CN103520106A - Salbutamol sulphate inhalation aerosol and preparation method thereof - Google Patents
Salbutamol sulphate inhalation aerosol and preparation method thereof Download PDFInfo
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- CN103520106A CN103520106A CN201210223696.5A CN201210223696A CN103520106A CN 103520106 A CN103520106 A CN 103520106A CN 201210223696 A CN201210223696 A CN 201210223696A CN 103520106 A CN103520106 A CN 103520106A
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- 239000000443 aerosol Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000001856 aerosol method Methods 0.000 title description 3
- 239000003814 drug Substances 0.000 claims abstract description 33
- 239000003380 propellant Substances 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 3
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 32
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
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- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- GTLACDSXYULKMZ-UHFFFAOYSA-N pentafluoroethane Chemical compound FC(F)C(F)(F)F GTLACDSXYULKMZ-UHFFFAOYSA-N 0.000 claims description 2
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
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- JBRBWHCVRGURBA-UHFFFAOYSA-N broxaterol Chemical compound CC(C)(C)NCC(O)C1=CC(Br)=NO1 JBRBWHCVRGURBA-UHFFFAOYSA-N 0.000 description 1
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229940041682 inhalant solution Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to an inhalation aerosol medicine composition containing selective beta2-receptor stimulant salbutamol sulphate and a hydrofluoroalkane (HFA) propellant and a preparation method thereof. The inhalation aerosol medicine composition and the preparation method have the advantages that the preparation technology is simple and feasible, used raw materials and auxiliary materials have no toxic or side effects, the production cost is low, the prepared medicine has good particle size distribution and relatively high stability, and the quality and the human body bioavailability of the medicine are favorably improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, relate in particular to a kind of salbutamol sulfate inhalation aerosol and preparation method thereof.
Background technology
1956, Charles Thiel etc. has reported use pressurized metered-dose inhaler (pressurized metered dose inhaler, pMDI) be the medicine of doser, such medicine is used for the treatment of the disease that asthma, chronic obstructive pulmonary disease (COPD) etc. betide the positions such as pulmonary, bronchus, trachea.Adopt the medicine of pMDI doser can directly act on target site, there is the feature rapid-action, bioavailability is high; In addition, because such preparation can be avoided the first pass effect at liver of medicine by respiratory tract administration; In addition, adopt this device administration very convenient, user compliance is better.Due to above-mentioned special advantage, therefore pMDI has been widely used since its invention.But the normally used propellant of traditional pMDI is fluorine alkyl chloride, claim again freon (CFC), the modern CFC that studies confirm that has destruction to the ozone in atmosphere, and ozone has the effect that absorbs sunlight middle-ultraviolet lamp, therefore the use of CFC causes being irradiated to the ultraviolet on ground, increase, cause the various generations such as diseases such as skin carcinomas that too much cause due to ultraviolet radiation.Therefore, within 1987, in Canadian Montreal, more than 40 country signed Montreal Protocol on Substances that Deplete the Ozone Layer, and China added this tissue in 1993.According to protocol call, the propellant in traditional pMDI is by replaced, and China will forbid in 2015 freon (CFC) aerosol comprehensively.What in alternative material, commonly use is tetrafluoroethane (HFA-134a) and heptafluoro-propane (HFA-227a), the propellant of these two kinds of CFC alternative has obtained the approval of FDA Food and Drug Administration (FDA) and European drug administration (EMEA), therefore the hydrofluoroalkane hydro carbons (HFA) such as application HFA-134a or HFA-227a is as the salbutamol sulfate medicine of propellant, the responsibilities and obligations that Neng Shi China completes protocol defined have great importance, simultaneously because the product after substituting is owing to having used the propellant little to environmental effect, more be conducive to protect our living environment, minimizing is due to the generation of the excessive caused disease of ultraviolet radiation.But it is sizable different that HFA and the physicochemical property of CFC have, and for example the polarity of CFC is larger than HFA to the dissolubility of medicine than the little and CFC of HFA, so the suitable preparation that is prepared into suspension type of the propellant of HFA type.Because HFA has larger polarity, easily absorb airborne moisture simultaneously, absorb after airborne moisture, can cause flocculation or the caking of suspendible medicine, therefore higher than the product of CFC to the prescription requirement of product.
Chinese patent CN1312706 discloses the pressurized liquefied propellant mixture that a kind of aerosol of being invented by M Kai Leer is used, and wherein contains nitrous oxide and has the hydrofluoroalkane of 1-3 carbon atom, particularly 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, this mixture can improve the moistening character of pharmaceutically active compound, utilize thus hydrofluoroalkane to overcome the formulation problems existing in suspension or solution aerosol, and obtain the medicinal aerosol formulations improved.
Chinese patent CN101553210 disclose by Edward rein in the horse wait people's invention a kind of by drug administration the system and method to patient's respiratory system, it is malleation supply that its Chinese medicine be take with respect to atmospheric pressure.Particularly, medicine is transported to and can carries out the respiratory system without the patient of assisted respiartion.Use system and method disclosed by the invention, make the medicine that can utilize in a variety of forms with the form of aerosol, atomization or evaporation, enter into air-flow by controllable mode.
US6743413 discloses and has contained prescription and the preparation method for the treatment of the medicine of effective dose and the aerocolloidal compositions of pharmaceutical suspension of HFA-134a, HFA227a or their mixture.
US20040168950 discloses and has contained HFA as the packing method of the pMDI of propellant, and has listed and can be used in the various ingredients in HFA preparation, comprises each seed amino acid using as stabilizing agent; As compositions such as antioxidative vitamin E, vitamin Cs.
US6569406 discloses the spraying dry powder 4-spiral pencil protein powder sucking with minimized aggregation tendency, and its stabilizing agent comprises various saccharides, aminoacid and the polymer being comprised of 2-5 aminoacid.
According to Montreal Protocol, China should forbid the agent of freon aerosol in 2010 comprehensively, but due to domestic, there is no non-Freon aerosol independent research and development capacity, thus still do not have at present HFA aerosol to go through to go on the market, the quota that therefore the annual Xu Xiang international environment of China contracting organization applies for freon.But final, China will forbid in 2015 freon (CFC) aerosol comprehensively.
Summary of the invention
The present invention makes quantitative inhalation solution type aerosol by selectivity broxaterol, and this aerosol be take HFA as propellant, has dosage accurate, carry, transportation, easy to use, bioavailability is high, cost is low, process stabilizing, is suitable for the advantages such as commercialization batch production.
The object of the present invention is to provide a kind of salbutamol sulfate non-Freon aerosol.
Another object of the present invention is to provide the preparation method of above-mentioned aerosol.
Specifically, the invention provides a kind of salbutamol sulfate aerosol, described aerosol is comprised of following ingredients: a) active medicine; B) propellant; C) additives; D) surfactant;
A) active medicine
Described active medicine salbutamol sulfate is to obtain by the sulphuric acid of albuterol and suitable concentration is synthetic, refining.Sulfuric acid concentration is 0.5%-15%, is preferably 2%-10%.
B) propellant
Described propellant includes but not limited to one or more of the HFA such as tetrafluoroethane, pentafluoroethane, perfluoroethane, HFA-227ea, heptafluoro-propane, is preferably tetrafluoroethane and heptafluoro-propane.
C) additives
Described additives include but not limited to one or more of the organic solvents such as ethanol, glycerol, ethyl acetate, acetone, propylene glycol, Polyethylene Glycol, are preferably ethanol, propylene glycol, more preferably dehydrated alcohol.
D) surfactant
The preferred nonionic surfactant of described surfactant, includes but not limited to one or more of oleic acid, sorbester p37, oleyl alcohol, lauryl alcohol etc. be preferably oleic acid, sorbester p37, more preferably oleic acid.
As preferred embodiment, the salbutamol sulfate aerosol that to the invention provides a kind of HFA of take be propellant, is comprised of following ingredients: a) active medicine; B) propellant; C) additives; D) surfactant;
A) active medicine
Salbutamol sulfate is to obtain by the sulphuric acid of albuterol and suitable concentration is synthetic, refining.Sulfuric acid concentration is 0.5%-15%, is preferably 2%-10%.Salbutamol sulfate should adopt micronized technique to process in advance, is no less than 50% particle diameter and is no more than 5 μ m, is preferably and is no more than 3 μ m, is most preferably not exceeding 2 μ m.
B) propellant
Described propellant includes but not limited to one or more of tetrafluoroethane, heptafluoro-propane, is preferably tetrafluoroethane.
C) additives
Described additives include but not limited to ethanol, propylene glycol one or more, be preferably ethanol, more preferably dehydrated alcohol.
D) surfactant
The preferred nonionic surfactant of described surfactant, includes but not limited to one or more of oleic acid, sorbester p37 be preferably oleic acid.
The preparation method of salbutamol sulfate aerosol of the present invention, is characterized in that comprising the steps:
(1) raw material pre-treatment: get albuterol and mix homogeneously with sulphuric acid, then stir, filter and be dried and obtain fine salbutamol sulfate powder body;
(2) get salbutamol sulfate and add in dehydrated alcohol and dissolve, add oleic acid mix homogeneously, pour into salbutamol sulfate solution, then add HFA in aluminium pot, sealing aluminium pot, obtains the sample of preparation.
Preparation technology's simple possible of the present invention, raw and auxiliary material used all has no side effect, and production cost is low, and the diameter of aspirin particle of preparation distributes well, is difficult for flocculation, stability is better, is conducive to improve quality and the human bioavailability of medicine.
The interacting goals position of the preparation that application the present invention produces is trachea, bronchus and alveolar, and the special physiological structure of pulmonary requires the grain diameter sucking in preparation should be no more than 5 μ m, to facilitate medicine to reach site of action.Had document announcement drug particles in being inhaled into the process of pulmonary, can there is the variation of particle diameter, its numerical value is different from the initial size in prescription, this variation has close relationship with suction air-flow, doser, suction and prescription composition, therefore should be with the atomizing particle size effect of dynamic diameter characterization medicine.
The method that the pMDI of existing USP regulation detects comprises ACI (Anderson cascade impact) and NGI (Apparatus E), wherein uses ACI can detect easily ratio and the quantity of different-grain diameter scope after aerosol atomization.Because the particle diameter after atomization is directly relevant from its site of action: the position in the respiratory tract that granule of different-grain diameter can arrive is different, and more the granule of small particle diameter can arrive position darker in respiratory tract.In the aerosol characterizing at the ACI that uses 8 steps, the 3rd, 4,5 grades respectively representative can arrive tracheobronchial granule number, and trachea, bronchus are for we treat the Main Function position of asthma disease.
GSK produces the salbutamol sulfate aerosol commodity Wan Tuolin by name of listing in the world, ACI detection display Wan Tuolin can arrive tracheobronchial ratio and on average be respectively 12.1%, 9.4%, that is to say that medicine that this product can arrive useful effect position only accounts for 20% left and right of dosage.Owing to arriving, the dose at useful effect position is few, therefore just need to by strengthening the mode of dosage, make to arrive the medicine performance curative effect of site of action, and heavy dose of administration inevitably increases the probability of the side effect generations such as cardiovascular expansion.
We find to use oleic acid and ethanol under the condition of suitable ratio, can increase quantity and ratio that medicine can arrive ACI3,4,5 steps after materialization by experiment.The sample that the embodiment of the present invention 1 makes and the Wan Tuolin of GSK the results are shown in Table 1 in the particle size distribution of using ACI to record.
Table 1 embodiment 1 gained is made sample by oneself and contrasts medicine (Wan Tuolin) particle size distribution result
By data, we can significantly compare the ratio that homemade sample rests on ACI3,4,5 steps and can arrive quantity and the ratio of this position apparently higher than Wan Tuolin, show that this product can more effective arrival and rest on trachea and ，Gai position, bronchial position is the main target position that we treat asthma disease outbreak.Therefore,, reaching the use amount that effectively reduces albuterol under the prerequisite of identical effect, reduce risk or intensity that side effect occurs.
Sample prepared by the method is by being 40 ± 2 ℃ in temperature, under the condition that relative humidity is 75 ± 5%RH, through 6 months study on the stability, found that this product quality and particle size distribution within experimental period keep stable.
Accompanying drawing explanation
Fig. 1. embodiment 1 salbutamol sulfate micropowder electron microscope scanning figure
Fig. 2. embodiment 1 salbutamol sulfate micropowder laser particle analyzer is measured particle size distribution result
The specific embodiment
Embodiment 1
(1) prescription
(2) preparation method
Albuterol and 2.5mol/L sulphuric acid are mixed together evenly and are pumped in reactor, and controlling reaction temperature is 15 ℃, maintains 900rpm/min mixing speed, controls response time 10min.Filtering liquid medicine the dry fine salbutamol sulfate powder body obtaining, the results are shown in accompanying drawing 1 through powder electron microscope observation, adopts the particle size data of the salbutamol sulfate after crushed of laser particle analyzer mensuration to the results are shown in accompanying drawing 2.
Get salbutamol sulfate 2.84g, join in 39.27g dehydrated alcohol and dissolve, add after 14.76g oleic acid mix homogeneously, then to the HFA-113a that is filled with 14.83g in aluminium pot, sealing aluminium pot, obtains the sample of preparation.
Embodiment 2
(1) prescription
(2) preparation method
Albuterol and 5.0mol/L sulphuric acid are mixed together evenly and are pumped in reactor, and controlling reaction temperature is 15 ℃, maintains 900rpm/min mixing speed, controls response time 10min.Filtering liquid medicine the dry fine salbutamol sulfate powder body obtaining, the results are shown in accompanying drawing 1 through powder electron microscope observation, adopts the particle size data of the salbutamol sulfate after crushed of laser particle analyzer mensuration to the results are shown in accompanying drawing 2.
Get salbutamol sulfate 2.84g, join in 39.27g dehydrated alcohol and dissolve, add after 14.76g oleic acid mix homogeneously, then to the HFA-227 that is filled with 14.83g in aluminium pot, sealing aluminium pot, obtains the sample of preparation.
Claims (5)
1. a salbutamol sulfate inhalation aerosol, is characterized in that described aerosol is comprised of following ingredients: a) active medicine; B) propellant; C) additives; D) surfactant, wherein said active medicine is salbutamol sulfate; Described propellant includes but not limited to one or more of the HFA such as tetrafluoroethane, pentafluoroethane, perfluoroethane, HFA-227ea, heptafluoro-propane, is preferably tetrafluoroethane and heptafluoro-propane; Described additives include but not limited to one or more of the organic solvents such as ethanol, glycerol, ethyl acetate, acetone, propylene glycol, Polyethylene Glycol; The preferred nonionic surfactant of described surfactant, includes but not limited to one or more of oleic acid, sorbester p37, oleyl alcohol, lauryl alcohol etc.
2. salbutamol sulfate aerosol according to claim 1, is characterized in that described salbutamol sulfate is to obtain by the sulphuric acid of albuterol and suitable concentration is synthetic, refining.
3. salbutamol sulfate aerosol according to claim 2, is characterized in that sulfuric acid concentration is 0.5%-15%.
4. salbutamol sulfate aerosol according to claim 2, is characterized in that sulfuric acid concentration is 2%-10%.
5. a preparation method for salbutamol sulfate aerosol, is characterized in that comprising the steps:
(1) raw material pre-treatment: get albuterol and mix homogeneously with sulphuric acid, then stir, filter and be dried and obtain fine salbutamol sulfate powder body;
(2) get salbutamol sulfate and add in dehydrated alcohol and dissolve, add oleic acid mix homogeneously, pour into salbutamol sulfate solution, then add HFA in aluminium pot, sealing aluminium pot, obtains the sample of preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210223696.5A CN103520106A (en) | 2012-07-02 | 2012-07-02 | Salbutamol sulphate inhalation aerosol and preparation method thereof |
Applications Claiming Priority (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727318A (en) * | 2016-12-22 | 2017-05-31 | 山东京卫制药有限公司 | A kind of aerosol and preparation method thereof |
| CN113025277A (en) * | 2021-02-03 | 2021-06-25 | 天津科技大学 | Novel efficient, safe and environment-friendly water-based fogging agent |
| CN116392460A (en) * | 2023-04-18 | 2023-07-07 | 山东京卫制药有限公司 | Salbutamol aerosol |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0653204A2 (en) * | 1988-12-06 | 1995-05-17 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| CN1279942A (en) * | 2000-07-06 | 2001-01-17 | 中国药科大学 | Medicinal aerosol for curing respiratory system disease |
| CN1296814A (en) * | 2000-11-28 | 2001-05-30 | 中国药科大学 | Medical aerosol without freon for treating diseases in respiratory system |
| WO2001064524A2 (en) * | 2000-03-01 | 2001-09-07 | Glaxo Group Limited | Metered dose inhaler |
| CN1559389A (en) * | 2004-03-05 | 2005-01-05 | 山东京卫制药有限公司 | Levo-salbutamol sulfate inhaler, and its prepn. method |
| CN1566076A (en) * | 2003-06-11 | 2005-01-19 | 新加坡纳米材料科技有限公司 | Synthetic method for superfine sulfuric acid and salbutamol |
| CN1778390A (en) * | 2004-11-18 | 2006-05-31 | 山东京卫制药有限公司 | Preparation method of aerosol containing bioactive ingredients |
| CN101849928A (en) * | 2009-03-30 | 2010-10-06 | 北京利乐生制药科技有限公司 | Inhalation preparation for treating asthma, preparation method and application thereof |
-
2012
- 2012-07-02 CN CN201210223696.5A patent/CN103520106A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0653204A2 (en) * | 1988-12-06 | 1995-05-17 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| WO2001064524A2 (en) * | 2000-03-01 | 2001-09-07 | Glaxo Group Limited | Metered dose inhaler |
| CN1279942A (en) * | 2000-07-06 | 2001-01-17 | 中国药科大学 | Medicinal aerosol for curing respiratory system disease |
| CN1296814A (en) * | 2000-11-28 | 2001-05-30 | 中国药科大学 | Medical aerosol without freon for treating diseases in respiratory system |
| CN1566076A (en) * | 2003-06-11 | 2005-01-19 | 新加坡纳米材料科技有限公司 | Synthetic method for superfine sulfuric acid and salbutamol |
| CN1559389A (en) * | 2004-03-05 | 2005-01-05 | 山东京卫制药有限公司 | Levo-salbutamol sulfate inhaler, and its prepn. method |
| CN1778390A (en) * | 2004-11-18 | 2006-05-31 | 山东京卫制药有限公司 | Preparation method of aerosol containing bioactive ingredients |
| CN101849928A (en) * | 2009-03-30 | 2010-10-06 | 北京利乐生制药科技有限公司 | Inhalation preparation for treating asthma, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 续京等: "微细硫酸沙丁胺醇颗粒的制备", 《过程工程学报》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727318A (en) * | 2016-12-22 | 2017-05-31 | 山东京卫制药有限公司 | A kind of aerosol and preparation method thereof |
| CN113025277A (en) * | 2021-02-03 | 2021-06-25 | 天津科技大学 | Novel efficient, safe and environment-friendly water-based fogging agent |
| CN113025277B (en) * | 2021-02-03 | 2022-07-12 | 天津科技大学 | Efficient, safe and environment-friendly water-based fogging agent |
| CN116392460A (en) * | 2023-04-18 | 2023-07-07 | 山东京卫制药有限公司 | Salbutamol aerosol |
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