WO2017177930A1 - 布地奈德混悬喷雾剂 - Google Patents

布地奈德混悬喷雾剂 Download PDF

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Publication number
WO2017177930A1
WO2017177930A1 PCT/CN2017/080317 CN2017080317W WO2017177930A1 WO 2017177930 A1 WO2017177930 A1 WO 2017177930A1 CN 2017080317 W CN2017080317 W CN 2017080317W WO 2017177930 A1 WO2017177930 A1 WO 2017177930A1
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WIPO (PCT)
Prior art keywords
suspension spray
suspension
budesonide
spray
spray according
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PCT/CN2017/080317
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English (en)
French (fr)
Inventor
丁丹
牟丽秋
曹立
赵步文
黄芳芳
Original Assignee
广东东阳光药业有限公司
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Application filed by 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to CN201780023329.1A priority Critical patent/CN109310701A/zh
Publication of WO2017177930A1 publication Critical patent/WO2017177930A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a high-concentration suspension spray containing budesonide having a small particle size which can be used for inhalation treatment of asthma symptoms and can be administered in multiple doses.
  • Budesonide is a glucocorticoid with a highly effective local anti-inflammatory effect. It can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, inhibit immune response and reduce antibody synthesis, thereby reducing the release and activity of allergic active mediators such as histamine, and reducing the enzymes stimulated by antigen-antibody binding. Promotes the process, inhibits the synthesis and release of bronchoconstrictor and reduces the contractile response of smooth muscle.
  • the structural formula of budesonide is as follows:
  • the currently commercially available low-concentration budesonide suspension for inhalation requires the use of a specific atomizing device to atomize the suspension, and can only be given in a single dose.
  • the medicine has high noise, is inconvenient to use, and has low atomization efficiency and poor reproducibility.
  • the instrument needs to be cleaned after use, the risk of bacterial contamination is large, and the atomization duration is long, and the breathing process is continued during the atomization process. Airflow limitation, the patient does not inhale sufficiently, resulting in lower bioavailability.
  • a budesonide preparation which is stable to a specific amount, has high bioavailability and stability, and can be used for inhalation treatment of asthma, without being limited by a specific device. Good results.
  • the present invention provides a suspension spray containing budesonide having a small particle size which can be used for inhalation treatment of asthma symptoms.
  • the budesonide suspension spray has a high concentration, can be administered in multiple doses, and is convenient to carry and use; it has the advantages of not being easy to block, the content is basically unchanged before and after atomization, and the utilization rate is high; and the stability is good and not easy. Dyed bacteria.
  • the commercially available budesonide suspension is administered in a single dose at a dose of about 2 ml per dose, whereas the budesonide suspension spray of the present invention requires only a few microliters to several tens of each dose. It is microlitered and can be taken multiple times, the dosage is greatly reduced, and the effective therapeutic concentration of the distribution to the neutral is still guaranteed.
  • the suspended spray of the present invention and the commercially available budesonide suspension are respectively atomized by a commercially available atomizer, and the content of the small-sized budesonide suspension spray of the present invention is substantially unchanged. However, the content of the commercially available budesonide suspension was significantly reduced after atomization.
  • the budesonide suspension spray provided by the invention can solve the low atomization efficiency of the currently commercially available suspension preparation for budesonide for inhalation, can only be administered in a single dose, is inconvenient to carry or use, and has low bioavailability. It is easy to stain and other problems, and reduces the discomfort and safety risks during the use of the patient.
  • a suspension spray comprising budesonide having a D (90) of no greater than 7.5 ⁇ m; in some embodiments, the suspension The active ingredient of the spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m.
  • the small particle size of budesonide facilitates the suspension of the spray when atomized using a commercially available sprayer, and the content of budesonide before atomization and the content of budesonide after atomization remain substantially unchanged.
  • the above suspension spray may further comprise at least one of the following additional technical features:
  • the suspension spray comprises a surfactant, a chelating agent and an isotonicity adjusting agent to enhance the stability and safety of the suspended spray.
  • the suspension spray further comprises a pH adjusting agent; thereby helping to further enhance the stability of the active distribution to the concentration of the drug in the suspension spray.
  • the suspension spray further comprises a buffer; thereby helping to further enhance the stability of the active distribution to the concentration of the drug in the suspension spray.
  • the concentration of budesonide in the suspension spray is from 0.5 mg/mL to 50.0 mg/mL. In some embodiments, the concentration of budesonide is preferably from 2.0 mg/mL to 30 mg/mL; in some embodiments, the concentration of budesonide is more preferably from 2.5 mg/mL to 25 mg/mL. These concentrations of sprays are capable of ensuring that a few microliters to tens of microliters of a suspension spray can be administered at a therapeutically effective dose; at the same time, it facilitates multi-dose administration of a suspension spray.
  • the surfactant comprises polyoxyethylene sorbitan fatty acid ester, dehydrated Sorbitol fatty acid esters, poloxamers, phospholipids or polyoxyethylene castor oil.
  • the polyoxyethylene sorbitan fatty acid ester includes, for example, Tween 10, Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 65, Tween 80, Tween 81, and Tween 85; and the sorbitan fatty acid ester includes, for example, Span 20, Span 40, Span 60, Span65, Span80, Span85 and Span83, etc.;
  • the poloxamers include, for example, Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 338, Poloxamer 407, Poloxamer 181, Poloxamer 182, Poloxamer 184, Poloxamer 331, Poloxamer 123, Poloxamer 335,
  • the surfactant comprises Tween 20, Tween 80, Span 20, Span 60, Poloxamer 188 or Poloxamer 407 to further increase the suspended spray Stability.
  • the concentration of the surfactant is from 0.05 mg/mL to 10 mg/mL; in some embodiments, preferably the concentration of the surfactant is from 0.1 mg/mL to 3 mg/mL; more preferably the surface
  • the concentration of the active agent is from 0.2 mg/mL to 2 mg/mL; thereby further increasing the stability of the budesonide suspension spray.
  • the chelating agent comprises disodium edetate or sodium calcium edetate. This helps to improve the stability of the suspension spray.
  • the concentration of the chelating agent is from 0.01 mg/mL to 10 mg/mL; in some embodiments, preferably the concentration of the chelating agent is from 0.05 mg/mL to 1 mg/mL; in some embodiments More preferably, the concentration of the chelating agent is from 0.1 mg/mL to 0.75 mg/mL.
  • the chelating agent helps to further increase the stability of the suspended spray.
  • the isotonicity adjusting agent comprises sodium chloride, glucose, glycerol, mannitol or sorbitol.
  • the isotonicity adjusting agent can further enhance the safety of the suspended spray.
  • the pH adjusting agent may comprise an acidic pH adjusting agent or an alkaline pH adjusting agent to help further enhance the stability of the active distribution in the suspension spray.
  • the acidic pH adjusting agent is one or more of hydrochloric acid, acetic acid or phosphoric acid; in some embodiments, the alkaline pH adjustment The agent is one or more of sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or magnesium hydroxide.
  • the pH adjusting agent is hydrochloric acid or sodium hydroxide; thereby contributing to further enhancing the stability of the active distribution distribution of dexamethasone in a suspension spray.
  • the buffer comprises acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or a salt thereof; thereby contributing to further activity enhancement
  • acetic acid citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or a salt thereof.
  • the buffer is citric acid and/or sodium citrate; thereby helping to further enhance the stability of the active distribution to the concentration of dexamethasone in a suspension spray.
  • the concentration of the citric acid may be from 0.05 mg/mL to 20.0 mg/mL; preferably from 0.2 mg/mL to 1.5 mg/mL; in some embodiments, the concentration of sodium citrate is 0.5 mg/mL to 20.0 mg/mL; preferably 0.5 mg/mL to 2.0 mg/mL; thereby contributing to further improving the stability of the active-distributed dexamethasone in a suspension spray.
  • the suspension spray has a pH of from 3.5 to 6; in some embodiments, preferably the suspension spray has a pH of from 4 to 5; thereby helping to further increase the activity into a distribution. De stability in suspension sprays.
  • the suspension spray further comprises a preservative.
  • the suspension spray further comprises a suspending agent.
  • a suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further The suspension spray further comprises the following pharmaceutical excipients: Tween 80, disodium edetate and sodium chloride. These ingredients contribute to the suspension of the spray when atomized using a commercial sprayer, the content before atomization and the content after atomization remain substantially unchanged; improve the stability and safety of the suspension spray.
  • the above suspension spray may further comprise at least one of the following additional technical features:
  • the suspended spray further comprises benzalkonium chloride.
  • the suspension spray further comprises sodium carboxymethylcellulose.
  • a suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; Further comprising a surfactant, a chelating agent, an isotonicity adjusting agent, pH Modifiers and buffers; thereby helping to further enhance the stability of the active distribution to the concentration of dexamethasone in suspension sprays.
  • the above suspension spray may further comprise at least one of the following additional technical features:
  • the suspension spray further comprises a preservative.
  • the suspension spray further comprises a suspending agent.
  • the concentration of budesonide in the suspension spray is from 0.5 mg/mL to 50.0 mg/mL; in some embodiments, the concentration of budesonide is preferably from 2.0 mg/mL to 30 mg. /mL; In some embodiments, it is more preferred that the concentration of budesonide is from 2.5 mg/mL to 25 mg/mL; thereby ensuring that a few microliters to several tens of microliters of suspension spray can achieve an effective therapeutic dose; Helps achieve multiple doses of suspension sprays.
  • the surfactant comprises Tween 20, Tween 80, Span 20, Span 60, Poloxamer 188 or Poloxamer 407; thereby increasing the activity of the distribution to the dexthene Stability in suspension sprays.
  • the chelating agent comprises disodium edetate or sodium calcium edetate; thereby helping to increase the stability of the active distribution of dexamethasone in a suspension spray.
  • the isotonicity adjusting agent comprises sodium chloride, glucose, glycerol, mannitol or sorbitol; thereby further enhancing the safety of the budesonide suspension spray.
  • the pH adjusting agent is hydrochloric acid or sodium hydroxide; thereby contributing to further enhancing the stability of the active distribution distribution of dexamethasone in a suspension spray.
  • the buffer is citric acid and/or sodium citrate; thereby helping to further enhance the stability of the active distribution to the concentration of dexamethasone in a suspension spray.
  • a suspension spray according to the present invention wherein the active ingredient of the suspension spray comprises budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, The active ingredient of the suspension spray comprises budesonide having a D(50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m.
  • the suspension spray further comprises the following pharmaceutical excipients: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium edetate and sodium chloride. These ingredients contribute to the stability of the suspended spray and the safety of the suspended spray when the aerosol is sprayed using a commercially available sprayer, and the content before atomization and the content after atomization remain substantially unchanged.
  • the above suspension spray may further comprise at least one of the following additional technical features:
  • the suspension spray further comprises a preservative.
  • the suspension spray further comprises a suspending agent.
  • the concentration of budesonide in the suspension spray is from 0.5 mg/mL to 50.0 mg/mL; in some embodiments, the concentration of budesonide is preferably from 2.0 mg/mL to 30 mg. /mL; in some embodiments, More preferably, the concentration of budesonide is from 2.5 mg/mL to 25 mg/mL; thereby ensuring that a few microliters to several tens of microliters of the suspension spray can achieve an effective therapeutic dose; at the same time, it helps to achieve a large amount of suspended spray. Dosing.
  • the present invention provides a suspension spray comprising an active ingredient comprising D(90) of not more than 7.5 ⁇ m of budesonide; in some embodiments, the active ingredient of the suspension spray comprises D (50) budesonide not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further comprising a surfactant, a chelating agent , an isotonicity adjusting agent and a pH adjusting agent; thereby contributing to further improving the stability of the active distribution to the concentration of the dextromethorphan in the suspension spray.
  • the present invention provides a suspension spray comprising an active ingredient comprising D(90) of not more than 7.5 ⁇ m of budesonide; in some embodiments, the active ingredient of the suspension spray comprises D (50) budesonide not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further comprising a surfactant, a chelating agent , an isotonicity adjusting agent and a buffering agent; thereby contributing to further enhancing the stability of the active distribution to the concentration of the dextromethorphan in the suspension spray.
  • the pH adjusting agent may comprise an acidic pH adjusting agent or an alkaline pH adjusting agent to help further enhance the stability of the active distribution in the suspension spray.
  • the acidic pH adjusting agent is one or more of hydrochloric acid, acetic acid or phosphoric acid; in some embodiments, the alkaline pH adjusting agent is sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or One or more of magnesium hydroxide.
  • the pH adjusting agent is hydrochloric acid or sodium hydroxide; thereby contributing to further enhancing the stability of the active distribution distribution of dexamethasone in a suspension spray.
  • the buffer comprises acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or a salt thereof; thereby contributing to further activity enhancement
  • acetic acid citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or a salt thereof.
  • the buffer is citric acid and/or sodium citrate; thereby helping to further enhance the stability of the active distribution to the concentration of dexamethasone in a suspension spray.
  • the concentration of the citric acid may range from 0.05 mg/mL to 20.0 mg/mL.
  • the concentration of citric acid is from 0.2 mg/mL to 1.5 mg/mL; in some embodiments, preferably the concentration of sodium citrate is from 0.5 mg/mL to 20.0 mg/mL; more preferably sodium citrate The concentration is from 0.5 mg/mL to 2.0 mg/mL; thereby contributing to further improving the stability of the active distribution of dexamethasone in a suspension spray.
  • the suspension spray has a pH of from 3.5 to 6; in some embodiments, preferably the suspension spray has a pH of from 4 to 5; thereby helping to further increase the activity to the distribution of Ned Stability in suspension sprays.
  • the present invention provides a suspension spray, wherein the active ingredient of the suspension spray comprises D (90) not more than 7.5 ⁇ m Budesonide; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(50) of no greater than 3.5 [mu]m; in some embodiments, the active ingredient of the suspension spray comprises D(10) budesonide not more than 1.0 ⁇ m, further comprising a surfactant, a chelating agent and an isotonicity adjusting agent; the suspension spray containing these components is atomized before being atomized using a commercially available atomizer. The content after atomization remains basically unchanged; it has good stability and safety.
  • the present invention provides a suspension spray, the active ingredient of the suspension spray comprising D(90) not more than 7.5 ⁇ m of budesonide, a surfactant, a chelating agent, an isotonicity adjusting agent and a preservative; It helps to maintain the sterility of the spray during shelf life or during use, and improves the safety of budesonide suspension spray; and helps the active distribution to be dispersed in the particle form to form a uniform and stable Suspend the spray.
  • a suspension spray comprising an active ingredient comprising D(90) of not more than 7.5 ⁇ m of budesonide, a surfactant, a chelating agent, an isotonicity adjusting agent and a suspending agent; These ingredients help the spray to maintain sterility during shelf life or during use, improve the safety of budesonide suspension sprays; and help the active distribution to be dispersed in a particulate form to form a uniform dispersion in the spray. Stable suspension spray.
  • the invention provides a suspension spray, wherein the active ingredient of the suspension spray comprises budesonide having D (90) of not more than 7.5 ⁇ m, a surfactant, a chelating agent, an isotonicity adjusting agent, a preservative and a helper.
  • Suspending agents these ingredients help the spray to maintain sterility during shelf life or during use, improve the safety of budesonide suspension sprays; and help the active distribution to be dispersed in a particulate state in sprays.
  • a uniform and stable suspension spray is formed in the medium.
  • the concentration of budesonide in the suspension spray is from 0.5 mg/mL to 50.0 mg/mL; in some embodiments, the concentration of budesonide is preferably from 2.0 mg/mL to 30 mg. /mL; In some embodiments, it is more preferred that the concentration of budesonide is from 2.5 mg/mL to 25 mg/mL; thereby ensuring that a few microliters to several tens of microliters of suspension spray can achieve an effective therapeutic dose; Helps achieve multiple doses of suspension sprays.
  • the surfactant comprises Tween 20, Tween 80, Span 20, Span 60, Poloxamer 188 or Poloxamer 407; thereby increasing the activity of the distribution to the dexthene Stability in suspension sprays.
  • the chelating agent comprises disodium edetate or sodium calcium edetate; thereby helping to increase the stability of the active distribution of dexamethasone in a suspension spray.
  • the isotonicity adjusting agent comprises sodium chloride, glucose, glycerol, mannitol or sorbitol; thereby further enhancing the safety of the budesonide suspension spray.
  • a suspension spray comprising budesonide having a D(90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises D(10) is budesonide not greater than 1.0 ⁇ m; further, the suspension spray further comprises the following pharmaceutical excipients: Tween 80, disodium edetate, and sodium chloride. These ingredients contribute to the suspension of the spray when atomized using a commercial sprayer, the content before atomization and the content after atomization remain substantially unchanged; improve the stability and safety of the suspension spray.
  • a suspension spray comprising budesonide having a D(90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further The suspension spray further comprises the following pharmaceutical excipients: Tween 80, disodium edetate, sodium chloride and benzalkonium chloride.
  • a suspension spray comprising budesonide having a D(90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further The suspension spray further comprises the following pharmaceutical excipients: Tween 80, disodium edetate, sodium chloride and sodium carboxymethylcellulose.
  • a suspension spray comprising budesonide having a D(90) of not more than 7.5 ⁇ m; in some embodiments, the blending The active ingredient of the suspension spray comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further The suspension spray further comprises the following pharmaceutical excipients: Tween 80, disodium edetate, sodium chloride, benzalkonium chloride and sodium carboxymethylcellulose.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray also comprises a surfactant, a chelating agent, an isotonicity adjusting agent and a pH adjusting agent; these ingredients contribute to the content of the suspended spray and the content after atomization after atomization using a commercially available sprayer. Maintain the same; improve the stability and safety of the suspension spray.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray also comprises a surfactant, a chelating agent, an isotonicity adjusting agent and a buffering agent; these ingredients contribute to the suspension of the spray agent, which is substantially atomized and atomized after being atomized using a commercially available sprayer. Constant; improve the stability and safety of suspended sprays.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray also comprises a surfactant, a chelating agent, an isotonicity adjusting agent, a pH adjusting agent and a buffering agent; these ingredients contribute to the content of the suspended spray after atomization using a commercially available atomizer, and after atomization The content remains essentially the same; the stability and safety of the suspended spray are improved.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension Sprays also include surfactants, chelating agents, isotonicity adjusting agents, pH adjusting agents, buffers, and preservatives; these ingredients help the spray maintain sterility during shelf life or during use, and improve budesonide blending. The safety of the suspension spray.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray further comprises a surfactant, a chelating agent, an isotonicity adjusting agent, a pH adjusting agent, a buffering agent and a suspending agent; these components contribute to the active distribution of the dexterane dispersed in the particulate form to form a uniform and stable mixture. Suspended spray.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension Sprays also include surfactants, chelating agents, isotonicity adjusting agents, pH adjusting agents, buffering agents, preservatives, and suspending agents; these ingredients help the spray maintain sterility during shelf life or during use.
  • the concentration of budesonide in the suspension spray is from 0.5 mg/mL to 50.0 mg/mL; in some embodiments, the concentration of budesonide is preferably from 2.0 mg/mL to 30 mg. /mL; In some embodiments, it is more preferred that the concentration of budesonide is from 2.5 mg/mL to 25 mg/mL; thereby ensuring that a few microliters to several tens of microliters of suspension spray can achieve an effective therapeutic dose; Helps achieve multiple doses of suspension sprays.
  • the surfactant comprises Tween 20, Tween 80, Span 20, Span 60, Poloxamer 188 or Poloxamer 407; thereby increasing budesonide suspension spray The stability of the agent.
  • the chelating agent comprises disodium edetate or sodium calcium edetate; thereby helping to increase the stability of the active distribution of dexamethasone in a suspension spray.
  • the isotonicity adjusting agent comprises sodium chloride, glucose, glycerol, mannitol or sorbitol; thereby further enhancing the safety of the budesonide suspension spray.
  • the pH adjusting agent is hydrochloric acid or sodium hydroxide; thereby contributing to further enhancing the stability of the active distribution distribution of dexamethasone in a suspension spray.
  • the buffer is citric acid and/or sodium citrate; thereby helping to further enhance the stability of the active distribution to the concentration of dexamethasone in a suspension spray.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray also contains the following pharmaceutical excipients: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium edetate, sodium chloride and preservatives.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray Budesonide comprising D (50) not greater than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the suspension The spray also comprises the following pharmaceutical excipients: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium edetate, sodium chloride and a suspending agent.
  • a suspension spray wherein the active ingredient of the suspension spray comprises D (90) not greater than 7.5 ⁇ m budesonide; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D (50) of no greater than 3.5 ⁇ m; in some embodiments, the activity of the suspension spray
  • the composition comprises budesonide having D(10) of not more than 1.0 ⁇ m; further, the suspension spray further comprises the following pharmaceutical excipients: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, Disodium edetate, sodium chloride, preservatives or suspending agents.
  • the concentration of the surfactant may range from 0.05 mg/mL to 10 mg/mL. In some embodiments, it is preferred that the concentration of the surfactant is from 0.1 mg/mL to 3 mg/mL; more preferably the concentration of the surfactant is from 0.2 mg/mL to 2 mg/mL; thereby further increasing the budesonide suspension spray. stability.
  • the above suspension spray may further comprise at least one of the following additional technical features:
  • the suspension spray is a first suspension or/and a second suspension after lyophilization.
  • the suspension spray comprises a lyoprotectant.
  • a suspension spray is provided, and the particle size distribution of the suspension spray is substantially unchanged before and after lyophilization.
  • the active ingredient of the suspension spray comprising budesonide having a D (90) of not more than 7.5 ⁇ m; in some embodiments, the suspension spray
  • the active ingredient comprises budesonide having a D (50) of not more than 3.5 ⁇ m; in some embodiments, the active ingredient of the suspension spray comprises budesonide having a D(10) of not more than 1.0 ⁇ m; further, the The suspension spray also contained the following pharmaceutical excipients: Tween 80, glycine, PVP K29/32.
  • API refers to the active ingredient
  • D(10) refers to the particle size corresponding to a cumulative particle size distribution of a sample of 10%.
  • D(50) refers to the particle size corresponding to a cumulative particle size distribution of a sample of up to 50%.
  • D(90) refers to the particle size corresponding to a cumulative particle size distribution of a sample of 90%.
  • before nebulization refers to a sample of budesonide suspension prior to spraying.
  • after atomization refers to a sample of droplets collected after atomization of a budesonide suspension using an atomizer.
  • single dose refers to a dose that is used at one time.
  • multiple doses refers to the incorporation of multiple single doses of a drug into a single container for multiple doses.
  • Inhaled formulations typically contain 60 or 120 single doses of the drug in a single container, 60 or 120 times.
  • EDTA-2Na refers to disodium edetate.
  • CMC-Na refers to sodium carboxymethylcellulose
  • NaCl refers to sodium chloride
  • Tween-80 refers to sorbitan monooleate polyoxyethylene ether.
  • Teween-20 refers to polyoxyethylene (20) sorbitan monolaurate.
  • Span-20 refers to sorbitan monolaurate.
  • EL-35 refers to polyoxyethylene (35) castor oil.
  • RTD refers to the Reference Listed Drug.
  • PVP povidone
  • first suspension refers to a solution prepared by grinding budesonide and each excipient after grinding.
  • second suspension refers to a liquid medicine prepared by mixing and polishing budesonide and each excipient, and after lyophilization, reconstituted.
  • Mg/mL means mg/ml, ⁇ m means micron, mg means milligram, mL means milliliter, min means minute, r/min means revolution/minute, g means gram, mm means millimeter, cm means centimeter, °C means celsius, Hz means Hertz, s refers to seconds, h refers to hours, d refers to days, mbar refers to millibars.
  • the above budesonide suspension is ground by a planetary ball mill; the grinding power is 30 Hz, 1 mm zirconia grinding beads, and the mass ratio of the grinding beads to the budesonide suspension is 2:1, and the grinding time is 150 min;
  • the particle size distribution of budesonide suspension was determined by Malvern Mastersizer 2000 particle size analyzer. The test conditions were rotation speed 2500r/min; opacity was about 15%; measurement time 12s; unit ⁇ m; budesonide suspension particle size determination The results are as follows (unit: ⁇ m):
  • D(90) 5.414 ⁇ m
  • D(50) 1.595 ⁇ m
  • Example 2 Preparation of budesonide suspension by different types of surfactants
  • the above budesonide suspension is ground by a planetary ball mill; grinding power 30Hz, 0.3mm zirconia grinding beads, and the mass ratio of the grinding beads to budesonide suspension is 3:1, grinding time 4h;
  • a microporous atomizer spray was used to measure the content after spraying.
  • Table 2-2 Particle size distribution and post-atomization content of budesonide suspension prepared by different surfactants
  • the budesonide suspension prepared by different surfactants was prepared by atomization using a microporous atomizer, Tween-80, Tween-20, EL-35, Tween-80+Span-20.
  • the obtained budesonide suspension has a smaller particle size and a stable content after atomization.
  • the budesonide suspension prepared by using poloxamer 407 as a surfactant has a slightly larger particle size, and the content after spraying is slightly decreased. However, they are all within the acceptable range (the Chinese Pharmacopoeia 2015 edition stipulates that the content after spraying is 80%-120% of the labeled amount).
  • Example 3 Preparation of budesonide suspension with different ratios of Tween-80 and its stability
  • Example 4 Investigating the effect of different bead ratios and milling times on the particle size of budesonide suspension
  • Budesonide API 2.75 Tween-80 Surfactant 0.5 Citric acid Buffer 0.6 Sodium citrate Buffer 1.0 Benzalkonium chloride preservative 0.1 EDTA-2Na Chelating agent 0.1 Sodium chloride Isotonicity regulator 4.5 purified water Solvent Appropriate amount to 500mL
  • the above budesonide suspension was ground by a planetary ball mill; the grinding power was 30 Hz, 0.4-0.6 mm zirconia grinding beads, and the mass ratio of the grinding beads to the budesonide suspension was 3:1 and 4: 1, sampling at 90 min, 120 min, 180 min, 240 min, respectively, using a Malvern Mastersizer 2000 particle size analyzer to determine the particle size of budesonide suspension;
  • Table 4-2 Effect of mixing ratio and grinding time of different beads (0.4 ⁇ 0.6mm) on the particle size of budesonide suspension
  • Example 5 Study on Stability of Budesonide Suspension at Different pH Values (3.0, 4.0, 5.0, 6.0, 7.0)
  • Wavelength 240 nm; flow rate: 1.0 mL/min; injection amount: 20 ⁇ L; column temperature: 50 ° C;
  • Running time 31min (content), 60min (related substances); after operation: 5min;
  • Example 6 Accelerated and Intermediate Stability of Budesonide Suspension at Different pH Values (4.0, 4.7, 5.0, 5.5)
  • Table 6-2 Stability of budesonide suspension at different pH values at 60 °C
  • Table 6-4 Stability of intermediate conditions of budesonide suspension at different pH values at 30 °C
  • the Malvern Mastersizer 2000 particle size analyzer was used to determine the particle size distribution of the budesonide suspension after sampling at different milling times.
  • a budesonide suspension was obtained, and the particle size of the budesonide suspension was measured by a Malvern Mastersizer 2000 particle size analyzer.
  • a small particle size high concentration budesonide suspension can be prepared when the concentration of budesonide is 24 mg/ml and the concentration of surfactant is 3 ⁇ 5 mg/ml.
  • Example 9 Atomization of budesonide suspension using different nebulizers
  • Table 9-1 Atomization of a small particle size budesonide suspension using an OMRON air compression atomizer
  • Table 9-2 Atomization of small particle size budesonide suspension using a micropore atomizer
  • the budesonide suspension provided by the present invention has no significant change in particle size distribution and content after atomization using different atomizers.
  • Example 10 Comparison of content changes of self-made small-size budesonide suspension and aspirin pulcherine using atomized ultrasonic nebulizer and microporous atomizer
  • the content of the commercially available preparation of AstraZenem Mikulshu is relatively large, which may be larger and larger in particle size, and larger particles during atomization. It is related to the content of the sprayer nozzle being trapped, and the self-made small particle size budesonide suspension has a relatively small particle size and a narrow distribution during atomization, and the content is stable after atomization.
  • Budesonide API 1.1 Tween-80 Surfactant 0.1 Citric acid Buffer 0.12 Sodium citrate Buffer 0.2 Benzalkonium chloride preservative 0.01 EDTA-2Na Chelating agent 0.05 Sodium chloride Isotonicity regulator 0.9 purified water Solvent Appropriate amount to 100mL
  • the budesonide suspension was obtained after grinding for 6 hours.
  • the particle size of the budesonide suspension was measured by a Malvern Mastersizer 2000 granulometer, and the content of the suspension was measured by spraying with a microporous atomizer.
  • Example 12 Preparation of a budesonide suspension containing a suspending agent and detection of its atomization content
  • the above budesonide suspension is ground by a planetary ball mill; grinding power 30Hz, 0.3mm zirconia grinding beads, and the mass ratio of the grinding beads to budesonide suspension is 3:1;
  • the budesonide suspension was obtained after grinding for 6 hours, the particle size of the budesonide suspension was determined by a Malvern Mastersizer 2000 particle size analyzer, and the suspension was atomized by a microporous atomizer, and the atomized cloth was detected by HPLC. Ned content.
  • Example 13 Different concentrations of budesonide suspension and its content change before and after atomization
  • a microporous atomizer was used to atomize different concentrations of the suspension, and the content after atomization was detected by HPLC.
  • Table 13-2 Changes in the content of different concentrations of budesonide suspension after atomization
  • Example 14 Determination of atomization droplet size of budesonide suspension
  • the sampling rate was set 100 times per second, the background was measured, the spray was measured, and the particle size of the atomized droplets was measured.
  • Table 14-2 Homemade Budesonide Suspension Using Microporous Atomizer
  • Effective particles refer to particles that can be deposited in the lungs with a droplet size in the range of 1.0 to 5.0 ⁇ m.
  • the suspension was dispensed into a 7 mL vial, each filled with 3 mL, and freeze-dried.
  • the freeze-drying process was as follows: pre-freezing: first stage: -2 ° C, set time 20 min, duration 60 min;
  • the second stage -45 ° C, set time 40 min, duration 240 min;
  • the budesonide lyophilized powder was reconstituted with an appropriate amount of purified water and an auxiliary solution, and the particle size distribution of the budesonide suspension before and after reconstitution was determined, as shown in Table 15-3 and Table 15-4.

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Abstract

本发明涉及布地奈德混悬喷雾剂，具体地，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德。

Description

布地奈德混悬喷雾剂
优先权信息
本申请请求2016年04月14日向中国国家知识产权局提交的、专利申请号为201610235368.5的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及医药制剂领域，具体涉及可用于吸入治疗哮喘症状，可多剂量给药的含小粒径布地奈德的高浓度混悬喷雾剂。
背景技术
布地奈德是一种具有高效局部抗炎作用的糖皮质激素。它能增强内皮细胞、平滑肌细胞和溶酶体膜的稳定性，抑制免疫反应和降低抗体合成，从而使组胺等过敏活性介质的释放减少和活性降低，并能减轻抗原抗体结合时激发的酶促过程，抑制支气管收缩物质的合成和释放而减轻平滑肌的收缩反应。布地奈德的结构式如下：
Figure PCTCN2017080317-appb-000001
在过去20多年内，计量雾剂的使用成为治疗阻碍性肺疾病，特别是气喘的既定成份，通常是使用氟氯烃作为推进气体，自从这类推进气体的臭氧破坏性潜能被公认后，有越来越多的努力进行替代物的开发。其中一种替代物为喷雾器的开发，其中药物学活性物质的水溶液在高压下喷出而产生可吸入的粒子雾。这种喷雾器的优点是不需要任何推进气体。
然而，对于水溶解度较小的布地奈德来说，目前市售的低浓度布地奈德供吸入用混悬剂，需要使用特定的雾化装置使混悬液雾化，而且只能单剂量给药；其使用时噪音大，使用不方便，并且其雾化效率低，重现性差，使用过后仪器需要清洗，细菌污染风险大，且雾化持续时间较长，持续雾化过程中，受呼吸气流限制，患者不能充分吸入，导致生物利用度较低。需要一种不受特定装置限制，能使用市售普通喷雾器雾化，雾化前后含量稳定，生物利用度高且稳定性好的布地奈德制剂，以达到多剂量给药用于吸入治疗哮喘症的良好效果。
发明内容
本发明提供了一种可用于吸入治疗哮喘症状的含小粒径布地奈德的混悬喷雾剂。该布地奈德混悬喷雾剂浓度较高，可多剂量给药，携带、使用方便；有不容易堵塞，雾化前后含量基本保持不变，利用率高的优势；且稳定性好，不容易染菌。
市售的布地奈德混悬液单剂量给药，每次给药剂量约为2毫升，而本发明的布地奈德混悬喷雾剂每次的给药剂量大约只需要几微升至几十微升，而且可以多次取用，用药剂量大幅度减少，并且仍能保证有效成分布地奈德的有效治疗浓度。根据本发明的实施例，本发明的混悬喷雾剂和市售布地奈德混悬液，分别用市售喷雾器雾化后，本发明的小粒径布地奈德混悬喷雾剂含量基本无变化，而市售布地奈德混悬液雾化后含量却明显降低。本发明所提供的布地奈德混悬喷雾剂可解决目前市售的布地奈德供吸入用混悬制剂雾化效率低，只能单剂量给药，携带或使用不方便、生物利用度低、易染菌等问题，并且减少了患者使用过程中的不适感和安全风险。
根据本发明的一个方面，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德。小粒径的布地奈德有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前布地奈德的含量与雾化后布地奈德的含量基本保持不变。
根据本发明的实施例，上述混悬喷雾剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的一些实施例，所述混悬喷雾剂包含表面活性剂，螯合剂和等渗调节剂，从而提高混悬喷雾剂的稳定性以及安全性。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含pH调节剂；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含缓冲剂；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL-50.0mg/mL。在一些实施例中，优选布地奈德的浓度为2.0mg/mL-30mg/mL；在一些实施例中，更优选布地奈德的浓度为2.5mg/mL-25mg/mL。这些浓度的喷雾剂能够保证几微升至几十微升的混悬喷雾剂的给药剂量能够达到有效治疗剂量；同时，有助于实现混悬喷雾剂的多剂量给药。
根据本发明的一些实施例，所述表面活性剂包含聚氧乙烯脱水山梨醇脂肪酸酯、脱水 山梨醇脂肪酸酯、泊洛沙姆、磷脂或聚氧乙烯蓖麻油。所述聚氧乙烯脱水山梨醇脂肪酸酯包括例如Tween10、Tween20、Tween21、Tween40、Tween60、Tween61、Tween65、Tween80、Tween81和Tween85等；所述脱水山梨醇脂肪酸酯包括例如Span20、Span40、Span60、Span65、Span80、Span85和Span83等；所述泊洛沙姆包括例如Poloxamer124、Poloxamer188、Poloxamer237、Poloxamer338、Poloxamer407、Poloxamer181、Poloxamer182、Poloxamer184、Poloxamer331、Poloxamer123、Poloxamer335、Poloxamer288、Poloxamer402、Poloxamer238、Poloxamer183、Poloxamer231、Poloxamer108、Poloxamer403、Poloxamer217、Poloxamer282、Poloxamer234、Poloxamer122、Poloxamer334、Poloxamer101、Poloxamer284、Poloxamer401、Poloxamer212、Poloxamer235、Poloxamer105、Poloxamer215、Poloxamer333和Poloxamer185等；所述磷脂包括磷脂酰胆碱(卵磷脂)、磷脂酰乙醇胺(脑磷脂)、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、鞘磷脂、鞘糖脂和二磷脂酰甘油等；所述聚氧乙烯蓖麻油包括Cremophor EL10、Cremophor EL12、Cremophor EL20、Cremophor EL30、Cremophor EL40、Cremophor EL60、Cremophor EL80、Cremophor EL90、Cremophor EL35、Cremophor HEL40、Cremophor HEL20、Cremophor RH40和Cremophor RH60等。所述表面活性剂能够增加该混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407，从而进一步增加该混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述表面活性剂的浓度为0.05mg/mL-10mg/mL；在一些实施例中，优选表面活性剂的浓度为0.1mg/mL-3mg/mL；更优选表面活性剂的浓度为0.2mg/mL-2mg/mL；从而进一步增加该布地奈德混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠。从而有助于提高该混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述螯合剂的浓度为0.01mg/mL-10mg/mL；在一些实施例中，优选螯合剂的浓度为0.05mg/mL-1mg/mL；在一些实施例中，更优选螯合剂的浓度为0.1mg/mL-0.75mg/mL。所述螯合剂有助于进一步提高该混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇。所述等渗调节剂可进一步提高该混悬喷雾剂的安全性。
根据本发明的一些实施例，所述pH调节剂可包含酸性pH调节剂或碱性pH调节剂，从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。在一些实施例中，所述酸性pH调节剂为盐酸、乙酸或磷酸的一种或多种；在一些实施例中，所述碱性pH调节 剂为氢氧化钠，磷酸氢钠，碳酸钙或氢氧化镁的一种或多种。
根据本发明的一些实施例，所述pH调节剂为盐酸或氢氧化钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂包含乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸或它们的盐；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂为柠檬酸和/或柠檬酸钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述柠檬酸的浓度可为0.05mg/mL-20.0mg/mL；优选为0.2mg/mL-1.5mg/mL；在一些实施例中，柠檬酸钠的浓度为0.5mg/mL-20.0mg/mL；优选为0.5mg/mL-2.0mg/mL；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述混悬喷雾剂的pH为3.5-6；在一些实施例中，优选地混悬喷雾剂的pH为4-5；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含防腐剂。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含助悬剂。
根据本发明的再一个方面，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、乙二胺四乙酸二钠和氯化钠。这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；提高混悬喷雾剂的稳定性以及安全性。
根据本发明的实施例，上述混悬喷雾剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的一些实施例，所述混悬喷雾剂进一步包含苯扎氯铵。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含羧甲基纤维素钠。
根据本发明的又一个方面，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；其进一步包含表面活性剂，螯合剂，等渗调节剂，pH 调节剂和缓冲剂；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。根据本发明的实施例，上述混悬喷雾剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的一些实施例，所述混悬喷雾剂进一步包含防腐剂。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含助悬剂。
根据本发明的一些实施例，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL-50.0mg/mL；在一些实施例中，优选布地奈德的浓度为2.0mg/mL-30mg/mL；在一些实施例中，更优选布地奈德的浓度为2.5mg/mL-25mg/mL；从而保证几微升至几十微升的混悬喷雾剂能够达到有效治疗剂量；同时，有助于实现混悬喷雾剂的多剂量给药。
根据本发明的一些实施例，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407；从而增加活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠；从而有助于提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇；从而进一步提高布地奈德混悬喷雾剂的安全性。
根据本发明的一些实施例，所述pH调节剂为盐酸或氢氧化钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂为柠檬酸和/或柠檬酸钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的又一个方面，根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、盐酸或氢氧化钠、柠檬酸和/或柠檬酸钠、乙二胺四乙酸二钠和氯化钠。这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变，提高混悬喷雾剂的稳定性以及安全性。
根据本发明的实施例，上述混悬喷雾剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的一些实施例，所述混悬喷雾剂进一步包含防腐剂。
根据本发明的一些实施例，所述混悬喷雾剂进一步包含助悬剂。
根据本发明的一些实施例，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL-50.0mg/mL；在一些实施例中，优选布地奈德的浓度为2.0mg/mL-30mg/mL；在一些实施例中， 更优选布地奈德的浓度为2.5mg/mL-25mg/mL；从而保证几微升至几十微升的混悬喷雾剂能够达到有效治疗剂量；同时，有助于实现混悬喷雾剂的多剂量给药。
本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；其进一步包含表面活性剂，螯合剂，等渗调节剂和pH调节剂；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；其进一步包含表面活性剂，螯合剂，等渗调节剂和缓冲剂；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述pH调节剂可包含酸性pH调节剂或碱性pH调节剂，从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。在一些实施例中，所述酸性pH调节剂为盐酸、乙酸或磷酸的一种或多种；在一些实施例中，所述碱性pH调节剂为氢氧化钠，磷酸氢钠，碳酸钙或氢氧化镁的一种或多种。
根据本发明的一些实施例，所述pH调节剂为盐酸或氢氧化钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂包含乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸或它们的盐；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂为柠檬酸和/或柠檬酸钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述柠檬酸的浓度可为0.05mg/mL-20.0mg/mL。在一些实施例中，柠檬酸的浓度为0.2mg/mL-1.5mg/mL；在一些实施例中，优选柠檬酸钠的浓度为0.5mg/mL-20.0mg/mL；更优选柠檬酸钠的浓度为0.5mg/mL-2.0mg/mL；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述混悬喷雾剂的pH为3.5-6；在一些实施例中，优选混悬喷雾剂的pH为4-5；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm 的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德，还包含表面活性剂，螯合剂和等渗调节剂；含有这些成分的混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；具有较好的稳定性以及安全性。
本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德，表面活性剂，螯合剂，等渗调节剂和防腐剂；这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德，表面活性剂，螯合剂，等渗调节剂和助悬剂；这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德、表面活性剂、螯合剂、等渗调节剂、防腐剂和助悬剂；这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明的一些实施例，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL-50.0mg/mL；在一些实施例中，优选布地奈德的浓度为2.0mg/mL-30mg/mL；在一些实施例中，更优选布地奈德的浓度为2.5mg/mL-25mg/mL；从而保证几微升至几十微升的混悬喷雾剂能够达到有效治疗剂量；同时，有助于实现混悬喷雾剂的多剂量给药。
根据本发明的一些实施例，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407；从而增加活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠；从而有助于提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇；从而进一步提高布地奈德混悬喷雾剂的安全性。
根据本发明的一些实施例，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含 D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、乙二胺四乙酸二钠和氯化钠。这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；提高混悬喷雾剂的稳定性以及安全性。
根据本发明的一些实施例，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、乙二胺四乙酸二钠、氯化钠和苯扎氯铵。这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明的一些实施例，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、乙二胺四乙酸二钠、氯化钠和羧甲基纤维素钠。从而有助于喷雾剂在货架期或使用过程中的无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明的一些实施例，本发明提供一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、乙二胺四乙酸二钠、氯化钠、苯扎氯铵和羧甲基纤维素钠。这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂，螯合剂、等渗调节剂和pH调节剂；这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；提高混悬喷雾剂的稳定性以及安全性。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂，螯合剂、等渗调节剂和缓冲剂；这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；提高混悬喷雾剂的稳定性以及安全性。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂，螯合剂、等渗调节剂、pH调节剂和缓冲剂；这些成分有助于混悬喷雾剂在使用市售喷雾器雾化时，雾化前的含量与雾化后的含量基本保持不变；提高混悬喷雾剂的稳定性以及安全性。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂、螯合剂、等渗调节剂、pH调节剂、缓冲剂和防腐剂；这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂、螯合剂、等渗调节剂、pH调节剂、缓冲剂和助悬剂；这些成分有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含表面活性剂、螯合剂、等渗调节剂、pH调节剂、缓冲剂、防腐剂和助悬剂；这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于 喷雾剂中形成均匀稳定的混悬喷雾剂。根据本发明的一些实施例，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL-50.0mg/mL；在一些实施例中，优选布地奈德的浓度为2.0mg/mL-30mg/mL；在一些实施例中，更优选布地奈德的浓度为2.5mg/mL-25mg/mL；从而保证几微升至几十微升的混悬喷雾剂能够达到有效治疗剂量；同时，有助于实现混悬喷雾剂的多剂量给药。
根据本发明的一些实施例，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407；从而增加布地奈德混悬喷雾剂的稳定性。
根据本发明的一些实施例，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠；从而有助于提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇；从而进一步提高布地奈德混悬喷雾剂的安全性。
根据本发明的一些实施例，所述pH调节剂为盐酸或氢氧化钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明的一些实施例，所述缓冲剂为柠檬酸和/或柠檬酸钠；从而有助于进一步提高活性成分布地奈德在混悬喷雾剂中的稳定性。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、盐酸或氢氧化钠、柠檬酸和/或柠檬酸钠、乙二胺四乙酸二钠、氯化钠和防腐剂。这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、盐酸或氢氧化钠、柠檬酸和/或柠檬酸钠、乙二胺四乙酸二钠、氯化钠和助悬剂。这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于 7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、盐酸或氢氧化钠、柠檬酸和/或柠檬酸钠、乙二胺四乙酸二钠、氯化钠、防腐剂或助悬剂。这些成分有助于喷雾剂在货架期或使用过程中保持无菌性，提高布地奈德混悬喷雾剂的安全性；以及有助于活性成分布地奈德以微粒状态分散于喷雾剂中形成均匀稳定的混悬喷雾剂。
根据本发明的一些实施例，所述表面活性剂的浓度可为0.05mg/mL-10mg/mL。在一些实施例中，优选表面活性剂的浓度为0.1mg/mL-3mg/mL；更优选表面活性剂的浓度为0.2mg/mL-2mg/mL；从而进一步增加布地奈德混悬喷雾剂的稳定性。
根据本发明的实施例，上述混悬喷雾剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的一些实施例，所述混悬喷雾剂为第一混悬液或/和冻干复溶后的第二混悬液。
根据本发明的一些实施例，所述混悬喷雾剂包含冻干保护剂。
根据本发明实施例提供的一种混悬喷雾剂，所述混悬喷雾剂的粒度分布在冻干前后基本无变化。
根据本发明实施例提供的一种混悬喷雾剂，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(50)不大于3.5μm的布地奈德；在一些实施例中，所述混悬喷雾剂的活性成分包含D(10)不大于1.0μm的布地奈德；进一步地，所述混悬喷雾剂还包含以下药用辅料：吐温80、甘氨酸、PVP K29/32。这些成分有助于提高布地奈德冻干制剂的稳定性，以及有助于布地奈德冻干制剂在复溶后形成均匀稳定的混悬喷雾剂。
术语定义
发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见， 在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。
术语“API”是指活性成分。
术语“D(10)”是指一个样品的累计粒度体积分布百分数达到10％时所对应的粒径。
术语“D(50)”是指一个样品的累计粒度体积分布百分数达到50％时所对应的粒径。
术语“D(90)”是指一个样品的累计粒度体积分布百分数达到90％时所对应的粒径。
术语“雾化前”是指布地奈德混悬液在喷雾之前的样品。
术语“雾化后”是指使用雾化器在对布地奈德混悬液进行雾化后收集的雾滴样品。
术语“单剂量”是指一次使用完的剂量。
术语“多剂量”是指将多个单剂量药物装入一个容器内，可供多次定量取用。吸入制剂通常将60个或120个单剂量药物装入一个容器内，可取用60或120次。
术语“EDTA-2Na”是指乙二胺四乙酸二钠。
术语“CMC-Na”是指羧甲基纤维素钠。
术语“NaCl”是指氯化钠。
术语“Tween-80”是指失水山梨醇单油酸酯聚氧乙烯醚。
术语“Tween-20”是指聚氧乙烯(20)失水山梨醇酐单月桂酸酯。
术语“Span-20”是指失水山梨醇酐单月桂酸酯。
术语“EL-35”是指聚氧乙烯(35)蓖麻油。
术语“RLD”是指Reference Listed Drug(参比药物)。
术语“PVP”是指聚维酮。
术语“第一混悬液”指布地奈德和各辅料混合后研磨制备得到的药液。
术语“第二混悬液”指布地奈德和各辅料混合研磨后制备得到的药液，经冻干后，再经复溶得到的药液。
mg/mL指毫克/毫升，μm指微米，mg指毫克，mL指毫升，min指分钟，r/min指转/分钟，g指克，mm指毫米，cm指厘米，℃指摄氏度，Hz指赫兹，s指秒，h指小时，d指天数，mbar指毫巴。
具体实施方式
下面详细描述本发明的实施例，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
实施例
实施例1：布地奈德混悬液的制备
表1-1：处方表
组分 作用 用量(g)
布地奈德 API 0.55
柠檬酸 缓冲剂 0.03
柠檬酸钠 缓冲剂 0.05
Tween-80 表面活性剂 0.02
EDTA-2Na 螯合剂 0.01
NaCl 渗透压调节剂 0.9
苯扎氯铵 防腐剂 0.01
纯化水 溶剂 适量至100mL
制备方法：
(1)将处方量柠檬酸、柠檬酸钠、EDTA-2Na、NaCl、Tween-80和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，1mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为2:1，研磨时间150min；
(4)采用Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度分布，测试条件为转速2500r/min；遮光度约15％；测量时间12s；单位μm；布地奈德混悬液微粒粒度测定结果如下(单位：μm)：
结论：D(90)＝5.414μm，D(50)＝1.595μm，D(10)＝0.569μm表明，布地奈德混悬液90％左右的粒子粒度在5.5μm以下，50％左右的粒子粒度在1.6μm以下，10％左右的粒子粒度在0.6μm以下。
实施例2：不同类型的表面活性剂制备布地奈德混悬液
表2-1：处方表
Figure PCTCN2017080317-appb-000002
制备方法：
(1)分别称取处方量0.1g Tween-80、0.1g Tween-20、0.1g EL-35、0.1g泊洛沙姆407和0.1g Tween-80+0.1g Span-20于5份80％配制总量的纯化水中，搅拌分散均匀；
(2)将处方量柠檬酸、柠檬酸钠、EDTA-2Na、NaCl、Tween-80和苯扎氯铵分别加入上述每组体系中，搅拌使其完全溶解；
(3)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(4)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为3:1，研磨时间4h；
(5)采用Malvern Mastersizer 2000粒度测定仪(测定方法同实施例1)测定布地奈德混悬液粒径分布；
(6)采用微孔雾化器喷雾，测喷雾后含量。
表2-2：不同表面活性剂制备的布地奈德混悬液粒度分布和雾化后含量
Figure PCTCN2017080317-appb-000003
Figure PCTCN2017080317-appb-000004
注：雾化后含量＝雾化后浓度/雾化前浓度*100％。
结论：根据上述结果可知，不同表面活性剂制备得到的布地奈德混悬液采用微孔雾化器雾化后，Tween-80、Tween-20、EL-35、Tween-80+Span-20制备得到的布地奈德混悬液粒度较小，雾化后含量均较稳定，泊洛沙姆407作为表面活性剂时制备得到的布地奈德混悬液粒度略大，喷雾后含量略有降低，但均在可接受范围内(《中国药典》2015版规定，喷雾后含量为标示量的80％-120％)。
实施例3：不同比例的Tween-80制备布地奈德混悬液及其稳定性研究
表3-1：处方表
Figure PCTCN2017080317-appb-000005
制备方法：
(1)将处方量柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解，分别加入不同比例的Tween-80；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.4～0.6mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为2:1，分别于90min、120min取样，Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度大小，并于6℃和40℃放置考察稳定性情况；结果见下表3-2。
表3-2：布地奈德混悬液粒度测定和稳定性研究
Figure PCTCN2017080317-appb-000006
根据上述结果可知，不同比例的Tween-80对布地奈德混悬液最终粒度影响不大，且在加速和低温放置过程中，布地奈德混悬液稳定性较好，粒度变化较小。
实施例4：考察不同珠子配比和研磨时间对布地奈德混悬液粒度的影响
表4-1：处方表
组分 作用 用量(g)
布地奈德 API 2.75
Tween-80 表面活性剂 0.5
柠檬酸 缓冲剂 0.6
柠檬酸钠 缓冲剂 1.0
苯扎氯铵 防腐剂 0.1
EDTA-2Na 螯合剂 0.1
氯化钠 等渗调节剂 4.5
纯化水 溶剂 适量至500mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.4～0.6mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为3:1和4:1，分别于90min、120min、180min、240min取样，采用Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度大小；
表4-2：不同珠子(0.4～0.6mm)配比和研磨时间对布地奈德混悬液粒度影响
Figure PCTCN2017080317-appb-000007
结论：增加珠子配比和研磨时间均能在一定程度上降低布地奈德混悬液粒度大小。
实施例5：不同pH值(3.0，4.0，5.0，6.0，7.0)的布地奈德混悬液稳定性研究
表5-1：处方表
组分 作用 用量(g)
布地奈德 API 2.75
Tween 80 表面活性剂 0.5
柠檬酸 缓冲剂 0.3
柠檬酸钠 缓冲剂 0.5
苯扎氯铵 防腐剂 0.1
EDTA-2Na 螯合剂 0.1
氯化钠 等渗调节剂 4.5
纯化水 溶剂 适量至500mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，用稀盐酸或2％NaOH分别将混悬液pH值调至3.0，4.0，5.0，6.0，7.0左右，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.4～0.6mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1；
(4)将制备得到的不同pH值的布地奈德混悬液于40℃条件下进行加速稳定性研究，于10d时分别取样，HPLC测定布地奈德含量和有关物质。
色谱条件：
仪器：HPLC
色谱柱：YMC-Pack ODS-A(150×4.6mm，3μm)；
流动相A：无水乙醇：乙腈：磷酸缓冲液＝2:32:68，
流动相B：乙腈：磷酸缓冲液＝50:50；
波长：240nm；流速：1.0mL/min；进样量：20μL；柱温：50℃；
运行时间：31min(含量)、60min(有关物质)；后运行：5min；
梯度(含量)：
时间(min) 流动相A(％) 流动相B(％)
0-21 100 0
21-22 100→0 0→100
22-31 0 100
梯度(有关物质)：
时间(min) 流动相A(％) 流动相B(％)
0-38 100 0
38-50 100→0 0→100
50-60 0 100
表5-2：不同pH值的布地奈德混悬液40℃加速稳定性研究
Figure PCTCN2017080317-appb-000008
注：“/”表示含量降低较多，杂质增加较快，不标出。
结论：随着pH值的增加，布地奈德混悬液稳定性下降。
实施例6：不同pH值(4.0，4.7，5.0，5.5)的布地奈德混悬液加速和中间条件下稳定性研究
表6-1：处方表
组分 作用 用量(g)
布地奈德 API 5.5
Tween-80 表面活性剂 0.5
柠檬酸 缓冲剂 0.3
柠檬酸钠 缓冲剂 0.5
苯扎氯铵 防腐剂 0.05
EDTA-2Na 螯合剂 0.2
氯化钠 等渗调节剂 4.5
纯化水 溶剂 适量至500mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，用稀盐酸或2％NaOH分别将混悬液pH值调至4.0，4.7，5.0，5.5左右，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1；
(4)将制备得到的不同pH值的布地奈德混悬液于60℃/40℃/30℃条件下进行加速和中间条件下稳定性研究，于10d时分别取样测定布地奈德含量和有关物质。分析方法同实施例5。
表6-2：不同pH值的布地奈德混悬液60℃稳定性研究
Figure PCTCN2017080317-appb-000009
Figure PCTCN2017080317-appb-000010
表6-3：不同pH值的布地奈德混悬液40℃加速稳定性研究
Figure PCTCN2017080317-appb-000011
表6-4：不同pH值的布地奈德混悬液30℃中间条件稳定性研究
Figure PCTCN2017080317-appb-000012
结论：当布地奈德混悬液的pH值在4.0～5.5范围内时，稳定性较好。
实施例7：小粒径布地奈德混悬液的制备和稳定性研究
表7-1:处方表
组分 作用 用量(g)
布地奈德 API 2.2
Tween-80 表面活性剂 0.4
柠檬酸 缓冲剂 0.24
柠檬酸钠 缓冲剂 0.4
苯扎氯铵 防腐剂 0.04
EDTA-2Na 螯合剂 0.08
氯化钠 等渗调节剂 3.6
纯化水 溶剂 适量至400mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl、苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为3:1；
(4)于不同的研磨时间取样后Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度分布。
表7-2:不同研磨时间布地奈德混悬液粒度分布
Figure PCTCN2017080317-appb-000013
表7-3:不同条件下布地奈德混悬液稳定性研究
  0d 60℃10d 40℃10d 30℃10d
含量(％) 100.1 99.2 101.6 100.3
最大单杂(％) 1.45 1.43 1.46 1.46
总杂(％) 2.69 2.86 2.76 2.89
结论：采用0.3mm的氧化锆珠研磨后，可以得到粒度较小的布地奈德混悬液，且稳定性较好。
实施例8：高浓度布地奈德混悬液的制备
表8-1:处方表
Figure PCTCN2017080317-appb-000014
Figure PCTCN2017080317-appb-000015
制备方法：
(1)分别将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1；
(4)研磨6h后，得到布地奈德混悬液，Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度大小。
表8-2:高浓度布地奈德混悬液的粒度分布
Figure PCTCN2017080317-appb-000016
结论：布地奈德浓度在24mg/ml，表面活性剂浓度在3～5mg/ml时均可制备得到小粒度高浓度布地奈德混悬液。
实施例9：使用不同的雾化器对布地奈德混悬液进行雾化
表9-1:使用欧姆龙空气压缩雾化器对小粒度的布地奈德混悬液雾化
Figure PCTCN2017080317-appb-000017
表9-2:使用微孔雾化器对小粒度的布地奈德混悬液雾化
Figure PCTCN2017080317-appb-000018
Figure PCTCN2017080317-appb-000019
注：雾化后含量＝雾化后浓度/雾化前浓度*100％
结论：本发明提供的布地奈德混悬液在使用不同的雾化器雾化后，粒度分布和含量基本无明显变化。
实施例10：自制小粒度布地奈德混悬液和阿斯利康普米克令舒同时使用鱼跃超声雾化器和微孔雾化器雾化后含量变化对比
处方表10-1:自制小粒度布地奈德混悬液-01
组分 作用 用量(g)
布地奈德 API 0.55
Tween-80 表面活性剂 0.1
柠檬酸 缓冲剂 0.06
柠檬酸钠 缓冲剂 0.1
苯扎氯铵 防腐剂 0.02
EDTA-2Na 螯合剂 0.02
氯化钠 等渗调节剂 0.9
纯化水 溶剂 适量至100mL
处方表10-2:自制小粒度布地奈德混悬液-02
组分 作用 用量(g)
布地奈德 API 3.6
Tween-80 表面活性剂 0.3
柠檬酸 缓冲剂 0.18
柠檬酸钠 缓冲剂 0.3
苯扎氯铵 防腐剂 0.03
EDTA-2Na 螯合剂 0.06
氯化钠 等渗调节剂 2.7
纯化水 溶剂 适量至300mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl、苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，01处方采用0.4～0.6mm氧化锆研磨珠，02处方采用0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比均为4:1，研磨4h得到布地奈德混悬液。
分别取10mL自制小粒度布地奈德混悬液和阿斯利康(AstraZeneca)的普米克令舒于鱼跃超声雾化器和微孔雾化器中进行喷雾，分别收集雾化后的布地奈德混悬液，然后HPLC测定雾化后的布地奈德含量。
表10-3:两种混悬液使用超声雾化器雾化后含量变化
Figure PCTCN2017080317-appb-000020
表10-4:两种混悬液使用微孔雾化器雾化后含量变化
Figure PCTCN2017080317-appb-000021
注：雾化后含量＝雾化后浓度/雾化前浓度*100％
结论：无论使用超声雾化器还是微孔雾化器，市售制剂阿斯利康普米克令舒雾化后含量变化均较大，可能与粒径较大和分布较宽，雾化时较大粒子被喷雾器喷嘴截留导致含量降低有关，而自制小粒径的布地奈德混悬液在雾化时由于粒度较小，分布较窄，在雾化后含量较稳定。
实施例11：布地奈德混悬液的制备和雾化
表11-1:处方表
组分 作用 用量(g)
布地奈德 API 1.1
Tween-80 表面活性剂 0.1
柠檬酸 缓冲剂 0.12
柠檬酸钠 缓冲剂 0.2
苯扎氯铵 防腐剂 0.01
EDTA-2Na 螯合剂 0.05
氯化钠 等渗调节剂 0.9
纯化水 溶剂 适量至100mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，2mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1；
(4)研磨6h后得到布地奈德混悬液，Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度大小，并用微孔雾化器喷雾，HPLC测定混悬液喷雾后含量变化。
表11-2:布地奈德混悬液粒度分布和雾化后含量变化
Figure PCTCN2017080317-appb-000022
结论：自制D90约为7.0μm的布地奈德混悬液，在雾化后含量略有降低，但仍在可接受范围内(《中国药典》2015版规定，雾化后含量为标示量的80％-120％)。
实施例12：制备含有助悬剂的布地奈德混悬液及检测其雾化含量
表12-1:处方表
组分 作用 用量(g)
布地奈德 API 0.45
Tween-80 表面活性剂 0.10
CMC-Na 助悬剂 0.20
柠檬酸 缓冲剂 0.06
柠檬酸钠 缓冲剂 0.10
苯扎氯铵 防腐剂 0.01
EDTA-2Na 螯合剂 0.04
氯化钠 等渗调节剂 0.90
纯化水 溶剂 适量至100mL
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入50％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量CMC-Na加入30％配制总量的纯化水中，搅拌溶解完毕后缓慢加入(1)中得到混合溶液；
(3)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(4)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为3:1；
(5)研磨6h后得到布地奈德混悬液，Malvern Mastersizer 2000粒度测定仪测定布地奈德混悬液粒度大小，并采用微孔雾化器将混悬液雾化，HPLC检测雾化后布地奈德含量。
表12-2:粒度分布和雾化后含量
Figure PCTCN2017080317-appb-000023
结论：加入羧甲基纤维素钠作为助悬剂后，布地奈德混悬液雾化后含量略有变化，但仍在可接受范围内，(《中国药典》2015版规定，雾化后含量为标示量的80％-120％)，说明助悬剂羧甲基纤维素钠的加入对布地奈德混悬液雾化后的含量影响较小。
实施例13：不同浓度的布地奈德混悬液及其雾化前后含量变化
表13-1:处方表
Figure PCTCN2017080317-appb-000024
Figure PCTCN2017080317-appb-000025
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1，研磨6h得到布地奈德混悬液；
(4)采用微孔雾化器将不同浓度的混悬液雾化，HPLC检测雾化后含量。
表13-2:不同浓度的布地奈德混悬液雾化后含量变化
Figure PCTCN2017080317-appb-000026
结论：布地奈德浓度为3.0mg/mL-4.5mg/mL时，雾化后含量基本无较大变化，均在可接受范围内。
实施例14：布地奈德混悬液雾化液滴粒度测定
表14-1:处方表
Figure PCTCN2017080317-appb-000027
Figure PCTCN2017080317-appb-000028
制备方法：
(1)将处方量Tween-80、柠檬酸、柠檬酸钠、EDTA-2Na、NaCl和苯扎氯铵加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率30Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为4:1，研磨6h得到布地奈德混悬液。
粒径测试步骤和方案：
仪器：Malvern Spraytec喷雾粒度仪。
步骤：固定雾化器距检测与水平距离10cm，垂直距离5cm，试喷一次，保证检测的激光位于喷出的雾的中央。设定采样速度100次每秒，测定背景，喷雾，测定雾化液滴的粒径。
表14-2:使用微孔雾化器对自制布地奈德混悬液
Figure PCTCN2017080317-appb-000029
结论：使用微孔雾化器进行雾化后，三组混悬剂有效粒子的比例均较高，粒度在0.5～6.3μm之间的粒子占70～87％，粒度在1.0～5.5μm之间的粒子占59～78％。
注：有效粒子指的是雾滴粒度在1.0～5.0μm范围内能够沉积于肺部的粒子。
实施例15布地奈德混悬液的制备和冻干，以及复溶前后粒度分布测定
表15-1：冻干处方表
Figure PCTCN2017080317-appb-000030
制备方法：
(1)将处方量Tween-80、甘氨酸、PVP-K29/32加入80％配制总量的纯化水中，搅拌使其完全溶解；
(2)将处方量的布地奈德加入上述混合溶液中搅拌得到布地奈德混悬液，定容；
(3)将上述布地奈德混悬液用行星式球磨机进行研磨；研磨功率20Hz，0.3mm氧化锆研磨珠，且研磨珠与布地奈德混悬液质量比为3:1，研磨1h得到布地奈德混悬液；
(4)将混悬液分装于7mL西林瓶中，每支灌装3mL，进行冷冻干燥，冻干工艺如下：预冻：第一阶段：-2℃，设定时间20min，持续时间60min；
第二阶段：-45℃，设定时间40min，持续时间240min；
一次干燥：-10℃，设定时间60min，持续时间1080min，真空度0.13mbar；
二次干燥：30℃，设定时间35min，持续时间120min。
表15-2：辅料溶液处方表
组分 作用 用量(g)
柠檬酸 缓冲剂 0.06
柠檬酸钠 缓冲剂 0.10
苯扎氯铵 防腐剂 0.01
EDTA-2Na 螯合剂 0.02
氯化钠 等渗调节剂 0.9
纯化水 溶剂 适量至100mL
将布地奈德冻干粉分别加适量纯化水和辅料溶液复溶，测定复溶前后布地奈德混悬液粒度分布，如表15-3和表15-4所示。
表15-3：布地奈德混悬液冻干后水复溶粒度分布
Figure PCTCN2017080317-appb-000031
表15-4：布地奈德混悬液冻干后辅料溶液复溶粒度分布
Figure PCTCN2017080317-appb-000032
结论：由以上结果可知，布地奈德混悬液冻干前后，水或者辅料溶液复溶粒度分布均变化不大。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。
在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (36)

  1. 一种混悬喷雾剂，其特征在于，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德。
  2. 根据权利要求1所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂包含表面活性剂，螯合剂和等渗调节剂。
  3. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含pH调节剂。
  4. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含缓冲剂。
  5. 根据权利要求1～4任一所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL～50.0mg/mL；任选为2.0mg/mL～30mg/mL；任选为2.5mg/mL～25mg/mL。
  6. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述表面活性剂包含聚氧乙烯脱水山梨醇脂肪酸酯、脱水山梨醇脂肪酸酯、泊洛沙姆、磷脂或聚氧乙烯蓖麻油。
  7. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407。
  8. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述表面活性剂的浓度为0.05mg/mL～10mg/mL；任选为0.1mg/mL～3mg/mL；任选为0.2mg/mL～2mg/mL。
  9. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠。
  10. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述螯合剂的浓度为0.01mg/mL～10mg/mL；任选为0.05mg/mL～1mg/mL；任选为0.1mg/mL～0.75mg/mL。
  11. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇。
  12. 根据权利要求3所述的混悬喷雾剂，其特征在于，所述pH调节剂包含酸性pH调节剂或碱性pH调节剂，所述酸性pH调节剂为盐酸、乙酸或磷酸的一种或多种；所述碱性pH调节剂为氢氧化钠，磷酸氢钠，碳酸钙或氢氧化镁的一种或多种。
  13. 根据权利要求3所述的混悬喷雾剂，其特征在于，所述pH调节剂为盐酸或氢氧化钠。
  14. 根据权利要求4所述的混悬喷雾剂，其特征在于，所述缓冲剂包含乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸或它们的盐。
  15. 根据权利要求4所述的混悬喷雾剂，其特征在于，所述缓冲剂为柠檬酸和/或柠檬酸钠。
  16. 根据权利要求15所述的混悬喷雾剂，其特征在于，所述柠檬酸的浓度为0.05mg/mL～20.0mg/mL；任选为0.2mg/mL～1.5mg/mL；任选地，所述柠檬酸钠的浓度为0.5mg/mL～20.0mg/mL；任选为0.5mg/mL～2.0mg/mL。
  17. 根据权利要求1-16任一所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂的pH值为3.5～6；任选为4～5。
  18. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含防腐剂。
  19. 根据权利要求2所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含助悬剂。
  20. 一种混悬喷雾剂，其特征在于，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；且所述混悬喷雾剂包含吐温80、乙二胺四乙酸二钠和氯化钠。
  21. 根据权利要求20所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含苯扎氯铵。
  22. 根据权利要求20所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含羧甲基纤维素钠。
  23. 一种混悬喷雾剂，其特征在于，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；且所述混悬喷雾剂包含表面活性剂，螯合剂、等渗调节剂、pH调节剂和缓冲剂。
  24. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含防腐剂。
  25. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含助悬剂。
  26. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL～50.0mg/mL；任选为2.0mg/mL～30mg/mL；任选为2.5mg/mL～25mg/mL。
  27. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述表面活性剂包含吐温20、吐温80、司盘20、司盘60、泊洛沙姆188或泊洛沙姆407。
  28. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述螯合剂包含乙二胺四乙酸二钠或乙二胺四乙酸钙钠。
  29. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述等渗调节剂包含氯化钠、葡萄糖、甘油、甘露醇或山梨醇。
  30. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述pH调节剂包含盐酸或氢氧化钠。
  31. 根据权利要求23所述的混悬喷雾剂，其特征在于，所述缓冲剂为柠檬酸和/或柠檬酸钠。
  32. 一种混悬喷雾剂，其特征在于，所述混悬喷雾剂的活性成分包含D(90)不大于7.5μm的布地奈德；且所述混悬喷雾剂包含吐温80、盐酸或氢氧化钠、柠檬酸和/或柠檬酸钠、乙二胺四乙酸二钠和氯化钠。
  33. 根据权利要求32所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含防腐剂。
  34. 根据权利要求32所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂进一步包含助悬剂。
  35. 根据权利要求32所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂中布地奈德的浓度为0.5mg/mL～50.0mg/mL；任选为2.0mg/mL～30mg/mL；任选为2.5mg/mL～25mg/mL。
  36. 根据权利要求1～35任一所述的混悬喷雾剂，其特征在于，所述混悬喷雾剂为第一混悬液或/和冻干复溶后的第二混悬液。
PCT/CN2017/080317 2016-04-14 2017-04-12 布地奈德混悬喷雾剂 WO2017177930A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1574222A1 (en) * 2004-03-12 2005-09-14 Cipla Ltd. Sterilization process
CN101443018A (zh) * 2006-01-27 2009-05-27 伊兰制药国际有限公司 灭菌纳米微粒糖皮质激素制剂
CN104739811A (zh) * 2015-02-27 2015-07-01 上海臣邦医药科技有限公司 一种糖皮质激素雾化吸入混悬液及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1574222A1 (en) * 2004-03-12 2005-09-14 Cipla Ltd. Sterilization process
CN101443018A (zh) * 2006-01-27 2009-05-27 伊兰制药国际有限公司 灭菌纳米微粒糖皮质激素制剂
CN104739811A (zh) * 2015-02-27 2015-07-01 上海臣邦医药科技有限公司 一种糖皮质激素雾化吸入混悬液及其制备方法

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