WO2013026269A1 - 制备用于治疗呼吸道疾病的定量喷雾吸入剂的工艺方法 - Google Patents

制备用于治疗呼吸道疾病的定量喷雾吸入剂的工艺方法 Download PDF

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WO2013026269A1
WO2013026269A1 PCT/CN2012/071129 CN2012071129W WO2013026269A1 WO 2013026269 A1 WO2013026269 A1 WO 2013026269A1 CN 2012071129 W CN2012071129 W CN 2012071129W WO 2013026269 A1 WO2013026269 A1 WO 2013026269A1
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mixture
hfa
wav
alcohol
preparation
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PCT/CN2012/071129
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English (en)
French (fr)
Inventor
吴维修
赵彦钦
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益得生物科技股份有限公司
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Priority to AU2012300082A priority Critical patent/AU2012300082B2/en
Priority to SG2014011597A priority patent/SG2014011597A/en
Priority to CA2845258A priority patent/CA2845258C/en
Priority to RU2014104996/15A priority patent/RU2582218C2/ru
Priority to BR112014003907-0A priority patent/BR112014003907A2/pt
Priority to EP12825882.9A priority patent/EP2749275A4/en
Priority to JP2014526363A priority patent/JP5938476B2/ja
Priority to US14/239,722 priority patent/US9241904B1/en
Priority to KR1020147004283A priority patent/KR101586273B1/ko
Priority to NZ621362A priority patent/NZ621362B2/en
Publication of WO2013026269A1 publication Critical patent/WO2013026269A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides a medicated pressurized metered dose inhaler combination and a process for the preparation thereof for use in the treatment of a respiratory related disease such as asthma or chronic lung obstruction.
  • pMDI Pressurized Metered Dose Inhaler
  • DPI Dry Powder Inhaler
  • CFC chlorofluorocarbons
  • COPD Chronic Obstructive Pulmonary Disease
  • Conventional ingredients for the treatment of such conditions include corticosteroids, beta-2 agonists, anti-acetylcholine drugs (anticholinergic drugs), or drugs that make up the inhaled form of the above drugs. combination.
  • CFC-based propellants were found to be environmentally damaging to the ozone layer and faced a global ban.
  • the dry powder inhaler was replaced by a dry powder inhaler.
  • CFC chlorofluorocarbon
  • pMDI Quantitative inhalation
  • HFA hydrofluoroalkanes
  • corticosteroids such as salbutamol
  • a corticosteroid component such as beclomethasone dipropionate, adrenaline, choline and antihistamine or anti-inflammatory drugs
  • the class of compounds acts as a cosolvent.
  • the surfactant is a derivative of oleic acid, polyethylene glycol (PEG) 400 or Span, and is added in a weight ratio of 5% or less.
  • No. 6,743,413 is the main ingredient of HFA 134a and micronized drug, no other excipients. No.
  • 5,776,432 discloses a mixture of HFA 134a, HFA 227 or a mixture of the two as a propellant, and 2% to 12% ethanol as a main ingredient drug beclomethasone 17, 21 dipropionate, without any interface. Active agent.
  • a prescription patent containing HFA is disclosed by GlaxoSmithKline (GSK) in U.S. Patent Nos. 5,653,962, 5,658,549, 5,744,123.
  • the main component containing salmeterol, salbutamol, fluticasone propyl acetate, but no co-solvent and less than 0.0001% of surfactant.
  • Subsequent related patents are directed to correcting drug delivery uniformity.
  • Patent Nos. 6, 315, 173, and 6, 510, 969 are directed to an improved design of the showerhead.
  • Patent No. 6,479,035 uses Fluticasone and 7-20% alcohol as a co-solvent with 0.5-3% glycerol or PEG as the surfactant. Nos.
  • Aeropharm discloses a prescription patent containing HFA.
  • U.S. Patent No. 5,891,419 discloses that flimisolide only adds 0.5% to 2% ethanol.
  • Patent No. 5,891,420 discloses the addition of 1% to 3% ethanol to triamcinolone acetonide.
  • Patent No. 6,458,338 is directed to a metered spray formulation with an amino acid as a stabilizer.
  • Patent Nos. 6,447,750, 6,540,982, 6,540,983, 6,548,049, and 6,645,468 disclose the use of a primary component drug for the treatment of diabetes.
  • Type. Patent No. 6,464,959 discloses a metered spray formulation in which a main ingredient for treating diabetes is combined with an amino acid as a stabilizer.
  • U.S. Patent No. 6,004,537 to Baker Norton discloses the dissolution of the main component Budesonide, Formoterol with HFA promoter and cosolvent ethanol 10% to 40% w/w.
  • Fisons U.S. Patent No. 6,123,924 discloses major components such as beta 2 -receptor agonist: fenoterol hydrobromide, procaterol hydrochloride, albuterol sulfate, terbutaline sulfate, etc., assimilation steroids Or steroids; beclomethasone dipropionate, fluticasone propionate, tipredane, etc. and antihistamine or anti-inflammatory or acetyl-p-methylcholine bromide bile-like components: ejaculate isoethionate ⁇ tipredanene ⁇ docromil sodium, sodium cromoglycate , clemastine, budesonide, etc.
  • PVP polyvinylpyrrolidone
  • the Fuweitro's super-fine formula technology disclosed by Chiesi in China's 200,303,767 font contains 0.003-0.192% w/v of (R,R)-( ⁇ )-formoterol fumarate Adjust the pH with 10 ⁇ 20% ethanol and hydrochloric acid using a pressurized metered dose inhaler formula combination technique, and emphasize that the fraction of particles equal to or smaller than 1.1 microns is greater than or equal to 30%.
  • U.S. Patent No. 7,223,381 is a formulation of Budesonide, HFA propellant and cosolvent ethanol 13% and 0.2 ⁇ 2% glycerol.
  • U.S. Patent No. 6,638,495 to Nektar is directed to a combination of techniques for the formation of microstructures using phospholipids as excipients to disperse biologically active materials in pressurized metered dose inhalers.
  • U.S. Patent No. 6,932,962 to AstraZeneca is a HFA spray formulation containing a fatty acid or a salt thereof, a bile salt, a phospholipid or an alkyl sugar as a surfactant, and can be used in an amount of 5 to 20% ethanol.
  • Low-medium weight ethanol about 1 ⁇ 10% ethanol is combined with other excipients. At this time, the drug is partially dissolved and insoluble, which has a great influence on the stability of the prescription, and will follow the preservation time. Causes changes in the particle size of the drug.
  • Valois's formula has the advantage that the drug is in an insoluble suspension state, and the drug stability is preferred.
  • the disadvantage is that the drug uniformity is poor, and other drugs are required. The assistance of the agent and the process may be difficult.
  • Valois SAS has published a study on the Budesonide HFA MDI formula and used 0.1 to 5% PEG 300, 0.2-2% ethanol (Indian Journal of Pharmaceutical Science, Vol. 69, No. 5, P. 722-724). , Sep-Oct 2007), however, the prescription is to fill the container with a standard anodized aluminum canister to reduce the adsorption of the drug to the drug and to improve the uniformity of administration.
  • a standard anodized aluminum canister When applied to an amplification process or an aluminum canister, there are some quality issues. Therefore, when the actual mass production of a prescription is made in the pharmaceutical industry, even if the contents of the prescription are the same, the quality difference may still occur due to the difference in the order of composition mixing and the manner of filling the equipment.
  • the total amount of the main component is insufficient, the drug particles are not well bonded, and the homogeneity is not good.
  • the product containing the two main components is more likely to occur due to the difference in the physicochemical properties and the content ratio between the main components. Therefore, changes in the combination of excipients in the prescription content, especially in the order and homogenization of the combination of the main ingredient drug with the propellant and other excipients, can create a stable, safer and more effective quality. Pressure metered spray type.
  • the lungs are relatively fragile tissues, and when administered through the lungs, care must be taken to minimize damage to the lungs. Although the surface cells of the lungs have moving fibers to exclude inhaled foreign matter, after all, the elimination function is limited, so when designing the inhaled formulation, a small amount or less toxic excipient should be used whenever possible. Although the use of a large amount of co-solvent allows the product to exhibit a preferred uniformity, the stability will be relatively low. Therefore, the present invention develops a HFA MDI formulation policy in an attempt to prepare a safe and effective suspension dosage form with a minimum amount of excipients and co-solvents, and achieves good drug uniformity and long-term product stability, providing sufficient patient to enter the lungs effectively. Part dose ( ⁇ 5 microns).
  • HFA-containing prescription patents Amount it is easy to reduce the stability and uniformity of the drug of the product, especially when the product contains two main components, such as an ethylene-type synergist and a corticosteroid, and the difference in dose between the two is large and the physicochemical properties are different. It is more likely to cause a phenomenon in which the uniformity and stability of the main component in the dosage form are deteriorated. Moreover, since the main component in the suspension dosage form process cannot be uniformly mixed with the excipient, the drug particles are easily reaggregated, resulting in a serious decrease in the effective inhalation dose (Fine Particle Dose).
  • the present invention provides a method of preparing a metered dose inhalant composition comprising the following steps:
  • the present invention relates to a stable and uniform suspension dosage form formed by combining an inhaled drug with a suitable process.
  • a suitable process Combination of type B synergists (Procaterol, Salbutamol, Formoterol and Salmeterol), corticosteroids (Budesondie, fluticasone, Ciclesonide and Beclomethasone) or both, argon fluoride (HFA) propellant, selected 1,1,1,2 tetrafluoroethane (HFA 134a, HFC 134a) or 1,1,1,2,3,3,3-heptafluoropropane (Heptafluoro-n-propane, HFC 227ea, HFC 227, HFA 227), if necessary, can also be mixed.
  • type B synergists Procaterol, Salbutamol, Formoterol and Salmeterol
  • corticosteroids Budesondie, fluticasone, Ciclesonide and Beclomethasone
  • HFA arg
  • the surfactant is prepared by using a polyethylene glycol (PEG) excipient to stabilize the formulation, or the metering valve of the lubrication container is used to reduce the blocking condition, and the addition amount is 0.01% to 2.50% w/w%, and 0.05%. ⁇ 1.50% w/w% is preferred.
  • PEG polyethylene glycol
  • the PEG is preferably from 100 to 6000.
  • the addition amount can change the particle size distribution and can be regarded as a particle size regulator.
  • the absolute weight ratio of anhydrous ethanol is 0.05% to 10.0% w/w%, and preferably 0.25% to 2.0% w/w%.
  • anhydrous ethanol can not only assist the dissolution of PEG, but also reduce the phenomenon that the main component particles are aggregated due to the evaporation of HFA from the spray nozzle at the instant spray formulation.
  • the surfactant is a commercially available product having a molecular weight of polyethylene glycol of 100 to 6000, and the viscosity required is adjusted by the amount of ethanol.
  • the present invention provides a method of preparing a metered dose inhalant composition comprising the steps of:
  • the spray dosage form process part of the present invention in order to control the uniformity of the main component particles, it is an important step in the process to uniformly disperse the PEG in the HFA. Mix a small amount of alcohol and PEG first. Since the particles of the inhaled drug are quite fine, they tend to aggregate in the solution. In order for the PEG to uniformly disperse the particles, it is necessary to mix in an ultrasonically oscillating manner to form a concentrate.
  • the viscosity and volume of the mixed solution of alcohol and PEG may vary depending on the amount and characteristics of the main component, but should not exceed 2% w/w% of the total prescription amount.
  • the main component drug content is high and the appearance volume is much larger than the volume of the alcohol and PEG mixed solution, it is not necessary to mix with alcohol and PEG first.
  • the concentrated liquid prepared above or the mixed solution of alcohol and PEG is homogenized with HFA to form a homogenized liquid, and the main component having a high content is slowly added to the homogenizing liquid to be mixed.
  • This process has an immutable effect on the order in which the excipients are added and the manner of mixing.
  • the uniform dispersion of the drug particles and the amount of the main component drug adhered to the mixing tank have a considerable improvement, and finally The step of freezing or pressurizing filling is performed.
  • Tolerance range of spray nozzles stipulates that a batch of qualified nozzles has an average target value of ⁇ 10%, and individual nozzles have a target value of ⁇ 15%)
  • a dose sampling device (DUSA, Dose Unit Sampling Apparatus) in accordance with the USP Pharmacopoeia was used with a ⁇ glass fiber filter to perform a spray sampling at a specified pumping flow rate (28.3 L/min).
  • the instrument measures the amount of the drug in the Actuator (or mouthpiece) and the sampling device, and detects the three sprays, the middle four sprays, and the last three sprays in the whole bottle for single dose detection.
  • the main component of a single spray quantity should be within 25% of the indicated dose, and the average value of the total content of all 10 spray components should be within 15% of the indicated dose.
  • the acceleration stability condition is 40.
  • the relative humidity of 75% was maintained for 6 months, and the uniformity of administration was evaluated.
  • the spray sampling was performed according to the pumping flow rate (30.0 L/min) prescribed by the USP Pharmacopoeia, and the particle size analysis of the drug particles was carried out using the Next Generation Cascade Impactor. And the acceleration stability condition is 40. C. The relative humidity of 75% was maintained for 6 months, and the change of particle distribution in each layer was analyzed by Next Generation Cascade Impactor to evaluate the stability of the drug particles suspended in the prescription solution.
  • the administration homogeneity analysis was carried out in accordance with the spray of the spray formulation type formulation of the first embodiment of the present invention, as shown in the first figure.
  • each can spray contains a total of 10 sprays before, after, and after spraying.
  • a single spray complying with the Pharmacopoeia shall not exceed 25% of the indicated dose and the average shall not exceed 15% of the indicated dose.
  • a sprayed dose of 10 meg of procaterol hydrochloride (Clixrol HC1) after a 6-month accelerated stability test (40 ° C, relative humidity of 75%) each can spray
  • the dosage of 10 sprays containing the first, middle and the last, all in accordance with the Pharmacopoeia shall not exceed 25% of the indicated dose and the average value shall not exceed 15% of the indicated dose.
  • Budesonide uses the Next Generation Cascade Impactor to analyze each level, including the actuator (actuator). ), L-throat, Stage 1 , Stage 2, Stage 3, Stage 4, Stage 5 , Stage 6, Stage 7 and micro-orifice Collector; MOC), there was no significant difference in the content of budesonide between the starting point and the starting point (ANOVA test, ⁇ >0 ⁇ 05).
  • Formulation Example 9 Uniformity analysis of salbutamol sulfate (salbutamol sulfate) by spray, as shown in the seventh figure, showing a spray-labeled dose of 250 meg of salbutamol after 6 months accelerated stability test (40 ° C, relative humidity 75%) After that, each spray of the can contains a total of 10 sprays before and after the spray, which is consistent with the Pharmacopoeia specified that the single spray should not exceed 25% of the indicated dose and the average value should not exceed 15% of the indicated dose.
  • the analysis of the particle size distribution of salbutamol shows the content of salbutamol in each class analyzed by the Next Generation Cascade Impactor after a 6-month accelerated stability test face (40° (relative humidity 75%)). There was no significant change between the products at the beginning of the time (ANOVA test, ⁇ >0 ⁇ 05).
  • the invention aims at improving the content stability, the uniformity of drug administration and the quality stability during the filling process of the pressurized quantitative spray type, especially when the product combines two main components having different relative physicochemical properties, and the prescription application thereof It has considerable industrial value in the process and assists in applying according to law.
  • the "method of preparing a quantitative spray inhalant for treating respiratory diseases" proposed in the present application will be fully understood by the description of the following examples, so that those skilled in the art can complete it.
  • the embodiment of the present invention confirms that Not limited by this implementation type, Those skilled in the art will be able to devise other embodiments in the spirit of the disclosed embodiments, and these embodiments are within the scope of the appended claims.
  • a method of preparing a metered dose inhalant composition comprising the steps of:
  • a method of preparing a metered dose inhalant composition comprising the steps of:
  • a method of preparing a metered dose inhalant composition comprising the steps of:
  • corticosteroid drug is selected from the group consisting of budesonide, fluticasone, beclomethasone, ciclesonide and a salt form thereof, fluticasone propylacetate, beclomethasone dipropionate At least one of them.
  • ethylene-type synergist is selected from the group consisting of salbutamol, procaterol, formoterol and its base drug salbutamol sulfate, procaterol hydrochloride, and fumarate fumarate Luo at least one of them.
  • PEG polyethylene glycol
  • the second figure the formulation of the first embodiment of the formulation of Procaterol hydrochloride uniformity analysis.
  • Fig. 6 is a graph showing the particle size distribution analysis of fluticasone in Formulation Example 7.
  • FIG. 10 Micro-orifice collector (MOC)
  • Figure 7 shows the homogeneity analysis of salbutamol sulfate in Formulation Example 9.
  • Figure 8 is a graph showing the particle size distribution of salbutamol sulfate in Formulation Example 9. 1 ⁇ actuator (actuator)
  • Micro-orifice collector (MOC)

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Abstract

一种定量喷雾吸入剂组合物及其制备方法。所述定量喷雾吸入剂组合物含活性成分乙二型协同剂和皮质类固醇，其制备方法如下：（1）以0.05—10.0%w/w的酒精与界面活性剂混合形成第一混合液；（2）将乙二型协同剂分散于第一混合液中以形成第二混合液；（3）将氢氟烷推进剂添加到第二混合液中以形成第三混合液；（4）将皮质类固醇分散于第三混合液中；（5）进行填充步骤。

Description

制备用于治疗呼吸道疾病的定量喷雾吸入剂的工艺方法
【发明所属的技术领域】
本发明提供含药的加压定量喷雾吸入剂组合及其制备方法，该加压 定量喷雾吸入剂是用于治疗呼吸道相关疾病如气喘或慢性肺阻塞的医 药品。
【背景技术】
加压定量吸入剂（pressurized Metered Dose Inhaler; pMDI)可让吸 入的药物局部快速呈现药物活性，且相对于口服药物， 具有较低的全身 不良反应， 已与干粉吸入剂（Dry Powder Inhaler; DPI)共成为最广泛的 治疗哮喘（Asthma)或慢性肺阻塞病（Chronic Obstructive Pulmonary Disease, COPD)的投药模式， 被用来给予包括皮质固醇类药物、 乙二型 交感神经接受体兴奋剂（beta-2 agonists), 抗乙酰胆碱药物 (抗胆碱能药）, 或是上述成份并用的组合物。
自 1955年 3M开发出以氟氯破 (chlorofluorocarbons, CFC)为推进 剂的定量加压吸入剂产品以来， 已成为最广泛的治疗哮喘 (Asthma)或慢 性肺阻塞病（Chronic Obstructive Pulmonary Disease, COPD)的投药模 式。加压定量喷雾吸入剂比口服药物更能快速呈现活性， 并可提供药物 较低的系统性不良反应。 常规治疗此类病症的成分包括皮质固醇类、 乙 二型交感神经接受体兴奋剂（beta-2 agonists), 抗乙酰胆碱药物 (抗胆碱 能药）， 或是上述药物组成吸入性剂型的药物组合物。
氟氯碳推动剂在 1970年代被发现为有破坏臭氧层的环保问题， 面 临被全球禁用的处境。 1980s年代末期替代产品干粉吸入剂开发， 但因 为药品易受潮及病人使用时需要有足够的吸气流速才能有效给药 ,故一 直未能全面取代以氟氯碳 (CFC)为推动剂的加压定量吸入剂 (pMDI)。今 日 3M 的 Riker 公司开发第一个取代 CFC 推动剂的氢氟烷类 (hydrofluoroalkanes, HFA)推进剂： 1，1，1，2四氟乙燒 (tetrafluoroethane, HFA 134a, HFC 134a)或 1，1，1，2，3，3，3-七氟丙烷 (heptafluoro-n-propane， HFC 227ea, HFC 227， HFA227)。 但因必须克服制剂技术及安全性等问 题， HFA MDI专利配方直至 1996年才有第一个产品上市， 并在 2004 年蓬勃发展， 也促使 CFC MDI将于 2010后全面禁止生产。 Riker/3M公司在美国专利第 5,225,183、 5,439,670、 5,695,743、 5,766,573、 5,836,299、 6,352,684号等，揭示含有 HFA 134a的处方专利。 选用包括 salbutamol等的肾上腺素乙二型协同剂、 倍氯米松二丙酸盐 等的皮质类固醇成份、 腎上腺素成份、胆碱类及抗组织胺或抗发炎等药 物， 并使用 1~50%乙醇类化合物作为助溶剂。 界面活性剂是以油酸、 聚乙二醇 (PEG) 400 或 Span 等衍生物， 添加重量比率 5%以下。 第 6,743,413号是应用 HFA 134a与微粒化药物主成份，无其他赋形剂。第 5,776,432号则揭示以 HFA 134a, HFA 227或两者的混合物为推进剂， 并使用 2%~12%的乙醇做为主成分药物 beclomethasone 17， 21二丙酸 盐的助溶剂， 不含任何界面活性剂。
先灵公司（Schering)于第 5,474,759号美国专利中揭示包括以 HFA 227为推进剂 , 长链的丙二醇双酯 (propylene glycol diester)作为界面活 性剂。其中主成分包括 albuterol 沙丁胺醇硫酸盐、倍氯米松二丙酸盐 或糠酸莫米松等。
葛兰素史克 (GSK)公司于美国专利第 5,653,962、 5,658,549、 5,744,123号揭示含有 HFA的处方专利。 选用含有 salmeterol、 沙丁胺 醇、 丙醋氟替卡松等主成份，但无共溶剂及使用低于 0.0001%的界面活 性剂。后续相关专利是针对修正药物输送均一性。第 6，315，173、6，510，969 号专利是针对喷头的改良设计。 第 6,479,035 号专利则是使用 Fluticasone及 7~20%酒精为助溶剂， 并以 0.5~3%甘油或 PEG做为界 面活性剂。 第 5,736,124、 5,817,293、 5,916,540、 5,922,306、 6,333,023, 6,200,549及 6,222,339号专利揭示有关主成分 formoterol,使用 0.01-5% 乙醇。第 6,303,103及 6,238,647号专利揭示 salmeterol与抗胆碱药物并 用 ， 使用低于 0.0001%的赋形剂。 第 6,013,245 号专利关于 beclomethasone、沙丁胺醇，使用 HFA 227且无接口活性剂。第 5,833,950 号专利揭示 beclomethasone使用 HFA及低于 0.0001%的赋形剂。
Aeropharm 公司揭示含有 HFA 的处方专利。 于美国专利第 5,891,419号揭示 flimisolide只添加 0·5%~2%乙醇。 第 5,891,420号专 利揭示以曲安奈德添加 1%~3%乙醇。 第 6,458,338号专利则针对以氨 基酸为稳定剂的定量喷雾剂型配方。第 6,447,750、 6,540,982、 6,540,983、 6,548,049及 6,645,468号专利揭示主成份药物治疗糖尿病的定量喷雾剂 型。 而第 6,464,959号专利则揭示以治疗糖尿病的主成份药物合并使用 氨基酸为稳定剂的定量喷雾剂型。
Baker Norton (今日的 TEVA)公司美国专利第 6,004,537号揭示以 HFA推动剂及助溶剂乙醇 10%~40% w/w溶解主成分 Budesonide、 福 莫特罗。
Fisons美国专利第 6,123,924号揭示主成分如 β2-受体致效剂： 非诺 特罗氢溴酸盐、丙卡特罗盐酸盐、沙丁胺醇硫酸盐、特布他林硫酸盐等、 同化性类固醇或类固醇成份； 倍氯米松二丙酸盐、 氟替卡松丙酸盐、 tipredane等及抗组织胺或抗发炎或 acetyl-p-methylcholine bromide胆 械类成分：喷他脉 isoethionate^ tipredanene^ docromil sodium、 sodium cromoglycate、氯马斯汀、 budesonide等分散于 HFA，并使用 0·00001~10% w/w 的聚乙烯吡咯烷酮 (polyvinylpyrrolidone, PVP)为助悬剂及分子量 400-3,000的聚乙二醇作为润滑剂。
Chiesi公司于我国 200303767字号揭示的福莫特罗的超威细配方技 术， 其含有 0.003-0.192% w/v间的 (R，R)- (士) -福莫特罗反丁烯二酸盐， 以加压定量吸入器配方组合技术使用 10~20%乙醇及盐酸调整 pH值， 并强调等于或小于 1.1微米的颗粒部分大于或等于 30%。在美国专利第 7,223,381号则是 Budesonide、HFA推动剂与共溶剂乙醇 13%及 0.2~2% 甘油所构成的配方。
Nektar公司美国专利第 6,638,495号则涉及于使用磷脂为赋形剂形 成微结构将具生物活性物质散布于加压定量吸入器的配方组合技术。
AstraZeneca公司美国专利第 6,932,962号是含有脂肪酸或其盐基、 胆盐、 磷脂或烷基醣为界面活性剂的 HFA喷雾剂型， 其乙醇使用量可 达 5~20%。
University College Cardiff Consultants Limited 美国专利第 7,481,995号涉及以 基酸为助悬赋形剂的 HFA MDI配方技术。
在加压定量吸入喷雾剂型处方上整体观察上述的背景技术，除了药 物及 HFA气体之外， 依乙醇的使用状况主要可分为以下技术：
1) .无任何添加物：以 GSK公司为代表， 药物完全以悬液模式呈现， 但有给药较不易均一的问题。
2) .不使用乙醇， 单纯使用赋形剂:如 PVP或丙二醇双酯等。 3) .大量乙醇:大于 10%以上乙醇将药物完全溶解， 可加或不加其他 赋形剂，优点是给药均一性很好，缺点是药物稳定性可能较差及酒精异 味病人接受度差等。
4) .低中量乙醇:约 1~10%之间乙醇搭配其他赋型剂， 此时药物处于 部分溶解部分不溶解状态，对于处方的稳定性影响较大，会随着保存时 间的经过， 造成药物粒径的变化。
5) .极低量乙醇:约为 0.2~2%乙醇，如 Valois公司的配方，优点是药 物处于不溶解的悬液状态，药物稳定性优选，然而缺点是给药均一性差， 需有其他赋形剂的协助， 及在工艺上可能较为困难。
虽然 Valois SAS曾发表相关于 Budesonide HFA MDI配方研究且 使用 0·1~5%的 PEG 300、 0.2-2%的 乙醇（Indian Journal of Pharmaceutical Science, Vol. 69， No. 5， P. 722-724， Sep-Oct 2007), 然而 其处方为降低容器对于药品的吸附及提高给药均一性，仍需使用特殊表 面电镜过的容器 (Standard anodized aluminum canister)充填。当应用于 放大工艺或一般容器 (aluminum canister)时， 便会呈现一些质量问题。 所以在制药工业上处方实际量产时， 即使处方内容相同，但由于成分混 合顺序及充填设备方式的不同， 仍会造成质量差异。例如主成分总量不 足、 药物颗粒黏结及均一性不好等， 特别是含有两种主成分的产品， 由 于其主成分间物化性质及含量比例的差异， 更容易发生上述情形。所以 在处方内容赋形剂结合工艺上的改变，特别是在运用主成分药物与推动 剂及其他赋形剂混合的顺序与均质方式， 方能创造出质量稳定、 更安全 及更有效的加压定量喷雾剂型。
【发明内容】
肺部是较为脆弱的组织， 经肺投药时， 必需考虑到尽量降低对肺部 的伤害。 虽然肺部的表面细胞具有运动纤维可将吸入的异物排除，毕竟 其排除功能是有限度的， 所以在设计吸入剂型配方时，应尽可能使用少 量或毒性较低的赋形剂。虽然使用大量助溶剂能让产品呈现优选的均一 性， 但稳定性将相对地降低。 因此本发明研发 HFA MDI配方的方针， 是企图以最少量赋形剂及助溶剂来制备安全有效的悬液剂型，并实现良 好的给药均一性及产品长期稳定性，提供足以病人有效进入肺部的剂量 (<5微米)。 但由于降低赋形剂及助溶剂的揭示含有 HFA的处方专利用 量， 容易降低产品药物的稳定性及均一性， 特别是当产品同时含有两个 主成分， 例如为乙二型协同剂及皮质类固醇，且两者之间剂量的差异大 且物化性质不同时，更容易造成剂型中主成分的均匀度及稳定性变差的 现象。 又由于悬液剂型工艺中主成分无法与赋形剂之间均匀混合， 所以 药物颗粒容易再聚集而导致产品有效吸入剂量 (Fine Particle Dose)严重 降低的现象。
本发明是提供一种定量喷雾吸入剂组合物的制备方法，包括下列步 骤：
(a)以 0.05%~10.0%w/w%的酒精混合界面活性剂来形成第一混合 液；
(b)分散乙二型协同剂于该第一混合液中以形成第二混合液；
(c)添加氢氟烷推进剂（HFA)于该第二混合液中以形成第三混合液；
(d)再分散皮质类固醇于该第三混合液中；以及
(e)执行充填步骤。 根据上述构想本发明涉及将吸入性药物搭配适当工艺所形成安定 且均匀的悬液剂型。将乙二型协同剂（丙卡特罗、 沙丁胺醇、 Formoterol 及 Salmeterol)、 皮质类固醇 (Budesondie、 氟替卡松、 Ciclesonide 及 Beclomethasone)或两者药物的结合， 氬氟燒类 (hydrofluoroalkanes, HFA)推进剂， 选择采用 1，1，1，2四氟乙烷 (tetrafluoroethane，HFA 134a， HFC 134a)或 1，1，1，2，3，3，3-七氟丙烷 (heptafluoro-n-propane， HFC 227ea, HFC 227， HFA 227)， 必要时也可混合使用。 表面活性剂选用聚乙二醇 (PEG)赋形剂以安定处方， 或润滑容器的计量阀（metering valve)降低阻 塞情况， 其添加量为 0.01%~2.50% w/w%, 而以 0.05%~1.50% w/w% 优选。 一般 PEG在此浓度下不会影响主成分的溶解度而使其稳定性降 低。 其 PEG以 100~6000为宜， 除呈现助悬作用外， 添加量变更可改变 粒径的分布， 可视为粒径调节剂。 而无水乙醇的添加重量比率为 0.05%~10.0% w/w%, 而以 0·25%~2·0% w/w%优选。 在此浓度下， 无 水乙醇不但可协助 PEG溶解， 还可降低喷雾剂剂型喷出瞬间喷头挥发 HFA,所造成主成分颗粒聚集的现象。另外本发明中表面活性剂是选用 聚乙二醇 100~6000分子量的市售品， 而以乙醇量调整所需的黏性。 根据上述构想，具体而言本发明是所提供一种定量喷雾吸入剂组合 物的制备方法， 包括下列步骤：
(a)以 0·05%~10·0% w/w%酒精作为醇类溶媒混合界面活性剂形成 混合液，
(b) ^lt乙二型协同剂于混合液形成均匀溶液，
(c)添加 HFA于均匀溶液，
(d)再将皮质类固醇分散于该均匀溶液： 以及
(e)进行冷冻充填或加压充填的步骤。
本发明的喷雾剂剂型工艺部分， 为掌控主成分颗粒的均一性， 让 PEG均匀分散于 HFA是工艺上重要步骤。 先将少量酒精及 PEG混合 均匀， 由于吸入性药品的颗粒相当微细， 在溶液中仍容易聚集。 为了使 PEG能均匀分散颗粒， 这时必须以超音波震荡方式混合以形成浓缩液。 酒精及 PEG混合溶液的粘度及体积可随着主成分的用量及特性而变动， 但不宜超过总处方量的 2% w/w%。 但如主成分药物含量较高， 且外观 体积远大于酒精及 PEG混合溶液体积量时，不需先与酒精及 PEG混合。 而上述制备的浓缩液或酒精及 PEG混合溶液再与 HFA搅拌均质形成均 质液， 才緩慢将含量高的主成分加入均质液混合。此工艺于赋型剂加入 顺序及混合方式有着不可变更的影响， 特别是对于放大工艺时， 药物颗 粒的均匀分散程度及主成分药物沾粘于混合槽的量，有着相当明显的改 善， 最后才进行冷冻充填或加压充填的步骤。
【实施方式】
评估给药均一性 (Delivery dose uniformity):
喷雾剂型的药效及安全性受给药均一性影响； 包括
1.悬液能否于摇晃瓶身时快速地分布均匀
2.摇晃后维持均匀的悬浮状态达 5秒以上时间
3.喷雾剂喷头的公差范围（美国食品药物管理局规定合格范围一批 喷头的平均为目标值 ±10%， 个别喷头为目标值 ±15%)
为取得可信的均一性检测， 依据美国 USP药典规定的剂量取样装 置 (DUSA, Dose Unit Sampling Apparatus)搭配 Ιμιη玻璃纤维滤膜， 于 规定的抽气流速 (28.3 L/min)下进行喷雾取样后， 经由高效率层析分析 仪分别测量启动器 (Actuator，或称口含器 mouthpiece)及取样集药装置 内的药物量，检测整瓶中开始的三喷、 中间四喷及最后标示的三喷的个 别进行单一剂量的检测，其规格依据药典规范为单一喷量主成分需在标 示剂量的 25 %内， 其全部 10喷主成分含量的平均值需在标示剂量的 15 %内。 并经由加速稳定性条件为 40。C、 相对湿度 75%维持 6个月储 架期， 评估其给药均一性。
评估粒径分布分析 (Particle size distribution):
为确认药物颗粒粒径分布情形， 喷雾取样依据美国 USP药典规定 的抽气流速 (30.0 L/min)，使用 Next Generation Cascade Impactor进行 药物颗粒喷雾取样粒径分析。 并由加速稳定性条件为 40。C、 相对湿度 75%维持 6个月储架期， 观察其用 Next Generation Cascade Impactor 分析时每一阶层颗粒分布改变情形，评估药物颗粒悬浮于处方溶液中的 稳定性。 依照本发明喷雾剂剂型工艺配方实施例一的喷雾剂 ,进行给药均一 性分析，如第一图所示。一喷标示剂量为 180 meg的布地奈德经过 6个 月加速性稳定性试验 (40。C、相对湿度 75%)后， 每罐喷雾剂中包含前中 后共 10喷的给药剂量， 均合乎药典所规定的单喷不得超过标示剂量的 25%及平均值不得超过标示剂量的 15%以内。 另如第二图显示一喷标 示剂量为 10 meg的盐酸丙卡特罗（丙卡特罗 HC1)经过 6个月加速性稳 定性试验 (40°C、 相对湿度 75%)后， 其每罐喷雾剂包含前中后共 10喷 的给药剂量， 均合乎药典所规定的单喷不得超过标示剂量的 25%及平 均值不得超过标示剂量的 15%以内。
如第三图粒径分布分析显示布地奈德经过 6 个月加速性稳定性试 验 (40。C、相对湿度 75%)后，其使用 Next Generation Cascade Impactor 分析的每一阶层，包含启动器 (actuator)、L型管 (L-throat)、第一阶 (Stage 1)、 第二阶 (Stage 2)、 第三阶 (Stage 3)、 第四阶 (Stage 4)、 第五阶 (Stage 5)、 第六阶 (Stage 6)、 第七阶 (Stage 7)及微细孔径收集器 (micro-orifice collector; MOC)， 布地奈德的含量与起始时间点产品间在每一阶层并 无显著差异变化 (ANOVA test, ρ>0·05)。
如第四图粒径分布分析，显示盐酸丙卡特罗经过 6个月加速性稳定 性试驗 (40。C、 相对湿度 75%)后， 其使用 Next Generation Cascade Impactor分析的每一阶层盐酸丙卡特罗的含量与起始时间点产品间并 无显著变化 (ANOVA test, ρ>0·05)。 配方实施例七喷雾剂的氟替卡松给药均一性分析， 如第五图显示 1 喷标示剂量为 250 meg的氟替卡松经过 6个月加速性稳定性试验 (40。C、 相对湿度 75%)后，其每罐喷雾剂包含前中后共 10喷的给药剂量， 均合 乎药典所规定的单喷不得超过标示剂量的 25%及平均值不得超过标示 剂量的 15%以内。
配方实施例七喷雾剂的氟替卡松粒径分布分析，如第六图显示氟替 卡松经过 6 个月加速性稳定性试验 (40。C、 相对湿度 75%)后， 其使用 Next Generation Cascade Impactor分析的每一阶层氟替卡松的含量与 起始时间点产品间并无显著变化 (ANOVA test, p>0.05)„
配方实施例九喷雾剂的硫酸沙丁胺醇（沙丁胺醇硫酸盐)均一性分 析，如第七图显示 1喷标示剂量为 250 meg的沙丁胺醇经过 6个月加速 性稳定性试验 (40°C、相对湿度 75%)后，其每罐喷雾剂包含前中后共 10 喷的给药剂量， 均合乎药典所规定的单喷不得超过标示剂量的 25%及 平均值不得超过标示剂量的 15%以内。
沙丁胺醇粒径分布分析，如第八图显示沙丁胺醇经过 6个月加速性 稳定性试臉 (40° ( 、相对湿度 75%)后， 其使用 Next Generation Cascade Impactor分析的每一阶层沙丁胺醇的含量与起始时间点产品间并无显 著变化 (ANOVA test, ρ>0·05)。
本发明针对加压定量喷雾剂型于放大工艺时，提升产品充填时的含 量稳定性、给药均一性及质量稳定性， 特别是产品结合两种相对物化性 质差异大的主成分时， 其处方应用于工艺上深具相当产业价值，援依法 提出申请。本案所提出的「制备用于治疗呼吸道疾病的定量喷雾吸入剂 的工艺方法』将可由下列实施例的说明而得到充分了解，使得本领域技 术人员可据以完成。然而本案的实施例是证实，非受该实施型态所限制， 熟习本领域的人士当可依既揭露实施例的精神推演出其他实施例，则这 些实施例皆当属于本发明所附权利要求的所保护范畴。 工艺实施例一:
丙卡特罗 HC1 0.014% WAV%
布地奈德 0.252% WAV%
HFA 227 98.984% WAV%
无水酒精 0.500% WAV%
PEG 6000 0.250% WAV%
总量 100.000% WAV% 工艺说明
PEG 6000完全溶解于无水酒精形成混合液， 再将 Procaterol HC1 倒入混合液中以超音波震荡方式溶解成均质液。 HFA 227与均质液再进 行均质混合后， 緩慢加入布地奈德， 最后才进行冷冻充填或加压充填。 工艺实施例二：
丙醋氟替卡松 0.350% w/w%
HFA 134a 98.900% WAV%
无水酒精 0.500% w/w%
PEG 400 0.250% WAV%
总量 100.000%
WAV%
工艺说明
PEG 400完全溶解于无水酒精形成混合液。 HFA 134a与混合液再 进行均质混合后，緩慢加入丙醋氟替卡松， 最后才进行冷冻充填或加压 充填。 工艺实施例三:
沙丁胺醇硫酸盐 0.168% WAV% 丙醋氟替卡松 0.322% WAV%
HFA 134a 97.510% WAV%
无水酒精 1. ( WAV%
PEG 100 l.( WAV%
总量 WAV% 工艺说明
PEG 100完全溶解于无水酒精形成混合液，再将 Albuterol Salfatel 倒入混合液中以超音波震荡方式溶解成均质液。 HFA 227与均质液再进 行均质混合后，緩慢加入丙醋氟替卡松， 最后才进行冷冻充填或加压充 填。 工艺实施例四:
丙卡特罗 0.014% WAV%
HFA 227 99.286% WAV%
无水酒精 0.500% WAV%
PEG 2000 0.200% WAV%
总量 100.000% WAV% 工艺说明
PEG 2000完全溶解于无水酒精形成混合液， 再将 Procaterol HC1 倒入混合液中以超音波震荡方式溶解成均质液。 HFA 227与均质液再进 行均质混合， 最后才进行冷冻充填或加压充填。 配方实施例一
丙卡特罗 HC1 0.014% WAV%
布地奈德 0.280% WAV%
HFA 134a 98.906% WAV%
酒精 0.500% WAV%
PEG 2000 0.300% WAV%
总量 100.00% WAV% 配方实施例二:
丙卡特罗 HC1 0.014% w/w% 丙醋氟替卡松 0.350% WAV% HFA 227 98.886% WAV% 酒精 0.250% WAV% PEG 400 0.500% WAV% 总量 100.000% W/W% 配方实施例三:
沙丁胺醇硫酸盐 0.168% WAV% 丙醋氟替卡松 0.322% WAV% HFA 227 97.510% WAV% 无水酒精 1.500% WAV% PEG 400 0.500% W/W% 总量 100.000% WAV% 配方实施例四
丙卡特罗 0.014% WAV% HFA 134a 97.986% W/W% 无水酒精 1.000% WAV% PEG 100 1.000% WAV% 总量 100.000% WAV% 配方实施例五
丙卡特罗 HC1 0.014% WAV% 布地奈德 0.333% WAV% HFA 134a 98.903% WAV% 酒精 0.250% WAV% PEG 400 0.500% WAV% 总量 100.000% WAV% 配方实施例六:
布地奈德 0.330% WAV% HFA 227 99.530% WAV% 酒精 1.500% WAV%
PEG 2000 0.500% WAV% 总量 100.000% WAV% 配方实施例七:
丙醋氟替卡松 0.351% WAV% HFA 227 97.899% W/W% 酒精 1.500% WAV%
PEG 6000 0.250% WAV% 总量 WAV% 配方实施例八:
丙卡特罗 HC1 0.014% WAV% 环索奈德 0.286% W W% HFA 227 98.950% WAV% 酒精 0.500% WAV% PEG 100 1.000% WAV% 总量 100.000% WAV% 配方实施例九：
沙丁胺醇石 酸盐 0.396% WAV%
HFA 134a 96.604% WAV% 酒精 2.500% W W%
PEG 6000 0.500% WAV% 总量 100.000% WAV% 配方实施例十：
沙丁胺醇硫酸盐 0.168% WAV%
倍氯米松二丙酸盐 0.286% WAV%
HFA 134a 96.546% WAV%
酒精 1.500% WAV%
PEG 100 1.500% WAV%
总量 100.000% WAV% 配方实施例十一
丙卡特罗 HC1 0.014% WAV%
倍氯米松二丙酸盐 0.286% WAV%
HFA 227 98.950% WAV%
酒精 0.250% WAV%
PEG 400 0.500% WAV%
总量 100.000% WAV% 实施例
1.一种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0.05%~10.0%w/w%的酒精混合界面活性剂来形成第一混合
(b)分散乙二型协同剂于该第一混合液中以形成第二混合液；
(c)添加氢氟烷推进剂 (HFA)于该第二混合液中以形成第三混合液；
(d)再分散皮质类固醇于该第三混合液中；以及
(e)执行充填步骤。
2.—种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0.05%~10.0%w/w%酒精混合界面活性剂形成第一混合液，
(b)分散乙二型协同剂于第一混合液形成第二混合液，
(c)添加 HFA于第二混合液形成第三混合液： 以及
(d)再分散皮质类固醇于第三混合液。
3.—种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0·05%~0·25% w/w%酒精混合界面活性剂形成第一混合液： (b) ^*乙二型协同剂于第一混合液形成第二混合液： 以及
(c)添加 HFA于第二混合液形成第三混合液。
4.如实施例 1所述的制备方法， 其中皮质类固醇药物， 选自布地奈 德、 氟替卡松、 倍氯米松、 环索奈德及其盐基形态药物丙醋氟替卡松、 倍氯米松二丙酸盐至少其中之一。
5.如实施例 1所述的制备方法，其中乙二型协同剂，选自沙丁胺醇、 丙卡特罗、福莫特罗及其盐基药物硫酸沙丁胺醇、 盐酸丙卡特罗、 富马 酸福莫特罗至少其中之一。
6.如实施例 1所述的制备方法， 其醇类溶媒是无水乙醇。
7.如权利要求第 1项所述的制备方法， 其中混合， 是以震荡方式令 混合均匀。
8.如实施例 5所述的制备方法， 其醇类溶媒最优选添加重量比率为 0·25%~2·0% w/w%。
9.如权利要求第 1项所述的制备方法， 其界面活性剂是选用聚乙二 醇 (PEG) 100到聚乙二醇 6000至少其中之一。
10.实施例 9 所述的制备方法， 其界面活性剂优选添加量为 0.01%~2.50% w/w%。
11.实施例 9 所述的制备方法， 其界面活性剂优选添加量为 0.05%~1.50% w/w
12.实施例 1所述的制备方法，其中该氢氟烷推进剂（HFA)选用 HFA 134a或 HFA 227。
13.如实施例 12所述的制备方法，其中该氢氟烷推进剂可选用 HFA 134a与 HFA 227并用的组合。
14.一种定量喷雾吸入剂组合物， 依照权利要求第 1 项所述的制备 方法所制备， 该组合物供气喘或慢性肺阻塞病人气喘发作的紧急用药， 睡前或睡醒的偏极性控制用药。 虽然本发明已以优选实施例揭露如上，然其并非用以限定本发明的 范围， 任何本领域技术人员， 在不脱离本发明的精神和范围内， 当可作 各种更动与润饰，因此本发明的保护范围当视后附的权利要求所界定者 为准。 【附图说明】
第一图、 配方实施例一的布地奈德给药均一性分析。
第二图、 配方实施例一的盐酸丙卡特罗给药均一性分析。
第三图、 配方实施例一的布地奈德粒径分布分析。
1·启动器 (actuator)
2丄型管 (L-throat)
3.第一阶 +第二阶
4.第三阶
5.第四阶
6.第五阶
7·第六阶 +第七阶 +微细孔径收集器 (micro-orifice collector; MOC) 第四图、 配方实施例一的盐酸丙卡特罗粒径分布分析。
1·启动器 (actuator)
2丄型管 (L-throat)
3.第一阶 +第二阶
4.第三阶
5.第四阶
6.第五阶
7.第六阶 +第七阶 +微细孔径收集器 (micro-orifice collector; MOC) 第五图、 配方实施例七的氟替卡松给药均一性分析。
第六图、 配方实施例七的氟替卡松粒径分布分析。
1·启动器 (actuator)
2丄型管 (L-throat)
3.第一阶
4.第二阶 5.第三阶
6.第四阶
7.第五阶
8.第六阶
9.第七阶
10. 微细孔径收集器 (micro-orifice collector; MOC) 第七图、 配方实施例九的硫酸沙丁胺醇均一性分析。 第八图、 配方实施例九的硫酸沙丁胺醇粒径分布分析。 1·启动器 (actuator)
2丄型管 (L-throat)
3.第一阶
4.第二阶
5.第三阶
6.第四阶
7.第五阶
8.第六阶
9.第七阶
10. 微细孔径收集器 (micro-orifice collector; MOC)

Claims

权 利 要 求
1.一种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0.05%~10.0%w/w%的酒精混合界面活性剂来形成第一混合 液；
(b)分散乙二型协同剂于该第一混合液中以形成第二混合液；
(c)添加氢氟烷推进剂（HFA)于该第二混合液中以形成第三混合液；
(d)再分散皮质类固醇于该第三混合液中；以及
(e)执行充填步骤。
2.如权利要求第 1项所述的制备方法， 其中该皮质类固醇药物选自 布地奈德、 氟替卡松、倍氯米松、 环索奈德及其盐基形态药物丙醋氟替 卡松、 及倍氯米松二丙酸盐至少其中之一。
3.如权利要求第 1项所述的制备方法， 其中该乙二型协同剂选自沙 丁胺醇、 丙卡特罗、福莫特罗及其盐基药物硫酸沙丁胺醇、 盐酸丙卡特 罗、 及富马酸福莫特罗至少其中之一。
4.如权利要求第 1项所述的制备方法， 其中醇类溶媒的添加重量比 率为 0.25%~2.0% w/w
5.如权利要求第 1项所述的制备方法， 其中该界面活性剂选自聚乙 二醇 (PEG) 100到聚乙二醇 6000至少其中之一。
6.如权利要求第 1项所述的制备方法， 其中该界面活性剂的添加重 量比率为 0·01%~2·50% w/w%。
7.如权利要求第 1项所述的制备方法，其中该氢氟烷推进剂是 HFA 134a, HFA 227或其组合。
8.—种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0.05%~10.0%w/w%酒精混合界面活性剂来形成第一混合液;
(b)分散乙二型协同剂于该第一混合液中以形成第二混合液；
(c)添加氢氟烷推进剂于该第二混合液中以形成第三混合液；以及
(d)再分散皮质类固醇于该第三混合液中。
9.一种定量喷雾吸入剂组合物的制备方法， 包括下列步骤：
(a)以 0.05%~0.25% w/w%酒精混合界面活性剂来形成第一混合液;
(b)分歉乙二型协同剂于该第一混合液中以形成第二混合液;以及
(c)添加氢氟烷推进剂于该第二混合液中以形成第三混合液。
10.—种定量喷雾吸入剂组合物， 是依照权利要求第 1 项所述的制 备方法来制备，该组合物为供气喘或慢性肺阻塞病人气喘发作的紧急用 药， 及睡前或睡醒的偏极性控制用药。
PCT/CN2012/071129 2011-03-17 2012-02-14 制备用于治疗呼吸道疾病的定量喷雾吸入剂的工艺方法 WO2013026269A1 (zh)

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AU2012300082B2 (en) 2016-05-19
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