CN109310701A

CN109310701A - Budesonide suspension spray

Info

Publication number: CN109310701A
Application number: CN201780023329.1A
Authority: CN
Inventors: 丁丹; 牟丽秋; 曹立; 赵步文; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2016-04-14
Filing date: 2017-04-12
Publication date: 2019-02-05
Also published as: WO2017177930A1

Abstract

The present invention relates to budesonide suspension sprays, and specifically, the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm.

Description

Budesonide suspension spray

Priority information

The application requests the priority and right of patent application submitting to China State Intellectual Property Office, that number of patent application is 201610235368.5 on 04 14th, 2016, and by referring to being incorporated by herein.

Technical field

The present invention relates to field of medicine preparations, and in particular to can be used for Inhalation in Treating asthma symptoms, can multiple dose administration the budesonide containing small particle high concentration suspension spray.

Background technique

Budesonide is a kind of glucocorticoid with efficient local anti-inflammatory effect.It can enhance the stability of endothelial cell, smooth muscle cell and lysosome membrane, inhibit immune response and reduces antibody synthesis, to make, the release of the activities medium such as histamine is reduced and activity reduces, and the enzymatic processes that excite when antigen-antibody combines can be mitigated, inhibit bronchoconstriction substance synthesis and release and mitigate the contractile response of smooth muscle.The structural formula of budesonide is as follows:

Within more than 20 years of past, the use for measuring mist agent becomes treatment obstructive pulmonary disease, and the set composition especially panted usually uses fluorochlorohydrocarbon as propelling gas, after the ozone destructive potential of this kind of propelling gas is recognized, there are more and more exploitations for making great efforts to carry out substitute.One of substitute is the exploitation of sprayer, and wherein the aqueous solution of pharmacologic activity substance sprays under high pressure and generates inhalable particle mist.The advantages of this sprayer is not need any propelling gas.

However, presently commercially available low concentration budesonide needs to be atomized suspension using specific atomising device for sucking suspension for budesonide lesser for water solubility, and can only single dose administration；Noise is big when it is used, inconvenient to use, and its nebulization efficiency is low, poor reproducibility, instrument needs to clean after use, and germ contamination risk is big, and the atomization duration is longer, during standing cloud, it is limited by respiratory air flow, patient cannot sufficiently suck, and cause bioavilability lower.It needs one kind not limited by specific device, commercially available common sprayer can be used to be atomized, atomization front and back stable content, the budesonide formulation that bioavilability is high and stability is good, to reach the good result that multiple dose administration is used for Inhalation in Treating asthma.

Summary of the invention

The present invention provides a kind of suspension sprays of budesonide containing small particle that can be used for Inhalation in Treating asthma symptoms.The budesonide suspension spray concentration is higher, can multiple dose administration, carry, it is easy to use；Have and be not easy to block, atomization front and back content is held essentially constant, the high advantage of utilization rate；And stability is good, it is not easy to microbiological contamination.

Commercially available budesonide suspension single dose administration, each dosage is about 2 milliliters, and each dosage of budesonide suspension spray of the invention only about needs several microlitres to tens microlitres, and it can repeatedly take, dosage is greatly reduced, and still ensures that effective treatment concentration of effective component budesonide.Embodiment according to the present invention, suspension spray of the invention and commercially available budesonide suspension, after being atomized respectively with available nebulizers, the spraying agent content of small particle budesonide suspension of the invention is substantially unchanged, and content is substantially reduced after the atomization of commercially available budesonide suspension.It is low for sucking mixed suspension preparation nebulization efficiency that budesonide suspension spray provided by the present invention can solve presently commercially available budesonide, can only single dose administration, the problems such as carrying or be inconvenient to use, bioavilability is low, easy microbiological contamination, and reduce sense of discomfort and security risk in patient's use process.

According to an aspect of the present invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm.The budesonide of small particle facilitates suspension spray when being atomized using available nebulizers, and the content of budesonide is held essentially constant after the content and atomization of budesonide before being atomized.

According to an embodiment of the invention, above-mentioned suspension spray can further include at least one following additional technical feature:

According to some embodiments of the present invention, the suspension spray includes surfactant, chelating agent and isotonic regulator, to improve the stability and safety of suspension spray.

According to some embodiments of the present invention, the suspension spray further includes pH adjusting agent；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the suspension spray further includes buffer；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the concentration of budesonide is 0.5mg/mL-50.0mg/mL in the suspension spray.In some embodiments, preferably the concentration of budesonide is 2.0mg/mL-30mg/mL；In some embodiments, the concentration of more preferable budesonide is 2.5mg/mL-25mg/mL.The spray of these concentration can guarantee that the dosage of several microlitres to tens microlitres of suspension spray can reach dose therapeutically effective；Meanwhile helping to realize the multiple dose administration of suspension spray.

According to some embodiments of the present invention, the surfactant includes polyoxyethylene sorbitan fatty acid ester, dehydration Span, poloxamer, phosphatide or Emulsifier EL-60.The polyoxyethylene sorbitan fatty acid ester includes such as Tween10, Tween20, Tween21, Tween40, Tween60, Tween61, Tween65, Tween80, Tween81 and Tween85；The fatty acid esters of sorbitan includes such as Span20, Span40, Span60, Span65, Span80, Span85 and Span83；The poloxamer includes such as 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 and Poloxamer185 etc.；The phosphatide includes phosphatidyl choline (lecithin), phosphatidyl-ethanolamine (cephalin), phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, sphingomyelins, glycosyl sphingolipid and diphosphatidylglycerol etc.；The Emulsifier EL-60 includes Cremophor EL10, Cremophor EL12, Cremophor EL20, Cremophor EL30, Cremophor EL40, Cremophor EL60, Cremophor EL80, Cremophor EL90, Cremophor EL35, Cremophor HEL40, Cremophor HEL20, Cremophor RH40 and Cremophor RH60 etc..The surfactant can increase the stability of the suspension spray.

According to some embodiments of the present invention, the surfactant includes polysorbas20, Tween 80, span 20, sorbester p18, PLURONICS F87 or poloxamer188, to further increase the stability of the suspension spray.

According to some embodiments of the present invention, the concentration of the surfactant is 0.05mg/mL-10mg/mL；In some embodiments, the concentration of preferred surfactant is 0.1mg/mL-3mg/mL；The concentration of more preferable surfactant is 0.2mg/mL-2mg/mL；To further increase the stability of the budesonide suspension spray.

According to some embodiments of the present invention, the chelating agent includes disodium ethylene diamine tetraacetate or calcio-disodium edetate.To help to improve the stability of the suspension spray.

According to some embodiments of the present invention, the concentration of the chelating agent is 0.01mg/mL-10mg/mL；In some embodiments, the concentration of preferred sequestrant is 0.05mg/mL-1mg/mL；In some embodiments, the concentration of more preferable chelating agent is 0.1mg/mL-0.75mg/mL.The chelating agent helps to further increase the stability of the suspension spray.

According to some embodiments of the present invention, the isotonic regulator includes sodium chloride, glucose, glycerol, mannitol or sorbierite.The isotonic regulator can further improve the safety of the suspension spray.

According to some embodiments of the present invention, the pH adjusting agent may include acidic ph modifier or alkaline pH adjusting agent, to help to further increase stability of the active constituent budesonide in suspension spray.In some embodiments, the acidic ph modifier is the one or more of hydrochloric acid, acetic acid or phosphoric acid；In some embodiments, the alkaline pH is adjusted Agent is sodium hydroxide, dibastic sodium phosphate, calcium carbonate or magnesium hydroxide it is one or more.

According to some embodiments of the present invention, the pH adjusting agent is hydrochloric acid or sodium hydroxide；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the buffer includes acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or their salt；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the buffer is citric acid and/or sodium citrate；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the concentration of the citric acid can be 0.05mg/mL-20.0mg/mL；Preferably 0.2mg/mL-1.5mg/mL；In some embodiments, the concentration of sodium citrate is 0.5mg/mL-20.0mg/mL；Preferably 0.5mg/mL-2.0mg/mL；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the pH of the suspension spray is 3.5-6；In some embodiments, it is preferred that the pH of suspension spray is 4-5；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the suspension spray further includes preservative.

According to some embodiments of the present invention, the suspension spray further includes suspending agent.

According to a further aspect of the invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, disodium ethylene diamine tetraacetate and sodium chloride.These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant；Improve the stability and safety of suspension spray.

According to some embodiments of the present invention, the suspension spray further includes benzalkonium chloride.

According to some embodiments of the present invention, the suspension spray further includes sodium carboxymethylcellulose.

According to a further aspect of the invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；It further includes surfactant, chelating agent, isotonic regulator, pH Regulator and buffer；To help to further increase stability of the active constituent budesonide in suspension spray.According to an embodiment of the invention, above-mentioned suspension spray can further include at least one following additional technical feature:

According to some embodiments of the present invention, the concentration of budesonide is 0.5mg/mL-50.0mg/mL in the suspension spray；In some embodiments, preferably the concentration of budesonide is 2.0mg/mL-30mg/mL；In some embodiments, the concentration of more preferable budesonide is 2.5mg/mL-25mg/mL；To guarantee that several microlitres to tens microlitres of suspension spray can reach dose therapeutically effective；Meanwhile helping to realize the multiple dose administration of suspension spray.

According to some embodiments of the present invention, the surfactant includes polysorbas20, Tween 80, span 20, sorbester p18, PLURONICS F87 or poloxamer188；To increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the chelating agent includes disodium ethylene diamine tetraacetate or calcio-disodium edetate；To help to improve stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the isotonic regulator includes sodium chloride, glucose, glycerol, mannitol or sorbierite；To further increase the safety of budesonide suspension spray.

According to a further aspect of the invention, a kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium ethylene diamine tetraacetate and sodium chloride.These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant, and improve the stability and safety of suspension spray.

The present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；It further includes surfactant, chelating agent, isotonic regulator and pH adjusting agent；To help to further increase stability of the active constituent budesonide in suspension spray.

The present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；It further includes surfactant, chelating agent, isotonic regulator and buffer；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the pH adjusting agent may include acidic ph modifier or alkaline pH adjusting agent, to help to further increase stability of the active constituent budesonide in suspension spray.In some embodiments, the acidic ph modifier is the one or more of hydrochloric acid, acetic acid or phosphoric acid；In some embodiments, the alkaline pH adjusting agent is sodium hydroxide, dibastic sodium phosphate, calcium carbonate or magnesium hydroxide it is one or more.

According to some embodiments of the present invention, the concentration of the citric acid can be 0.05mg/mL-20.0mg/mL.In some embodiments, the concentration of citric acid is 0.2mg/mL-1.5mg/mL；In some embodiments, the concentration of optimization citric acid sodium is 0.5mg/mL-20.0mg/mL；The concentration of more preferable sodium citrate is 0.5mg/mL-2.0mg/mL；To help to further increase stability of the active constituent budesonide in suspension spray.

According to some embodiments of the present invention, the pH of the suspension spray is 3.5-6；In some embodiments, the preferably pH of suspension spray is 4-5；To help to further increase stability of the active constituent budesonide in suspension spray.

A kind of suspension spray provided by the invention, the active constituent of the suspension spray include that D (90) are not more than 7.5 μm Budesonide；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm, also includes surfactant, chelating agent and isotonic regulator；When being atomized using available nebulizers, the content after content and atomization before atomization is held essentially constant suspension spray containing these ingredients；With preferable stability and safety.

The present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm, surfactant, chelating agent, isotonic regulator and preservative；These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray is provided according to the present invention, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm, surfactant, chelating agent, isotonic regulator and suspending agent；These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray provided by the invention, the active constituent of the suspension spray include budesonide, surfactant, chelating agent, isotonic regulator, preservative and suspending agent that D (90) are not more than 7.5 μm；These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

According to some embodiments of the present invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes D (10) is not more than 1.0 μm of budesonide；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, disodium ethylene diamine tetraacetate and sodium chloride.These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant；Improve the stability and safety of suspension spray.

According to some embodiments of the present invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, disodium ethylene diamine tetraacetate, sodium chloride and benzalkonium chloride.These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

According to some embodiments of the present invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, disodium ethylene diamine tetraacetate, sodium chloride and sodium carboxymethylcellulose.To facilitate aseptic of the spray in shelf life or use process, the safety of budesonide suspension spray is improved；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

According to some embodiments of the present invention, the present invention provides a kind of suspension spray, and the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, disodium ethylene diamine tetraacetate, sodium chloride, benzalkonium chloride and sodium carboxymethylcellulose.These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator and pH adjusting agent；These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant；Improve the stability and safety of suspension spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator and buffer；These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant；Improve the stability and safety of suspension spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator, pH adjusting agent and buffer；These ingredients facilitate suspension spray when being atomized using available nebulizers, and the content after content and atomization before atomization is held essentially constant；Improve the stability and safety of suspension spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator, pH adjusting agent, buffer and preservative；These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator, pH adjusting agent, buffer and suspending agent；These ingredients facilitate active constituent budesonide and are scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes surfactant, chelating agent, isotonic regulator, pH adjusting agent, buffer, preservative and suspending agent；These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitates active constituent budesonide and be scattered in graininess Uniform and stable suspension spray is formed in spray.According to some embodiments of the present invention, the concentration of budesonide is 0.5mg/mL-50.0mg/mL in the suspension spray；In some embodiments, preferably the concentration of budesonide is 2.0mg/mL-30mg/mL；In some embodiments, the concentration of more preferable budesonide is 2.5mg/mL-25mg/mL；To guarantee that several microlitres to tens microlitres of suspension spray can reach dose therapeutically effective；Meanwhile helping to realize the multiple dose administration of suspension spray.

According to some embodiments of the present invention, the surfactant includes polysorbas20, Tween 80, span 20, sorbester p18, PLURONICS F87 or poloxamer188；To increase the stability of budesonide suspension spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium ethylene diamine tetraacetate, sodium chloride and preservative.These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium ethylene diamine tetraacetate, sodium chloride and suspending agent.These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

A kind of suspension spray provided according to the present invention, the active constituent of the suspension spray include that D (90) are not more than 7.5 μm of budesonide；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium ethylene diamine tetraacetate, sodium chloride, preservative or suspending agent.These ingredients facilitate spray and keep aseptic in shelf life or use process, improve the safety of budesonide suspension spray；And facilitate active constituent budesonide and be scattered in graininess to form uniform and stable suspension spray in spray.

According to some embodiments of the present invention, the concentration of the surfactant can be 0.05mg/mL-10mg/mL.In some embodiments, the concentration of preferred surfactant is 0.1mg/mL-3mg/mL；The concentration of more preferable surfactant is 0.2mg/mL-2mg/mL；To further increase the stability of budesonide suspension spray.

According to some embodiments of the present invention, the suspension spray is the second suspension after the first suspension or/and freeze-drying redissolution.

According to some embodiments of the present invention, the suspension spray includes freeze drying protectant.

A kind of suspension spray provided according to embodiments of the present invention, the size distribution of the suspension spray are substantially unchanged before and after freeze-drying.

A kind of suspension spray provided according to embodiments of the present invention, the active constituent of the suspension spray include the budesonide that D (90) are not more than 7.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (50) are not more than 3.5 μm；In some embodiments, the active constituent of the suspension spray includes the budesonide that D (10) are not more than 1.0 μm；Further, the suspension spray also includes following pharmaceutic adjuvant: Tween 80, glycine, PVP K29/32.These ingredients help to improve the stability of budesonide lyophilized preparation, and facilitate budesonide lyophilized preparation and form uniform and stable suspension spray after redissolution.

Term definition

Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the scope of the invention defined such as claim.Those skilled in the art will appreciate that many can be used in the practice present invention with similar or equivalent method and material described herein.The present invention is not limited to method described herein and material.Document, patent and the similar material combined one or more from the application is different or contradicts in the case where (including but not limited to defined in term, term application, described technology etc.), be subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, be described in a number of independent embodiments, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, all scientific and technical terminologies used in the present invention, which have, is generally understood identical meaning with those skilled in the art of the invention.All patents of the present invention and public publication are integrally incorporated the present invention by reference.

In the context of the present invention, wordings such as " about " or " about " whether or not using, all numbers being disclosed are approximation.The numerical value of each number is possible to will appear the differences such as 1%, 2% or 5%.

Term " API " refers to active constituent.

Term " D (10) " refers to that the cumulative particle sizes volume percentile an of sample reaches partial size corresponding when 10%.

Term " D (50) " refers to that the cumulative particle sizes volume percentile an of sample reaches partial size corresponding when 50%.

Term " D (90) " refers to that the cumulative particle sizes volume percentile an of sample reaches partial size corresponding when 90%.

Term " before atomization " refers to the sample of budesonide suspension before the spraying.

Term " after atomization " refers to the droplet sample collected after being atomized to budesonide suspension using atomizer.

Term " single dose " refers to the complete dosage of first use.

Term " multi-dose ", which refers to, is packed into multiple single dose of drug in one container, takes for fixed quantity.It sucks preparation usually 60 or 120 single dose of drug are packed into a container, can take 60 or 120 times.

Term " EDTA-2Na " refers to disodium ethylene diamine tetraacetate.

Term " CMC-Na " refers to sodium carboxymethylcellulose.

Term " NaCl " refers to sodium chloride.

Term " Tween-80 " refers to sorbitan monooleate polyoxyethylene ether.

Term " Tween-20 " refers to polyoxyethylene (20) anhydrous sorbitol acid anhydride monolaurate.

Term " Span-20 " refers to anhydrous sorbitol acid anhydride monolaurate.

Term " EL-35 " refers to polyoxyethylene (35) castor oil.

Term " RLD " refers to Reference Listed Drug (reference agent).

Term " PVP " refers to povidone.

Term " the first suspension " grinds the medical fluid being prepared after referring to budesonide and the mixing of each auxiliary material.

Term " the second suspension " refers to the medical fluid being prepared after budesonide and each auxiliary material mixed grinding, after freeze-dried, then through redissolving obtained medical fluid.

Mg/mL refers to mg/ml, μm refers to that micron, mg refer to milligram, and mL refers to milliliter, and min refers to minute, and r/min refers to rev/min, and g refers to gram, and mm refers to millimeter, and cm refers to centimetre, DEG C refers to degree Celsius, and Hz refers to that hertz, s refer to the second, and h refers to hour, and d refers to that number of days, mbar refer to millibar.

Specific embodiment

The embodiment of the present invention is described below in detail, in which the same or similar labels are throughly indicated same or similar element or elements with the same or similar functions.It is exemplary below with reference to embodiment, it is intended to be used to explain the present invention, and be not considered as limiting the invention.

Embodiment

Embodiment 1: the preparation of budesonide suspension

Table 1-1: prescription table

Component	Effect	Dosage (g)
Budesonide	API	0.55
Citric acid	Buffer	0.03
Sodium citrate	Buffer	0.05
Tween-80	Surfactant	0.02
EDTA-2Na	Chelating agent	0.01
NaCl	Osmotic pressure regulator	0.9
Benzalkonium chloride	Preservative	0.01
Purified water	Solvent	In right amount to 100mL

Preparation method:

(1) recipe quantity citric acid, sodium citrate, EDTA-2Na, NaCl, Tween-80 and benzalkonium chloride are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved；

(2) budesonide of recipe quantity is added in above-mentioned mixed solution and stirs to get budesonide suspension, constant volume；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 1mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 2:1, milling time 150min；

(4) budesonide suspension size distribution is measured using 2000 particle size analyzer of Malvern Mastersizer, test condition is revolving speed 2500r/min；Obscurity about 15%；Time of measuring 12s；Unit μm；Budesonide suspension particle size measurement result is following (unit: μm):

Conclusion: D (90)=5.414 μm, D (50)=1.595 μm, D (10)=0.569 μm shows, the particle size of budesonide suspension 90% or so is at 5.5 μm or less, 50% or so particle size is at 1.6 μm hereinafter, 10% or so particle size is at 0.6 μm or less.

Embodiment 2: different types of surfactant prepares budesonide suspension

Table 2-1: prescription table

Preparation method:

(1) it weighs in the purified water that recipe quantity 0.1g Tween-80,0.1g Tween-20,0.1g EL-35,0.1g poloxamer188 and 0.1g Tween-80+0.1g Span-20 prepare total amount in 5 part 80%, is dispersed with stirring uniformly respectively；

(2) recipe quantity citric acid, sodium citrate, EDTA-2Na, NaCl, Tween-80 and benzalkonium chloride are separately added into above-mentioned every group of system, stirring makes it completely dissolved；

(3) budesonide of recipe quantity is added in above-mentioned mixed solution and stirs to get budesonide suspension, constant volume；

(4) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 3:1, milling time 4h；

(5) budesonide suspension particle diameter distribution is measured using 2000 particle size analyzer of Malvern Mastersizer (measuring method is with embodiment 1)；

(6) spraying using micropore atomization device, survey spraying rear content.

Table 2-2: content after the budesonide suspension size distribution and atomization of the preparation of different surfaces activating agent

Note: concentration * 100% before concentration/atomization after content=atomization after atomization.

Conclusion: according to the above results, after the budesonide suspension that different surfaces activating agent is prepared is using the atomization of micropore atomization device, the budesonide suspension granularity that Tween-80, Tween-20, EL-35, Tween-80+Span-20 are prepared is smaller, content is more stable after atomization, the budesonide suspension granularity being prepared when poloxamer188 is as surfactant is bigger, content slightly reduces after spraying, but (" Chinese Pharmacopoeia " 2015 editions regulations, spraying rear content are the 80%-120% of labelled amount) within an acceptable range.

Embodiment 3: the Tween-80 of different proportion prepares budesonide suspension and its stability study

Table 3-1: prescription table

Preparation method:

(1) recipe quantity citric acid, sodium citrate, EDTA-2Na, NaCl and benzalkonium chloride are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved, and is separately added into the Tween-80 of different proportion；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.4~0.6mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 2:1, it is sampled respectively at 90min, 120min, 2000 particle size analyzer of Malvern Mastersizer measures budesonide suspension granule size, and investigates steadiness in 6 DEG C and 40 DEG C placements；As a result it see the table below 3-2.

Table 3-2: budesonide suspension granulometry and stability study

According to the above results it is found that the Tween-80 of different proportion influences less budesonide suspension final size, and accelerating in low temperature placement process, budesonide suspension stability is preferable, and granularity variation is smaller.

Embodiment 4: different pearl proportions and influence of the milling time to budesonide suspension granularity are investigated

Table 4-1: prescription table

Component	Effect	Dosage (g)
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	Isotonic regulator	4.5
Purified water	Solvent	In right amount to 500mL

Preparation method:

(1) recipe quantity Tween-80, citric acid, sodium citrate, EDTA-2Na, NaCl and benzalkonium chloride are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.4~0.6mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 3:1 and 4:1, it is sampled respectively at 90min, 120min, 180min, 240min, budesonide suspension granule size is measured using 2000 particle size analyzer of Malvern Mastersizer；

Table 4-2: different pearl (0.4~0.6mm) proportions and milling time are to budesonide suspension particle size influences

Conclusion: budesonide suspension granule size can be reduced to a certain extent by increasing pearl proportion and milling time.

Embodiment 5: the budesonide suspension stability study of different pH value (3.0,4.0,5.0,6.0,7.0)

Table 5-1: prescription table

Component	Effect	Dosage (g)
Budesonide	API	2.75
Tween 80	Surfactant	0.5
Citric acid	Buffer	0.3
Sodium citrate	Buffer	0.5
Benzalkonium chloride	Preservative	0.1
EDTA-2Na	Chelating agent	0.1
Sodium chloride	Isotonic regulator	4.5
Purified water	Solvent	In right amount to 500mL

Preparation method:

(2) budesonide of recipe quantity is added in above-mentioned mixed solution and stirs to get budesonide suspension, suspension pH value is adjusted to 3.0,4.0,5.0,6.0,7.0 or so respectively with dilute hydrochloric acid or 2%NaOH, constant volume；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.4~0.6mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1；

(4) budesonide suspension for the different pH value being prepared is subjected to acceleration for stabilization Journal of Sex Research under the conditions of 40 DEG C, separately sampled when 10d, HPLC measures budesonide content and related substance.

Chromatographic condition:

Instrument: HPLC

Chromatographic column: YMC-Pack ODS-A (150 × 4.6mm, 3 μm)；

Mobile phase A: dehydrated alcohol: acetonitrile: phosphate buffer=2:32:68,

Mobile phase B: acetonitrile: phosphate buffer=50:50；

Wavelength: 240nm；Flow velocity: 1.0mL/min；Sample volume: 20 μ L；Column temperature: 50 DEG C；

Runing time: 31min (content), 60min (related substance)；It runs afterwards: 5min；

Gradient (content):

Time (min)	Mobile phase A (%)	Mobile phase B (%)
0-21	100	0
21-22	100→0	0→100
22-31	0	100

Gradient (related substance):

Time (min)	Mobile phase A (%)	Mobile phase B (%)
0-38	100	0
38-50	100→0	0→100
50-60	0	100

Table 5-2: 40 DEG C of acceleration for stabilization Journal of Sex Research of budesonide suspension of different pH value

Note: it is more that "/" indicates that content reduces, and impurity increases comparatively fast, does not mark.

Conclusion: with the increase of pH value, the decline of budesonide suspension stability.

Embodiment 6: the budesonide suspension of different pH value (4.0,4.7,5.0,5.5) accelerates and the research of intermediate conditions stability inferior

Table 6-1: prescription table

Component	Effect	Dosage (g)
Budesonide	API	5.5
Tween-80	Surfactant	0.5
Citric acid	Buffer	0.3
Sodium citrate	Buffer	0.5
Benzalkonium chloride	Preservative	0.05
EDTA-2Na	Chelating agent	0.2
Sodium chloride	Isotonic regulator	4.5
Purified water	Solvent	In right amount to 500mL

Preparation method:

(1) recipe quantity Tween-80, citric acid, sodium citrate, EDTA, NaCl and benzalkonium chloride are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved；

(2) budesonide of recipe quantity is added in above-mentioned mixed solution and stirs to get budesonide suspension, suspension pH value is adjusted to 4.0,4.7,5.0,5.5 or so respectively with dilute hydrochloric acid or 2%NaOH, constant volume；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1；

(4) budesonide suspension for the different pH value being prepared is carried out accelerating under the conditions of 60 DEG C/40 DEG C/30 DEG C and intermediate conditions stability inferior is studied, budesonide content and related substance is measured by sampling respectively when 10d.Analysis method is the same as embodiment 5.

Table 6-2: 60 DEG C of stability studies of budesonide suspension of different pH value

Table 6-3: 40 DEG C of acceleration for stabilization Journal of Sex Research of budesonide suspension of different pH value

Table 6-4: 30 DEG C of intermediate conditions stability studies of budesonide suspension of different pH value

Conclusion: when the pH value of budesonide suspension is in 4.0~5.5 ranges, stability is preferable.

Embodiment 7: the preparation of small particle budesonide suspension and stability study

Table 7-1: prescription table

Component	Effect	Dosage (g)
Budesonide	API	2.2
Tween-80	Surfactant	0.4
Citric acid	Buffer	0.24
Sodium citrate	Buffer	0.4
Benzalkonium chloride	Preservative	0.04
EDTA-2Na	Chelating agent	0.08
Sodium chloride	Isotonic regulator	3.6
Purified water	Solvent	In right amount to 400mL

Preparation method:

(1) recipe quantity Tween-80, citric acid, sodium citrate, EDTA-2Na, NaCl, benzalkonium chloride are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 3:1；

(4) 2000 particle size analyzer of Malvern Mastersizer measures budesonide suspension size distribution after the milling time sampling of Yu Butong.

Table 7-2: different milling time budesonide suspension size distributions

Table 7-3: budesonide suspension stability study under different condition

	0d	60℃10d	40℃10d	30℃10d
Content (%)	100.1	99.2	101.6	100.3
Largest single impurity (%)	1.45	1.43	1.46	1.46
Total miscellaneous (%)	2.69	2.86	2.76	2.89

Conclusion: after the zirconium oxide bead grinding of 0.3mm, the available lesser budesonide suspension of granularity, and stability is preferable.

Embodiment 8: the preparation of high concentration budesonide suspension

Table 8-1: prescription table

Preparation method:

(1) recipe quantity Tween-80, citric acid, sodium citrate, EDTA-2Na, NaCl and benzalkonium chloride are added in the purified water that 80% prepares total amount respectively, stirring makes it completely dissolved；

(4) after grinding 6h, budesonide suspension is obtained, 2000 particle size analyzer of Malvern Mastersizer measures budesonide suspension granule size.

Table 8-2: the size distribution of high concentration budesonide suspension

Conclusion: small grain size high concentration budesonide suspension is prepared in 3~5mg/ml Shi Junke in 24mg/ml, surfactant concentration in budesonide concentration.

Embodiment 9: budesonide suspension is atomized using different atomizers

Table 9-1: it is atomized using budesonide suspension of the Omron Compressed air nebulization device to small grain size

Table 9-2: it is atomized using budesonide suspension of the micropore atomization device to small grain size

Note: concentration * 100% before concentration/atomization after content=atomization after atomization

Conclusion: budesonide suspension provided by the invention is after using different atomizer atomizations, and size distribution and content are substantially without significant change.

Embodiment 10: self-control small grain size budesonide suspension and AstraZeneca Pulmicort Respules use changes of contents after fish dive ultrasonic atomizer and the atomization of micropore atomization device to compare simultaneously

Prescription table 10-1: self-control small grain size budesonide suspension -01

Component	Effect	Dosage (g)
Budesonide	API	0.55
Tween-80	Surfactant	0.1
Citric acid	Buffer	0.06
Sodium citrate	Buffer	0.1
Benzalkonium chloride	Preservative	0.02
EDTA-2Na	Chelating agent	0.02
Sodium chloride	Isotonic regulator	0.9
Purified water	Solvent	In right amount to 100mL

Prescription table 10-2: self-control small grain size budesonide suspension -02

Component	Effect	Dosage (g)
Budesonide	API	3.6
Tween-80	Surfactant	0.3
Citric acid	Buffer	0.18
Sodium citrate	Buffer	0.3
Benzalkonium chloride	Preservative	0.03
EDTA-2Na	Chelating agent	0.06
Sodium chloride	Isotonic regulator	2.7
Purified water	Solvent	In right amount to 300mL

Preparation method:

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 01 prescription use 0.4~0.6mm zirconium oxide abrasive pearl, and 02 prescription uses 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1, and grinding 4h obtains budesonide suspension.

The Pulmicort Respules of 10mL self-control small grain size budesonide suspension and AstraZeneca (AstraZeneca) are taken to be sprayed in fish dive ultrasonic atomizer and micropore atomization device respectively, the budesonide suspension after atomization is collected respectively, then the budesonide content after HPLC measurement atomization.

10-3: two kinds of suspensions of table use changes of contents after ultrasonic atomizer atomization

10-4: two kinds of suspensions of table use changes of contents after the atomization of micropore atomization device

Conclusion: no matter ultrasonic atomizer or micropore atomization device are used, changes of contents is larger after the atomization of commercial preparation AstraZeneca Pulmicort Respules, it may and wider distribution larger with partial size, larger particle, which is atomized the retention of device nozzle, when atomization causes content reduction related, and the budesonide suspension of small particle is made by oneself in atomization since granularity is smaller, narrow distribution, content is more stable after atomization.

Embodiment 11: the preparation and atomization of budesonide suspension

Table 11-1: prescription table

Component	Effect	Dosage (g)
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	Isotonic regulator	0.9
Purified water	Solvent	In right amount to 100mL

Preparation method:

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 2mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1；

(4) budesonide suspension is obtained after grinding 6h, 2000 particle size analyzer of Malvern Mastersizer measures budesonide suspension granule size, and spraying with micropore atomization device, changes of contents after HPLC measures suspension by spraying.

Table 11-2: changes of contents after budesonide suspension size distribution and atomization

Conclusion: the budesonide suspension that self-control D90 is about 7.0 μm, content slightly reduces after atomization, but still within an acceptable range (" Chinese Pharmacopoeia " 2015 editions regulations, content is the 80%-120% of labelled amount after atomization).

Embodiment 12:, which preparing the budesonide suspension containing suspending agent, and detects its is atomized content

Table 12-1: prescription table

Component	Effect	Dosage (g)
Budesonide	API	0.45
Tween-80	Surfactant	0.10

CMC-Na	Suspending agent	0.20
Citric acid	Buffer	0.06
Sodium citrate	Buffer	0.10
Benzalkonium chloride	Preservative	0.01
EDTA-2Na	Chelating agent	0.04
Sodium chloride	Isotonic regulator	0.90
Purified water	Solvent	In right amount to 100mL

Preparation method:

(1) recipe quantity Tween-80, citric acid, sodium citrate, EDTA-2Na, NaCl and benzalkonium chloride are added in the purified water that 50% prepares total amount, stirring makes it completely dissolved；

(2) recipe quantity CMC-Na is added in the purified water that 30% prepares total amount, is slowly added to obtain mixed solution in (1) after stirring and dissolving；

(4) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 3:1；

(5) budesonide suspension is obtained after grinding 6h, and 2000 particle size analyzer of Malvern Mastersizer measures budesonide suspension granule size, and suspension is atomized using micropore atomization device, budesonide content after HPLC detection atomization.

Table 12-2: content after size distribution and atomization

Conclusion: after sodium carboxymethylcellulose is added as suspending agent, content is slightly changed after budesonide suspension atomization, but still within an acceptable range, (" Chinese Pharmacopoeia " 2015 editions regulations, content is the 80%-120% of labelled amount after atomization), it is smaller to illustrate that the addition of suspending agent sodium carboxymethylcellulose influences the content after budesonide suspension atomization.

Embodiment 13: the budesonide suspension and its atomization front and back changes of contents of various concentration

Table 13-1: prescription table

Preparation method:

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1, grinding 6h obtains budesonide suspension；

(4) suspension of various concentration is atomized using micropore atomization device, content after HPLC detection atomization.

Table 13-2: changes of contents after the budesonide suspension atomization of various concentration

Conclusion: when budesonide concentration is 3.0mg/mL-4.5mg/mL, content is substantially without large change after atomization, within an acceptable range.

Embodiment 14: budesonide suspension atomized drop granulometry

Table 14-1: prescription table

Preparation method:

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 30Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 4:1, grinding 6h obtains budesonide suspension.

Partial size testing procedure and scheme:

Instrument: Malvern Spraytec granularity of spray instrument.

Step: for fixed atomizer away from detection and horizontal distance 10cm, vertical range 5cm, examination spray is primary, guarantees that the laser of detection is located at the center of the mist sprayed.Setting sample rate 100 times per second, measures background, spraying, measures the partial size of atomized drop.

Table 14-2: using micropore atomization device to self-control budesonide suspension

Conclusion: after being atomized using micropore atomization device, the ratio of three groups of effective particles of suspension is higher, and particle of the granularity between 0.5~6.3 μm accounts for 70~87%, and particle of the granularity between 1.0~5.5 μm accounts for 59~78%.

Note: effective particle refers to that mist droplet granularity can be deposited on the particle of lung in 1.0~5.0 μ ms.

The preparation and freeze-drying of 15 budesonide suspension of embodiment, and redissolve front and back size distribution measurement

Table 15-1: freeze-drying prescription table

Preparation method:

(1) recipe quantity Tween-80, glycine, PVP-K29/32 are added in the purified water that 80% prepares total amount, stirring makes it completely dissolved；

(3) above-mentioned budesonide suspension is ground with planetary ball mill；Grinding power 20Hz, 0.3mm zirconium oxide abrasive pearl, and grinding bead and budesonide suspension mass ratio are 3:1, grinding 1h obtains budesonide suspension；

(4) suspension is sub-packed in 7mL cillin bottle, every filling 3mL is freeze-dried, lyophilized technique is as follows: pre-freeze: first stage: -2 DEG C, setting time 20min, duration 60min；

Second stage: -45 DEG C, setting time 40min, duration 240min；

Primary drying: -10 DEG C, setting time 60min, duration 1080min, vacuum degree 0.13mbar；

Redrying: 30 DEG C, setting time 35min, duration 120min.

Table 15-2: auxiliary material solution prescription table

Component	Effect	Dosage (g)
Citric acid	Buffer	0.06
Sodium citrate	Buffer	0.10
Benzalkonium chloride	Preservative	0.01
EDTA-2Na	Chelating agent	0.02
Sodium chloride	Isotonic regulator	0.9
Purified water	Solvent	In right amount to 100mL

Appropriate purified water and auxiliary material solution is added to redissolve respectively budesonide freeze-dried powder, front and back budesonide suspension size distribution is redissolved in measurement, as shown in table 15-3 and table 15-4.

Table 15-3: water redissolves size distribution after budesonide suspension freeze-drying

Table 15-4: auxiliary material solution redissolves size distribution after budesonide suspension freeze-drying

Conclusion: it can be seen from the above result that, budesonide suspension freeze-drying front and back, water or auxiliary material solution redissolve size distribution and change less.

Method of the invention is described by preferred embodiment, and related personnel obviously can within that content, spirit and scope of the present invention be modified or appropriate changes and combinations method described herein and application, carrys out implementation and application the technology of the present invention.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are apparent to those skilled in the art, they are considered as being included in the present invention.

In the description of the present invention, the meaning of " plurality " is at least two, such as two, three etc., unless otherwise specifically defined.

Although the embodiments of the present invention has been shown and described above, it can be understood that, above-described embodiment is exemplary, and is not considered as limiting the invention, and those skilled in the art can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.

Claims

A kind of suspension spray, which is characterized in that the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm.
Suspension spray according to claim 1, which is characterized in that the suspension spray includes surfactant, chelating agent and isotonic regulator.
Suspension spray according to claim 2, which is characterized in that the suspension spray further includes pH adjusting agent.
Suspension spray according to claim 2, which is characterized in that the suspension spray further includes buffer.
Suspension spray according to any one of claims 1 to 4, which is characterized in that the concentration of budesonide is 0.5mg/mL~50.0mg/mL in the suspension spray；Optionally 2.0mg/mL~30mg/mL；Optionally 2.5mg/mL~25mg/mL.
Suspension spray according to claim 2, which is characterized in that the surfactant includes polyoxyethylene sorbitan fatty acid ester, fatty acid esters of sorbitan, poloxamer, phosphatide or Emulsifier EL-60.
Suspension spray according to claim 2, which is characterized in that the surfactant includes polysorbas20, Tween 80, span 20, sorbester p18, PLURONICS F87 or poloxamer188.
Suspension spray according to claim 2, which is characterized in that the concentration of the surfactant is 0.05mg/mL~10mg/mL；Optionally 0.1mg/mL~3mg/mL；Optionally 0.2mg/mL~2mg/mL.
Suspension spray according to claim 2, which is characterized in that the chelating agent includes disodium ethylene diamine tetraacetate or calcio-disodium edetate.
Suspension spray according to claim 2, which is characterized in that the concentration of the chelating agent is 0.01mg/mL~10mg/mL；Optionally 0.05mg/mL~1mg/mL；Optionally 0.1mg/mL~0.75mg/mL.
Suspension spray according to claim 2, which is characterized in that the isotonic regulator includes sodium chloride, glucose, glycerol, mannitol or sorbierite.
Suspension spray according to claim 3, which is characterized in that the pH adjusting agent includes acidic ph modifier or alkaline pH adjusting agent, and the acidic ph modifier is the one or more of hydrochloric acid, acetic acid or phosphoric acid；The alkaline pH adjusting agent is sodium hydroxide, dibastic sodium phosphate, calcium carbonate or magnesium hydroxide it is one or more.
Suspension spray according to claim 3, which is characterized in that the pH adjusting agent is hydrochloric acid or sodium hydroxide.
Suspension spray according to claim 4, which is characterized in that the buffer includes acetic acid, citric acid, sodium citrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid or their salt.
Suspension spray according to claim 4, which is characterized in that the buffer is citric acid and/or sodium citrate.
Suspension spray according to claim 15, which is characterized in that the concentration of the citric acid is 0.05mg/mL~20.0mg/mL；Optionally 0.2mg/mL~1.5mg/mL；Optionally, the concentration of the sodium citrate is 0.5mg/mL~20.0mg/mL；Optionally 0.5mg/mL~2.0mg/mL.
- 16 any suspension spray according to claim 1, which is characterized in that the pH value of the suspension spray is 3.5~6；Optionally 4~5.
Suspension spray according to claim 2, which is characterized in that the suspension spray further includes preservative.
Suspension spray according to claim 2, which is characterized in that the suspension spray further includes suspending agent.
A kind of suspension spray, which is characterized in that the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；And the suspension spray includes Tween 80, disodium ethylene diamine tetraacetate and sodium chloride.
Suspension spray according to claim 20, which is characterized in that the suspension spray further includes benzalkonium chloride.
Suspension spray according to claim 20, which is characterized in that the suspension spray further includes sodium carboxymethylcellulose.
A kind of suspension spray, which is characterized in that the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；And the suspension spray includes surfactant, chelating agent, isotonic regulator, pH adjusting agent and buffer.
Suspension spray according to claim 23, which is characterized in that the suspension spray further includes preservative.
Suspension spray according to claim 23, which is characterized in that the suspension spray further includes suspending agent.
Suspension spray according to claim 23, which is characterized in that the concentration of budesonide is 0.5mg/mL~50.0mg/mL in the suspension spray；Optionally 2.0mg/mL~30mg/mL；Optionally 2.5mg/mL~25mg/mL.
Suspension spray according to claim 23, which is characterized in that the surfactant includes polysorbas20, Tween 80, span 20, sorbester p18, PLURONICS F87 or poloxamer188.
Suspension spray according to claim 23, which is characterized in that the chelating agent includes disodium ethylene diamine tetraacetate or calcio-disodium edetate.
Suspension spray according to claim 23, which is characterized in that the isotonic regulator includes sodium chloride, glucose, glycerol, mannitol or sorbierite.
Suspension spray according to claim 23, which is characterized in that the pH adjusting agent includes hydrochloric acid or sodium hydroxide.
Suspension spray according to claim 23, which is characterized in that the buffer is citric acid and/or sodium citrate.
A kind of suspension spray, which is characterized in that the active constituent of the suspension spray includes the budesonide that D (90) are not more than 7.5 μm；And the suspension spray includes Tween 80, hydrochloric acid or sodium hydroxide, citric acid and/or sodium citrate, disodium ethylene diamine tetraacetate and sodium chloride.
Suspension spray according to claim 32, which is characterized in that the suspension spray further includes preservative.
Suspension spray according to claim 32, which is characterized in that the suspension spray further includes suspending agent.
Suspension spray according to claim 32, which is characterized in that the concentration of budesonide is 0.5mg/mL~50.0mg/mL in the suspension spray；Optionally 2.0mg/mL~30mg/mL；Optionally 2.5mg/mL~25mg/mL.
Any suspension spray according to claim 1~35, which is characterized in that the suspension spray is the second suspension after the first suspension or/and freeze-drying redissolution.