NZ621362B2 - Method for preparing metered dose sprayed inhaler for treating respiratory disease - Google Patents

Abstract

metered dose sprayed inhaler composition and a preparation method thereof. The metered dose sprayed inhaler composition comprises active ingredients, namely, ethylene synergist and corticosteroids. The preparation method thereof comprises: (1) mixing 0.05-10.0%w/w alcohol with a surfactant such as polyethylene glycol (PEG) to form a first mixed solution; (2) dispersing the ethylene synergist in the first mixed solution to form a second mixed solution; (3) adding a hydrofluoroalkane propellant to the second mixed solution to form a third mixed solution; (4) dispersing corticosteroids in the third mixed solution; (5) performing the filling step. polyethylene glycol (PEG) to form a first mixed solution; (2) dispersing the ethylene synergist in the first mixed solution to form a second mixed solution; (3) adding a hydrofluoroalkane propellant to the second mixed solution to form a third mixed solution; (4) dispersing corticosteroids in the third mixed solution; (5) performing the filling step.

Description

METHOD FOR PREPARING D DOSE SPRAYED INHALER FOR TREATING RESPIRATORY DISEASE FIELD OF THE INVENTION The present invention provides a pressurized metered dose inhaler composition with ceuticals and a preparing method thereof, wherein the pressurised metered dose inhaler is a medicine used for treating respiratory diseases such as asthma and chronic obstructive pulmonary disease.

BACKGROUND OF THE INVENTION Pressurized metered dose r (pMDI) can make the inhaled pharmaceuticals topically and rapidly present the activity of the medicine, and has lower systemic adverse reaction when compared with an oral drug. The pMDI and dry powder inhaler (DPI) are the most general administrations for asthma or chronic obstructive pulmonary disease , which are used to administer the composition being one seleceted from a group consisting of a osteroid drug, a beta-2 agonist, an anticholinergics and a combination thereof.

Since 1995, Company 3M developed a product of pMDI with chlorofluorocarbons (CFC) as a propellant, and the product has become most popular administration for treating asthma or COPD. Compared with the oral drug, the prIDI may present activity more rapidly and e lower systemic adverse reaction of the medicine. Typical components for treating such diseases e a corticosteroid drug, a beta-2 t, an anticholinergics, or a pharmaceutical composition being a dose inhaler and consisting of the mentioned drugs.

In the 1970s, it is found that the propellant of CFC may result in environmental protection problems in ying ozonosphere, and thus the CFC is confronted by the situation of global restriction. In the end of 19803, a substitute product of the DPI was developed, but the substitute product can not completely replace the pMDI with the CFC propellant all along, since the product tends to suffer moisture and the patient needs enough speed of inhaling when using the product to be efficiently administered. Until now, Company Riker of 3M firstly develops a substitute propellant for ing the CFC propellant, i.e. the lant of hydrofluoroalkanes (HFA), which includes l,l,1,2-tetrafluoroethane (HFA 134a, HFC 134a) or 2,3,3,3— heptafluoro—n-propane (HFC 227ea, HFC 227, HFA227). However, because there are some problems, such as ques of preparation and drug safety, to be overcome, the first product of the formulation of HFA MDI did not enter into the market until 1996, and was booming in 2004, which results in the complete restriction on. producing the CFC MDI after 2010.

In the US Patent Nos. 5,225,183, 5,439,670, 5,695,743, 573, ,836,299 and 6,352,684 owned by Company 3M, the patented formulation including HFA 134a has been disclosed. The formulation includes components of fi-Z—adrenergic agonists including such as salbutamol, corticosteroid such as beclomethasone dipropionate, adrenergic components, choline and anti—histamine or anti—inflammatory drugs, and uses 1-50% ethanol compound as a solubilizer, and the surfactant, which may be the derivatives such as oleic acid, polyethylene glycol G 400) or Span, is added with a weight ratio less than 5%. In the US Patent No. 6,743,413, HFA 134a and micronized drugs are used as main components without other excipients. The US Patent No. 5,776,432 discloses that HFA 134a, HFA 227, or a combination thereof is used as the propellant, and 2%—12% ethanol is used as the solubilizer ofthe main drug ent, beclomethasone 17, 21 dipropionate, Without surfactant.

The US Patent No. 5,474,759 owned by Company Schering discloses that I-TFA 227 is used as the propellant, and ene glycol diester with a long chain is used as the surfactant, wherein the main components thereof include compounds such as albuterol, albuterol sulfate, beclomethasone dipropionate, or mometasone furoate.

In the US Patent Nos. 5,653,962, 5,658,549 and 5,744,123 owned by Company GSK, the ed formulation including HFA has been disclosed.

The formulation includes main components such as salmeterol, salbutamol and fluticasone propionate, but does not have co-solvent, and uses the surfactant less than 0.001%. The subsequent patents thereof relate to the modification of drug delivery uniformity. The US Patent Nos. 6,315,173 and 6,510,969 relate to the ement of the sprinkle—nozzle. The US Patent No. 6,479,035 uses Fluticasone and 7-20% alcohol as the solubilizer, and uses 053% ol or PEG as the surfactant. In the US Patent Nos. 5,736,124, 5,817,293, 5,916,540, ,922,306, 6,333,023, 6,200,549 and 339, the main ent of formoterol has been disclosed, and 0.01—5% l is adopted. The US Patent Nos. 6,303,103 and 6,238,647 disclose that salmeterol and anti—cholinergics are incorporated, and the excipient used thereby is less than 0.0001%. The US Patent No. 6,013,245 relates to beclomethasone and amol, uses HFA 227 and does not use the surfactant. The US Patent No. 5,833,950 discloses beclomethasone, and uses HFA and the excipient less than 0.0001%.

Company Aeropharm has disclosed a patented formulation including HFA. The US Patent No. 5,891,419 discloses flunisolide with an addition of 0.5%—2% ethanol only. The US Patent No. 5,891,420 discloses triamcinolone acetonide with an addition of 1%-3% ethanol. The US Patent No. 6,458,338 relates to a metered dose formulation with amino acid as the stabilizer. In the US Patent Nos. 6,447,750, 6,540,982, 6,540,983, 6,548,049 and 6,645,468, a metered dose formulation of a main component of a drug treating diabetes has been disclosed. The US Patent No. 6,464,959 discloses a metered dose formulation of a main component of a drug treating diabetes, which is incorporated with amino acid as the stabilizer.

The US Patent No. 6,004,537 owned by Company Baker Norton (now TEVA) discloses that HFA is used as the propellant, and uses 10%-40% (w/w) ethanol as the solubilizer to dissolve the main components of Budesonide and Formoterol.

The US Patent No. 6,123,924 owned b§ Fisons discloses main components such as Bz—receptor agonist: fenoterol hydrobromide, procaterol hloride, salbutamol sulphate, terbutaline sulphate, anabolic steroid or steroid components; beclomethasone dipropionate, fluticasone propionate, tipredane, anti—histamine, anti—inflammation or —B-methylcholine e; cholinergic components: pentamidine isoethionate, tipredanene, docromil sodium, sodium cromoglycate, clemastine, budesonide and so on, which are distributed in HFA, and uses of polyvinylpyrrolidone (PVP) of 0.00001~10% w/w as the suspending agent and PEG 400-3000 as the ating agent.

The TW Patent Application No. 200303767 owned by Company Chiesi discloses formoterol superfine formulation, which includes 0.003- 0.192% W/V of (i)—formoterol fumarate, wherein the combination technique of pressurized d inhaler formulation is used and 10~20% l and HCl are used to adjust pH value. It is emphasized that the ratio of particles equal to or less than 1.1 micrometer is larger than or equal to 30%.

In the US Patent No. 7,223,381, the ation is consisting of Budesonide, HFA propellant, and co-solvents of 13% ethanol and O.2~2% glycerol.

The US Patent No. 495 owned by Company Nektar relates to a formulation combination technique where the phospholipid is used as the excipient to form a microstructure and materials having biological activities are distributed in the pressurized metered inhaler.

The US Patent No. 6,932,962 owned by Company AstraZeneca relates to I-IFA atomization dose including fatty acid or a salt f, bile salts, phospholipid or alkyl glycosides as the surfactant, wherein the amount of the ethanol used thereby can be 5—20%.

The US Patent No. 7,481,995 owned by University College Cardiff Consultants Limited relates to a HFA MDI ation technique which uses amino acid as the suspending excipient.

When observing the mentioned prior arts based on the pressurized metered dose inhaler prescription, in addition to the medicine and HFA gas, the techniques can be classified according to using conditions of the ethanol as follows. 1). Without any additives, as represented by y GSK, which provides the medicine completely presented by a suspending solution mode, while such medicine has a problem that it is more lt to make the administration uniform. 2). Without the use of ethanol and a simple use of an excipient, such as PVP or propanediol bischloroacetate. 3). Large amount of ethanol (more than 10%), which would tely dissolve the medicine, and other excipients may be added or not.

In this case, the advantage is good uniformity of the administration, and the disadvantage are possibly worse stability of the medicine and the rare cy of l that has bad acceptance for patients. 4). Medium—low amount of ethanol (about 1% to 10%) ated with other excipients, in which the medicine is in a condition of partially being ved and partially without being dissolved. It has bigger effect on the stability of the formula that the particle diameter of the medicine would be caused to change with passing ofthe preserving time. 5). Extreme—low amount of ethanol (about 0.2% to 2%), such as the formula of y Valois. In this case, the advantage is the better stability of the medicine since it is in a suspending solution station without being dissolved, while the disadvantage is the bad uniformity of the administraion and thus the assistance of other excipients may be needed. er, it may have more difficulty in the cturing process.

Although Valois SAS has published the formula about Budesonide HFA MIDI, which uses 0.1—5% ofPEG 300 and 0.2—2% of ethanol (referring to Indian Journal of Pharmaceutical Science, Vol. 69, No. 5, P. 722—724, Sep-Oct 2007). However, in order to reduce the absorbtion of the containter with the drug and increase the unifomity of the administration, the mentioned formula needs a use of a special surface—anodized ner, such as a standard anodized aluminum canister, to be filled therewith. When it is used in an scale-up production or a general container, such as an aluminum canister, some problems about quality would be generated. Accordingly, when actually mass produing the ned formula in pharmaceutical industry, even though the formula components are the same, the differenes of y would still be resulted from different mixture orders of components and ent ways and equipments of filling. The examples of the differenes of quality are insufficient amount of the main component, cohering of the particals of the medicine, bad uniformity and so on. Particularly, the mentioned conditions would occur more easily when a t contains two kinds of main components, since there are ences of physical and chemical characteristics as well as ratio of content existing between said two main components. Therefore, a change of the producing process in combining the excipient with the contents ofthe formula, ally the application in mixture orders and homogenizing methods of the main components with the lant and other excipients, may generate a rized metered dose inhaler with stable, safer and more efficacious qualities.

SUMMARY OF THE INVENTION Lung is a tender tissue, and thus it is necessary to consider making harm to lung as low as possible when performing a pulmonary administration.

Although surface cells of lung have motor fibers capable of excluding the inhalded foreign body, the ing function is limited. Therefore, when designing the dose inhaler formula, it shall use excipients as few as possible or those with lower ty. Although the use of large amount of solubilizer cause the product to present a better uniformity, the stability thereof would reduce correspondingly.- Accordingly, the policy of HFA MDI formula is researched in the present invention, which intends to prepare a safe and efficient suspending solution dose with fewest excipient and solubilizer, to achieve good uniformity of administration and long stability of products, and to provide the patients with efficient dose (< 5 micrometer) capable of entering into the lung. However, the ng of amounts of the excipient and solubilizer in the patented HFA formula would easily reduce the stability and uniformity of the produced medicines, especially when the t contains two main ents, such as beta—2 ts and osteroids. Besides, large difference of dosages and different physical and chemical characteristics between the two main components would more easily result in the phenomenon of worse uniformity and stability of the main components in the dose. Moreover, because the main components cannot be uniformly mixed the excipient during the producing process of the suspending solution dose, the particles of medicine may easily cohere again, which results in the enon of significant reducing of efficiently inhaled dose (fine particle dose).

The present invention es a method ofpreparing a metered dose inhaler ition, comprising steps of: a) mixing 0.05%—10 % (w/W %) alcohol with a tant to form a first mixture; b) dispersing a beta-2 agonist in the first mixture to form a second mixture; c) adding a hydrofluoroalkane (HFA) propellant into the second e to form a third mixture; d) dispersing a corticosteroid in the third mixture; and e) ming a filling step.

According to the mentioned t, a stable and well-mixed suspending solution dose is formed in the present invention by using an inhaled medicine with proper producing process. The medicine includes a beta-2 t such as procaterol, salbutamol, formoterol and salmeterol, a corticosteroid such as budesondie, fluticasone, ciclesonide and ethasone, or a combination thereof. The hydrofluoroalkanes (HFA) propellant includes one of l,l,l,2—tetrafluoroethane (HFA 134a, HFC 134a) or l,l,l,2,3,3,3- heptafluoro—n—propane (HFC 2276a, HFC 227, I-lFA227), and the mentioned two HFA propellants may be mixed for use if necessary. The surfactant includes a polyethylene glycol (PEG) excipient for stabilizing the formula or lubricating the metering valve of container to prevent blocking, and the addition amount thereof is ranged from 0.01%—2.50% (w/W %), preferably 0.05%~l.50 % (w/w %). Generally, the PEG having the mentioned concentation would not affect the lity of the main components that results in reduction of ity. The PEG preferably has a molecular weight ranged from 100 to 6000, and in on to the function of helping suspending, the PEG may be deemed as a correcter for particle diameter since the modification of the addition amount thereof may change the distribution of particle diameters. The ethanol absolute is added and the addition percent thereof is ranged from 0.05%—10.0% (w/W %), preferably 0.25%—2 % (W/w %).

With the mentioned concentation, the ethanol te may not only ant in the dissolution of PEG, but also improve the phenomenon that the particles of the main component aggregate, which results from the HFA evaporated from the sprinkle—nozzle of the spray dose in the sprinkling moment.

Furthermore, the surfactant, i.e. PEG 100-6000 molecular weight, used in the present invention is a commercially available product, and the needed viscidity can be adjusted by the amount of ethanol.

According to the mentioned concept, the present ion specifically provides a method of ing a metered dose inhaler composition, comprising steps of: a) using 0.05%-10% (w/w%) alcohol as an alcohol t to be mixed with a surfactant to form a mixture solution; b) dispersing a beta—2 agonist in the mixture solution to form a uniform solution; c) adding HFA into the uniform solution; (1) dispersing a corticosteroid in the m solution; and e) performing a freeze filling step or a re filling step.

In the producing process of the spray dose provided in the present invention, a step of uniformly dispersing PEG in HFA is an important step for controlling the uniformity of particles of the main component. Firstly, little amount of alcohol is uniformly mixed with PEG. Because the particles of drug of inhaling type are very fine, the particles are apt to aggregate. For mly dispersing the particles by PEG, it is necessary to perform the mixing step by onic vibration for forming a concentrated solution. The viscosity and volume of the mixture solution of alcohol and PEG may be changed with the quantity and property of the main ent, while the amount thereof shall not be larger than 2% (w/w %) ofthe total amonut of the formula. However, if the quantity of the main component medicine is more and the appeared volume is much larger than the volume of the mixture solution of alcohol and PEG, it is not necessary to mix the alcohol with PEG in advance. Next, the mentioned concentrated solution or the mixture solution of alcohol and PEG would be homogenizedly stirred with EPA to for a homogenized on, and then the main component with large quantity is slowly added into and mixted with the homogenized solution. In the abovementioned process, the order of adding the ent and the way of mixing have cant effect. Particularly, when in a scale-up production, there are ct improvements in the extent of unifomly dispersing of drug particles and the quantity of the main ent medicine stained in the mixing tank. Finally, the freeze filling or pressure filling steps is performed.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Evaluation of ry dose uniformity: The drug efficacy and safety of spray dose are affected by delivery dose uniformity, which includes: 1. the suspending solution is dispersed uniformly and quickly when shakng the bottle; 2. the uniformly suspending state is maintained at least 5 seconds after shaking; and 3. the nce range of the sprinkle—nozzle of the spray (the USA Food and Drug Administration requires that a qualified range is that an average of a group of le—nozzles is the target value :1: 10%, and the respective sprinkle—nozzle is the target value :1: 15%).

For obtaining a le uniformity test, a dose unit sampling apparatus (DUSA) as required by United States Pharmacopeia (USP) is used with glass fiber filter (1 pm). After performing a spray sampling under a required air-extracting flow rate (28.3 L/rnin), the quantities of drugs in the actuator (or mouthpiece) and the sampling/drug—collecting apparatus are measured respectively by high-efficient chromatography. The initial three sprayings, medium four sprayings and final indicated three sprayings of a bottle are respeatively tested for a single dosage. The specification requires that the main components in a single spraying shall be less than 25% of the indicated dosage ing to the requirements of the Pharmacopeia, and an average amount of the main components of all ten sprayings shall be less than % of the indicated dosage. Moreover, the delivery dose uniformity is evaluated under the conditions of 40°C, relative humidity 75% and maintenance of six-months storing period for tating the stability.

Evaluation ofparticle size distribution: For determining the condition of particle size distribution of the drugs, a spray sampling is med under an air—extracting flow rate (30.0 L/min) required by USP, and the is of particle size of the drugs in the spray sampling is med by using Next Generation Cascade Impactor. The distribution and changing circumstances of the particles in every level when using Next Generation Cascade or are observed under the conditions of 40 "C, relative humidity 75% and maintenance of six-months storing period for tating the stability, so as to te the stability of the drug particles suspending in the formula solution.

The delivery dose uniformity is analyzed for the spray according to Formula Example I of the process of the spray dose ed in the present invention. As shown in Fig. l where Budesonide in the first spraying has an indicated dosage of 180 mcg, after the six-months test of facilitating stability (40°C and relative humidity 75%), every bottle of the sprays including totally ten sprayings of delivery dosages is complying with the requirement that the main component in a single spraying shall be less than 25% of the indicated dosage and an average value shall be less than 15% of the indicated dosage according to the Pharmacopeia. As shown in Fig. 2 where Procaterol HCl in the first spraying has an ted dosage of 10 mcg, after the six~months test of facilitating stability (40 "C and relative humidity 75%), every bottle of the sprays including totally ten sprayings of delivery dosages is complying with the requirement that the main component in a single spraying shall be less than % ofthe indicated dosage and an average value shall be less than 15% ofthe ted dosage according to the Pharmacopeia.

As shown in Fig. 3 illustrating the analysis of particle size distribution, after the six-months test of facilitating stability (40°C and relative humidity 75%), Budesonide is analyzed by using Next Generation e Impactor for all levels, which include actuator, at, Stage 1, Stage 2, Stage 3, Stage 4, Stage 5, Stage 6, Stage 7 and micro—orifice collector (MOC).

There are no sigificant ences (ANOVA test, p>0.05) in ty of Budesonide, when compared with that at initial time point, among the products in every level.

As shown in 4 _ Fig. illustrating the analysis of particle size bution, after the six-months test of tating stability (40°C and relative humidity 75%), erol HCl is analyzed by using Next Generation Cascade Impactor for every level, and there are no sigificant differences (ANOVA test, p>0.05) in quantity of Procaterol HCl, when compared with that at initial time point, among the products in every level.

Fig. 5 illustrates the analysis of the delivery dose uniformity for Fluticasone in the spray of Formula Example VII, wherein the asone in the first spraying has an indicated dosage of 250 mcg. After the six~months test of facilitating stability (40°C and relative humidity 75%), every bottle of the sprays including totally ten sprayings of ry dosages is complying with the ement that the main component in a single spraying shall not be over 25% of the indicated dosage and an average value shall not be over 15% ofthe indicated dosage according to the Pharmacopeia. [003 6] Fig. 6 illustrates the analysis of particle size bution for Fluticasone in the spray of Formula Example VII. After the six-months test of facilitating stability (40°C and relative humidity 75%), it is analyzed by using Next Generation Cascade Impactor for every level, and there are no sigificant ences (ANOVA test, p>0.05) in quantity of Fluticasone, when compared with that at initial time point, among the ts in every level.

Fig. 7 illustrates the analysis of the delivery dose uniformity for Albuterol sulfate in the spray of Formula e IX, wherein the Albuterol sulfate in the first spraying has an indicated dosage of 250 mcg. After the six- months test of facilitating stability (40°C and relative humidity 75%), every bottle of the sprays which includes totally ten sprayings of delivery dosages is complying with the requirement that the main component in a single spraying shall not be over 25% of the indicated dosage and an average value shall not be over 15% ofthe indicated dosage according to the Pharmacopeia. [003 8] Fig. 8 illustrates the is of particle size bution for rol sulfate. After the six-months test of facilitating stability (40°C and relative humidity 75%), it is analyzed by using Next Generation Cascade Impactor for every level, and there are no sigificant differences (ANOVA test, p>0.05) in quantity of Albuterol sulfate, when compared with that at l time point, among the ts in every level.

The object of the present invention is to promote the stability of amounts, the delivery dose uniformity and the stability of quality when producing the pressurized metered spray dose in the scale-up production. The a applied to the producing process would deeply have industrial value especially when two main components having much differences in relative phsysical and chemical properties are combined in the product. Accordingly, the t invention is sought to be protected by operation of law. The “process of preparing metered dose inhaler for treating respiratory diseases” provided in the present invention will become more readily apparent to those ordinarily skilled in the art after reviewing the following examples. However, it is to be understood that the invention needs not be limited to the disclosed embodiments. The person skilled in the art could derive various embodiments according to the spirit of the disclosed embodiments, all of which shall belong to the scope of the appended claims in the present invention. s Example I: Procaterol HCl 0.014% W/W% nide 0.252% W/W% HFA 227 98.984% W/W% ethanol absolute 0.500% W/W% PEG 6000 0.250% W/W% Total Amount 100.000% W/W% Descriptions For Process: PEG 6000 is completely dissolved in the ethanol absolute to form a mixture solution, and then Procaterol HCl is poured into the mixture solution and dissolved by onic Vibration to form an homogenized solution. After homogenizedly mixing I-IFA 227 with the homogenized solution, Budesonide is slowly added nto. Finally, freeze filling or pressure filling is performed.

Process e II: asone propionate 0.350% W/W% HFA 134a 98.900% W/W% ethanol absolute 0.500% W/W% PEG 400 0.250% W/W% Total Amount 100.000% W/W% Descriptions For s: PEG 400 is completely dissolved in the ethanol absolute to form a mixture solution. After homogenizedly mixing HFA 134a with the mixture solution, Fluticasone is slowly added thereinto. Finally, freeze filling or pressure filling is performed.

Process Example III: Albuterol sulfate 0. l 68% W/W% Fluticasone propionate 0.322% W/W% HFA 134a 97.510% W/W% ethanol absolute 1.000% W/W% PEG 100 1.000% W/W% Total Amount 100.000% W/W% Descriptions For Process: PEG 100 is completely dissolved in the ethanol absolute to form a mixture on, and then Albuterol sulfate is poured into the mixture on and dissolved by ultrasonic vibration to form an homogenized solution. After homogenizedly mixing HFA 227 with the homogenized solution, Fluticasone propionate is slowly added thereinto. Finally, freeze filling or pressure filling is med.

Process Example IV: Procaterol 0.014% W/W% HFA 227 99.286% W/W% ethanol te 0.500% W/W% PEG 2000 0.200% W/W% Total Amount 100.000% W/W% Descriptions For Process: PEG 2000 is completely dissolved in the ethanol absolute to form a mixture solution, and then Procaterol HCl is poured into the mixture solution and dissolved by ultrasonic vibration to form an homogenized solution. HFA 227 is homogenizedly mixed with the homogenized on. Finally, freeze filling or re filling is performed.

Formula Example I: Procaterol HCl 0.014% W/W% Budesonide 0.280% W/W% EPA 134a 98.906% W/W% alcohol 0.500% W/W% PEG 2000 0.300% W/W% Total Amount 100.000% W/W% Formula Example II: Procaterol HCl 0.014% W/W% Fluticasone propionate 0.350% W/W% HFA 227 % W/W% alcohol 0.250% W/W% PEG 400 0.500% W/W% Total Amount 0% W/W% Formula Example III: Albuterol sulfate 0.168% W/W% Fluticasone propionate 0.322% W/W% HFA 227 97.510% W/W% ethanol absolute 1.500% W/W% PEG 400 0.500% W/W% Total Amount 100.000% W/W% Formula Example IV: Procaterol 0.014% W/W% HFA 134a 97.986% W/W% alcohol 1.000% W/W% PEG 100 1.000% W/W% Total Amount 100.000% W/W% Formula Example V: Procaterol HCl 0.014% W/W% nide 0.333% W/W% HFA 134a 98.903% W/W% alcohol 0.250% W/W% PEG 400 0.500% W/W% Total Amount 100.000% W/W% Formula Example VI: Budesonide 0.330% W/W% HFA 227 99.530% W/W% alcohol 1.500% W/W% PEG 2000 0.500% W/W% Total Amount 100.000% W/W° o Formula Example VII: Fluticasone propionate 0.351% W/W% HFA 227 97.899% W/W% alcohol 1.500% W/W% PEG 6000 0.250% W/W% Total Amount 100.000% W/W% Formula Example VIII: erol HCl 0.014% W/W% Ciclesonide 0.286% W/W% HFA 227 98.950% W/W% alcohol 0.500% W/W% PEG 100 1.000% W/W% Total Amount 100.000% W/W% Formula Example IX: Albuterol sulfate 0.396% W/W% I-IFA 134a 96.604% W/W% alcohol 2.500% W/W% PEG 6000 0.500% W/W% Total Amount 100.000% W/W% Fonnula Example X: Albuterol e 0.168% W/W% Beclomethasone dipropionate 0.286% W/W% HFA 134a 96.546% W/W% l 1 .500% W/W% PEG 100 1.500% W/W% Total Amount 100.000% W/W% Formula Example XI: Procaterol HCl 0.014% W/W% Beclomethasone dipropionate 0.286% W/W% HFA 227 98.950% W/W% alcohol 0.250% W/W% PEG 400 0.500% W/W% Total Amount 100.000% W/W0 o Embodiments l. A method of ing a metered dose inhaler composition, comprising steps of: a) mixing 0.05%-10% (w/w%) alcohol with a surfactant to form a first mixture; b) sing a beta-2 t in the first mixture to form a second mixture; 0) adding a hydrofluoroalkane (HFA) propellant into the second mixture to form a third mixture; d) dispersing a corticosteroid in the third mixture; and e) performing a filling step. 2. A method of preparing a metered dose inhaler composition, comprising steps of: a) mixing 0.05%~lO% (w/w%) alcohol with a surfactant to form a first mixture; b) dispersing a beta-2 agonist in the first mixtureto form a second mixture; c) adding HFA into the second mixture to form a third mixture; and d) dispersing a corticosteroid in the third mixture. 3. A method of preparing a metered dose inhaler composition, sing steps of: a) mixing 0.05%—0.25% (w/w%) alcohol with a surfactant to form a first mixture; b) dispersing a beta-2 agonist in the first mixture to form a second mixture; and 0) adding HFA into the second mixture to form a third mixture. 4. A method of ment 1, wherein the the corticosteroid includes one selected from a group consisting of budesonide, fluticasone, beclomethasone, ciclesonide, fluticasone propionate, beclomethasone dipropionate and a ation thereof. 5. A method of ment 1, wherein the beta-2 agonist includes one selected from a group consisting of albuterol, procaterol, formoterol, albuterol sulfate, procaterol hydrochloride, formoterol fumarate and a ation thereof. 6. A method of embodiment 1, wherein the l solvent is ethanol absolute. 7. A method of embodiment 1, wherein the mixing step is performed by ultrasonic vibration. 8. A method of embodiment 5, wherein the alcohol solvent preferably has an addition percent ranged from 0.25%—2% (w/w%). 9. A method of embodiment 1, wherein the surfactant includes a polyethylene glycol (PEG) having a molecular weight ranged from 100 to 6000. 10. A method of ment 9, wherein the surfactant preferably has an addition percent ranged from 0.01%-2.5% (w/w%). 11. A method of embodiment 9, wherein the surfactant preferably has an addition percent ranged from 0.05%~l.5% (w/W%). 12. A method of embodiment 1, wherein the HFA propellant includes one ofHFA 134a and HFA 227. 13. A method of ment 12, wherein the HFA propellant may include a combination ofHFA 134a and HFA 227. 14. A d dose inhaler ition prepared according to the method as claimed in embodiment 1, wherein the composition is used as one of an emergency drug for a subject suffering an asthma attack and a drug during an eccentric therapy for the t, wherein the subject has one of asthma and chronic obstructive pulmonary disease, and the drug in the eccentric therapy is administrated to the subject when the subject is in a condition being one of before and after sleeping.

While the invention has been described in terms of what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention needs not be limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications and similar arrangements included within the spirit and scope of the appended claims which are to be accorded with the broadest interpretation so as to encompass all such modifications and similar structures.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. l is a diagram illustrating the analysis of the delivery dose uniformity for nide ofFormula Example I.

Fig. 2 is a diagram illustrating the analysis of the ry dose mity for Procaterol HCI ofFormula Example I.

Figs. 3 is a m illustrating the analysis of particle size distribution for Budesonide ula Example I. 1: actuator 2: L—throst 3: Stage 1 + Stage 2 4: Stage 3 : Stage 4 6: Stage 5 7: Stage 6 + Stage 7 + orifice collector (MOC) Fig. 4 is a m illustrating the analysis of particle size distribution for Procaterol HCl ofFormula Example I. 1: actuator 2: L—throst 3: Stage 1 + Stage 2 4: Stage 3 : Stage 4 6: Stage 5 7: Stage 6 + Stage 7 + micro—orifice collector (MOC) Fig. 5 is a diagram illustrating the analysis of the delivery dose uniformity for Fluticasone ofFormula e VII.

Fig. 6 is a m rating the analysis of particle size distribution for Fluticasone ofFormula Example VII. 1: actuator 22 L—throst 3: Stage 1 4: Stage 2 : Stage 3 6: Stage 4 7: Stage 5 8: Stage 6 9: Stage 7 : micro—orifice collector (MOC) Fig. 7 is a diagram illustrating the analysis of the delivery dose uniformity for Albuterol e ofFormula Example IX.

Fig. 8 is a diagram illustrating the analysis of particle size distribution for Albuterol sulfate ofFormula Example IX. 1: actuator 2: L-throst 3: Stage 1 4: Stage 2 : Stage 3 6: Stage 4 7: Stage 5 8: Stage 6 9: Stage 7 : orifice collector (MOC)

Claims (9)

WHAT IS CLAIMED IS:

1. A method ofpreparing a metered dose inhaler composition, comprising steps of: a) mixing 0.05%-10.0% (w/w%) alcohol with 0.01%-2.5% (w/w%) polyethylene glycol (PEG) to form a first mixture; b) dispersing a beta-2 agonist in the first e to form a second e; c) adding a hydrofluoroalkane (HFA) propellant into the second mixture to form a third mixture; and d) dispersing a corticosteroid in the third mixture.

2. A method as claimed in Claim 1, wherein the corticosteroid includes one selected from a group consisting of budesonide, fluticasone, ethasone, ciclesonide, fluticasone propionate, beclomethasone dipropionate and a combination thereof.

3. A method as claimed in Claim 1 or 2, wherein the beta-2 agonist includes one selected from a- group consisting of albuterol, procaterol, erol, albuterol sulfate, procaterol hydrochloride, erol fumarate and a combination thereof.

4. A method as claimed in any one of Claims 1 to 3, wherein the alcohol has an addition percent ranged from 2.0% (w/W%).

5. A method as claimed in any one of Claims 1 to 4, wherein the polyethylene glycol (PEG) has a molecular weight ranged from 100 to 6000.

6. A method as d in any one of Claims 1 to 5, wherein the polyethylene glycol (PEG) has an addition percent ranged from 0.05%-l.50% (w/w%).

7. A method as claimed in any one of Claims 1 to 6, wherein the HFA propellant es at least one ofHFA 134a and HFA 227.

8. A method as claimed in any one of Claims 1 to 7, wherein the method further comprises the step of: e) performing a filling step.

9. A metered dose inhaler composition which is prepared according to the method as claimed in any one of Claims 1 to 8.