WO2017177930A1 - 布地奈德混悬喷雾剂 - Google Patents
布地奈德混悬喷雾剂 Download PDFInfo
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- 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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- suspension spray
- suspension
- budesonide
- spray
- spray according
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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
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- 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
Description
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
Claims (36)
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
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Publication number | Priority date | Publication date | Assignee | Title |
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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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Publication number | Priority date | Publication date | Assignee | Title |
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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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