CN101513524A - Alpha-interferon dry powder inhalant for pigs and method for producing same - Google Patents
Alpha-interferon dry powder inhalant for pigs and method for producing same Download PDFInfo
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- CN101513524A CN101513524A CNA2008101542007A CN200810154200A CN101513524A CN 101513524 A CN101513524 A CN 101513524A CN A2008101542007 A CNA2008101542007 A CN A2008101542007A CN 200810154200 A CN200810154200 A CN 200810154200A CN 101513524 A CN101513524 A CN 101513524A
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Abstract
The invention discloses a formulation of an alpha-interferon dry powder inhalant and a method for producing the same. The method comprises the following steps: adding a protective agent mainly comprising tween-80 into an alpha-interferon first; preparing the mixture into the dry powder inhalant mainly comprising the alpha-interferon through rotary evaporation and vacuum freezing and drying; and filling the dry powder inhalant into a rotary inhaler to prepare a finished product. The method prolongs the storage time of the interferon, and the interferon is convenient to use and advantageous for absorbing, thus the clinical using effect of the alpha-interferon is brought into play better.
Description
Technical field
The present invention relates to novel form Foradil Aerolizer formoterol fumarate of alpha-interferon and preparation method thereof, relate to novel form Foradil Aerolizer formoterol fumarate of the alpha-interferon that pig uses and preparation method thereof specifically, belong to field of pharmaceutical preparations.
Background technology
(interferon is to have bioactive glycoproteins such as antiviral, antitumor and immunoloregulation function by a class of emiocytosis under specific antigenic stimulus IFN) to interferon.And a kind of interferon can suppress the propagation of multiple virus, medically being a class broad-spectrum antiviral drugs, can be divided into three types of α, β, γ.Wherein alpha-interferon is mainly produced by mononuclear cell, also is to study and use maximum interferoids at present.
The main biologic activity of IFN-α has: (1) suppresses virus replication, mainly is to synthesize plurality of enzymes and produce paracrine action by inducing cell; (2) suppress the increment of cell, as tumor cell etc.; (3) ability of reinforcement NK cell killing virus infected cell, the NK cell has interferon receptors; (4) change the expression of MHC molecule, strengthen the expression of MHC I quasi-molecule and suppress the expression of MHC II quasi-molecule.
Because protein and peptide drugs is inactivation very easily, so the overwhelming majority is a drug administration by injection, for example Interferon Alpha-2b is treated hepatitis, and drug administration by injection is 3-5 time weekly, thereby have the following shortcoming that is difficult to overcome: what patient's bad adaptability, syringe needle infected is dangerous high, expense costliness etc.; In addition in the aqueous solution of interferon usually end user's serum albumin (HSA) thereby have unavoidably and pollute and pathophorous potential danger as protective agent; After the patient injects often with generate heat, shiver, side effect such as myalgia, also relevant, so the clinical practice of interferon is restricted greatly with drug administration by injection.
In view of the gastrointestinal administration of protein medicaments slowly fails to break through technical obstacle, pulmonary administration then is more satisfactory replacement route of administration.Pulmonary administration has following advantage: 1, the enzyme of pulmonary mainly is some pulmonary surfactants than digestive tract much less; 2, absorption area height; 3, blood flow is big, can reach 5000mL/min; 4, alveolar wall is also thinner than capillary wall, and thickness is less than 0.1 μ m, and permeability is good, and protein macromolecule is easy to see through; 5, walked around the first pass effect of liver; 6, drug absorption is rapid, and is rapid-action after the administration; 7, directly enter the body circulation after the drug absorption, reach the purpose of whole body therapeutic; When 8, playing local therapeutic effects, dosage obviously reduces, and toxic and side effects is little.
The present invention is with the in addition unmanned sero-abluminous protective agent of alpha-interferon; and make Foradil Aerolizer formoterol fumarate based on alpha-interferon by rotary evaporation and vacuum lyophilization; prolonged the storage life of interferon; and easy to use, be beneficial to absorption, better brought into play the clinical result of use of alpha-interferon.
Summary of the invention
It is a kind of alpha-interferon dry powder inhalant that first purpose of the present invention provides, and is made up of following material: alpha-interferon, osmotic pressure regulator, protective agent, proppant, buffer agent.Wherein, described protective agent effect is to make the preservation of interferon long-term stability and biological activity does not descend or have trace to descend.At present, many personnel selections of the protective agent of inhalant or poultry serum albumin (as bSA).Although end user or poultry serum albumin have certain advantage as activity protecting agent; but people or poultry serum albumin are as the endogenous material from human body or animal; may carry multiple disease (for example hepatitis, acquired immune deficiency syndrome (AIDS); thereby have highly potential danger in using clinically rabies virus etc.) and disease virus such as other infectious disease.Therefore, the used activity protecting agent of the present invention is selected from tween 80 (polyoxyethylene 20 sorbitan monooleate), lysine, 2-HP-or soybean lecithin etc.Wherein, tween 80 is used in the pharmaceutical preparation of a large amount of per os approach or non-digestive tract approach; have safe; advantages such as good dispersion; recently discover that tween 80 has various biological and pharmacological activity; comprise anti-tumor activity etc., therefore, protective agent is tween 80 preferably.
In a specific embodiments, described alpha-interferon dry powder inhalant is made up of following:
Alpha-interferon 10000-100000000IU/m
Osmotic pressure regulator 4-15mg/mL
Protective agent 0.02-0.20mL/mL
Proppant 50-120mg/mL
Buffer agent 2-15mg/mL
In a specific embodiments, described inhalant dry powder should be able to be easy to disperse, and can arrive pulmonary by breathing subsequently, that is to say that this powder can be inhaled into.Thereby the particle diameter of dry powder microgranule should be preferably less than 5 μ m less than 10 μ m.Preferable particle size is about 0.1-5 μ m, is most preferably 2-4 μ m.Dry powder particle size range of the present invention is all at 1-4 μ m.
In a specific embodiments, described osmotic pressure regulator is a sodium chloride.
In a specific embodiments, described proppant is a mannitol.
In a specific embodiments, described buffer agent is a phosphoric acid salt.Wherein, phosphoric acid salt sodium hydrogen phosphate preferably.
Second purpose of the present invention provides the preparation method that is used to prepare above-mentioned alpha-interferon dry powder inhalant; it is characterized in that: with the activity protecting agent of tween 80 as alpha-interferon; come dry alpha-interferon with rotary evaporation and vacuum freezing drying method, to prepare highly active alpha-interferon dry powder inhalant.
In a specific embodiments, according to aforementioned proportion interferon, protective agent, osmotic pressure regulator, proppant, buffer agent are mixed, be configured to the interferon liquid phase mixture.Then above-mentioned liquid-phase system is rotated evaporation and vacuum lyophilization under 40 ℃, promptly makes the granule (preferable particle size be about 0.1-5 μ m, be most preferably 2-4 μ m) of mean diameter less than 10 μ m.
The 3rd purpose of the present invention provides the purposes that above-mentioned alpha-interferon dry powder inhalant is used for disease treatment.
In a specific embodiments, described alpha-interferon is a porcine alpha-interferon, described disease is diseases such as animal asthma, contagious pleuropneumonia, infectious atrophic rhinitis, influenza, or is used for the treatment of the disease such as asthma, contagious pleuropneumonia, infectious atrophic rhinitis, influenza of pig.
Technique effect:
1. alpha-interferon dry powder inhalant has higher chemical stability and microbial stability than liquid spray or injection, so the storage life that has prolonged alpha-interferon, can be for 2 years.
2. alpha-interferon dry powder inhalant is by the administration of dry powder rotation inhaler, and aerosolization and the pulmonary by the host carry out fast Absorption fast, and easy to use, assimilation effect is better.
3. the conventional atomizing freeze drying loss of activity of the preparation method of alpha-interferon dry powder inhalant is littler.
4. alpha-interferon dry powder inhalant provides a kind of more direct, effective method for the clinical practice of alpha-interferon.
5. alpha-interferon dry powder inhalant does not contain propellant, thereby does not relate to the environmental hazard problem
6. do not contain antiseptic and ethanol equal solvent, to pathological changes mucosa nonirritant;
7. dosage is big, is particularly useful for the administration of polypeptide and protein medicaments.
The specific embodiment:
Be described in further detail the present invention below by embodiment.
Embodiment 1: the preparation of porcine alpha-interferon Foradil Aerolizer formoterol fumarate
With the porcine alpha-interferon is example:
Press following set of dispense system porcine alpha-interferon solution (A) 5L to be dried:
Porcine alpha-interferon 2.12 * 10
7IU/mL
NaCl 8mg/mL
Tween 80 0.05mL/mL
Mannitol 70.3mg/mL
Sodium hydrogen phosphate 4.0mg/mL
Press following set of dispense system porcine alpha-interferon solution (B) 5L to be dried:
Porcine alpha-interferon 2.12 * 10
7IU/mL
NaCl 4mg/mL
Tween 80 0.02mL/mL
Mannitol 50mg/mL
Sodium hydrogen phosphate 2mg/M1
Press following set of dispense system porcine alpha-interferon solution (C) 5L to be dried:
Porcine alpha-interferon 2.12 * 10
7IU/mL
NaCl 15mg/mL
Tween 80 0.20mL/mL
Mannitol 120mg/mL
Sodium hydrogen phosphate 15mg/mL
Above-mentioned 3 kinds of liquid-phase system A, B, C are rotated evaporation and vacuum lyophilization under 40 ℃, promptly make the granule of mean diameter less than 10 μ m, the porcine alpha-interferon dry powder particle that drying is the good rotation inhaler of packing into is made porcine alpha-interferon Foradil Aerolizer formoterol fumarate finished product A, B, C.
Wherein, through test, the particle diameter of above-mentioned porcine alpha-interferon Foradil Aerolizer formoterol fumarate finished product A, B, C meets the requirement of clinical use all at 1-5 μ m.
Embodiment 2: the activity level test of porcine alpha-interferon Foradil Aerolizer formoterol fumarate
By the biological activity of identical dilution factor mensuration porcine alpha-interferon stock solution and its Foradil Aerolizer formoterol fumarate finished product, adopt the half cell to suppress the pathological changes method, use the VSV-MDBK system measurement.(the method reference " Pharmacopoeia of People's Republic of China version in 2005)
Experimental data is as follows:
| Sample | Biological activity (IU/mL) |
| Porcine alpha-interferon stock solution | 2.12×10 7 |
| Foradil Aerolizer formoterol fumarate finished product A | 2.10×10 7 |
| Foradil Aerolizer formoterol fumarate finished product B | 2.08×10 7 |
| Foradil Aerolizer formoterol fumarate finished product C | 2.07×10 7 |
By experimental result as can be known, with in addition protective agent and the basic free of losses of biological activity by porcine alpha-interferon in the Foradil Aerolizer formoterol fumarate of rotary evaporation and vacuum freezing drying method preparation of porcine alpha-interferon.
Embodiment 3: the preservation test of porcine alpha-interferon Foradil Aerolizer formoterol fumarate
Place 4 ℃ of refrigerators to preserve porcine alpha-interferon stock solution and its Foradil Aerolizer formoterol fumarate finished product, regularly carry out biological activity assay, adopt the half cell to suppress the pathological changes method, use the VSV-MDBK system measurement.(method is with reference to Pharmacopoeia of the People's Republic of China version in 2005)
Experimental data is as follows:
| Sample | 0 month | 4 months | 8 months | 12 months | 16 months | 20 months | 24 months |
| Porcine alpha-interferon stock solution (biological activity 10 6IU/mL) | 21.2 | 19.8 | 13.7 | 8.6 | 3.2 | 0.16 | 0.03 |
| Foradil Aerolizer formoterol fumarate finished product (biological activity 10 6IU/mL) | 21.0 | 21.0 | 20.3 | 19.7 | 19.2 | 19.0 | 18.8 |
By above-mentioned experimental data as can be known, porcine alpha-interferon Foradil Aerolizer formoterol fumarate finished product stores 2 years down at 4 ℃, its biological activity has trace to reduce, do not influence clinical use, 2 years active declines of storage will be nearly a hundred times down and porcine alpha-interferon stock solution is at 4 ℃, this shows that the storage life of porcine alpha-interferon Foradil Aerolizer formoterol fumarate of the present invention obviously prolongs, and is more conducive to production and selling.
Claims (10)
1, a kind of alpha-interferon dry powder inhalant; comprise alpha-interferon, osmotic pressure regulator, protective agent, proppant and buffer agent, wherein protective agent is selected from polyoxyethylene 20 sorbitan monooleate (tween 80), lysine, 2-HP-or soybean lecithin.
2, alpha-interferon dry powder inhalant according to claim 1, wherein osmotic pressure regulator is a sodium chloride, protective agent is that polyoxyethylene 20 sorbitan monooleate (tween 80), proppant are that mannitol, buffer agent are phosphoric acid salt.
3, alpha-interferon dry powder inhalant according to claim 1 and 2, the particle diameter 0.1-10 μ m of dry powder microgranule wherein, preferable particle size is 0.1-5 μ m, most preferably is 2-4 μ m.
4, alpha-interferon dry powder inhalant according to claim 3, wherein constituent content is:
Alpha-interferon 10000-100000000IU/mL
NaCl 4-15mg/mL
Tween 80 0.02-0.20mL/mL
Mannitol 50-120mg/mL
Sodium hydrogen phosphate 2-15mg/mL.
5, alpha-interferon dry powder inhalant according to claim 4, wherein constituent content is:
Alpha-interferon 10
7IU/mL
NaCl 8mg/mL
Tween 80 0.05mL/mL
Mannitol 70.3mg/mL
Sodium hydrogen phosphate 4.0mg/mL.
6, according to each described alpha-interferon dry powder inhalant among the claim 1-5, wherein alpha-interferon is a porcine alpha-interferon.
7, a kind ofly be used for preparing each the method for alpha-interferon dry powder inhalant of claim 1-6; it is characterized in that: at first alpha-interferon is added protective agent based on tween 80; and make Foradil Aerolizer formoterol fumarate based on alpha-interferon by rotary evaporation and vacuum lyophilization, the rotation inhaler of packing into is made finished product.
8, the described method of claim 7; wherein interferon, protective agent, osmotic pressure regulator, proppant, buffer agent are mixed by described constituent content; be configured to the interferon liquid phase mixture; then above-mentioned liquid-phase system is rotated evaporation and vacuum lyophilization under 40 ℃; promptly make the granule of mean diameter less than 10 μ m, preferable particle size is 0.1-5 μ m, most preferably particle diameter is the granule of 2-4 μ m.
9, the prepared alpha-interferon dry powder inhalant of the described alpha-interferon dry powder inhalant of claim 1-5, or the method for claim 7-8 is used for preparing the purposes of disease treatment.
10, the described purposes of claim 9, wherein said disease is diseases such as animal asthma, contagious pleuropneumonia, infectious atrophic rhinitis, influenza, or is used for the treatment of the disease such as asthma, contagious pleuropneumonia, infectious atrophic rhinitis, influenza of pig.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101542007A CN101513524A (en) | 2008-12-17 | 2008-12-17 | Alpha-interferon dry powder inhalant for pigs and method for producing same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101542007A CN101513524A (en) | 2008-12-17 | 2008-12-17 | Alpha-interferon dry powder inhalant for pigs and method for producing same |
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|---|---|
| CN101513524A true CN101513524A (en) | 2009-08-26 |
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|---|---|---|---|
| CNA2008101542007A Pending CN101513524A (en) | 2008-12-17 | 2008-12-17 | Alpha-interferon dry powder inhalant for pigs and method for producing same |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727467A (en) * | 2012-07-07 | 2012-10-17 | 北京三元基因工程有限公司 | Dry powder inhalant of interferon alpha |
-
2008
- 2008-12-17 CN CNA2008101542007A patent/CN101513524A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727467A (en) * | 2012-07-07 | 2012-10-17 | 北京三元基因工程有限公司 | Dry powder inhalant of interferon alpha |
| CN102727467B (en) * | 2012-07-07 | 2014-03-12 | 北京三元基因工程有限公司 | Dry powder inhalant of interferon alpha |
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Open date: 20090826 |