CN102716469B - Dry powder inhalant of interferon alpha - Google Patents
Dry powder inhalant of interferon alpha Download PDFInfo
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- CN102716469B CN102716469B CN 201210236604 CN201210236604A CN102716469B CN 102716469 B CN102716469 B CN 102716469B CN 201210236604 CN201210236604 CN 201210236604 CN 201210236604 A CN201210236604 A CN 201210236604A CN 102716469 B CN102716469 B CN 102716469B
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Abstract
The invention belongs to the field of preparations of protein drugs, and relates to a dry powder inhalant of interferon alpha. The dry powder inhalant contains consensus interferon of treatment effective dose and pharmaceutic adjuvant of the dry powder inhalant of proper dose; the interferon alpha consists of interferon alpha1b and the consensus interferon at a weight ratio of (4:6)-(6:4); and the pharmaceutic adjuvant of the dry powder inhalant comprises one or more of active protective agent, dispersive assistant, pH stability regulator, diluent and/or large-granularity carrier. In an optimized scheme, the dry powder inhalant of interferon alpha in single administration contains 1-200mu g of interferon alpha. The dry powder inhalant of interferon alpha provided by the invention has better stability and safety than the dry powder inhalant of interferon alpha of the prior art.
Description
Technical field
The inhalation dosage form that relates to interferon-ALPHA that the present invention is general relates to the Foradil Aerolizer formoterol fumarate of interferon-ALPHA especially.
Background technology
Interferon (interferon, IFN) be a kind of cytokine class medicine with broad-spectrum disease resistance toxic action that is produced by animal body at first, produce according to it that position is different with the mechanism of action can be divided into big type such as α, β, γ, λ, and every kind big type can be divided into some little hypotypes, in the same big type between different hypotype on primary structure difference very little, very approaching on the above higher structure of secondary.In several big types, the α type is most widely used a kind of, and this kind of interferon of clinical practice at present mainly comprises interferon-ALPHA 2a, interferon alpha 2 b, interferon-ALPHA 1b, Interferon Alfacon-1 etc.
The report that much is used for the respiration system virus disease therapeutic about interferon-ALPHA is arranged in the prior art.In diseases of respiratory system toxicity treatment of diseases, the mode administration that interferon-ALPHA generally sucks or sprays with injection, atomizing is prepared into injection, atomized inhalation and spray respectively.The curative effect of injecting recombinant human interferon alpha 1 b treatment infantile viral pneumonia reported in the article " interferon therapy viral pneumonia observation of curative effect " that for example is published on 2006 the 3rd volumes of " Chinese modern internal medicine " magazine the 6th phase 645-647 page or leaf, and credit is analysed and shown to add to compare in curative effect between the treatment group for the treatment of with recombinant human interferon alpha 1 b and the matched group that adopts conventional therapy that significant difference is arranged by statistics.The article " interferon atomization inspiration treatment viral pneumonia efficacy analysis " that and for example is published on " China practical medicine " 2009 the 4th volumes the 9th phase 151-152 page or leaf has reported that atomizing sucks the curative effect of recombinant human interferon-alpha treatment infantile viral pneumonia, and credit is analysed and shown to add to compare in curative effect with the matched group of employing general treatment with the treatment group of recombinant human interferon-alpha atomization inspiration treatment that significant difference is arranged by statistics.Chinese patent CN 03147580.9 discloses a kind of recombinant human interferon-alpha spray for the treatment of viral pneumonia for another example; it is equipped with adequate protective agent, mucosa absorption promoter, antibacterial etc. by recombinant human interferon-alpha stock solution and makes; pH value is at 5.0-8.0, and the extracorporeal antivirus effect test shows that the recombinant human interferon-alpha spray of above-mentioned prescription is to respiratory tract or the susceptible HSV of pulmonary
1And HSV
2Virus all has stronger inhibitory action, but to HSV
2The inhibitory action of virus is more responsive.
For diseases of respiratory system toxicity treatment of diseases clear and definite curative effect is arranged though interferon-ALPHA is prepared into injection, atomized inhalation or spray, the characteristics of general metabolism are had a greatly reduced quality the dosage of the actual performance of injection dosage form drug effect; Atomized inhalation and spray dosage form then exist effective inhalation dose low, the shortcoming that dosage can't accurately be controlled.
Interferon-ALPHA is prepared into Foradil Aerolizer formoterol fumarate, also is that atomized inhalation then can overcome these shortcomings that above injection, atomized inhalation and spray dosage form exist fully through pulmonary's inhalation from formulation characteristic.For example Chinese patent 95193669.7 discloses a kind of Foradil Aerolizer formoterol fumarate of interferon, it is by interferon aqueous solution preparation and contain the interferon of the treatment effective dose of being combined with the medicine acceptable auxiliary, and this Foradil Aerolizer formoterol fumarate does not preferably contain penetration enhancer but preferably contains the adjuvant human serum albumin.And for example Chinese patent application 200410018796.X discloses a kind of interferon powder spray; its material by following percentage by weight is formed: interferon 0.0002%-0.8%; diluent 70%-97.9%; activity protecting agent 0.01%-5%; the buffer salt system of dispersibility auxiliary agent 0%-25% and maintenance pH 4-9 scopes, this powder spray does not preferably contain human albumin and absorption enhancer.
The preparation that the Foradil Aerolizer formoterol fumarate of the interferon-ALPHA of above prior art report is mainly formed from kind and the content research optimization of C of Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries, but do not relate to the optimization of principal agent interferon-ALPHA hypotype and content substantially, therefore might be by the Foradil Aerolizer formoterol fumarate of the more excellent interferon-ALPHA of the optimization obtained performance of principal agent interferon-ALPHA hypotype and content, better to be used for the treatment of viral diseases such as viral pneumonia.
Summary of the invention
The Foradil Aerolizer formoterol fumarate that the purpose of this invention is to provide a kind of interferon-ALPHA, the Foradil Aerolizer formoterol fumarate of its more existing interferon-ALPHA has better stability and safety concurrently.
For realizing this purpose; in the embodiment on basis; the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA; it contains the interferon-ALPHA for the treatment of effective dose and the Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries of Sq; described interferon-ALPHA is made up of interferon-ALPHA 1b and the Interferon Alfacon-1 of weight proportion 4:6 – 6:4, and described Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries is divided by function and comprised in activity protecting agent, dispersibility auxiliary agent, the agent of pH stable regulation, diluent and/or the coarsegrain carrier one or more.
Activity protecting agent play the protection interferon-ALPHA Foradil Aerolizer formoterol fumarate preparation, store with transportation in activity do not lose or the effect of less forfeiture; it can be one or more the combination in albumin, aminoacid, polyhydric alcohol, cyclodextrin, the lecithin matter; the combination of one or more in preferred albumin, lysine, 2-hydroxy propyl-Beta-cyclodextrin, the soybean lecithin, and more preferably do not comprise one or more combination in the albuminous preferred substance.
The dispersibility auxiliary agent plays the granule of the Foradil Aerolizer formoterol fumarate that disperses the interferon-ALPHA prepare to suitable dispersion, prevent between the granule reuniting each other and the effect of adhesion, can be one or more the combination in tyrosine, leucine, phenylalanine, the glycine, preferred leucine, phenylalanine.
The effect that the pH after the Foradil Aerolizer formoterol fumarate dissolving is stabilized in the physiology appropriate pH is played in the agent of pH stable regulation, including, but not limited to phosphate buffered solution system, citrate buffer solution system, Ascorbate buffer solution system, require physiological safety and can and be stabilized between the 5.0-8.0 pH regulator.
Diluent plays on the basis of drug content and other pharmaceutically acceptable auxiliaries content and fills increase Foradil Aerolizer formoterol fumarate particle weight to the effect of required loadings or suction volume, it can be one or more the combination in polyhydric alcohol, the amino acids material, the combination of one or more in preferred mannitol, xylitol, lactose, trehalose, cottonseed sugar, leucine, threonine, the glycine, and the more preferably combination of one or more in mannitol, lactose, leucine, the threonine.
The coarsegrain carrier plays help is transported to the Foradil Aerolizer formoterol fumarate granule throat from medicine-feeding part effect.When less and dispersion is higher when the Foradil Aerolizer formoterol fumarate grain graininess of the interferon-ALPHA for preparing, it is suitable for being transported to pulmonary from the throat by respiratory tract, but be not suitable for being transported to the throat from medicine-feeding part, need add the coarsegrain carrier this moment in the Foradil Aerolizer formoterol fumarate granule for preparing; Thereby though and when the Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA for preparing single less but have looser adhesion can form that (a little applied external force when granularity reached the loose aggregates of 50-100 μ m to each other, as increase ambient air stream, the Foradil Aerolizer formoterol fumarate granule of adhesion will be dispersed into each other independently Foradil Aerolizer formoterol fumarate granule), then need not in the granule of the Foradil Aerolizer formoterol fumarate of the interferon-ALPHA for preparing, to add the coarsegrain carrier.Such coarsegrain carrier can be selected one or more the combination in the materials such as lactose, mannitol, phospholipid, aminoacid, the combination of one or both in preferred lactose and the mannitol, and more preferably lactose.The particle mean size of coarsegrain carrier should be between 25-300 μ m, preferably between the 50-200 μ m, and more preferably between the 50-100 μ m.The ratio that the Foradil Aerolizer formoterol fumarate granule mixes with the coarsegrain carrier by weight should be between 100:1-1:100, preferably between 50:1-1:50, and more preferably between 20:1-1:20.
Should be pointed out that the situation of selecting for use an a kind of or class material to play the function of above-mentioned multiple Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries simultaneously of not getting rid of.
The Foradil Aerolizer formoterol fumarate granule of above-mentioned interferon-ALPHA can adopt preparation such as the method that well known to a person skilled in the art lyophilizing-mechanical crushing method, spray drying method, supercritical fluid method, crystallization process, preferably adopts spray drying method for preparation.When adopting the Foradil Aerolizer formoterol fumarate granule of spray drying method for preparation interferon-ALPHA, should at first prepare the solution that spray drying is used, the various compositions that also soon constitute Foradil Aerolizer formoterol fumarate except the coarsegrain carrier dissolve back merging or the unified solution state of being dissolved into respectively, then this solution are used for follow-up spray drying.Spray drying can influence the performance of the Foradil Aerolizer formoterol fumarate granule that spray-dired efficient and spray drying obtain with the solid content in the solution, and it generally should be at 0.5-10%(m/v) between, preferably at 1-5%(m/v) between, and more preferably at 1-3%(m/v) between.
In spray drying, the main preparation technology parameter of the performance of the Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA that influence prepares comprises spray drying gas feed temperature, spray gas flow, hydrojet flow etc.
Spray drying gas feed temperature is more high, rate of drying is more fast, the material disposal ability is more big, but interferon-ALPHA and Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries be more easy generation bioinactivation and/or chemical degradation/reaction in spray-drying process, therefore suitable inlet temperature is 80-140 ℃, preferred 90-130 ℃, and more preferably 100-120 ℃.
The spray gas flow is more high, rate of drying is more fast, the material disposal ability is more big, but power consumption simultaneously is more big, interferon-ALPHA and Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries be more easy generation bioinactivation and/or chemical degradation/reaction in spray-drying process, therefore for the small-sized spray drying instrument as Buchi B-290, suitable gas flow is 200-1000L/h, preferred 300-800 L/h, and more preferably 500-700 L/h, the spray gas flow of the spray drying instrument of other types can utilize and well known to a person skilled in the art that the General Principle that reactor amplifies operating parameter conversion when dwindling converts.
The hydrojet flow is more low, the gas-liquid flow-rate ratio is more big, rate of drying is more fast, the granularity of the Foradil Aerolizer formoterol fumarate granule that obtains is more little, but treating capacity can obviously reduce simultaneously, processing time can obviously prolong, and bioinactivation and/or chemical degradation/reaction take place in long easier interferon-ALPHA and the pharmaceutically acceptable auxiliaries of causing of processing time in spray-drying process, therefore for the small-sized spray drying instrument as Buchi B-290, suitable hydrojet flow is 1-10ml/min, preferred 2-8ml/min, and more preferably 3-5ml/min, the gas flow of the spray drying instrument of other types can utilize and well known to a person skilled in the art that the General Principle that reactor amplifies operating parameter conversion when dwindling converts.
Other spray drying condition aspects, kind to spray drying gas does not generally have specific (special) requirements, get final product with air, but in order to prevent spray drying gas and interferon-ALPHA and Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries generation chemical reaction, also can select nitrogen or noble gas as spray drying gas.The temperature of hydrojet generally selects freezing point temperature (0 ℃) to the temperature between room temperature (25 ℃).
By the control to operating parameter in the above-mentioned spray-drying process, should make between the granularity 0.1-10 μ m of 50% above granule in the Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA for preparing, the granularity of preferred 70% above granule between 1-5 μ m, and more preferably the granularity of 80% above granule between 2-4 μ m.
The Foradil Aerolizer formoterol fumarate of the interferon-ALPHA for preparing is mobile to be reduced because the too high meeting of moisture causes, grain graininess increases in storage process, the principal agent biologic activity reduces, therefore the control by operating parameter in the above-mentioned spray-drying process, should make in the Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA for preparing moisture control below 5%, preferred below 3%, and most preferably below 2.5%.
The Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA that obtains by method for preparing should determine whether mix with the carrier of coarsegrain according to circumstances.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, contain the interferon-ALPHA of 1-200 μ g in the single-dose dosage.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, contain the interferon-ALPHA of 50-200 μ g in the single-dose dosage.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, contain the activity protecting agent of 0.3-1mg among every 20mg; 0.6 the dispersibility auxiliary agent of-5mg; the pH stable regulation agent of 1-4.8mg, the diluent of 3-9mg, the coarsegrain carrier of 0-15mg.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, wherein said activity protecting agent is selected from one or more the combination in albumin, lysine, 2-HP-, the soybean lecithin.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, wherein said dispersibility auxiliary agent is selected from one or more the combination in tyrosine, leucine, phenylalanine, the glycine.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, the agent of wherein said pH stable regulation is selected from one or more the combination in phosphate buffered solution, citrate buffer solution, the ascorbic acid salt buffer solution.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, wherein said diluent is selected from one or more the combination in mannitol, lactose, leucine, the threonine.
In a kind of embodiment preferred, the invention provides a kind of Foradil Aerolizer formoterol fumarate of interferon-ALPHA, wherein said coarsegrain carrier is selected from one or both the combination in lactose and the mannitol.
The term that uses among the present invention " Foradil Aerolizer formoterol fumarate " (Dry Power Inhalation, DPI), be also referred to as " powder spray ", refer to micronized medicine and/or carrier with single dose or multiple dose depot forms, adopt special powder inhaler, by the patient initiatively or passive suction atomization medicine to the preparation of respiratory tract and even pulmonary.
The term that uses among the present invention " treatment effective dose " expression is used for the treatment of or during prevent disease, the amount of active constituents of medicine is enough to realization to treatment of diseases or prevention when the drug administration active component.The treatment effective dose will be different according to age of active constituents of medicine, disease and its seriousness and the patient that treats, body weight etc.
The term that uses among the present invention " Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries " refers to when the design of Foradil Aerolizer formoterol fumarate prescription, be problems such as the mouldability that solves Foradil Aerolizer formoterol fumarate, effectiveness, stability, safety, join in the Foradil Aerolizer formoterol fumarate prescription except active constituents of medicine self to other auxiliary elements of human body or animal body safety.
The term that uses among the present invention " Interferon Alfacon-1 " (consensus interferon or integrated interferon) refer in Chinese patent application CN02159950.5 in sequence table 3 open sequences and in description embodiment the Interferon Alfacon-1 of open preparation method.
The specific embodiment
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 the Foradil Aerolizer formoterol fumarate granule of interferon-ALPHA
By as each spray drying solution of the formulated in the following table 1, and by the spray drying condition of table 2 correspondence with this solution of Buchi B-290 spray drying instrument spray drying (whole liquid sprays finish after continuation maintenance spray drying gas feed temperature and flow 15 minutes) thus prepare the Foradil Aerolizer formoterol fumarate granule of interferon-ALPHA.
The spray drying solution formula of the Foradil Aerolizer formoterol fumarate granule of table 1 preparation interferon-ALPHA
The spray drying condition of the Foradil Aerolizer formoterol fumarate of table 2 interferon-ALPHA
Embodiment 2: the quality evaluation of the Foradil Aerolizer formoterol fumarate granule of interferon-ALPHA
Measure the activity (IU/ml) of interferon-ALPHA in the Foradil Aerolizer formoterol fumarate granule dissolving back solution of interferon-ALPHA of each prescription for preparing by the regulation of " Chinese Pharmacopoeia 2010 editions (three ones) " appendix " interferon biological activity algoscopy "; Measure the concentration (mg/ml) of interferon-ALPHA in the Foradil Aerolizer formoterol fumarate granule dissolving back solution of interferon-ALPHA of each prescription for preparing by the regulation of " Chinese Pharmacopoeia 2010 editions (three ones) " appendix " protein determination " second method Lowry method, both the be divided by specific activities (IU/mg) of interferon-ALPHA in the Foradil Aerolizer formoterol fumarate granule of interferon-ALPHA of each prescription of obtaining preparing.Each spray drying of blank determination specific activity of interferon-ALPHA in the solution, and the reservation of calculating spray-dried back interferon-ALPHA specific activity thus.
Measure the moisture in the Foradil Aerolizer formoterol fumarate granule of interferon-ALPHA of each prescription for preparing by the regulation of " Chinese Pharmacopoeia 2010 editions (three ones) " appendix " aquametry " first method.
Measure the particle mean size of Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA of each prescription for preparing by the regulation of " Chinese Pharmacopoeia 2010 editions (two ones) " appendix " granularity and particle size distribution method " first method.
All measurement results are as shown in table 3 below.
The quality evaluation of the Foradil Aerolizer formoterol fumarate granule of the interferon-ALPHA that table 3 spray drying prepares
Embodiment 3: by the Foradil Aerolizer formoterol fumarate of the Foradil Aerolizer formoterol fumarate preparation of granules interferon-ALPHA of interferon-ALPHA
The Foradil Aerolizer formoterol fumarate particulate samples of the interferon-ALPHA of the prescription 1-20 in each prescription that will obtain by the method for embodiment 1 does not mix with the coarsegrain carrier, directly carries out after the packing as the research for embodiment 4-5 of the Foradil Aerolizer formoterol fumarate of interferon-ALPHA with the amount of every capsule 20mg; The Foradil Aerolizer formoterol fumarate particulate samples of the interferon-ALPHA of prescription 21-40 is with mass ratio and the commercially available coarsegrain lactose carrier granule mix homogeneously of 1:3, carries out after the packing as the research for embodiment 4-5 of the Foradil Aerolizer formoterol fumarate of interferon-ALPHA with the amount of every capsule 20mg.
Embodiment 4: the accelerated stability test of the Foradil Aerolizer formoterol fumarate of interferon-ALPHA
Each many of the capsules of each prescription are placed in 40 ℃, the environment of 75%RH is placed March, and the Foradil Aerolizer formoterol fumarate that sampling in every month is once measured the interferon-ALPHA of each prescription for preparing by the regulation of " Chinese Pharmacopoeia 2010 editions (three ones) " appendix " interferon biological activity algoscopy " takes out after the dissolving activity (IU/ml) of interferon-ALPHA in the solution in capsule; Measure the Foradil Aerolizer formoterol fumarate of the interferon-ALPHA of each prescription for preparing takes out interferon-ALPHA in the solution of dissolving back in capsule concentration (mg/ml) by the regulation of " Chinese Pharmacopoeia 2010 editions (three ones) " appendix " protein determination " second method Lowry method, both the be divided by specific activities (IU/mg) of interferon-ALPHA in the Foradil Aerolizer formoterol fumarate of each interferon-ALPHA of filling a prescription of obtaining preparing.The specific activity that each sample of filling a prescription records with taking a sample in January, February, March respectively obtains the specific activity relative retention value of interferon-ALPHA in the accelerated stability test process divided by specific activity that sampling in corresponding 0 month records, and the result is as shown in table 4 below.
The accelerated stability test result of the Foradil Aerolizer formoterol fumarate of table 4 interferon-ALPHA
Embodiment 5: the normal human bronchial epithelial cell line toxicity test of the Foradil Aerolizer formoterol fumarate of interferon-ALPHA
Be (normal human bronchial epithelial cells by being published in the Foradil Aerolizer formoterol fumarate that article " cigarette smoke extract is to the influence of the damage of human respiratory epithelial cell dna and apoptosis " 1.1-1.4 on " cancer (Chinese Journal of Cancer) " 2006 the 25th volume the 10th phase 1191-1197 page or leaf saves the interferon-ALPHA of each prescription that disclosed materials and methods research prepares to normal person's bronchial epithelial cell, NHBE) toxicity, but do following 3 changes:
1) general's " preparation of cigarette smoke extract " step wherein changes the dissolving step again of the Foradil Aerolizer formoterol fumarate of interferon-ALPHA into, method is: each 200mg(10 of Foradil Aerolizer formoterol fumarate times single-dose dosage of the interferon-ALPHA of each prescription that the method by embodiment 3 that takes by weighing prepares), and respectively with deionized water dissolving and dilute standardize solution to 200 μ l;
2) adding with the cigarette smoke extract CSE of each concentration in " cell culture and processing " step changes the undiluted respectively Foradil Aerolizer formoterol fumarate adding of solvent soln again (every hole adds 20 μ l) of the interferon-ALPHA of prescription of single concentration into;
3) change the Foradil Aerolizer formoterol fumarate that adds interferon-ALPHA in " MTT cytoactive mensuration " step into 6h, 12h the action time behind the solvent soln again, but still establish blank.
The result of the test that obtains according to the method described above is as shown in table 5.
The normal human bronchial epithelial cell line toxicity test result of the Foradil Aerolizer formoterol fumarate of table 5 interferon-ALPHA
Claims (5)
1. the Foradil Aerolizer formoterol fumarate of interferon-ALPHA; it is characterized in that containing in the single-dose dosage interferon-ALPHA of 1-200 μ g and the Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries of Sq; described interferon-ALPHA is made up of interferon-ALPHA 1b and the Interferon Alfacon-1 of weight proportion 4:6-6:4; described Interferon Alfacon-1 is the Interferon Alfacon-1 of SEQ ID No.3 among the CN02159950.5; described Foradil Aerolizer formoterol fumarate pharmaceutically acceptable auxiliaries is divided by function and is comprised activity protecting agent; the dispersibility auxiliary agent; the agent of pH stable regulation; in diluent and/or the coarsegrain carrier one or more; described dispersibility auxiliary agent is selected from tyrosine; leucine; phenylalanine; the combination of one or more in the glycine, described coarsegrain carrier are selected from one or both the combination in lactose and the mannitol.
2. the Foradil Aerolizer formoterol fumarate of interferon-ALPHA according to claim 1; it is characterized in that containing in the Foradil Aerolizer formoterol fumarate of every 20mg the activity protecting agent of 0.3-1mg; 0.6 the dispersibility auxiliary agent of-5mg; the pH stable regulation agent of 1-4.8mg; the diluent of 3-9mg, the coarsegrain carrier of 0-15mg.
3. the Foradil Aerolizer formoterol fumarate of interferon-ALPHA according to claim 1 and 2 is characterized in that described activity protecting agent is selected from one or more the combination in albumin, lysine, 2-HP-, the soybean lecithin.
4. the Foradil Aerolizer formoterol fumarate of interferon-ALPHA according to claim 1 and 2 is characterized in that the agent of described pH stable regulation is selected from one or more the combination in phosphate buffered solution, citrate buffer solution, the ascorbic acid salt buffer solution.
5. the Foradil Aerolizer formoterol fumarate of interferon-ALPHA according to claim 1 and 2 is characterized in that described diluent is selected from one or more the combination in mannitol, lactose, leucine, the threonine.
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| HPLC法测定重组人干扰素A1b粉雾剂的含量;刘阿娜等;《中国生物工程杂志》;20101231;第30卷(第5期);第92-85页 * |
| Protein Inhalation Powders: Spray Drying vs Spray Freeze Drying;Yuh-Fun Maa et al.,;《Pharmaceutical Research 》;19980228;第16卷(第2期);第249-254页 * |
| Yuh-Fun Maa et al.,.Protein Inhalation Powders: Spray Drying vs Spray Freeze Drying.《Pharmaceutical Research 》.1998,第16卷(第2期),第249-254页. |
| 刘阿娜等.HPLC法测定重组人干扰素A1b粉雾剂的含量.《中国生物工程杂志》.2010,第30卷(第5期),第92-95页. |
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