CN101420935A

CN101420935A - Sterilization of corticosteroids with reduced mass loss

Info

Publication number: CN101420935A
Application number: CNA2007800135685A
Authority: CN
Inventors: M·R·希尔; C·利卡尔西
Original assignee: Tika Lakemedel AB
Current assignee: Tika Lakemedel AB
Priority date: 2006-02-15
Filing date: 2007-02-15
Publication date: 2009-04-29
Also published as: CN101478954A

Abstract

The present invention relates to corticosteroid solution sterilization method capalbe of improving the final yield of corticosteroid component.

Description

The corticosteroid sterilizing methods that mass loss reduces

The cross reference of priority request and related application

According to 35 U.S.C. § 120 (e), the application requires the U.S. Provisional Patent Application No.60/774 of application on February 15th, 2006,152 priority, with its whole introducing the application as a reference.According to 35 U.S.C. § 119 (e), the application further requires the U.S. Provisional Patent Application No.60/774 of application on February 15th, 2006,073 priority, with its whole introducing the application as a reference.According to 35 U.S.C. § 119 (e), the application further requires the U.S. Provisional Patent Application No.60/774 of application on February 15th, 2006,151 priority, with its whole introducing the application as a reference.

The application relate on February 15th, 2007 application " producing the method for corticosteroid solutions " by name, act on behalf of case number for the common pending application of 31622-718/201 _/_, _, with its whole introducing the application as a reference.The application also relate on February 15th, 2007 application " stable mixture of corticosteroids " by name, act on behalf of case number for the common pending application of 31622-719/201 _/_, _, with its whole introducing the application as a reference.

Background of invention

The water slurry of budesonide is known.Up to now, also can not because micronized budesonide granule can block filter membrane, cause budesonide too much to be detained by filtering to this suspension sterilization in filter membrane inside and back.Like this, yet owing to multiple reason, other sterilizing methods has been proved to be not meet and has needed, and these reasons comprise the complexity and the corticosteroid weak stability under these conditions of corticosteroid sterilization.

The existing report of aqueous solutions of budesonide.Referring to, for example WO2005/065649, WO2005/065435 and WO2005/065651 have instructed and have comprised as solubilizing agent

Budesonide solution.The sterilizing methods of budesonide solution has been instructed in these applications, yet considers that from commercial angle the mass loss of budesonide is unacceptable under the condition of being reported.

Therefore need improve the terminal sterilization method of the improved corticosteroid solutions of mass loss.

Summary of the invention

Aforementioned and other needs further satisfy by embodiment of the present invention, it provides the method for the corticosteroid solutions of preparation sterilization, comprise making compound mixture of corticosteroids reach following state that the mass loss between the corticosteroid solutions of wherein initial corticosteroid solutions and sterilization is less than is about 30%, it is about 25% to be less than, it is about 20% to be less than, it is about 15% to be less than, it is about 10% to be less than, it is about 5% to be less than, it is about 3% to be less than, be less than about 2% or about 1% or still less.In certain embodiments, corticosteroid solutions comprises solubilizing agent, as cyclodextrin.In certain preferred aspects, corticosteroid is a budesonide.In certain preferred aspects, the invention provides the method for the corticosteroid solutions of preparation sterilization, it comprises provides compound corticosteroid solutions and filters compound corticosteroid solutions to produce the corticosteroid solutions of sterilization by filter, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m, about 0.15 μ m is to 0.45 μ m, about 0.15 μ m is to 0.30 μ m, about 0.15 μ m is to 0.25 μ m.The mass loss that is caused by sterilization process is less than the about 30% of corticosteroid in compound (unpasteurized) corticosteroid solutions, is less than approximately 25%, is less than about 20%, be less than approximately 15%, be less than approximately 10%, be less than about 5%, be less than approximately 3%, be less than about 2% or about 1% or still less.In certain preferred aspects, budesonide solution is filtering by 0.22 μ m filter, 0.22 μ m PVDF filter particularly, for example

CVGL71TP3 0.22 μ m filter.In some particularly preferred embodiment, the scope of the mass loss of corticosteroid that is caused by filtration is about 0.5% to about 30%, about 0.5% to about 25%, about 0.5% to about 20%, about 0.5% to about 15%, about 0.5% to about 10%, about 0.5% to about 5%, about 0.5% to about 2%, about 0.5% to about 1.5% or about 0.5% to about 1.2%.

Aforementioned and other needs further satisfy by embodiment of the present invention, it provides the method that reduces mass loss of corticosteroid in the sterilization process, comprise making compound mixture of corticosteroids reach following state, wherein realized being less than about 30%, be less than about 25%, be less than about 20%, be less than about 15%, be less than about 10%, be less than about 5%, be less than about 3%, be less than about 2% or about 1% or mass loss of corticosteroid still less.In certain embodiments, corticosteroid solutions comprises solubilizing agent, as cyclodextrin.In certain preferred aspects, corticosteroid is a budesonide.In certain preferred aspects, the invention provides the method that reduces mass loss of corticosteroid in the sterilization process, it comprises provides compound corticosteroid solutions and filters compound corticosteroid solutions by filter, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m or about 0.15 μ m to about 0.45 μ m.Mass loss of corticosteroid between the corticosteroid solutions of compound (unpasteurized) and sterilization is less than about 30%, is less than approximately 25%, is less than about 20%, be less than approximately 15%, be less than approximately 10%, be less than about 5%, be less than approximately 3%, be less than about 2% or about 1% or still less.In certain preferred aspects, budesonide solution is filtering by 0.22 μ m filter, 0.22 μ m PVDF filter particularly, for example

Aforementioned and other needs further satisfy by embodiment of the present invention, it provides the method for the mixture of corticosteroids of preparation sterilization, comprise and make compound mixture of corticosteroids reach following state, wherein the concentration of Mie Jun mixture of corticosteroids be based on the corticosteroid initial mass theoretical concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.In certain embodiments, corticosteroid solutions comprises solubilizing agent, as cyclodextrin.In certain preferred aspects, corticosteroid is a budesonide.In certain preferred aspects, the invention provides the method for the corticosteroid solutions of preparation sterilization, the compound corticosteroid solutions that wherein will comprise the initial mass corticosteroid is by the corticosteroid solutions of filter with the production sterilization, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m.The corticosteroid concentration of the corticosteroid solutions of the sterilization of gained be based on the corticosteroid initial mass theoretical concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.

Aforementioned and other needs further satisfy by embodiment of the present invention, it provides the method that reduces corticosteroid concentration loss in the sterilization process, comprise and make compound mixture of corticosteroids reach following state, wherein the corticosteroid concentration of corticosteroid solutions be based on the corticosteroid initial mass theoretical concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.In certain embodiments, corticosteroid solutions comprises solubilizing agent, as cyclodextrin.In certain preferred aspects, corticosteroid is a budesonide.In certain preferred aspects, the invention provides the method that reduces corticosteroid concentration loss in the sterilization process, this method comprises filtering by filter and comprises the compound corticosteroid solutions of initial mass corticosteroid to produce filtering corticosteroid solutions, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m.The concentration of filtering corticosteroid solutions be based on the corticosteroid initial mass theoretical concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.

When considering following disclosure, other features and advantages of the present invention will become apparent to those skilled in the art.

The accompanying drawing summary

In appending claims, elaborated new feature of the present invention.To understand the feature and advantage of certain embodiments of the invention better with reference to following detailed description book and accompanying drawing thereof, description has been set forth illustrative embodiment, has wherein utilized principle of the present invention:

Fig. 1 is the flow chart of diagram according to the embodiment of budesonide solution production method of the present invention.

The introducing of list of references

All publications that this description is mentioned and patent application all by same degree be incorporated among the application as a reference, just as every piece of single publication or patent application all expressly and are individually pointed out to be introduced into as a reference.Pay special attention to the disclosed patent application of following WIPO, the U.S. all specified in each piece of writing, and they are integrally introduced the present invention: WO2005/065649, WO2005/065435 and WO2005/065651 especially.

Detailed Description Of The Invention

The present invention relates to mixture of corticosteroids, particularly the sterilization of budesonide solution. Especially, the invention provides the terminal sterilization method of mixture of corticosteroids, it is applicable to produce for people and other mammiferous pharmaceutical preparation. The present invention is specially adapted to the sterilization of corticosteroid solutions, especially budesonide solution. The present invention further provides the method that reduces in the sterilization process such as the mass loss of corticosteroid of budesonide. The present invention further provides the method that reduces in the sterilization process such as the corticosteroid concentration loss of budesonide. Like this, the present invention is mixture of corticosteroids, particularly the production of corticosteroid solutions provides useful improvement, and the sterilizing methods of the practicality that need not to heat is provided, thereby has improved the economic benefit of corticosteroid solution manufacture and the quality of final products. When the general description below considering and embodiment, other advantage of the present invention and feature will become apparent to those skilled in the art.

Term used herein " mixture " has the implication of its art-recognized wide region, comprises suspension and solution. Term " solution " means in fact uniformly mixture, and they are is in fact limpid and does not contain suspended particulates. Term " compound mixture " refers to that pharmacy activity component has wherein evenly mixed and prepared the mixture of sterilization with water. Term " compound solution " refers to that pharmacy activity component wherein is evenly soluble in water and prepare the solution of sterilization.

In certain embodiments, the invention provides the method for the corticosteroid solutions of preparation sterilization, wherein compound corticosteroid solutions filters by filter, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m, about 0.15 μ m is to about 0.45 μ m, and about 0.15 μ m arrives about 0.25 μ m to about 0.30 μ m or about 0.15 μ m. So just produced the corticosteroid solutions of sterilization. It is about 30% that mass loss between the corticosteroid solutions of initial corticosteroid solutions and sterilization is less than, and is less than approximately 25%, is less than about 20%, be less than approximately 15%, be less than approximately 10%, be less than about 5%, be less than approximately 3%, be less than about 2% or about 1% or still less. In certain embodiments, the average pore size of filter is about 0.2,0.22 or 0.45 μ m. In certain embodiments, filter is

CVGL71TP3 0.22 μ m filter. In specific embodiment, corticosteroid is budesonide, although can use the low corticosteroid of dissolubility in other corticosteroid, particularly water. Except budesonide, the particular corticosteroids that can substitute the budesonide in the inventive method has more detailed elaboration hereinafter. In certain embodiments, filter is methylcellulose filter or PVDF filter. The filter of other type is as known in the art and can uses. In certain preferred aspects, filter is the PVDF filter. In certain preferred aspects, filter is that average pore size is the PVDF filter of about 0.22 μ m, for exampleCVGL71TP3 0.22 μ m filter. Especially, the corticosteroid solutions that comprises solubilizer is considered to preferred. A preferred class solubilizer is such as sulfoalkyl ether cyclodextrin derivative illustrated among WO2005/065649, WO2005/065435 and the WO2005/065651 (SAE-CD derivative). Especially, use the solubilizer excessive with respect to the corticosteroid molal quantity to be considered to favourable. A particularly preferred class SAE-CD derivative is SBE-β-CD compound, as from CyDex, and Inc., Lenexa, SBE7-β-CD that KS obtains

Other solubilizer that can be included in the solution comprises polyoxyethylene sorbitan monoleate. If exist, the preferred concentration of polyoxyethylene sorbitan monoleate comprises 0.01% and lower, 0.005% and lower and 0.001% and lower; But can use higher concentration, for example up to 1% and Geng Gao. In certain preferred aspects, the polyoxyethylene sorbitan monoleate that uses cyclodextrin and be less than about 0.005% (for example about 0.001%) is as solubilizer. Especially, comprise such as the SAE-CD of SBE7-β-CD but do not comprise that the composition of polyoxyethylene sorbitan monoleate is preferred. In certain preferred aspects, corticosteroid solutions also comprises other active component, particularly water-soluble active ingredient. A compounds that is preferably included in the solution is water-soluble fugitive β 2-activator, such as salbutamol. In certain preferred aspects, it is about 25% that the mass loss of the corticosteroid that the method causes is less than, and is less than approximately 20%, is less than approximately 15%, is less than approximately 10%, is less than approximately 5%, is less than approximately 3%, is less than about 2% or about 1% or still less. Preferred filtration step is unique terminal sterilization step. Yet in certain preferred aspects, can comprise one or many intermediate filtered step in the method according to this invention.

In other embodiments, the invention provides the method that reduces mass loss of corticosteroid in the sterilization process. In certain embodiments, method comprises by filter filters initial corticosteroid solutions, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m, about 0.15 μ m is to about 0.45 μ m, and about 0.15 μ m arrives about 0.25 μ m to about 0.30 μ m or about 0.15 μ m. It is about 30% that the mass loss that has realized corticosteroid is less than, and is less than approximately 25%, is less than approximately 20%, is less than approximately 15%, is less than approximately 10%, is less than approximately 5%, is less than approximately 3%, is less than about 2% or about 1% or still less. In certain embodiments, the average pore size of filter is about 0.2,0.22 or 0.45 μ m. In specific embodiment, corticosteroid is budesonide, although can use other corticosteroid, and water-soluble low corticosteroid particularly. Except budesonide, the particular corticosteroids that can substitute the budesonide in the inventive method has more detailed elaboration hereinafter. In certain embodiments, filter is methylcellulose filter or PVDF filter. The filter of other type is as known in the art and can uses. In certain preferred aspects, filter is the PVDF filter. In certain preferred aspects, filter is that average pore size is the PVDF filter of about 0.22 μ m, for exampleCVGL71TP3 0.22 μ m filter. Especially, the corticosteroid solutions that comprises solubilizer is considered to preferred. A preferred class solubilizer is the sulfoalkyl ether cyclodextrin derivative (SAE-CD derivative) as describing among WO2005/065649, WO2005/065435 and the WO2005/065651. Especially, use the solubilizer excessive with respect to the corticosteroid molal quantity to be considered to favourable. A particularly preferred class SAE-CD derivative is SBE-β-CD compound, for example from CyDex, and Inc., Lenexa, SBE7-β-CD that KS obtains

Other solubilizer or the compound that can be included in the solution comprise polyoxyethylene sorbitan monoleate. If exist, the preferred concentration of polyoxyethylene sorbitan monoleate comprises 0.01% and lower, 0.005% and lower and 0.001% and lower. Especially, comprise such as the SAE-CD of SBE7-β-CD but the composition that do not comprise polyoxyethylene sorbitan monoleate is preferred. In certain preferred aspects, corticosteroid solutions also comprises other active component, particularly water-soluble active ingredient. A compounds that is preferably included in the solution is water-soluble fugitive β 2-activator, such as salbutamol. In certain preferred aspects, it is about 30% that the mass loss of the corticosteroid that method causes is less than, and is less than approximately 25%, is less than approximately 20%, is less than approximately 15%, is less than approximately 10%, is less than approximately 5%, is less than approximately 3%, is less than about 2% or about 1% or still less. Preferred filtration step is unique terminal sterilization step.

In certain embodiments, the invention provides the method for the corticosteroid solutions of preparation sterilization, it comprises by filter and filters the compound corticosteroid solutions of the corticosteroid comprise initial mass to produce the corticosteroid solutions of sterilization, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m, about 0.15 μ m is to about 0.45 μ m, about 0.15 μ m arrives about 0.25 μ m to about 0.30 μ m or about 0.15 μ m, wherein the concentration of corticosteroid solutions of sterilization be based on the corticosteroid initial mass theoretical concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more. In certain embodiments, the average pore size of filter is about 0.2,0.22 or 0.45 μ m. In specific embodiments, corticosteroid is budesonide, although can use other corticosteroid, and water-soluble low corticosteroid particularly. Except budesonide, the particular corticosteroids of the budesonide in alternative the inventive method has in further detail hereinafter to be set forth. In certain embodiments, filter is methylcellulose filter or PVDF filter. The filter of other type is as known in the art and can uses. In certain preferred aspects, filter is the PVDF filter. In certain preferred aspects, filter is that average pore size is the PVDF filter of about 0.22 μ m, for example

CVGL71TP3 0.22 μ m filter. Especially, the corticosteroid solutions that comprises solubilizer is considered to preferred. A preferred class solubilizer is such as the sulfoalkyl ether cyclodextrin derivative (SAE-CD derivative) described in WO2005/065649, WO2005/065435 and the WO2005/065651. Especially, use the solubilizer excessive with respect to the corticosteroid molal quantity to be considered to favourable. A particularly preferred class SAE-CD derivative is SBE-β-CD compound, as from CyDex, and Inc., Lenexa, SBE7-β-CD that KS obtains

Other solubilizer that can be included in the solution comprises polyoxyethylene sorbitan monoleate. If exist, the preferred concentration of polyoxyethylene sorbitan monoleate comprises 0.01% and lower, 0.005% and lower and 0.001% and lower. Especially, comprise such as the SAE-CD of SBE7-β-CD but the composition that do not comprise polyoxyethylene sorbitan monoleate is preferred. In certain preferred aspects, corticosteroid solutions also comprises other active component, particularly water-soluble active ingredient. A compounds that is preferably included in the solution is water-soluble fugitive β 2-activator, such as salbutamol. In certain preferred aspects, it is about 30% that the mass loss of the corticosteroid that method causes is less than, and is less than approximately 25%, is less than approximately 20%, is less than approximately 15%, is less than approximately 10%, is less than approximately 5%, is less than approximately 3%, is less than about 2% or about 1% or still less. Preferred filtration step is unique terminal sterilization step.

The present invention further provides the method that reduces corticosteroid concentration loss in the sterilization process, it comprises by filter and filters the compound corticosteroid solutions of the corticosteroid comprise initial mass to produce filtering corticosteroid solutions, the average pore size of described filter be about 0.1 μ m to about 1.5 μ m (for example, about 0.1,0.15,0.2,0.22,0.25,0.3,0.35,0.4,0.45,0.5,0.6,0.7,0.8,0.9,1.0 μ m or up to 1.5 μ m), particularly about 0.1 μ m is to 0.5 μ m, about 0.15 μ m is to about 0.45 μ m, about 0.15 μ m arrives about 0.25 μ m to about 0.30 μ m or about 0.15 μ m, wherein the concentration of filtering corticosteroid solutions be based on the theoretical concentration of corticosteroid initial mass at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.In certain embodiments, the average pore size of filter is about 0.2,0.22 or 0.45 μ m.In specific embodiments, corticosteroid is a budesonide, although can use the low corticosteroid of other corticosteroid, particularly water solublity.Except budesonide, the particular corticosteroids that can substitute the budesonide in the inventive method has more detailed elaboration hereinafter.In certain embodiments, filter is methylcellulose filter or PVDF filter.The filter of other type is as known in the art and can uses.In certain preferred aspects, filter is the PVDF filter.In certain preferred aspects, filter is that average pore size is the PVDF filter of about 0.22 μ m, for example CVGL71TP3 0.22 μ m filter.Especially, the corticosteroid solutions that comprises solubilizing agent is considered to preferred.A preferred class solubilizing agent is as the sulfoalkyl ether cyclodextrin derivant (SAE-CD derivant) described in WO2005/065649, WO2005/065435 and the WO2005/065651.Especially, use the solubilizing agent excessive to be considered to favourable with respect to the corticosteroid molal quantity.A particularly preferred class SAE-CD derivant is SBE-β-CD chemical compound, as from CyDex, and Inc., Lenexa, SBE7-β-CD that KS obtains

Other solubilizing agent that can be included in the solution comprises polyoxyethylene sorbitan monoleate.If exist, the preferred concentration of polyoxyethylene sorbitan monoleate comprises 0.01% and lower, 0.005% and lower and 0.001% and lower.Especially, comprise as the SAE-CD of SBE7-β-CD but the compositions that do not comprise polyoxyethylene sorbitan monoleate is preferred.In certain preferred aspects, corticosteroid solutions also comprises other active component, particularly water-soluble active ingredient.A compounds that is preferably included in the solution is the fugitive β 2-of a water solublity antagonist, as albuterol.In certain preferred aspects, it is about 30% that the mass loss of the corticosteroid that method causes is less than, and is less than approximately 25%, is less than approximately 20%, is less than approximately 15%, is less than approximately 10%, is less than approximately 5%, is less than approximately 3%, is less than about 2% or about 1% or still less.Preferred filtration step is unique terminal sterilization step.

In certain embodiments of the invention, mixture of corticosteroids further comprises solubilizing agent.Term " solubilizing agent " be meant strengthen corticosteroid in water dissolubility or strengthen the pharmacy inert fraction that corticosteroid forms the ability of the clarified mixture that does not have particle in fact.In certain embodiments, the concentration of solubilizing agent (w/v) can be about 0.0001% in about 25% scope.In other embodiments, the concentration of solubilizing agent (w/v) can be about 0.01% in about 20% scope.In other embodiments, the concentration of solubilizing agent (w/v) can also be about 0.1% in about 15% scope.In other embodiments, the concentration of solubilizing agent (w/v) can also be about 1% in about 10% scope.In preferred embodiments, when solubilizing agent was cyclodextrin or cyclodextrin derivative, the concentration of solubilizing agent (w/v) can be about 5% in about 10% scope.

" solubilizing agent " that the present invention uses comprises increases corticosteroid deliquescent one or more chemical compounds at the mixture of corticosteroids aqueous phase.Generally speaking, solubilizing agent strengthen corticosteroid in water dissolubility and chemically do not changing corticosteroid.Especially, the dissolubility of solubilizing agent enhancing corticosteroid does not reduce the activity of corticosteroid in fact, has strengthened the activity of corticosteroid in certain embodiments.

Solubilizing agent is as known in the art, in for example U.S. Patent No. 5,134,127,5,145,684,5,376,645,6,241,969 and U.S. publication application Nos.2005/0244339 and 2005/0008707 in description is arranged, wherein each a piece of writing all expressly introduce the present invention as a reference.In addition, the example of suitable solubilizing agent has description hereinafter.

Be applicable to that solubilizing agent of the present invention includes but not limited to propylene glycol, non-ionic surface active agent, phospholipid, cyclodextrin and derivant thereof and surface modifier and/or stabilizing agent.

Being used for the example that shows the non-ionic surface active agent with good especially physiological compatibility of the present invention is tyloxapol, Polysorbate, include but not limited to polyoxyethylene (20) Arlacel-20, polyoxyethylene (20) Arlacel-40, polyoxyethylene (20) Arlacel-60 (trade name polysorbas20-40-60 etc.), polyoxyethylene sorbitan monoleate, PEG400; Sodium lauryl sulphate; Sorbitan laurate, sorbitan palmitate, sorbitan monostearate (trade name span 20-40-60 etc.), benzalkonium chloride, PPO-PEO block copolymer (Pluronics), polyoxyethylene ether (35) Oleum Ricini (Cremophor-EL), vitamin E-TPGS (for example d-alpha-tocopherol-Polyethylene Glycol-1000-succinate), Solutol-HS-15, oleic acid PEO ester, stearic acid PEO ester, Triton-X100, Nonidet P-40, and as the polyethylene glycol hydroxystearate of Polyethylene Glycol-15-hydroxy stearic acid ester.

In certain embodiments, will be applicable to that non-ionic surface active agent of the present invention is prepared with corticosteroid forms Liposomal formulation, micelle or mixed micelle.The method of preparation and characterization of liposomes and Liposomal formulation is as known in the art.When the amphiphilic lipids hydration, often spontaneously form multilamellar vesicle, and the formation of little unilamellar vesicle need relate to the process of substantive energy input usually, as ultrasonic or high pressure homogenizing.The more multi-method of preparation and characterization of liposomes is described to some extent, for example S.Vemuri etc. is (as the preparation and the sign (Preparation andcharacterization of liposomes as therapeutic delivery systems) of the liposome of treatment induction system: the summary of Pharm ActaHeIv, 1995,70 (2): 95-111) with United States Patent(USP) Nos. 5,019,394,5,192,228,5,882,679,6,656,497, wherein each piece of writing is all expressly introduced the present invention as a reference.

For example, in some cases, micelle or mixed micelle can form by surfactant, and wherein poorly soluble activating agent can be dissolved.In general, micelle is considered to the substantial spherical structure spontaneous and that dynamic combination forms by amphiphile, amphiphilic molecule such as surfactant.The micelle that mixed micelle is made up of dissimilar amphiphile, amphiphilic molecules.In the context of the present invention, micelle and mixed micelle all should not be construed as solid particle, because their structure, character and behavior are all very big with the solid difference.It is normally temporarily bonded to form micellar amphiphile, amphiphilic molecule.In micellar solution, exist form micellar amphiphile, amphiphilic molecule and also exist in solution with the dynamic exchange between the dispersive amphiphile, amphiphilic molecule of unimolecule.The structure and the employed surfactant of these molecules depended in the position that is dissolved in the drug molecule in these micelles or the mixed micelle.For example, suppose that specific nonpolar molecule mainly is positioned the inside of colloform texture, and more likely find polar substances from the teeth outwards.In an embodiment of micelle or mixed micelle solution, micellar mean size can be less than about 200nm (measuring as the photon correlation spectroscopy method), as from about 10nm to about 100nm.Particularly preferably be the micelle of the about 10nm of average diameter to about 50nm.The method of producing micelle and mixed micelle is as known in the art, for example at United States Patent(USP) Nos. 5,747, describes in 066 and 6,906,042, and wherein each piece of writing is all expressly introduced the present invention as a reference.

Phospholipid is phosphorated amphiphilic lipids.Extensively exist by the phospholipid that phosphatidic acid obtains by chemical method, also through being usually used in the pharmacy purpose.This acid is (two) acidylate glycerol-3-phosphate ester normally, and fatty acid residue wherein can be a different length.Phosphatidic acid derivative comprises for example phosphocholine or phosphatidylcholine, and the wherein other and choline esterification of phosphate group also has PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols or the like in addition.Lecithin is the natural mixture of various phospholipid, contains a high proportion of phosphatidylcholine usually.According to specific lecithin source with and extraction and/or enrichment method, these mixture also may comprise a large amount of sterols, fatty acid, triglyceride and other material.

Especially, be suitable for other phospholipid of the present invention because of its physiological property and comprise mixture of phospholipids, this mixture of phospholipids is the mixture of phospholipids that extracts with the lecithin form from the natural origin as Semen sojae atricolor (Semen Glycines) or egg yolk, preferred hydrogenated form and/or do not contain LYSOLECITHIN SUNLECITHIN A, and purification, enrichment or part is by the phospholipid of synthetic preparation, preferably has polyunsaturated fatty acid ester.In mixture of phospholipids, lecithin is particularly preferred.Enrichment or the medium chain of part by synthetic preparation on acyl chain, do not have unsaturated bond substantially to the zwitterionic phospholipid of long-chain, and do not contain LYSOLECITHIN SUNLECITHIN A and peroxide.The example of enrichment or pure chemical compound is two myristoyl phosphatidylcholines (DMPC), distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidyl choline (DPPC).In these chemical compounds, more preferably DMPC at present.Alternatively, has the phospholipid of oily alkene residue and do not have the phosphatidyl glycerol of choline residue to be suitable for certain embodiments of the present invention and application.

In certain embodiments, will be applicable to that non-ionic surface active agent of the present invention and phospholipid prepares the formation colloform texture with corticosteroid.Colloid solution is single_phase system, and the colloidal materials that wherein is dispersed in the colloid solution does not have the measurable physical property relevant with solid material usually.The method of producing aqueous colloidal dispersion is as known in the art, for example in U.S. Patent No. 6,653, description is arranged in 319, expressly this patent is introduced the present invention as a reference.

It is on the books in the art to be used for suitable cyclodextrin of the present invention and derivant, Challa etc. for example, AAPS PharmSciTech 6 (2): E329-E357 (2005), United States Patent(USP) Nos. 5,134,127,5,376,645,5,874,418, wherein each piece of writing is all expressly introduced the present invention as a reference.In certain embodiments, be used for suitable cyclodextrin of the present invention or cyclodextrin derivative and include but not limited to alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, SAE-CD derivant (SBE-α-CD for example, SBE-β-CD With (the CyDex of SBE-γ-CD), Inc.Lenexa, KS), ethoxy, hydroxypropyl (comprising 2-and 3-hydroxypropyl) and dihydroxypropyl ether, their corresponding compound ethers, also has the blended ether that has methyl or ethyl, as dimethyl hydroxyethyl, ethyl-hydroxyethyl and the ethyl hydroxypropyl ether of α, β, gamma-cyclodextrin; And α-, β-and maltose derivant, glucosan derivative and the maltotriose derivant of gamma-cyclodextrin, they can contain one or more saccharide residues, for example glucosyl group or glucosulfone base, malt-base or two malt-bases, and their various mixture, for example mixture of maltose and two maltose derivants.The specific cyclodextrin derivative that the present invention uses comprises HP-; hydroxyethyl-; hydroxypropyl-gamma-cyclodextrin; ethoxy-gamma-cyclodextrin; dihydroxypropyl-beta-schardinger dextrin-; glucosyl group-alpha-cyclodextrin; the glucose group-beta-cyclodextrin; the glucosulfone group-beta-cyclodextrin; malt-base-alpha-cyclodextrin; malt sugar group-beta-cyclodextrin; malt-base-gamma-cyclodextrin; G 3-; maltotriose glycosyl-gamma-cyclodextrin; two malt sugar group-beta-cyclodextrins; DE-; glucosyl group-alpha-cyclodextrin; the glucose group-beta-cyclodextrin; the glucosulfone group-beta-cyclodextrin; three-O-methyl-beta-schardinger dextrin-; three-O-ethyl-beta-schardinger dextrin-; three-O-butyryl group-beta-cyclodextrin; three-O-valeryl group-beta-cyclodextrin; two-O-hexanoyl group-beta-cyclodextrin; and methyl-beta-schardinger dextrin-, and their mixture such as malt sugar group-beta-cyclodextrin/two malt sugar group-beta-cyclodextrins.The method for preparing these cyclodextrin derivative is known, and for example U.S. Patent No. 5,024,998, and this list of references is introduced the present invention as a reference.Be applicable to that other cyclodextrin of the present invention comprises the carboxyalkyl sulfide derivative, ORG 26054 and ORG 25969 as ORGANON (AKZO-NOBEL), the hydroxyl butylene ether derivant of EASTMAN, sulfo group alkyl-hydroxy alkyl ether derivant, sulfo group alkyl-alkyl ether derivative and other derivant, for example at U.S. Patent application Nos.2002/0128468,2004/0106575,2004/0109888 and 2004/0063663 or United States Patent(USP) Nos. 6,610,671,6,479,467,6,660,804 or 6,509, described in 323, wherein each piece of writing is all expressly introduced the present invention as a reference.

Can be from Research Diagnostics Inc. (Flanders, NJ) acquisition HP-.Exemplary HP-product comprises

(substitution value～4) and

(substitution value～8); Yet the embodiment that comprises other substitution value also is available, and within the scope of the present invention.

From FLUKA Chemie (Buchs, CH) or Wacker (Iowa) obtain the dimethyl cyclodextrin.The cyclodextrin that is applicable to other derivatization of the present invention comprises the cyclodextrin of water-soluble derivatized.The cyclodextrin of exemplary water-soluble derivatized comprises carboxylated derivant; Sulfated derivative; Alkyl derivative; The hydroxy alkylated derivant; Derivant methylates; And carboxyl-beta-schardinger dextrin-, for example succinyl-beta-schardinger dextrin-(SCD).These all materials can prepare and/or commercial the acquisition according to procedures known in the art.The cyclodextrin of suitable derivatization is documented in Modified Cyclodextrins:Scaffolds and Templates for Supramolecular Chemistry (Eds.Christopher J.Easton, Stephen F.Lincoln, Imperial College Press, London, UK, 1999).

Being used for suitable surface modifier of the present invention has description in the art, and for example United States Patent(USP) Nos. 5,145, and 684,5,510,118,5,565,188 and 6,264,922, wherein each piece of writing is all expressly introduced the present invention as a reference.The example that is applicable to surface modifier of the present invention and/or surface stabilizer includes but not limited to, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium lauryl sulphate, dioctylsulfosuccinat, gelatin, casein, lecithin (phospholipid), glucosan, arabic gum, cholesterol, the tragakanta, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, 18 hexadecanol (cetostearyl alcohol), cetomacrogol emulsifying wax (cetomacrogol emulsifying wax), Isosorbide Dinitrate, polyoxyethylene alkyl ether (polyglycol ether for example, as cetomacrogol 1000), castor oil derivatives, polyoxyethylene sorbitan fatty acid ester (for example can the commercial tween (Tweens that obtains ^TM), for example Tween 20 ^TMWith Tween 80 ^TM(ICI Specialty Chemicals)), Polyethylene Glycol (Carbowaxs 3550 and 934 for example ^TM(Union Carbide)), polyglycol distearate, silica sol, phosphate ester (salt) (phosphates), carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropylmethyl cellulose phthalate, the amorphous cellulose element, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), the 4-(1 that contains ethylene oxide and formaldehyde, 1,3,3-tetramethyl butyl)-cascophen (is also referred to as tyloxapol (tyloxapol), superione and triton), poloxamer (Pluronics F68 for example ^TMAnd F108 ^TM, they are block copolymers of oxirane and expoxy propane), (for example Tetronic 908 for the husky amine in pool Lip river ^TM, be also referred to as Poloxamine 908 ^TM, it is expoxy propane and oxirane to be added on the ethylenediamine in proper order and the four functional group block copolymers that obtain (BASF Wyandotte Corporation, Parsippany, NJ.)), Tetronic 1508 ^TM(T-1508) (BASF Wyandotte Corporation), Tritons X-200 ^TM, it is alkyl aryl polyether sulphonic acid ester (Rohm and Haas), Crodestas F-100 ^TM, it is the mixture (Croda Inc.) of sucrose stearate and sucrose distearate, right-different Nonylphenoxy gathers-((+)-2,3-Epoxy-1-propanol), is also referred to as Olin-10G ^TMOr Surfactant 10 ^TM(Conn.), (Croda, Inc.) and SA9OHCO, it is C to Crodestas SL-40.RTM. for Olin Chemicals, Stamford ₁₈H ₃₇CH ₂(CON (CH ₃)-CH ₂(CHOH) ₄(CH ₂OH) ₂(Eastman Kodak Co.); capryl-N-methyl glucoside amide; just-decyl-β-D-pyranglucoside; just-decyl-β-D-pyrans maltoside; just-dodecyl-β-D-pyranglucoside; just-dodecyl-β-D-maltoside; heptanoyl group-N-methyl glucoside amide; just-heptyl-β-D-pyranglucoside; just-heptyl-β-D-thioglycoside; just-hexyl-β-D-pyranglucoside; pelargonyl group-N-methyl glucoside amide; just-pelargonyl group-β-D-pyranglucoside; caprylyl-N-methyl glucoside amide; just-octyl group-β-D-pyranglucoside; octyl group-β-D-sulfo-pyranglucoside, PEG-phospholipid, PEG-cholesterol; the PEG-cholesterol derivative; the PEG-vitamin A, PEG-vitamin E, lysozyme; random copolymer of vinylpyrrolidone and vinylacetate or the like (hydroxypropyl emthylcellulose for example; hydroxypropyl cellulose, polyvinylpyrrolidone, the copolymer of vinylacetate; vinylpyrrolidone, sodium lauryl sulphate and dioctyl sodium sulfosuccinate).

Other useful cationic stabilized agent includes but not limited to: cation lipid, sulfonium Phosphonium, quaternary ammonium compound is as octadecyl trimethyl ammonium chloride, benzyl-two (2-chloroethyl) ethyl ammonium bromide, cocoyl trimethyl ammonium chloride or ammonium bromide, cocoyl methyl dihydroxy ethyl ammonium chloride or ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or ammonium bromide, C _12-15Dimethyl hydroxyethyl ammonium chloride or ammonium bromide, cocoyl dimethyl hydroxyethyl ammonium chloride or ammonium bromide, myristyl trimethyl-methylsulfuric acid ammonium, dodecyl dimethyl benzyl ammonium chloride or ammonium bromide, dodecyl dimethyl (ethyleneoxy) ₄Ammonium chloride or ammonium bromide, N-alkyl (C _12-18) dimethyl benzyl ammonium chloride, N-alkyl (C _14-18) dimethyl-benzyl ammonium chloride, N-myristyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C _12-14) dimethyl-1-menaphthyl ammonium chloride, trimethyl-ammonium halide, alkyl trimethyl ammonium salt and dialkyl group-dimethyl ammonium, Dodecyl trimethyl ammonium chloride, the alkyl amide alkyl dialkyl ammonium salt of ethoxylation and/or the trialkyl ammonium salts of ethoxylation, dialkyl phenyl organic dialkylammonium chloride, N-DDAC, N-myristyl dimethyl benzyl ammonium chloride monohydrate, N-alkyl (C _12-14) dimethyl-1-menaphthyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammomium chloride, Dodecyl trimethyl ammonium chloride, alkyl benzyl ammonio methacrylate, alkyl benzyl dimethyl ammonium bromide, C ₁₂, C ₁₅, C ₁₇Trimethylammonium bromide, the dodecylbenzyl triethyl ammonium chloride, gather (diallyldimethylammonium chloride) (DADMAC), alkyl dimethyl ammonium chloride, alkyl dimethyl ammonium halide, three (cetyl) ammonio methacrylate, the decyl trimethylammonium bromide, dodecyl triethyl group ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, (ALIQUAT 336 for methyl trioctylphosphine ammonium chloride ^TM), POLYQUAT 10 ^TMTetrabutyl ammonium bromide, benzyltrimethylammonium bromide, cholinester (as fatty acid choline ester), benzalkonium chloride, oronain (stearalkonium chloride) chemical compound (as octadecyl trimethyl ammonium chloride and two (octadecyl) alkyl dimethyl ammonium chloride), cetyl pyridinium bromide or chloride draw in department, the halogen of quaternised polyoxy ethyl alkylamine, Mirapol ^TMAnd ALKAQUAT ^TM(Alkaril Chemical Company), Fixanol, amine is as alkylamine, dialkylamine, alkanolamine, polyethylenepolyamine, N, N-dialkyl aminoalkyl acrylate, vinylpyridine, amine salt is as the dodecyl ammonium acetate, the octadecyl ammonium acetate, Fixanol, alkyl imidazole salt, amine oxide, imidazole salts, protonated acryloyl quaternary amine, methylated season polymer (quaternary polymer) is as poly-(diallyldimethylammonium chloride) and poly-(N-ethylene methacrylic pyridinium chloride) and cation guar gum.

Except the aqueous mixture that comprises corticosteroid and solubilizing agent, the present invention's expection is equally applicable to present invention disclosed by the moisture suction mixture that strengthens deliquescent method preparation.Therefore, in the context of the present invention, " solubilizing agent " comprises by strengthening the moisture suction mixture of deliquescent method preparation, wherein contains or do not contain the chemical reagent as solubilizing agent.These methods comprise, for example prepare supercritical fluid.According to these methods, will make the narrow granule of the particle size distribution scope of 200 nanometers (normally less than) as the corticosteroid composition of budesonide, the average grain hydrodynamic radius in 50 nanometers in the scope of 700 nanometers.Use supercritical fluid (SCF) method, comprise that the rapid expanding (RESS) of supercritical solution or the solution of supercritical fluid strengthen dispersion (SEDS), and any other technology that relates to supercritical fluid prepares nano level corticosteroid granule, as the budesonide granule.Use the SCF method to form particulate summary and see Palakodaty, S., Deng, among the Pharmaceutical Research 16:976-985 (1999), in Bandi etc., Eur.J.Pharm.Sci 23:159-168 (2004), U.S. Patent No. 6,576,264 and U.S. Patent application No.2003/0091513 in description is arranged, wherein each a piece of writing all expressly introduce the present invention as a reference.These methods can form the micron of different shape and the granule of sub-micron, and it depends on method selected and parameter.In addition, these nano-particle can reduce particulate conventional method by spray drying, lyophilizing, volume-exclusion and any other and prepare.

The specific solubility enhancers that can mention comprises polyoxyethylene sorbitan monoleate and SAE-CD derivant, SBE-α-CD, SBE-β-CD, SBE-γ-CD and dimethyl beta-CD, HP-, 2-HP-β-CD within the scope of the invention.In specific embodiment, preferred SAE-CD derivant.In particularly preferred embodiments, the SAE-CD derivant that preferably belongs to the SBE-β-CDYan Shengwu.In specific embodiment, particularly preferred solubilizing agent is SBE7-β-CD.In certain embodiments, the concentration that is included in the polyoxyethylene sorbitan monoleate in the preparation is about 0.01% or lower, particularly about 0.005% or lower, more especially about 0.001% or lower; And in other embodiments, preferably from corticosteroid solutions, get rid of polyoxyethylene sorbitan monoleate in fact.In certain preferred aspects, corticosteroid solutions comprises with respect to corticosteroid budesonide molal quantity excessive SAE-CD derivant, particularly SBE7-β-CD particularly.

The term corticosteroid will have whole implications that those skilled in the art understand.The particular corticosteroids of being considered generally is water insoluble to a certain extent and be applicable to the corticosteroid of drug administration within the scope of the invention, needs the existence of solubilizing agent that they are dissolved in the aqueous solution like this.About this point, the particular corticosteroids that can mention comprises those that are proposed among WO2005/065649, WO2005/065435 and the WO2005/065651.Referring to the 46th page of WO2005/065651, be introduced into the present invention as a reference especially.Can replace the corticosteroid of budesonide to comprise aldosterone, beclometasone, betamethasone, ciclesonide, cloprednol, cortisone, cortivazol, deoxycorticosterone, ground Suo Naide, desoximetasone, dexamethasone, diflucortolone (difluorocortolone), fluorine chlorine dragon (fluclorolone), flumetasone, flunisolide, fluocinolone acetonide (flucinolone), fluocinonide (fluocinonide), fluocortin butyl, fluorine cortisone (fluocortisone), fluocortolone (flurocortolone), fluorometholone, flurandrenolide, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone and their pharmaceutical active derivant comprise prodrug and pharmaceutically acceptable salt.In certain embodiments, can in solution according to the present invention, make up the corticosteroid of two or more aforementioned list.In certain embodiments, budesonide can make up with the corticosteroid of one or more aforementioned list.

Corticosteroid concentration in the corticosteroid composition can be from about 1 μ g/ml to about 2000 μ g/ml, about 1 μ g/ml is to about 1000 μ g/ml or about 1 to about 500 μ g/ml, particularly about 50 μ g/ml are to about 500 μ g/ml, and perhaps about 100 to about 400 μ g/ml variation.The particular value that can mention is about 1, about 5 μ g/ml, about 10 μ g/ml, about 20 μ g/ml, about 50 μ g/ml, about 100 μ g/ml and about 200 μ g/ml and about 250 μ g/ml.In certain preferred aspects, the corticosteroid range of concentrations in the sterile solution is that about 80 μ g/ml are to about 480 μ g/ml, particularly about 80 μ g/ml, about 120 μ g/ml, about 240 μ g/ml or about 480 μ g/ml.

Except corticosteroid, corticosteroid solutions can comprise other active component, particularly other water-soluble active ingredient.Specially suitable active component is and corticosteroids or synergism, be used for the treatment of one or more respiratory disorders (as asthma or chronic obstructive pulmonary disease (COPD)) or respiratory disorder symptom, as the active component that bronchospasm, bronchitis, expectorant viscosity increase, vital capacity reduces etc.Corticosteroid can mix with one or more other medicines like this, as beta 2 adrenoreceptor agonists (as albuterol), dopamine D ₂Receptor antagonist, anticholinergic agent or local anesthetic.The given activity composition is as known in the art, and the 48-49 page or leaf of WO2005/065651 has been set forth embodiment preferred, and these pages or leaves are integrally specially introduced the present invention as a reference.

In certain embodiments, other active component particularly water-soluble active ingredient be included in the corticosteroid solutions.In certain preferred aspects, corticosteroid solutions comprises the fugitive β of water solublity ₂-agonist is as albuterol.Therefore, some embodiment preferred comprises budesonide, and the cyclodextrin solubility enhancer of molal quantity excessive (with respect to budesonide) is as SBE7-β-CD and albuterol.

In certain preferred aspects, corticosteroid solutions is to mix with other composition by the corticosteroid initiation material with certain mass to be less than about 5 hours in high shear mixer, be less than about 4 hours, be less than about 3 hours, particularly about 2 hours or still less the time produces.Preferably, this mixing is under the atmosphere of oxygen consumption, as at nitrogen or argon direct draught, particularly carries out under nitrogen.In specific embodiments, mixing is to be at least about 10L at capacity, at least about 50L, at least about 100L, at least about 250L or at least about carrying out in the high shear mixer of 500L.In some such preferred embodiment, mixing is with vacuum and applies noble gas (as N ₂Or Ar) alternate cycles of malleation is carried out together.In certain embodiments, after mixing, solution is stored in applies, at least about 100mbar, at least about 200mbar, at least about 500mbar or about 1200mbar or more noble gas (N for example at least about 50mbar ₂Or Ar) under the condition.Mixing, storage or both are applying the N of about 1200mbar ₂Condition under carry out.(all pressure all are gauge pressures, except as otherwise noted).

Although with regard to filtration, the present invention has been described as it unique sterilization steps, those skilled in the art will recognize that filtration can with the combination of other sterilization technology, as heat treatment and/or radiation.To compound mixture of corticosteroids heat-treat, radiation or both also are possible, although preferred terminal is filtered.

The term " mass loss " that the present invention uses is meant the difference that the budesonide quality in the budesonide solution of sterilization is compared with the budesonide quality in the initial budesonide solution.Measure the mass loss of representing with the percentage ratio mass loss easily according to following formula:

% mass loss=100%* (M ₁-M ₂)/M ₁,

M wherein ₁Be the budesonide quality in the initial budesonide solution, M ₂It is the budesonide quality in the budesonide solution of sterilizing.

The minimizing of percent concentration can be calculated with similar mode.So the formula that percent concentration reduces is:

% concentration reduces=100%* (C ₁-C ₂)/C ₁,

C wherein ₁Be the corticosteroid concentration in the solution before filtering, C ₂Be the corticosteroid concentration of filtering in the solution afterwards.Concentration value C ₁And C ₂Can express with any suitable unit, molarity (mol) for example, the gram number of solute in the gram number of the solute in the molality (mole/kilogram), every liter of solution or the every kilogram solution is as long as they are all represented with same units.Concentration C wherein ₁Do not detect before filtering, it can calculate according to the amount (quality) of the corticosteroid initiation material that joins mixing arrangement and the quality or the volume of gained solution.

Use the prepared according to the methods of the invention corticosteroid solutions to treat one or more respiratory disorders.Compound corticosteroid solutions is favourable, so that wherein contained pharmacy activity component provides with the unit dose based on the treatment effective dose.Treatment effective dose or effective dose are the amounts that reaches the medicine of pharmacological action." the treatment effective dose " comprises and for example prevents effective dose term.As " effective dose " of the corticosteroid of budesonide is to reach that the pharmacological action of expectation or treatment improve and the amount that do not have unsuitable adverse side effect.Effective dose as the corticosteroid of budesonide will be selected according to specific patient and disease degree by those skilled in the art.Be understood that " effective dose " or " treatment effective dose " can change with the experimenter is different, this owing to as age of the metabolism of the corticosteroid of budesonide, experimenter, body weight, the seriousness of situation, the symptom of being treated, the symptom of being treated and medical practitioner's the difference of judgement.

The term that uses in the content about the bronchoconstriction obstacle " treatment (treat) " and " treatment (treatment) " are meant any obstacle relevant with bronchoconstriction or treatment of diseases, obstacle or disease occur as the experimenter who prevents easily to suffer from obstacle or disease, still also is not diagnosed as obstacle or disease; Suppress obstacle or disease, for example stop obstacle or advancing of disease, alleviate obstacle or disease, cause disappearing of obstacle or disease, alleviate the caused symptom of obstacle or disease, perhaps stop the symptom of disease or obstacle.Therefore, the term " treatment " and term " prevention " synonym of the present invention's use.

Can include but not limited to the particular obstacle of combination treatment of the present invention: with bronchospasm, bronchitis, expectorant viscosity increase, vital capacity reduces etc. is the respiratory disorder of feature.Treatable specific symptom comprises asthma, reactive respiratory tract disease and chronic obstructive pulmonary disease (COPD).

Produce corticosteroid solutions

Fig. 1 has illustrated the method according to this invention.Discriminated union is analyzed dry ingredients 200 to determine their water content in S100.Dry ingredients 200 comprises corticosteroid (for example budesonide, particularly micronized budesonide) and cyclodextrin (for example

Cyclodextrin), and other composition, as citric acid, sodium citrate, sodium chloride and EDTA sodium (sodium ethylene diamine tetracetate).In S102, composition 200 is moved on to dispensarium, weighing and being placed on is applicable to composition is assigned in the container of blending tank 204.Advantageously cyclodextrin is divided into three parts; Corticosteroid (for example budesonide) is placed in the suitable containers.Water for injection (WFI) 202 is released in the blending tank 204.Then dry ingredients 200 is added in the blending tank 204.Partially mixed at least in the blending tank 204 carried out under the oxygen consumption condition.For example, WFI 202 can spray to remove dissolved oxygen through nitrogen or argon.Alternatively, blending tank 204 can seal, and experiences the circulation of one or many (preferred 2 times) vacuum/maintenance/noble gas 216 (as nitrogen or argon) superpressure in the married operation process.The superpressure of noble gas 216 can be to be higher than atmospheric value (any positive gauge pressure), can arrive in the scope of about 3000mbar at for example 100mbar.In present embodiment preferred, superpressure is the nitrogen of about 1200mbar.In certain embodiments, blending tank 204 has assembled and has designed the homogenate device that is used for forming shear conditions.In certain embodiments, blending tank 204 is FrymaKoruma

(FrymaKorumaGmbH, Neuenburg, Germany) complex mixer, the funnel that it comprises the holding vessel that has water leg, the inlet of introducing liquid parts (for example WFI), homogenizer, agitator, short loop, long loop and introduces dry ingredients.FrymaKoruma

Shear conditions in the complex mixer for about 1000rpm to 4000rpm, preferably about 1500rpm arrives about 3000rpm.For the design maximum volume is that the mixing of 500L is irritated for 204, and the in batches preferred homogenate speed of 500L is about 2, and 500rpm is although those skilled in the art can select other numerical value.For the design maximum volume is that the mixing of 500L is irritated for 204, and the in batches preferred homogenizer rotating speed of 50L is about 1, and 700rpm is although those skilled in the art can select other numerical value.Blending tank 204 can be sealed with deaeration gas.Blending tank 204 can be any suitable size, and particularly about 50L is to the volume of 1000L.The pattern of at present preferred 500L.In blended last (for example 30 to 600 minutes, preferred about 120 minutes), corticosteroid (for example budesonide) solution is discharged in the holding vessel 208 by pressure.In certain embodiments, filter 206 is between blending tank 204 and holding vessel 208.Filter can be that average pore size is the filter of the suitable composition (for example PVDF) of 0.1 to 0.22 μ m (preferred average pore size is 0.22 μ m), for example

CVGL71TP3 0.22 μ m filter.

Corticosteroid (for example budesonide) solution can be retained in a period of time in the holding vessel 208, for example reaches 7 days.Holding vessel 208 can be gastight, and can bear the superpressure as the noble gas 218 of nitrogen or argon.Usually, inert gas pressure should keep suitably being higher than atmospheric pressure, for example about 2000mbar.Then corticosteroid (for example budesonide) solution is discharged in the surge tank 212 by pressure.Provide mechanical damping between the filling machine of surge tank 212 in holding vessel 208 and blow fill seal step S104.Surge tank also can apply noble gas 220.Filter 210 can be placed between holding vessel 208 and the surge tank 212.When existing, filter 210 can be suitable composition (for example PVDF) filter of average pore size 0.1 to 0.22 μ m (average pore size of preferred 0.22 μ m), for example

CVGL71TP3 0.22 μ m filter.

In step S104, budesonide solution is discharged into the blow fill seal apparatus from surge tank 212.In step S104, filter 214 can place between surge tank 212 and the blow fill seal apparatus.When existing, filter 214 can be the filter (preferred 0.22 μ m PVDF filter) of 0.1 to 0.22 μ m, for example CVGL71TP3 0.22 μ m filter.Blow fill seal step S104 makes liquid corticosteroid (for example budesonide) solution be assigned in the one pharmaceutically acceptable container (other parts of the present invention are meant bottle, ampoule or bottle) and seals one container.In certain embodiments, container is that nominal capacity is the LDPE ampoule of 0.5ml, although the container of other material and size is arranged in the art.In certain embodiments, blow fill seal step S104 can be in the oxygen consumption condition, as carrying out under noble gas 220 (for example nitrogen) positive pressure.Then in pouch step S106 with one container package in sack.In certain embodiments, pouch step S106 can be in the oxygen consumption condition, as carrying out at noble gas 222 (for example nitrogen) direct draught.Each sack can comprise one or more corticosteroid (for example budesonide) container (for example ampoule or bottle).In certain embodiments, each sack comprises 1,2, and 3,4,5,6,7,8,9,10,11,12,13,14 or more a plurality of container.In some present embodiment preferred, each sack comprises 5 ampoules.In vanning step S108 with bag packaging paper feed case in.

As used in the present invention, sterility is to come by means commonly known in the art to determine, for example by USP＜71 〉, PhEur 2.6.1 or other method well known in the art of measuring sterility are determined.

Embodiment

The preparation of embodiment 1-120 mcg/ml budesonide solution

Prepare 50L budesonide solution (nominal 120 μ g/ml) in batches according to following method: in weighing

Analyze initiation material before cyclodextrin (cyclodextrin) and the budesonide.The operational analysis value is calculated the cyclodextrin used in the prescription and the actual amount of budesonide initiation material.Find that cyclodextrin contains 4.9% water (95.1% cyclodextrin).Therefore, the total amount of cyclodextrin initiation material increases by proportional amount.The amount that calculates required cyclodextrin initiation material is 935.8569g (representing the 890.0g cyclodextrin).Measure by three kinds and to weigh up this cyclodextrin initiation material: 735.86g, 100.0g and 100.0g.Similarly analyze the initiation material of budesonide, find to contain 98.2% budesonide base substance.The amount of calculating the budesonide initiation material then is 5.95g/.982=6.06g.Like this, weigh up the budesonide initiation material of 6.06g.

Weigh up following other composition: the 15.0g anhydrous citric acid; 25.0g Trisodium citrate dihydrate USP.The water for injection of enough producing 50kg solution also is provided.

Mixing arrangement comprises high shear mixer, the feeder hopper in the separator, and vacuum equipment and source nitrogen.High shear mixer is sealed, and making like this can be to the content evacuation of blender in mixed process.

Accurately 40kg water is incorporated into mixing arrangement (FrymaKouma

700 vacuum processors, the 500L maximum volume) in.On mixing arrangement, take out the 224mbar vacuum, and kept 5 minutes.Nitrogen with 1278mbar (gauge pressure) is incorporated in the mixer then, the isolated from atmosphere of this container outside maintenance and blender during the mixed process.With about 1/3rd Cyclodextrin (cyclodextrin) is added in the funnel of separator.Cyclodextrin that then will about 100.0g is added in the budesonide initiation material in the conical flask, and jolting is until forming uniform mixture.Then this mixture is added in the feeder hopper.Cyclodextrin with 100.0g is added in the conical flask again, and jolting is until evenly.Content with conical flask is added in the funnel then.At last 15.0g anhydrous citric acid, 25.0g Trisodium citrate dihydrate USP, 5.0g EDTA sodium dihydrate and 325.0g sodium chloride are added in the funnel respectively successively.After all compositions make up in funnel, suck in whole compositions introducing blenders by vacuum.

Then with the content of blender under about 17 ℃ about 5 minutes with 1500rpm homogenate.The flushing of the about 150ml water of reuse comprised twice of the conical flask of budesonide initiation material originally; And flushing water is added in the funnel.Only about half of surplus water is added in the funnel, sucks by vacuum the content of funnel is introduced in the blender.The water that will be left at last is added in the funnel then, and sucks in the introducing blender by vacuum.At last homogenizer speed is increased to 1700rpm homogenate 120 minutes.

In 120 minutes homogenate processes, remove oxygen in the blending tank by following step: (1) is at first taken out the vacuum of about 200mbar and was kept about 5 minutes; (2) apply the nitrogen pressure of 1200mbar; (3) take out the vacuum of about 200mbar and keeping about 5 minutes once more; And (4) apply the nitrogen pressure of about 1215mbar once more to blender.When homogenate finishes, get the budesonide solution sample of homogenate, send quality inspection.

Embodiment 2-sterilizing methods

To filter by 0.22 μ m Millipore (CVGL71 TP3) filter from the budesonide solution of the homogenate of embodiment 1, by

Flexible pipe enters the holding vessel of sterilization.Apply about 1200mbar nitrogen overpressure to filtering solution.

After the budesonide solution of sterilization is collected in the holding vessel, it is analyzed.Find that budesonide solution has 98.2 ± 0.5% budesonide theoretical concentration, this theoretical concentration is based on the amount of the budesonide in the budesonide initiation material.This solution meets according to USP＜71〉and the sterility of PhEur 2.6.1.

As among the embodiment 2 as seen, the invention provides the sterilizing methods of budesonide solution, wherein the reduction of mass loss and budesonide concentration level is few.The invention provides the suitable practical approach that sucks the budesonide solution of the sterilization for the treatment of of preparation.

Embodiment 3:80 mcg/ml budesonide solution (GI059 batch)

The budesonide solution for preparing the 50L about 80 μ g/ml of final concentration in batches according to following method.At first analyze budesonide and Cyclodextrin (cyclodextrin) is to determine the percentage ratio of the water in each sample.The aimed quality of the cyclodextrin in the 50L batch is 595g; The aimed quality of budesonide is 4.1g.Analyze numerical value that cyclodextrin draws and be 4.8% water or 95.2% cyclodextrin; The percent budesonide value that the analysis budesonide draws is 99.2%.Therefore the amount of ring dextrin is the 595g/0.952=625g cyclodextrin; The quality of calculating budesonide is the 4.1g/0.992=4.133g budesonide.

Weigh up three parts of cyclodextrin: 100g respectively, 100g and 425g cyclodextrin.Accurately weighing up the 4.133g budesonide is put in the container (budesonide container).

The holding vessel of cleaning is carried out steam sterilization, the water for injection (WFI) of 40kg is injected in the holding vessel.The clean rustless steel FrymaKoruma of 500L (maximum volume) that will have agitator and homogenizer

Mixer (blending tank) steam sterilization 10 minutes is also dry.Blending tank has been equipped with short homogenate loop (short loop) and has been used to introduce the funnel (drying-charging hopper of dry ingredients; Funnel).Then 40kg water is transferred to blending tank from holding vessel under pressure.Only about half of being added in drying-charging hopper of that part of 425g cyclodextrin that will weigh up in advance then.Then the entire contents in the budesonide container is added in the funnel, notes not allowing any budesonide contact hopper walls.Cyclodextrin with first part of 100g is added in the budesonide container then, and jolting is to remove the budesonide of any remnants.Again the content in the budesonide container is added in the funnel.The cyclodextrin of second part of 100g repeats this process.

Composition with following amount is added in the funnel then: 15.0g anhydrous citric acid, 25.0g Trisodium citrate dihydrate, 5.0g sodium edetate dihydrate, 395.0g sodium chloride and from second half of that part of 425g cyclodextrin.Agitator is set at 25rpm, homogenizer is set at 1500rpm, the entire contents in the dried funnel is added in the blending tank under suction.Then by short loop with about 10 minutes of the content homogenate in the blending tank.

WFI with two parts of 150g cleans budesonide container then: be added in the budesonide container WFI of first part of 150g and jolting.Then the content in the budesonide container is added in the funnel.WFI with second part of 150g repeats this process, again with the entire contents in the funnel (～300ml) be added in the blending tank by suction.The only about half of of WFI of 8.631kg is added in the funnel.By suction the WFI in the funnel is added in the blending tank then.Repeat this process with remaining only about half of 8.631kgWFI.

Homogenizer speed is elevated to 1700rpm.Use nitrogen (N then ₂) purge blending tank: apply-200mbar vacuum and keeping five minutes to blending tank; Pressurize to blending tank with 1200mbar nitrogen then.Repeat this process once.When the 60th minute, 90 minutes and 120 minutes, from blending tank, draw the budesonide solution sample by 0.22 μ mPVDF filter.When finishing in the 124th minute, the entire contents in the blending tank is passed through

PTFE flexible pipe and 0.22 μ m

The PVDF cartridge filter is discharged in the holding vessel.The budesonide solution of the 80.2 μ g/ml (assay value) of this method clear 46.6kg.The fill bottle that the budesonide solution hydraulic reclamation is contained 0.53ml/ bottle (budesonides of 42.1 μ g/ bottles) in the LDPE bottle with production.Solution meets according to USP＜71〉and the sterility of PhEur 2.6.1.

The budesonide solution of embodiment 4:40,60,120 and 240 μ g/0.5mL dosage

According to the universal method of describing among the foregoing description 1-3, having prepared concentration is the budesonide solution of 80,120,240 and 480 μ g/mL, also packs as mentioned above in LDPE bottle (ampoule) by the 0.5mL dose distribution.In the 0.5mL dosage of gained, every 0.5mL dosage contains 40,60,120 and 240 μ g budesonides.The amount of the every kind of composition that contains in each ampoule is presented in the following table 1.Solution meets according to USP＜71〉and the sterility of PhEur 2.6.1.

The budesonide of table 1:40,60,120 and 240 μ g/0.5mL dosage

Composition	240mcg/0.5 mL	120mcg/0.5 mL	60mcg/0.5 mL	40mcg/0.5 mL
Composition	240mcg/0.5 mL	120mcg/0.5 mL	60mcg/0.5 mL	40mcg/0.5 mL	Budesonide	0.048	0.024	0.012	0.008
Captisol	7.5	3.57	1.78	1.19	Budesonide	0.048	0.024	0.012	0.008
Captisol	7.5	3.57	1.78	1.19	Citric acid	0.03	0.03	0.03	0.03
Trisodium citrate dihydrate USP	0.05	0.05	0.05	0.05	Citric acid	0.03	0.03	0.03	0.03
Trisodium citrate dihydrate USP	0.05	0.05	0.05	0.05	NaCl	0.45	0.57	0.73	0.79
Na-EDTA	0.01	0.01	0.01	0.01	NaCl	0.45	0.57	0.73	0.79
Na-EDTA	0.01	0.01	0.01	0.01	Water	Be added to 100.0	Be added to 100.0	Be added to 100.0	Be added to 100.0

The value that shows is [w%]; The osmotic pressure concentration adjustment is to 290mOsm/kg; PH 4.5

Embodiment 5: stride multiple batches of mass loss

According to the general production method of describing among the foregoing description 1-4, provide in the preparation table 2 batch.Every batch nominal concentration (about 80 μ g/mL, 120 μ g/mL, 240 μ g/L or 480 μ g/L) is presented in the hurdle that indicates " nominal μ g/mL ".Test in the process of carrying out, wherein after dissolving, from solution, draw budesonide solution with 0.22 μ m PVDF injection filter.Budesonide IPC concentration data provides in the hurdle that indicates " IPC μ g/mL. ".The hurdle that indicates Δ % IPC has shown the difference between nominal concentration and the IPC filtering solution.When process finishes, analyze final budesonide solution (" discharging (Release) "), and determine the budesonide concentration in " discharging (Release) " solution.These data of each batch are summarised in the hurdle that indicates " Release μ g/mL "." discharging (the Release) " concentration of every batch of budesonide and the percent difference between the nominal concentration are listed in the hurdle that indicates " Δ %Release. ".Every kind of solution all meets according to USP＜7l〉and the sterility of PhEur 2.6.1.

Table 2: multiple batches of dissolution data

Although shown in this article and described the preferred embodiments of the invention, these embodiments only provide as an example, and this will be conspicuous for a person skilled in the art.Not deviating from multiple variation of the present invention, change and substitute will be conspicuous to those skilled in the art.Should be understood that the various alternatives of embodiment of the present invention described herein all can be used to implement the present invention.Plan limits scope of the present invention with following claim, and the present invention has been contained at the scope of these claim and the method and structure in the equivalent thereof.

Claims

1. method for preparing the corticosteroid solutions of sterilization, it comprises by filter and filters compound corticosteroid solutions to produce the corticosteroid solutions of sterilization that the mass loss between the corticosteroid solutions of wherein initial corticosteroid solutions and sterilization is less than about 30%.

2. the described method of claim 1, the average pore size of wherein said filter are that about 0.1 μ m is to about 1.5 μ m.

3. the described method of claim 2, the average pore size of wherein said filter are that about 0.1 μ m is to about 0.5 μ m.

4. method according to claim 3, the average pore size of wherein said filter are about 0.22 μ m.

5. the described method of claim 1, wherein said corticosteroid is a budesonide.

6. the described method of claim 1, wherein said filter is methylcellulose filter or PVDF filter.

7. the described method of claim 6, wherein said filter is that average pore size is the PVDF filter of about 0.22 μ m.

8. the described method of claim 1, wherein said initial corticosteroid solutions further comprises solubilizing agent.

9. the described method of claim 8, wherein said initial corticosteroid solutions comprise compares the excessive solubilizing agent of molal quantity with corticosteroid.

10. the described method of claim 9, wherein said solubilizing agent is selected from sulfoalkyl ether cyclodextrin (SAE-CDs).

11. the described method of claim 10, wherein said solubilizing agent be sulfoalkyl ether cyclodextrin SBE7-β-CD (

).

12. the described method of claim 1, wherein said corticosteroid solutions further comprises albuterol.

13. the described method of claim 1, wherein said solubilizing agent comprise the polyoxyethylene sorbitan monoleate of cyclodextrin and about 0.001%.

14. the described method of claim 1, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 10%.

15. the described method of claim 14, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 5%.

16. the described method of claim 15, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 2%.

17. a method that reduces mass loss of corticosteroid in the sterilization process, it comprises by filter and filters initial corticosteroid solutions to produce the corticosteroid solutions of sterilization that wherein the mass loss of corticosteroid is less than about 30%.

18. the described method of claim 17, the average pore size of wherein said filter are that about 0.1 μ m is to about 1.5 μ m.

19. the described method of claim 18, the average pore size of wherein said filter are that about 0.1 μ m is to about 0.5 μ m.

20. method according to claim 19, the average pore size of wherein said filter are about 0.22 μ m.

21. the described method of claim 17, wherein said corticosteroid are budesonide.

22. the described method of claim 17, wherein said filter are methylcellulose filter or PVDF filter.

23. the described method of claim 22, wherein said filter are average pore size is the PVDF filter of about 0.22 μ m.

24. the described method of claim 17, wherein said initial corticosteroid solutions further comprises solubilizing agent.

25. comprising, the described method of claim 24, wherein said initial corticosteroid solutions compare the excessive solubilizing agent of molal quantity with corticosteroid.

26. the described method of claim 25, wherein said solubilizing agent are selected from sulfoalkyl ether cyclodextrin (SAE-CDs).

27. the described method of claim 26, wherein said solubilizing agent be sulfoalkyl ether cyclodextrin SBE7-β-CD (

).

28. the described method of claim 17, wherein said corticosteroid solutions further comprises albuterol.

29. the described method of claim 17, wherein said solubilizing agent comprise the polyoxyethylene sorbitan monoleate of cyclodextrin and about 0.001%.

30. the described method of claim 17, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 10%.

31. the described method of claim 30, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 5%.

32. the described method of claim 31, the mass loss of the corticosteroid solutions of wherein said sterilization is less than about 2%.

33. method for preparing the corticosteroid solutions of sterilization, it comprises by filter and filters the compound corticosteroid solutions of the corticosteroid comprise initial mass to produce the corticosteroid solutions of sterilization, wherein the concentration of Mie Jun corticosteroid solutions be in the compound corticosteroid solutions corticosteroid concentration at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.

34. the described method of claim 33, the average pore size of wherein said filter are that about 0.1 μ m is to about 1.5 μ m.

35. the described method of claim 34, the average pore size of wherein said filter are that about 0.1 μ m is to about 0.5 μ m.

36. method according to claim 35, the average pore size of wherein said filter are about 0.22 μ m.

37. the described method of claim 33, wherein said corticosteroid are budesonide.

38. the described method of claim 33, wherein said filter are methylcellulose filter or PVDF filter.

39. the described method of claim 38, wherein said filter are average pore size is the PVDF filter of about 0.22 μ m.

40. the described method of claim 33, wherein said initial corticosteroid solutions further comprises solubilizing agent.

41. comprising, the described method of claim 40, wherein said initial corticosteroid solutions compare the excessive solubilizing agent of molal quantity with corticosteroid.

42. the described method of claim 40, wherein said solubilizing agent are selected from sulfoalkyl ether cyclodextrin (SAE-CDs).

43. the method for claim 42, wherein said solubilizing agent be sulfoalkyl ether cyclodextrin SBE7-β-CD (

).

44. the described method of claim 33, wherein said corticosteroid solutions further comprises albuterol.

45. the described method of claim 33, wherein said solubilizing agent comprise the polyoxyethylene sorbitan monoleate of cyclodextrin and about 0.001%.

46. the described method of claim 33, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 95%.

47. the described method of claim 46, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 96%.

48. the described method of claim 47, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97%.

49. the described method of claim 48, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97.5%.

50. the described method of claim 49, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97.7%.

51. method that reduces corticosteroid concentration loss in the sterilization process, it comprises the compound corticosteroid solutions that filters the corticosteroid comprise initial mass by filter to produce filtering corticosteroid solutions, wherein the concentration of filtering corticosteroid solutions be based on the theoretical concentration of corticosteroid initial mass at least about 90.0%.

52. the described method of claim 51, the average pore size of wherein said filter are that about 0.1 μ m is to 0.5 μ m.

53. according to the described method of claim 51, the average pore size of wherein said filter is about 0.22 μ m.

54. the described method of claim 51, wherein said corticosteroid are budesonide.

55. the described method of claim 51, wherein said filter are methylcellulose filter or PVDF filter.

56. the described method of claim 55, wherein said filter are average pore size is the PVDF filter of about 0.22 μ m.

57. the described method of claim 51, wherein said initial corticosteroid solutions further comprises solubilizing agent.

58. comprising, the described method of claim 57, wherein said initial corticosteroid solutions compare the excessive solubilizing agent of molal quantity with corticosteroid.

59. the described method of claim 58, wherein said solubilizing agent are selected from sulfoalkyl ether cyclodextrin (SAE-CDs).

60. the described method of claim 59, wherein said solubilizing agent be sulfoalkyl ether cyclodextrin SBE7-β-CD (

).

61. the described method of claim 51, wherein said corticosteroid solutions further comprises albuterol.

62. the described method of claim 51, wherein said solubilizing agent comprise the polyoxyethylene sorbitan monoleate of cyclodextrin and about 0.001%.

63. the described method of claim 51, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 95%.

64. the described method of claim 63, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 96%.

65. the described method of claim 64, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97%.

66. the described method of claim 65, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97.5%.

67. the described method of claim 66, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97.7%.

68. the described method of claim 67, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 97.9%.

69. the described method of claim 68, the concentration of the corticosteroid solutions of wherein said sterilization be based on the theoretical concentration of corticosteroid initial mass at least about 98.2 ± 0.5%.

70. method for preparing the corticosteroid solutions of sterilization, it comprises makes compound corticosteroid solutions reach such situation, and that the mass loss between the corticosteroid solutions of wherein initial corticosteroid solutions and sterilization is less than is about 30%, it is about 25% to be less than, it is about 20% to be less than, it is about 15% to be less than, it is about 10% to be less than, it is about 5% to be less than, it is about 3% to be less than, be less than about 2% or about 1% or still less.

71. method that reduces mass loss of corticosteroid in the sterilization process, it comprises makes compound corticosteroid solutions reach such state, and that the mass loss that has wherein realized corticosteroid is less than is about 30%, it is about 25% to be less than, it is about 20% to be less than, it is about 15% to be less than, it is about 10% to be less than, it is about 5% to be less than, it is about 3% to be less than, be less than about 2% or about 1% or still less.

72. method for preparing the corticosteroid solutions of sterilization, it comprises makes compound corticosteroid solutions reach such state, wherein the concentration of Mie Jun corticosteroid solutions be based on the theoretical concentration of corticosteroid initial mass at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.

73. method that reduces corticosteroid concentration loss in the sterilization process, it comprises makes compound corticosteroid solutions reach such state, wherein the concentration of the corticosteroid in the corticosteroid solutions be based on the theoretical concentration of corticosteroid initial mass at least about 95%, at least about 96%, at least about 97%, at least about 97.5%, at least about 97.7%, at least about 97.9%, for example about 98.2 ± 0.5% or more.