon solution formulations of stabilization, no
Derivative products containing blood of human body (including human serum albumins) but comprising：(a)0.1×106-100×106The α-type interference of IU/ml
Element；(b) buffer systems of the pH in the range of 4.5-7.1 is kept；(c) a effective amount of chelating agent；(d) it is enough to stablize α-type interferon
Poly- (oxygen -1,2- second diyl) ester of a certain number of anhydro sorbitol list -9- octadecenoic acids for tackling the loss of α-type interferon spreads out
Biology；(e) a effective amount of tonicity agents；(f) a effective amount of antibiotic antiseptic；(g) it is enough to prepare the above-mentioned solution for listing component
A certain number of waters for injection.The aqueous solution preparation is claimed keeps α-type interference in the long-term storage timeliness of at least 24 months
Height chemistry, high physics and the high biological stability of element.
For another example Chinese patent application CN00815919.X discloses a kind of aqueous solution formulation of alpha-interferon, the aqueous solution
Preparation includes alpha-interferon, stabilizer, osmotic pressure regulator, antibiotic antiseptic and buffer system, not comprising human serum albumins
And chelating agent, pH 4.5-6.0, the antibiotic antiseptic are selected between the phenol of 0.1-0.3w/v%, 0.1-0.15w/v%
Cresols or the mixture of the phenol and metacresol.The aqueous solution formulation claims the activity that can keep alpha-interferon for a long time,
By the way that the amount of preservative is reduced the potential danger eliminated to human body, and very stable.
Invention content
The object of the present invention is to provide a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, to solve multiple injection, repeatedly
It is exposed to the more common interferon-' alpha ' parenteral solution brought using process to interferon-' alpha ' multi-dose parenteral solution of ambient enviroment more
Prominent stability problem, antibacterial sex chromosome mosaicism or even the safety issue brought by stability and antibacterial sex chromosome mosaicism.
In order to achieve this, in the embodiment on basis, the present invention provides a kind of interferon-' alpha ' multi-dose pen note of stabilization
Liquid is penetrated, the parenteral solution pharmaceutically acceptable auxiliaries of interferon-' alpha ' and appropriate amount containing therapeutically effective amount, the parenteral solution is pharmaceutically acceptable auxiliary
Material includes albumin and antiseptic phenols.
Albumin is also known as albumin, is content highest in human or animal's blood plasma, can play and maintain plasma colloid osmotic pressure, knot
Substance is closed and transported, coordinates the integrity of endothelium, haemocyte is protected to adjust blood coagulation, do not activate inflammatory reaction, Organoprotective, resist
A kind of native protein of the effects that oxidation, injury repair.Albumin is applied in pharmaceutical preparation, especially biotech drug
Effect played in injection formulation is mainly to aid in maintaining the biological activity of biotech drug, reduces container wall to life
The absorption of object technical agent, and adjust the osmotic pressure of biotech drug.
Animal serum albumin, such as bovine serum albumin(BSA) or human serum albumins may be selected in the albumin of the present invention, but
In order to reduce immunogenicity, preferably human serum albumins.
The total concentration of the albumin of the present invention should be between 5-50mg/ml, preferably between 10-20mg/ml.
Pharmaceutical preservative with no toxicity is that one kind is added in drug, inhibits micro- during the production of drug, transport, storage and use
Biological growth, especially harmful microorganism are grown, and prevent microorganism and its metabolite from destroying drug ingedient, particularly active
The substance of ingredient.Antiseptic phenols are the preservatives that chemical constitution belongs to phenolic compound, and phenolic compound is aromatic ring
The quasi-aromatic compound that upper hydrogen is optionally substituted by a hydroxyl group.
The present invention antiseptic phenols include but is not limited to phenol, cresols (and including o-cresol, metacresol, to first
Phenol), one kind in paraben esters (i.e. p-hydroxybenzoate, including methyl p-hydroxybenzoate, ethyl ester, propyl ester, butyl ester etc.)
Or several combinations, preferably cresols, paraben esters or combination thereof, and more preferable metacresol.
The total concentration of the antiseptic phenols of the present invention should be between 0.2-3mg/ml, preferably between 0.5-2mg/ml.
Other than albumin and antiseptic phenols, parenteral solution pharmaceutically acceptable auxiliaries of the invention further preferably include pH stable regulations
Agent, a greater variety of osmotic pressure regulators, a greater variety of interferon-' alpha ' activity protecting agents and/or a greater variety of absorption inhibit
Agent.
PH stable regulation agent, which is played, stablizes the pH of interferon-' alpha ' multi-dose parenteral solution at physiology appropriate pH (5.0-8.0)
Effect, and require physiological safety, selectable range includes but is not limited to phosphate buffer solution system, citrate delays
Rush solution system, ascorbate buffer solution system, preferably phosphate buffer solution system.Such pH stable regulations agent
Total concentration should be between 0.1-500mmol/L, preferably between 1-100mmol/L, and more preferably between 5-20mmol/L.
Osmotic pressure regulator, which plays, adjusts the osmotic pressure of interferon-' alpha ' multi-dose parenteral solution to isotonic with blood of human body
Effect, in addition to albumin, it is also an option that the combination of one or more of substances such as sodium chloride, mannitol, glucose.
Interferon-' alpha ' activity protecting agent plays protection interferon-' alpha ' and prepares, transports, stores and use in multi-dose parenteral solution
Middle activity does not lose or the effect of less forfeiture, in addition to albumin, it is also an option that amino acid, polyalcohol, cyclodextrin, lecithin
The combination of one or more of class substance.
Adsorption inhibitor play inhibition or reduce the container for the multi-dose parenteral solution for containing interferon-' alpha ' to interferon-' alpha ' and
The effect of the absorption of other auxiliary materials, in addition to albumin, it is also an option that surfactant, and preferably Tweens non-ionic surface is lived
Property agent.
It should be pointed out that a kind of or a kind of substance may simultaneously play in the interferon-' alpha ' multi-dose parenteral solution of the present invention
The effect of above-mentioned a variety of pharmaceutically acceptable auxiliaries functions.Except albumin plays osmotic pressure regulator, activity protecting agent, absorption inhibition simultaneously
Outside the effect of agent, if for example containing mannitol, can simultaneously it be risen in the interferon-' alpha ' multi-dose parenteral solution of the present invention
To the effect of osmotic pressure regulator and activity protecting agent.
The interferon-' alpha ' multi-dose parenteral solution of the present invention should be dissolved in process for preparation by preparation aequum first respectively can medicine
With auxiliary material, then in the volume for adjusting solution after mixing with the stoste of interferon-' alpha ' to targeted injection liquid dose volume.Respectively may be used
The dissolving of pharmaceutic adjuvant can be carried out at the same time, and can also be carried out respectively, but the preparation of slightly solubility pharmaceutically acceptable auxiliaries should individually carry out, and regard
Situation heats and/or adds in certain cosolvent.Should at least bacteria removing, the method for processing be carried out to the parenteral solution of mixing gained
Mainly membrane filtration；It is preferred that all carrying out bacteria removing after the dissolving of each pharmaceutically acceptable auxiliaries, then prepared again with aseptic processing
Interferon-' alpha ' stoste mixes, and the method for each pharmaceutically acceptable auxiliaries bacteria removing can be membrane filtration and/or high pressure moist heat sterilization, but
Thermal instability pharmaceutically acceptable auxiliaries are unsuitable for high pressure moist heat sterilization.Water needed for preparing is preferably through the processing of ion exchange deionization
It is handled with distillation.Parenteral solution after bacteria removing is aseptically sub-packed in special container, such as block by packing volume requirement
In formula bottle, final interferon-' alpha ' multi-dose injection products are obtained.
The interferon-' alpha ' multi-dose injection products being prepared are in addition to the sampling side according to regular injection liquid product requirement
It is more in reality further preferably in the preservation condition of actual requirement outside method, detection method and detection project evaluation stability, biocidal property
It is secondary use point in time sampling evaluation stability, biocidal property, and more preferably the preservation condition than actual requirement condition difference and/
Or than actually using more frequent point in time sampling evaluation stability, biocidal property.
The project of Detection of Stability includes but is not limited to one or more in the following：Appearance detects, pH is detected,
Interferon-' alpha ' biological activity detects, and preferably appearance detection is detected with interferon-' alpha ' biological activity.
Appearance detection sees the color and turbidity of solution using observation method of naked eye.
PH detections preferably use《Pharmacopoeia of People's Republic of China version (three) in 2010》" pH value is surveyed as defined in annex V A
Determine method ".
Interferon-' alpha ' Activity determination preferably uses《Pharmacopoeia of People's Republic of China version (three) in 2010》Annex X C are provided
" interferon biological activity measuring method ".
The project of biocidal property detection includes but is not limited to one or more in the following：The detection of bacteriostatic agent effect,
Bacteriostatic agent content detection, sterility test detection, preferably sterility test detect.
Bacteriostatic agent effect detects preferably reference《Pharmacopoeia of People's Republic of China version (three) in 2010》Annex XVII is provided
" bacteriostatic agent (preservative) effect inspection technique guideline " carry out.
Bacteriostatic agent content detection preferably uses《Pharmacopoeia of People's Republic of China version (three) in 2010》Annex VI N are provided
" metacresol measuring method ".
Sterility test detection preferably uses《Pharmacopoeia of People's Republic of China version (three) in 2010》As defined in annex XIIA
" Sterility Test ".
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, contains
There is the interferon-' alpha ' of 0.1-1000 μ g/ml.
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
It contains the interferon-' alpha ' of 1-100 μ g/ml.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The interferon-' alpha ' is selected from the group of one or more of Interferon a2a, interferon alpha 2 b, Interferon α1 b, Interferon Alfacon-1
It closes.
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
The wherein described interferon-' alpha ' is Interferon α1 b.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The total concentration of the albumin is 5-50mg/ml.
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
The total concentration of the wherein described albumin is 10-20mg/ml.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The total concentration of the antiseptic phenols is 0.2-3mg/ml.
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
The total concentration of the wherein described antiseptic phenols is 0.5-2mg/ml.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The antiseptic phenols are selected from the combination of one or more of phenol, cresols, paraben esters.
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
The wherein described antiseptic phenols are metacresols.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The parenteral solution pharmaceutically acceptable auxiliaries include pH stable regulation agent, molten selected from phosphate buffer solution system, citrate buffering
The combination of one or more of liquid system, ascorbate buffer solution system.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The parenteral solution pharmaceutically acceptable auxiliaries include osmotic pressure regulator in addition to albumin, in sodium chloride, mannitol, glucose
One or more of combinations.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The parenteral solution pharmaceutically acceptable auxiliaries include interferon-' alpha ' activity protecting agent in addition to albumin, selected from amino acid, polyalcohol, ring
The combination of one or more of dextrin, lecithin matter.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, wherein
The parenteral solution pharmaceutically acceptable auxiliaries include adsorption inhibitor in addition to albumin, in Tweens nonionic surfactant
One or more of combinations.
In a preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, contains
There are the interferon-' alpha ' of 0.1-1000 μ g/ml, the human serum albumins of 5-50mg/ml, the metacresol of 0.2-3mg/ml, 1-
100mmol/L disodium hydrogen phosphates-sodium dihydrogen phosphate, pH7.0 solution and adjusting infiltration are depressed into isotonic with blood of human body
NaCl。
In a kind of more preferred embodiment, the present invention provides a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization,
It contains the interferon-' alpha ' of 1-100 μ g/ml, the human serum albumins of 10-20mg/ml, the metacresol of 0.5-2mg/ml, 5-
20mmol/L disodium hydrogen phosphates-sodium dihydrogen phosphate, pH7.0 solution and adjusting infiltration are depressed into the NaCl isotonic with blood of human body.
The term " interferon-' alpha ' " used in the present invention is generated including human body under the stimulation of extraneous pathogenic agent by leucocyte
Native sequences antiviral active substance, also include selecting that suitable expression vector expresses by gene engineering method with it is upper
The identical recombinant molecule of native sequences is stated, further includes the collection for suitable expression vector being selected to express by gene engineering method
Into the molecule of the engineer of above-mentioned natural interferon alpha conserved sequence, i.e. Interferon Alfacon-1 molecule.Therefore, Interferon Alfacon-1
Refer to a kind of interferon-' alpha ' molecule rather than a kind of interferon-' alpha ' molecule of specific amino acid sequence, but in an embodiment of the present invention
It is representative to refer in particular in Chinese patent application CN02159950.5 in the open sequence of sequence table 3 and the public affairs in specification embodiment
Open the Interferon Alfacon-1 of preparation method.
The term " therapeutically effective amount " used in the present invention, which represents to work as, applies active constituents of medicine for treating or preventing disease
When sick, the amount of active constituents of medicine is enough to realize the treatment or prevention to disease.Therapeutically effective amount will be according to active constituents of medicine, disease
Disease and its seriousness are different with age, weight of patient etc. is treated.
The term " parenteral solution pharmaceutically acceptable auxiliaries " used in the present invention refers to when injection formula designs, and is injected to solve
The problems such as dissolubility of liquid, validity, stability, safety, be added in injection formula in addition to active constituents of medicine
Itself other auxiliary element to human body or animal body safety.
The term " total concentration " used in the present invention refers to the summation of the concentration of such all substance, such as albumin is total
Concentration refers to the summation of the concentration of various albumin class substances (such as human serum albumins, bovine serum albumin(BSA))；Phenols anti-corrosion
The total concentration of agent refers to the summation of the concentration of various antiseptic phenols (such as phenol, cresols, paraben esters).
The term " isotonic with blood of human body " used in the present invention refers to the osmotic pressure of solution in blood of human body Standard physiological
In the range of ± the 10% of osmotic pressure (300mOsm/L) (270-330mOsm/L).
It should be pointed out that in the meaning of some terms used in the present invention of above-mentioned explanation and the above-mentioned unaccounted present invention
The meaning of other terms used is well known to those skilled in the art.Why to these terms for being used in the present invention
Meaning is made explanations, and is for the ease of auditor and the relevant technical staff of the present invention, market sale personnel, legal staff's reason
The solution present invention, therefore these are not construed as limitation of the present invention to the explanation of the meaning of the term used in the present invention.
Specific embodiment
The implementation of the present invention is described further, but embodiments of the present invention are not limited to by examples below
In examples below.
Embodiment 1：The preparation of different formulations interferon-' alpha ' multi-dose parenteral solution
The interferon-' alpha ' multi-dose parenteral solution of different formulations is prepared according to the formula composition of such as the following table 1.
The formula composition of the interferon-' alpha ' multi-dose parenteral solution of 1 different formulations of table
The amount that the prepared interferon-' alpha ' multi-dose parenteral solution being respectively formulated aseptically is propped up with 3.3ml/ respectively
Dispense 3 milliliters of transparent mode clamped bottle (product codes of SCHOTT Glass Technology's manufacture：1406096).
Embodiment 2：The stability of different formulations interferon-' alpha ' multi-dose parenteral solution is tested with biocidal property
It will dispensed by the interferon-' alpha ' multi-dose parenteral solution being respectively formulated of the method for previous embodiment 1 packing clamped bottle
After be immediately placed on the preservation of (2-8 DEG C, similarly hereinafter) of cold compartment of refrigerator.1 clamped bottle packaging is respectively taken in being respectively formulated for the 0th day for preservation, is shaken
Even rear observation appearance is shaken to mixed, then loads onto the matching used needle of Ou Man Ford's medical instruments (Shanghai) Co., Ltd. manufacture sale
Be fitted into after head is all that the said firm is manufactured in the pen-type injector sold.By the multi-dose parenteral solution of each formula in daily air
Under environment cold compartment of refrigerator is immediately placed on to the liquid of propelling for propelling the collection of 500 μ l, EP pipes into line blank through autoclaved EP pipes
It preserves and carries out the detection of interferon-' alpha ' biological activity respectively as early as possible and detected with sterility test.Respectively matching after being propelled into line blank
After the multi-dose parenteral solution of side continues storage 1 hour under daily atmospheric environment, each cassette is taken out from pen-type injector
Bottle packaging puts back to cold compartment of refrigerator preservation, and is carried out after being taken out again at the 2nd, 4,6,8,10 day respectively and the 0th day same behaviour
Make.
Appearance detection sees the color and turbidity of solution, specific testing result is as shown in table 2 below using observation method of naked eye.
The stability appearance testing result of 2 different formulations interferon-' alpha ' multi-dose parenteral solution of table
| Formula number | It samples within 0 day | It samples within 2 days | It samples within 4 days | It samples within 6 days | It samples within 8 days | It samples within 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 |
The detection of interferon-' alpha ' biological activity uses《Pharmacopoeia of People's Republic of China version (three) in 2010》Annex X C are advised
Fixed " interferon biological activity measuring method ", specific testing result is as shown in table 3 below.
The stabilization biologic activity testing result of 3 different formulations interferon-' alpha ' multi-dose parenteral solution of table
Sterility test detection uses《Pharmacopoeia of People's Republic of China version (three) in 2010》" nothing as defined in annex XII A
Bacterium inspection technique ", prepared by strain, bacterium solution and test sample processing uses membrane-filter procedure.Specific testing result is as shown in table 4 below.
The Bacteriostatic Sterile testing inspection result of 4 different formulations interferon-' alpha ' multi-dose parenteral solution of table
| Formula number | It samples within 0 day | It samples within 2 days | It samples within 4 days | It samples within 6 days | It samples within 8 days | It samples within 10 days |
| Formula 1 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 2 | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 3 | It is qualified | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified |
| Formula 4 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 5 | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 6 | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 7 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 8 | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 9 | It is qualified | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified |
| Formula 10 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 11 | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 12 | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 13 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 14 | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 15 | It is qualified | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified |
| Formula 16 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 17 | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 18 | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 19 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 20 | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 21 | It is qualified | It is qualified | It is qualified | It is qualified | It is unqualified | It is unqualified |
| Formula 22 | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified | It is qualified |
| Formula 23 | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
| Formula 24 | It is qualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified | It is unqualified |
Claims (12)
1. a kind of interferon-' alpha ' multi-dose parenteral solution of stabilization, it is characterized in that the interferon-' alpha ' containing 0.1-1000 μ g/ml is with fitting
The parenteral solution pharmaceutically acceptable auxiliaries preferably measured, the parenteral solution pharmaceutically acceptable auxiliaries include total concentration be 5-50mg/ml albumin with
Total concentration is the antiseptic phenols of 0.2-3mg/ml, and the antiseptic phenols are metacresols.
2. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the interferon containing 1-100 μ g/ml
α。
3. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the interferon-' alpha ' is selected from interference
The combination of one or more of plain α 2a, interferon alpha 2 b, Interferon α1 b, Interferon Alfacon-1.
4. interferon-' alpha ' multi-dose parenteral solution according to claim 3, it is characterized in that the interferon-' alpha ' is interferon-' alpha '
1b。
5. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the total concentration of the albumin is
10-20mg/ml。
6. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the antiseptic phenols is total dense
It spends for 0.5-2mg/ml.
7. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the parenteral solution pharmaceutically acceptable auxiliaries
It is molten selected from phosphate buffer solution system, citrate buffer solution system, ascorbic acid salt buffer comprising pH stable regulation agent
The combination of one or more of liquid system.
8. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the parenteral solution pharmaceutically acceptable auxiliaries
Comprising osmotic pressure regulator in addition to albumin, the combination selected from one or more of sodium chloride, mannitol, glucose.
9. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the parenteral solution pharmaceutically acceptable auxiliaries
Comprising interferon-' alpha ' activity protecting agent in addition to albumin, one in amino acid, polyalcohol, cyclodextrin, lecithin matter
Kind or several combinations.
10. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the parenteral solution is pharmaceutically acceptable auxiliary
Material is comprising adsorption inhibitor in addition to albumin, the combination selected from one or more of Tweens nonionic surfactant.
11. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that dry containing 0.1-1000 μ g/ml
Disturb plain α, the human serum albumins of 5-50mg/ml, the metacresol of 0.2-3mg/ml, 1-100mmol/L disodium hydrogen phosphates-di(2-ethylhexyl)phosphate
Hydrogen sodium, pH7.0 solution and adjusting infiltration are depressed into the NaCl isotonic with blood of human body.
12. interferon-' alpha ' multi-dose parenteral solution according to claim 1, it is characterized in that the interference containing 1-100 μ g/ml
The human serum albumins of plain α, 10-20mg/ml, the metacresol of 0.5-2mg/ml, 5-20mmol/L disodium hydrogen phosphates-biphosphate
Sodium, pH7.0 solution and adjusting infiltration are depressed into the NaCl isotonic with blood of human body.
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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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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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