TW200529882A - Stable medicinal solution formulations for pressurized matered dose inhalers - Google Patents

Abstract

A medicinal aerosol solution formulation product comprising a pressurized metered dose inhaler and a medicinal aerosol formulation for use in the metered dose inhaler which comprise 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-ethylethyl]amino] ethyl]-2(1H)-quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), as an active ingredient, a propellant containing a hydrofluoroalkane, and a cosolvent, wherein the active ingredient is stabilized by addition of a specific small amount of a high concentrated phosphoric acid and optionally by the use of a suitable canister having part or all of its internal metallic surfaces lined with an inert organic coating and equipped with a metering valve provided with sealing rings made of a vulcanisate of an elastomeric composition of a butyl rubber.

Description

200529882 (1) IX. Description of the invention [Technical field to which the invention belongs] The present invention relates to a stable pharmaceutical aerosol formulation product, which includes an HFA solution formulation and a pressurized formulation suitable for aerosol administration Dose inhalers (MDIs). In particular, the present invention relates to solution formulations delivered by pressurized given-dose inhalers (MDIs) that are suitable for aerosol administration, and which contain 8-hydrazone-5-[(1R)-1-trend 2-([(1R) — 2- (4-monomethoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1H) -D quinolinone or its salt (salt Acid salt, hereinafter referred to as TA2 005), which is stable at room temperature for a pharmaceutically acceptable storage period [prior art] Pressurized given-dose inhalers (MDIs) are well-known for inhaling pharmaceutical products through inhalation Device for delivery to the respiratory tract. MDIs include a pressure-resistant aerosol can or container, typically filled with a pharmaceutical formulation such as a drug dissolved in a liquefied propellant or micronized particles suspended in a liquefied propellant, where the tank is equipped with a metering device. valve. The activation of the metering valve can cause the release of a small amount of spray product, and the pressure of the liquefied propellant will bring the dissolved or micronized drug particles out of the container to the patient. The valve actuator is used to direct the aerosol to the patient's oropharynx. Typically, the valve includes a rubber valve seal (diaphragm or gasket) designed to cause the valve stem to move back and forth while preventing the propellant from leaking out of the container. The rubber valve seal is often made of an elastomer material based on the traditional technology of synthetic or natural rubber polymer sulfur -5- 200529882 (2). _ As mentioned above, 'MDIs use propellants to expel droplets containing pharmaceutical products into the respiratory tract as aerosols. Administration through MDIs aerosols can be formulated as solutions or suspensions. Solution formulations can provide the advantage of uniform distribution of active ingredients and excipients that are completely dissolved in the propellant vehicle or its mixture with a suitable co-solvent such as ethanol. Solution formulations also avoid the physical stability issues associated with suspension formulations to ensure more uniform p-dosing. Since halogenated propellants such as chlorofluorocarbons, often referred to as Freon or CFCs, have been banned because they are known to deplete the ozone layer, there have been considerations of appropriate propellant systems, HFCs or HFAs. This is an alkyl molecule with fluorine and hydrogen moieties on the carbon backbone. The formulation of the present invention contains a liquefied propellant, that is, an HFA propellant, which is selected from the group consisting of HFA 134a (l, 1,1,2-tetrafluoroethane) and HFA 227 (1,1,1,2,3,3 , 3-Heptafluoropropane) and their mixture. φ The formulation is preferably in the form of a solution in which the active ingredient is completely dissolved. Due to the higher polarity of HFA propellants, especially HFA 134a (dielectric constant t D > 9.5) relative to CFC vehicle (D22.3), HFA solution formulations may suffer from a greater degree of chemical stability issues. ν When considering the bronchodilator / 3 2 -agonist, which belongs to the class of benzylamine derivatives, the preparation of stable HFA solution formulations is more critical, especially 8-hydroxyl 5- [(1R) — 1 -Hydroxy-2-[[((1R) — 2 -— (4-monomethoxyphenyl) -1-methylethyl] amino]]-6-6 200529882 (3) Qualitative Questions The oxy D quinolinone is dosed, and its chemistry is provided for drug supply ([(Base) acetate (under storage). Preparation of inhaler [(1R base) -based base]-2 (1 Η) -Zolinolinone suffers from chemical stability in such vehicles and is highly sensitive to chemical degradation. It also has experimental codes TA 2 005 and CHF 4226 of 8 — ^-[(1 R) — 1 monohydroxy-2 — [[(1R) — 2- (4-phenyl) -1-methylethyl] amino] ethyl] -2 (1H) -hydrochloride is a high potency / 5 2 -adrenergic agonist And many other drugs that can be administered with MDIs are significantly lower. Because the concentration in aerosol formulations is very low and this factor, coupled with physical properties, increases the Difficulty in formulating qualitatively and using GDI for a good dose of attention. In consideration of the above problems, it is very advantageous to improve the formulation of HFA solution in the form of MDI s. The goal is to learn the dosage 8-Hydroxy-5-[(1R) — 1-Hydroxy-2-1R) — 2 — (4-Methoxyphenyl) -1-methylethyl] amino] -2 (1 Η)- Quinolinone and its therapeutic salt, especially the salt, that is, TA 200 5), does not need to be refrigerated, and maintains chemical and physical stability during the period of temperature storage and has a longevity. [Summary of the Invention] in The technical problem underlying the present invention is to provide a pharmaceutical aerosol product, which includes an HFA solution formulation and a given dose (MDI). The inhaler can convert a pharmaceutical dose of 8-hydroxyl-5-)-1-hydroxyl — 2 — [[(1R) — 2 — (4-monomethoxy_ 1 monomethylethyl] amino] ethyl] —2 (1Η) —quinolinone or its salt as 200529882 (4) is active Ingredients are supplied into the lower respiratory tract of patients with lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), where the activity The chemical stability of the compound can be improved, and the lifespan of the drug aerosol formulation product containing such active compounds can be prolonged. [Embodiment] Detailed description of preferred specific examples According to the present invention, a drug aerosol formulation product with improved chemical stability is provided. The product includes a pharmaceutical composition including 8-based groups as active compounds in a liquefied HFA propellant solution. (1 R) — 1—Cyclo-2— [[(1 R) — 2- (4-methoxyphenyl)-1-methylethyl] amino] ethyl] -2 (1H)- D quinolinone or a salt thereof, especially a hydrochloride salt, a co-solvent selected from pharmaceutically acceptable alcohols, and a specific amount of high concentration (ie, higher than about 10M ', preferably higher than about 12M and especially about 15M) phosphoric acid. The composition φ of the present invention is contained in a pressurized given-dose inhaler. The inhaler includes an aerosol canister. The canister is equipped with a metering valve. The crosslinking agent used in butyl rubber and the accelerator used in the crosslinking agent. A ring and / or gasket made of a vulcanizing agent for an elastomer composition, wherein the accelerator includes a polysulfide compound derived from a substituted dithiocarbonic acid or a derivative thereof. Part or all of the internal metal surface of the pressurized MDI is made of stainless steel 'anodized aluminum or lined with an inert organic coating. In fact, it has been found that in the 8-hydroxy-5-[(1 R)-1 --8-200529882 (5) hydroxy-2-[[(1R)-2-(4 -methoxyphenyl)- In the case of 1-methylethyl] amino] ethyl] -1 2 (1 Η) -D quinolinone or its salt, the chemical stability in the HFA solution formulation can be due to the specific amount of high concentration phosphoric acid contained And by choosing the right tank type and type of metering valve gasket material, huge improvements have been made. As proven and detailed below, TA 2005 can be stabilized better with high concentrations of phosphoric acid, and especially with 15 M phosphoric acid. Furthermore, it has been noted that the stabilizing effect of phosphoric acid is not strictly related to its w / w% amount in the formulation, and its content concentration range is from 0.0004 to 0.040% by weight based on the total weight of the formulation. The apparent pH range of the solution is 2.5-5.5, preferably 3.0-5.5, and more preferably 3.5-5.0 ° On the other hand, it has been observed that the formulation of compound TA 2005 in HFA propellant solution is stable Performance can be improved when stored in an MDI container equipped with a valve containing a seal ring and / or gasket of an elastic material including a special type of butyl rubber. According to a first specific example of the present invention, a pressurized MDI is provided for administering a medicament. The pressurized MDI includes a container containing a medical composition including 8-hydroxyl 5-[(1 R )-1 monohydroxy-2— [[(1R) — 2- (4-methoxyphenyl) -1 monomethylethyl]

Amine] ethyl] -2 (1 Η)-D quinolinone in HF A 1 34a as a propellant solution, the matrix in turn contains from about 8 to about 1 5% w / w ethanol as A co-solvent, and further comprising 85% phosphoric acid (15.2M) from 0.0004% w / w to 0.075%. 200529882 (6) The apparent pH of the solution is between 3.0 and 5.5. The unit "% w / w" means the weight percentage of the ingredient relative to the total weight of the composition. The adjective "apparent" is the actual characteristic of an aqueous liquid when it is used at pH when water is the main component (mol fraction> 0.95). In quite aprotic solvents, such as the HFA-ethanol vehicle used in these studies, the protons are not hydrated; their activity coefficients are significantly different from those in aqueous solutions. Although the Nernst equation for EMF can be applied here and the pH meter glass electrode system will produce a variable milli-volt output 値 based on the proton concentration and the polarity of the vehicle, the “pH” reading 値 is not the actual pH value. The count 値 represents an apparent p Η or acidity function (p Η ′). The apparent pH of the pharmaceutical solution formulation of the present invention can be measured according to the mode described in the applicant's EP 1 1 5 7 6 8 9. The active ingredients contained in these compositions filled in the container have good chemical stability at room temperature and storage period and are related to "Stability Testing of new Active Substances (and Medicinal φ Paducts)" (new active substance (And stability testing of pharmaceutical products) as described in the ICH Guideline QIA, where significant changes to pharmaceutical products are defined as those that have a 5% change from the beginning of the test. • The pharmaceutical composition of the present invention may further contain other excipients and especially < low volatile ingredients to increase the mass aerodynamic diameter (MMAD) of the aerosol particles when the inhaler is actuated. However, in a preferred embodiment, the addition of other ingredients to the composition is avoided. In WO 9 8/3 4 5 9 6 the applicant describes a solution composition for use in an aerosol inhaler -10- 200529882 (7) comprising an active substance, a hydrofluoroalkane (HF A ), A co-solvent and further includes a low volatility component to increase the mass aerodynamic diameter (M MAD) of the aerosol particles when the inhaler is actuated. The application does not address the issue of chemical stability of the active ingredients, but rather concerns drug delivery to the lungs. In the application filed on 23/11/99, International Patent Application No. PCT / EP99 / 09002 published on June 2, 2000, the applicant disclosed that the active ingredient contained in a HFC propellant, a co-solvent and The pressurized M DI s used for the distribution of the solution of the selected low-volatile component is characterized in that part or all of the inner surface of the inhaler is made of stainless steel or anodized aluminum, or is coated with an inert organic coating. lining. The '60 8 application does not mention mineral acids and, in particular, carbonic acid serves to improve the chemical stability of the active ingredients contained in the composition. Instead, it states that ipratvopium bromide (one of the possible active ingredients) is stable in a particular type of tank, with or without acid. EP 6 7 3 2 4 0 proposes the use of acids as stabilizers to prevent chemical degradation of the active ingredients in aerosol solution formulations including H F A s. Most of its examples are related to i Pratr opia p i u m b 1 · 0 m i d e, an anticholinergic drug, and only one example is proposed for a / 5 2 -agonist, namely fenoterol. Although salbutamol is claimed, no example formulation is proposed. Its stability is reported based on ipratropium bromide only and no distinction is made between the use of organic and inorganic acids. Among the possible inorganic acids, phosphoric acid is the only quoter. Furthermore, in addition to ip 1.atr 〇piumbr 〇mide, in EP 6 7 3 2 4 0, for the need to add -11-200529882 (8) to stabilize the drug without damaging the entire composition in the tank No guidance is given on the amount of acid required for stability. The only hint appears on page 5, lines 15 to 16 where it is mentioned that the amount of inorganic acid must be added to obtain a pH 从 from 1 to 7, and is therefore a very broad and general range. In the applicant's EP 1 157 689 ('689), stability data of HFA 134a solution formulations stabilized by different amounts of HC1 0.08M (1.0 and 1.4 microliters) are reported, the formulations containing 8-hydroxyl groups -5-[(_ 1R) — 1—hydroxyl 2— [[(1R) — 2— (4-methoxyphenyl) 1 1 methylethyl] amino] ethyl] 2 (1H ) -Quinolinone hydrochloride (TA 200 5) 3.5 μg / 50 μl dose, 12% w / w ethanol, 1 ° / 0 w / w isopropyl myristate (Example 7). The formulation appears to impart very good stability. However, when the inventors of the present case repeated the test, they found that the active ingredient was gradually degraded in the formulation. Furthermore, the formulation exemplified in '6 89 contains isopropyl myristate as φ as a low-volatile compound in order to increase the MM A D (mass intermediate aerodynamic diameter) of the particles to be delivered. It was subsequently discovered that it is extremely advantageous to provide highly efficient TA 2 0 5 formulations, which are characterized by a significant amount of at least 30%, with fine particles having a diameter equal to or less than 1.1 micrometers to reach deeper lungs Infiltrate. Therefore, the use of low-volatile compounds must be avoided. It was also later found that in such a localized formulation having the characteristics of particles equal to or less than 1.1 micrometers containing a component, higher than 30%, and even higher than 50% or higher, It can contain very low concentrations of τα 2 05, based on the total volume of the composition, starting from 0.0005% w / xv. -12- 200529882 (9) The constituent property is described in any of the applicant's previous applications, 03 / 074〇25 (f〇25), in which it is reported that the one stabilized by HC1 includes 8-hydroxyl 5 — [(1R) — 1—hydroxy—2-[% 1R) — 2— (4-methoxyphenyl) —1—methylethyl] amino] —2 (1 Η)-D Stability data for HFA formulations of quinolinone hydrochloride (TA 2 00 5). Stability is measured at 5 ° C when stored upright: In this refrigerated condition, after 9 months, 4 micrograms of active compound can be delivered per actuation of the formulation, and its TA 2005 test is higher than 95%. However, the inventors of the present case have found that the active ingredients in the formulation are rapidly degraded when present in lower concentrations and under storage conditions. On the other hand, refrigeration is not appropriate because many patients need aerosol cans on their bodies. According to the first aspect of the present invention, the inventor of the present case found that although the preferred mineral acid of hydrochloric acid is W 2 5, 8 -hydroxyl 5-_ 1R)-i -hydroxyl 2-[[(1R)- The chemical stability of 2- (4-methoxybenzo-1-methylethyl] amino] ethyl] -2 (ih) -quinolinone can be from a small amount of high-concentration phosphoric acid, preferably 5M phosphoric acid Enclosed between 0.00 0 8 and 0.001% w / w in the acid regulator, the active ingredient can be increased by 8 -hydroxy-5-[(1 R) —;! -Hydroxy-2 [[(1R) — 2— (4-Methoxyphenyl) -1-methylethyl]] ethyl] -2 (1 Η) -D quinolinone and its salts more preferably stabilize the mineral acid in the substance to be phosphoric acid. The aerosol formulation of phosphoric acid can surprisingly be WO-qualified at room temperature. [(] B solution is subjected to other gas ((base) salt, encapsulation. Other amine-based preparation stable-13- 200529882 (10) Generally long life. As mentioned above, the pharmaceutical aerosol solution formulation of the present invention may be contained in a pressurized given-dose inhaler, which includes an aerosol can Advantageously, a metering valve is equipped, which is equipped with a sealing ring made of butyl rubber, a crosslinking agent used in the butyl rubber, and a vulcanizate of an elastomer composition of the accelerator used in the crosslinking agent, and / Or gaskets, where the accelerator includes a polysulfide compound derived from substituted disulfuric carbonic acid or a derivative thereof. P In certain prior art documents, such as W 0 9 3/1 1 7 4 3 p. 8, p. Line 4-9, WO 02/02167, page 13, line 16 to page 14, line 23, among which halobutyl or butyl rubber and other elastomeric materials such as low density polyethylene, black and White butadiene-acrylonitrile rubber, neoprene rubber, and many others are equally described as valves for a given dose inhaler to be pressurized with a hydrogen carbon compound (HFA or HFC) propellant Materials for gaskets in the same. Separately, described in EP 7 0 8 8 0 5, including diaphragms (ie, pads 0 ring or seal ring), etc. made of neo-flat rubber (polychloroprene), butyl rubber or butyl Traditional device made of diene-acrylonitrile (buna) rubber Will cause HFC-1 3 4 a or HFC — 2 2 7 to leak from some formulations over time. Such leaks may cause a substantial increase in the concentration of the active ingredient in the formulation, leading to incorrect dosages In addition, in some formulations, during the actuation cycle, the valve stem tends to stick, stop, or brake. In order to solve these problems, in ep 7 0 8 8 0 5 It is stable to dimensional changes when exposed to HFC-134, including diaphragm material of ethylene-propylene-diene (EPDM) rubber. -14- 200529882 (11) Recently, W 0 0 3/0 7 8 5 3 8 in Bespak claims a seal for a valve used in a medicine dispensing device, which consists of one or more Polyisobutylene, polybutene, butyl rubber, halogenated butyl rubber, and derivatives of special elastomeric compositions. The particular elastomeric composition actually includes an isobutylene polymer or copolymer, a cross-linking agent, and an accelerator for the cross-linking agent, wherein the accelerator includes a polysulfide compound derived from dithiocarbonic acid or a derivative thereof . In EP 1 15 7 689 of the applicant of this application, it is mentioned that the metering valve provided with a gasket made of rubber based on chloroprene can be used to reduce the possibility of adversely affecting drug stability. Immersion of water vapor (pages 5-14). Furthermore, in WO 03/024 025 of the applicant of the present case, butyl rubber is listed in many other suitable elastomeric materials used in the mat. Preferred are EPDM (ethylene-propylene-diene monomer) rubber and EP (thermoplastic elastomer). EP DM is particularly preferred (page 16, lines 8-12). However, the inventors of the present case have now discovered that the active compound of the present invention dissolved in a solution containing HFA propellant and co-solvent and further including phosphoric acid, is stored in a valve equipped and has a composition consisting of WO 03/0 7 8 5 3 8 The gasket and / or sealing ring made of the special type of butyl rubber elastic material has good chemical stability when placed in a tank. Butyl rubber is a copolymer made from a small amount of diene, such as isoprene (2-methylbutane 1,3-diene). Typically, according to the present invention, butyl rubber includes about 97% isobutene and about 3% isoprene, and it can be polymerized using an aluminum chloride catalyst. -15- 200529882 (12) For the purpose of the present invention, particularly preferred is a halogenated butyl rubber having the above composition (about 97% isobutyl i: Greek and about 3% isoprene storage), the best of which For bromobutyl rubber. Crosslinkers (also known as curing agents) can provide or assist in network formation to lead to three-dimensional polymer network construction. The cross-linking agent can act by reacting with the functional group of the polymer chain. Crosslinking agents typically include sulfur or sulfur-containing compounds. The cross-linking agent is preferably substantially free of any peroxide curing agent such as diisopropyl peroxide. The polysulfide compound used as an accelerator is preferably one derived from substituted xanthic acid or a derivative thereof, and more preferably R 0 C (S) S Η type, wherein R is typically C 1 -C6 alkane base. The substituent in the polysulfide compound typically includes an isopropyl group. The polysulfide compound preferably includes three or more bridged sulfur atoms, and more preferably 3, 4 or 5 bridged sulfur atoms. The polysulfide compound is preferably substantially free of nitrogen, phosphorus and metal elements. Advantageously, the polysulfide compound system comprises diisopropylxanthine polysulfide. The elastomer composition used to prepare the vulcanizate typically includes up to 3% by weight of the accelerator based on the total weight of the accelerator and butyl rubber in the composition, and more typically the accelerator and butyl in the composition The total rubber weight is as high as 1.5 weight based on the total weight. The accelerator is still more typically up to 1% by weight based on the total weight of the accelerator and the butyl rubber. The weight ratio of the accelerator to the crosslinking agent in the elastomer composition is better -16-200529882 (13) is in the range from 1: 1 to 3: 1, and more preferably from 1: 1 to 2: 1 . The sealing ring and / or gasket may further include a material, preferably a mineral material, a processing aid, preferably a low molecular weight polyethylene, and other auxiliary components, such as in WO 03/0 78538, page 9 , Lines 28 to 10, as defined in line 26, the disclosure of which is explicitly included in this application 0 The sealing ring and / or gasket of the metering valve may be incorporated in separate components or may be combined with the valve Formed integrally. Preferably, these rubbers are extracted into the given metered-dose inhaler after extraction with a suitable pharmaceutically acceptable solvent, and preferably warm ethanol. In general, controls that are pharmaceutically acceptable and have sufficient ability to extract oxides and peroxides can be used. According to another aspect of the present invention, there is provided a method for loading an aerosol inhaler with the composition of the present invention, the method comprising: (a) preparing 8-Cyclo-5— [(1R) — 1-Cyclo-2 -[[(1R) — 2- (4-methoxyphenyl)-1-methylethyl] amino] ethyl]-2 (1H)-D quinolinone or a salt thereof The solution in the solvent, if necessary, contains another active ingredient or excipient or an appropriate amount of low-volatile ingredients; (b) using the solution to decorate the device; (c) adding a predetermined amount of phosphoric acid; (d) adding containing Hydroflurane (HFA) propellant; and (e) compacted and aerated with a valve. The active ingredient used in the aerosol composition of the present invention is long-term acting -17- 200529882 (14) / 3 2 —adrenergic agonist 8-hydroxy-5-5 [(1 r) -1 1-hydroxy-2— [[(1R) — 2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] -2 (1 Η)-D quinolinone or a pharmaceutically acceptable salt thereof It is also combined with other active ingredients and in particular corticosteroids or antimonocarpine drugs. Examples of corticosteroids are: beclomethasone dipropionate, fluticasone propionate, butixocort, mometasone furoate 'triamcinolone acetonide, budesonide and its 22R-epomeromer (22R- epimer), ciclesonide and roflep ο n ide. Examples of antimuscarinic drugs are ipratropium bromide, oxitropium bromide, and tiotropiuni bromide. 0—Cyclo-5— [(1R) — 1—Cyclo 2— [[(ir) — 2 — (4 —methoxy Phenyl)-1-methylethyl] amino] ethyl] _2 (1 Η)-The preferred salt of quinolinone is the hydrochloride salt, sometimes called TA 2 0 0 5 〇 Although the present invention is preferred The formulation is in the form of a solution. In the case of a composition, one of the two active ingredients may be present in the suspension. TA 2 0 0 5 can be prepared as described in US Patent No. RE 3 3,024. 0 We prefer to make the formulation suitable for administering a therapeutic amount of active ingredient in one or two actuations. Preferably, the formulation is suitable for administration of 0.5-6 micrograms / dose, more preferably 1 to 4 micrograms / dose and especially 1 to 2 micrograms / dose, or 2 to 3 micrograms / dose, alone Or in combination. "Dose" herein means the amount of active ingredient delivered by a single actuation of the inhaler. -18- 200529882 (15) The formulation of the present invention is preferably provided with a pad on part or all of its internal surface In a pot with an inert organic coating. Examples of preferred coatings are epoxy-benzene resins, perfluorinated oxygen compounds, perfluorinated oxygen compounds, perfluorinated oxyalkynes such as polytetrafluoroethylene, fluorinated Copolymer of ethylene-propylene, polyether, and fluorinated ethylene-propylene polyether. Other suitable coatings may be polyamine, polyimide, polyimide, polyphenylene ether, or a combination thereof In order to further improve the stability, cans with rolled edges and some or more rolled edges can be used. The formulation is capable of delivering between 50 microliters and 100 micrometers. The metering valve of the volume between liters is actuated. As mentioned before, in order to further improve the stability of the active ingredient in the formulation 'preferably, the metering valve is equipped with butyl rubber, especially in WO 03 / 0 7 8 5 3 8 Types of bromobutyl rubber, gaskets made of them The propellant is preferably selected from the group consisting of HFA 134a, HFA φ 2 2 7 and their mixtures. The co-solvent is usually an alcohol, preferably ethanol. The apparent pH range is in the range of favorable Between 2.5 and 5.5, the better is between • 3 · 0 and 5 · 5, and even better is between 3.5 and 5.0. It is quite thick, that is, higher than 10 Μ, the better is higher At 1 2 M and the best is about 15 M,% phosphoric acid is used as a stabilizer and is used to adjust the apparent pH. The amount of acid to be added to achieve the desired apparent pH can be used in EP 1 1 5 7 68 9 It is predetermined in the model vehicle reported in the report. Active ingredient 8 -hydroxyl 5 — [(1 R)-1 -hydroxyl 2 — [-19- 200529882 (16) [(1R) — 2— (4 Monomethoxyphenyl)-1-methylethyl] amino] ethyl] -2 (1 Η) —quinolinone or a salt thereof is stabilized with a relatively concentrated 'preferable' 15 M phosphoric acid In particular, it is preferable that the amount of phosphoric acid added is equal to 0.004 to 0.04 0% w / w of 15 M phosphoric acid based on the total weight of the composition, and more preferably the total weight of the composition is Baseline 0.0 0 0 8 to 0.0 2 0% w / w of 1 5M phosphoric acid, more preferably 0.00 1 to 0.0 1 0% w / w of 1 5M phosphoric acid, and even more preferably 0.002 to 0.0075 based on the total weight of the composition φ % w / w of 1 5M phosphoric acid. For the purpose of the present invention, phosphoric acid with a low concentration other than 15 M can still be used. In this case, those skilled in the art can obtain from the Reveal the correct percentage usage. In this specific example, it is also preferred to avoid adding other excipients or low volatility ingredients to increase the particle size of particles less than or equal to 1.1 microns to at least 30%, and to provide deeper lung penetration . 8 —Cyclo-5— [(1R)-1—Cyclo—2— [[(1R)-φ 2— (4-Methoxyphenyl) -1-methylethyl] amino] ethyl 〕 -2 (1 Η) -Quinolinone concentration varies between 0.00 55% and 0.02 4% w / v based on the total volume of the composition to deliver 0.5-6 micrograms / actuation •, better This is at 0.001 ° / based on the total volume of the composition. And 0.016% w / v to deliver 1 to 4 micrograms / actuation, more preferably between 0.001% and 0.00 8% w / v based on the total volume of the composition to deliver 1 to 2 Μg / actuation. For example, for 1 and 2 micrograms / dose, when using 63 microliters of metered volume, the final concentration of the hydrochloride TA 200 5 delivered per actuation is -20 respectively based on the total volume of the composition -200529882 (17) 0.0 0 16% and 0.0 0 3 2 ° / 〇w / V. The co-solvent content in the composition is suitably 6 to 30% based on the total weight of the composition, preferably 5 to 25% w / w, more preferably 5 to 20% w / w, or even more preferably In these cases, the stability of TA 2 0 5 is improved even at very low dose concentrations of 0.5 or 1 μg / actuation in these cases. The stabilizing effect of phosphoric acid is also included in another active ingredient, budes nide I, an anti-inflammatory 20-keto steroid, tested in TA 2005 HFA formulations and in compliance with the formulation in HFA aerosol solution formulations. Chemical stability issues. Other features of the invention will become apparent from the following description of specific examples given to illustrate the invention without intending to limit it. EXAMPLES In the following examples and comparative examples, and throughout this specification, all parts and percentages of φ are by weight, and all temperatures are in ° C unless explicitly stated otherwise. Comparative Example 1 (Example 7 corresponding to EP 1 1 5 7 6 8 9) Acidified 8-hydroxyl 5-[(1 R)-1 -hydroxyl 2-[

[(1R) — 2 -— (4-methoxyphenyl) -1 methylethyl] amino] ethyl] -2 (1H) quinolinone hydrochloride (TA 2005) — HFA 1 3 4 a. Stability of solution in fluorocarbon polymer coated tanks. Via 8-hydroxy-5— [(1R) — 1 monohydroxy-2 — [[-21-200529882 (18) (1R) — 2— (4-methoxyphenyl) -1-methylethyl ] Amino] ethyl] -2 (1H) -quinolinone hydrochloride (TA 2005) (0.84 mg) dissolved in 12% w / w ethanol and 1.0% w / w myristic acid isopropyl A formulation of this active ingredient was prepared in the ester HTA 134a (3.5 μg / 50 μl). Filled with 1.0 and 1.4 microliters of 0.0 8 M hydrochloric acid (corresponding to the apparent pH of approximately 4.8 and 3.2, respectively), stored upright at 50 ° C, and sampled at appropriate intervals to analyze TA 2005 content . Table 1 shows the obtained stability data. Each figure is expressed as a percentage of the nominal drug concentration. The results indicate that formulations containing 1.0 to 1.4 microliters of 0.08M HC1, with an apparent pH 値 between 3.0 and 5.0, are stable for almost three months at 50 ° C. Table 1: 8-Hydroxy-5-[(1 R)-1 -Hydroxy-2-[[(1R)-2-(4-Methoxyphenyl) -1-methylethyl] Amine] ethyl] -2 (1H) -D quinolinone hydrochloride (TA 2005) formulation at 5 (TC stability data table 1 0.08M HC1 storage conditions microliter / tank starting 50 ° C; 22 Days Upright 5 (TC; 8 3 Days Upright 1.0 100.0 98.3 99.4 1 .4 100.0 98.2 98.8 -22- 200529882 (19) Comparative Example 2 (Example 1 corresponding to WO 03/0 7402 5) Use Table 2 below The formulation shown is prepared to deliver 1 μg of active ingredient per nominal dose of actuation. Table 2 Ingredient amount mg per unit nominal dose mg μg TA 2005 0.15 0.0 0 1 6 w / v 1 ethanol 1650 1 5 w / v-HC1 0.1M 2.0 * 0 · 0 1 8 w / w-HFA 134a, appropriate amount to 9.45 ml 9378.85--* equivalent to 2.0 microliters of this preparation (1 2 0 actuation / can, average 30 times (Motion) Installed in a φ aluminum can. The inner surface of the can is coated with Teflon and equipped with a metering valve with a 63 microliter metering cavity. An actuator with a caliber of 0.22 mm is used. Similar formulations at a nominal dose of 3 or 4 micrograms of active ingredient per actuation. Use 1 microgram / dose formulation to determine aerodynamic particle size distribution. Stabilize formulations capable of delivering 4 micrograms / actuation The study of sex started with the tank being stored upright at 5 ° C. The result was an average of 2 tanks. -23- 200529882 (20) After 9 months, 8-hydroxyl 5- [(1R ) — 1-Hydroxy-2— [[(1R) — 2— (4-methoxyphenyl)-1-methylethyl] amino] ethyl] -2 (1 Η) — D Quinolinone The hydrochloride test is higher than 95%, so it meets the requirements of ICH Guideline Q1 Α for "stability testing of new active substances (and pharmaceutical products)." Comparative Example 3 A two-aluminum can equipped with a commercially available valve with a 63 // 1 metering chamber was charged with the formulation shown in Table 3. Table 3 Ingredients per unit ___ mg% mg% 8-hydroxy-5-[(1 R)- 1-Hydroxy-2-[[(lR) -2- (4-methoxyphenyl) -bumethylethyl] amino] ethyl] -2 (1H) -D-quinolinone salt (TA2005) (1 μg / 63 μl) 〇 1 54 0 .00 1 6w / v 0.1 54 0.0016 w / v ethanol ΐ65〇〇15w / w 1 6 5 0.0 1 5 w / w hydrochloric acid 0.1 Μ 2 * ° 〇0.01 8w / w 3.00 0.0 2 7 w / w HF A 1 34a to 9.45 ml 9347 · 85-9346.85--24- 200529882 (21) Stability studies were performed by storing the formulation in an upright tank at 110 ° C and 75% relative temperature. After three months of storage under these conditions, the percentages of TA 2 0 5 were 73% and 77%, respectively. According to the results of Comparative Examples 1 to 3, if TA 2 0 5 is present in the solution formulation at a relatively high concentration (3.5 μg / 50 μl; 4 μg / 63 μl, respectively), JTA 2 00 5 (8 —Hydroxy-5— [(1R) — 1 —Hydroxy-2— [[(1R) — 2— (4-methoxyphenyl) -methylethyl] amino] ethyl] -2] (1 Η) -quinolinone hydrochloride) can be stabilized by using hydrochloride and refrigerated conditions. However, if it is present in a relatively low concentration of such active ingredients (eg 1 μg / 6 3 μl), it can no longer be stabilized with hydrochloric acid. Active ingredient 8 —Hydroxy-5 — [(1R) — 1-Hydroxy-2 — [[(1R) — 2 — (4-Methoxyphenyl) -1Methylethyl] amino] ethyl] -2 (1Η)-D Quinolinone hydrochloride is a very potent, long-acting Θ 2 -agonist that is active at very low dose strengths and should be administered at low concentrations. Furthermore, storage in refrigerators should also be avoided. However, as demonstrated by the results of the examples below, by using 0.0004 to 0.040% w / w equivalent based on the total weight of the composition, preferably 0.0008 to 0.020% w / w, and more preferably 0.001 To 〇 · 〇〇１〇% w / w, and more preferably 0.0 0 2 to 0.0 0 75% w / W of 1 5 M phosphoric acid, can be even very low concentrations (such as 1 μg / 63 μl) of 8 —Hydroxy-5 — [(1R) — 1—Hydroxy-2— [[(1R) — 2- (4-methoxyphenyl) — 1-methylethyl] amino] ethyl] -2 ( 1)) — 11 Quinolinone hydrochloride -25-200529882 (22) for stabilization. Example 1: Preparation using the following composition, using phosphoric acid instead of hydrochloric acid as a stabilizing agent-similar formulation% (see Table 4) to deliver 8-hydroxy-5-[(1R)- 1-hydroxy-2 — [[(1R) -2 — (4-monomethoxyphenyl) -1 1-methylethyl] amino] ethyl] -2

(1 Η) —Quinolinone hydrochloride i (TA 2005) Table 4: Nominal dose. Ingredient _ __ Amount per milligram% TA 2005 (1 μg / 63 μl) 0.154 0.00 1 6w / w (0.001 4w / v) ethanol 1650.0 15.000w / w phosphoric acid 1 5.2 μ 0.05 to 0.6 0.00045 to 0.0054w / w HFA 134a moderate to 9.72 milligrams to-liter 1 1,000 similarly 'can be prepared to be able to administer 0.5, 1.5, 2, 2.5, 3, 3 · 5 or 4 micrograms of active ingredient per actuated target Weigh the formulation. Fill the formulation in Table 4 (20 actuations / can, average 30 actuations) into an aluminum can. The inner surface of the can is coated with Tetlon and equipped with a metering valve with a 63 microliter metering cavity. . The formulation was stored in upright and inverted tanks, and the stability was investigated at 40 ° C and 75% phase -26- 200529882 (23). After 6 months of storage under these conditions, there is a very good percentage recovery of the active ingredient, with a residual TA 2 00 5 5% in the range of 0.001 to 0.0 027% w / λν phosphoric acid ^ specific content . A similar formulation was filled in a jar equipped with a metering valve fitted with a butyl rubber gasket as described in wo 0 3/0 7 8 5 3 8 (Bespak) above. In particular, the gasket is a bromobutyl rubber made of about 97% isobutene and about 3% isoprene, polymerized with an aluminum chloride catalyst, and treated with bromine to obtain the isoprene-isobutylene rubber. Made by. The same formulation was filled in the same type of tank, which was fitted with a valve with an EPDM rubber gasket. After three months, the percentage of TA 2 005 in a tank equipped with a bromobutyl rubber gasket in an upright and inverted position was 98% and 97%, respectively. The difference was stored in the upright and inverted position. On the contrary, the percentages of TA 2 0 5 in the formulation of the tank equipped with the valve with the EPD M rubber φ rubber gasket were 98 and 77%, respectively. The results obtained are the average of two cans. The obtained results show that the material of the valve will affect the chemical stability of the compound of the present invention. Valves with special bromobutyl rubber gaskets improve the stability of the compound in HFA solution formulations. «Stability tests are performed in both upright and inverted tanks. In the inverted position Φ 'throughout the duration of the test, the formulation system and the valve material directly ig check for possible chemical interactions with the valve material that may have a negative effect on the stability of the active ingredients in the formulation. In upright tanks, the interaction between the valve material -27- 200529882 (24) and the formulation is very limited and therefore the possible negative effects on the stability of the active ingredients in the formulation can be ignored. The stability of T A 2 0 0 5 may also be affected by the presence of metal ions released from the metal parts of the valve, especially the springs that may come in contact with the formulation. For this reason, particularly preferred is a spring made of a stainless steel alloy containing titanium.

Example 2: Two compositions were tested, which contained TA 2 0 0 5 and b u d e s n i d e as active ingredients and two different concentrations of phosphoric acid. Ingredient mg% w / W Budesonide 30.8 0.2800 TA200 5 (CHF 4226) 0.154 0.0014 Absolute ethanol 1650 15.0000 Water 16.5 0.1500 Phosphoric acid 8 5% (1 5 · 2 Μ) 0.35 or 0.7 0.003 2 or 0.0064 HFA 134a 9 3 02, 196 or 93 0 1.846 84,5 65 4 or 84.5 622 Total 1 1000 100.0000 Volume of valve: 63 microliters; concentration: TA 2 00 5 1 microgram + budes〇nide 200 micrograms / actuation; number of actuations: 120 (3 4塡 full dose). -28- 200529882 (25) After storage at 40 ° C and 75% relative humidity for three months, both active ingredients in the composition are stable, and TA 2005 with a residual content of at least 95% and about 100% Budesonide. Therefore, in the combination and in the presence of a small amount of water, phosphoric acid can also effectively stabilize T A 2 0 0 5.槪 Important: 'The present invention provides a pharmaceutical aerosol formulation product with improved chemical stability, which includes a pressurized given metered-dose inhaler (MDI), using a suitable mineral acid and using butyl rubber Aerosol formulations that are specifically stabilized as the material of the p-ring and / or gasket in the metering valve. Obviously, many modifications and variations can be made to the present invention from the above description. Therefore, it should be understood that, within the scope of the attached patent application, the present invention can be implemented in ways other than those specifically described herein. All patents and other references cited above are incorporated herein by reference in their entirety, as if fully listed.

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Claims (1)

200529882 (1) X. Patent application scope 1 · A drug aerosol formulation product with improved chemical stability, which includes a pressurized given dose inhaler, including an aerosol canister, wherein the aerosol canister Filled with a pharmaceutical aerosol formulation comprising 8-hydroxy-5— [(1 R) — 1-hydroxy-2 — [[(1 R) — 2 — (4 — methoxyphenyl)) 1 1 Methylethyl] amino] ethyl] -2 (1H) -D quinolinone or its salt, especially its hydrochloride (TA 2005), a liquefied HFA propellant, one selected from pharmaceutically acceptable Alcohol solvents and high concentration phosphoric acid, and the composition is in the form of a solution. 2 · A pharmaceutical aerosol formulation, which is in the form of a solution, and which includes 8 -hydroxyl 5-[(1R) _1 -hydroxyl 2-[[(1 R)-2-(4 -methoxy Phenyl) —1-methylethyl] amino] ethyl] 2 (1H) —D quinolinone or its salt, especially its hydrochloride (τα 2005), a liquefied HFA propellant, a A co-solvent selected from pharmaceutically acceptable alcohols, and a high concentration of phosphoric acid. 3. The pharmaceutical aerosol formulation according to item 2 of the patent application range, wherein the liquefied HFA propellant is at least one selected from the group consisting of HFA 134a, HFA 227, and mixtures thereof. 4. The pharmaceutical aerosol formulation according to item 2 or 3 of the patent application scope, wherein the co-solvent is ethanol. 5. The pharmaceutical aerosol formulation according to item 2 or 3 of the patent application, wherein the content of the phosphoric acid is 15M phosphoric acid equivalent to 0.0004 to 0.040% w / w based on the total weight of the composition. 6 · If the pharmaceutical aerosol formulation of the second or third item of the patent application-30-30200529882 (2) is used as a reference, the content of the phosphoric acid is equivalent to 0.0008 of the composition, BM + 1.5M phosphoric acid to 0.020% w / w. 7. The pharmaceutical aerosol formulation 1 according to the second or third item of the patent application, wherein the content of the phosphoric acid is equivalent to 0.001 to 0.0075% w / w of 1 5M phosphoric acid based on the total weight of the composition. 8. The pharmaceutical aerosol formulation according to item 2 or 3 of the patent application, which has an epidermal pH of 2.5 to 5.5. ^ 9. The pharmaceutical aerosol formulation according to item 2 or 3 of the patent application scope, which has an apparent pH of 3.0 to 5.0. 1 0 · The pharmaceutical aerosol formulation according to item 2 or 3 of the patent application scope, wherein the 8-hydroxy-5— [(1R) — 1 -hydroxyl 2 — [[(1R) — 2— (4 — The content of methoxyphenyl) -1methylethyl] amino] ethyl] -2 (1H) -quinolinone or a salt thereof is 0.0005% to 0.024 〇 / 〇w / v 〇11 · As applied The pharmaceutical aerosol formulation φ of the patent scope item 2 or 3, wherein the 8-hydroxy-5-5- [(1R) -1-hydroxy-1 2-[[((1R) — 2— (4-methoxymethoxybenzene Group)-1-methylethyl] amino] ethyl] -2 (1 Η) -quinolinone or a salt thereof in an amount of 0. 〇01% to 〇. 6% 6 w / v ° 1 2. The% of the pharmaceutical aerosol formulation as claimed in item 2 or 3 of the patent application, wherein the content of the co-solvent is 6% to 30% w / v. 1 3 · The pharmaceutical aerosol formulation according to item 2 or 3 of the scope of patent application, wherein the content of the co-solvent is 6% to 25% w / v. 1 4 · A pressurized given-dose inhaler comprising an aerosol canister containing a buckle ^ -31-200529882 (3) substance, wherein the composition includes 8 -hydroxyl 5-[(1 R)- 1-hydroxy-2— [[(1R) — 2— (4-methoxyphenyl) — 1 monomethylethyl] amino] ethyl] 2 (1H) —quinolinone or a salt thereof, Especially hydrochloride (TA 2005), a liquefied HFA propellant, a co-solvent selected from pharmaceutically acceptable alcohols, and a high concentration of phosphoric acid, wherein the composition is in the form of a solution, and the solution has 2 Apparent pH between 5 and 5 · 5. 15. If part or all of the internal metal surface of a pressurized given-dose inhaler such as item 14 of the scope of patent application is lined with an inert organic coating. 16 A pressurized given-dose inhaler 'is lined with a material selected from the group consisting of epoxy-phenol resins, perfluoroalkoxyalkanes, perfluoroalkoxyenes, perfluoroenes, polyethers, fluorinated -An inert organic coating in the group consisting of ethylene-propylene polyether master copolymer, or a combination thereof. 1 7 · If the pressurized given-dose inhaler according to item 14 or 15 of the scope of patent application is equipped with a metering valve with a sealing ring and / or gasket, the sealing ring and / or gasket is a Butyl rubber, a cross-linking agent used for the butyl rubber, and a sulfide of an elastomer composition of the accelerator used for the cross-linking agent, wherein the accelerator includes a dithiocarbonic acid or Polysulfide compounds derived from its derivatives. 18. The pressurized given-dose inhaler according to item 14 or 15 of the scope of the patent application, wherein the metering valve includes a valve spring made of a stainless steel alloy containing titanium. -32- 200529882 (4) 1 9. The pressurized given-dose inhaler according to item 14 or 15 of the scope of patent application, wherein the butyl rubber is composed of about 97% isobutene and about 3% isoprene And made of aluminum chloride catalyst for polymerization. 2 0. The pressurized given metered-dose inhaler according to item 19 of the scope of patent application, wherein the butyl rubber is bromobutyl rubber. 2 1 · A pressurized given-dose inhaler according to item 14 or 15 of the scope of patent application, wherein the crosslinking agent includes sulfur or a sulfur-administering compound. _ 22 · —A method of aerosol aerosol inhaler, the method comprises: (a) preparing a solution of one or more active ingredients in one or more co-solvents; (b) filling the inhaler with the solution; c) adding a predetermined amount of phosphoric acid to the solution; (d) adding a propellant including Hydrogen Fluorine (HFA) to the solution; and φ (e) using the metering valve to compact and pressurize, wherein the At least one of the active ingredients is 8-hydroxy-5 — [(1R) — 1 trivalent — 2 — [[(1R) — 2 — (4-methoxyphenyl) — 1 monomethylethyl ] Amino] ethyl] -2 (1H) -D quinolinone or its salt, especially its hydrochloride (TA 2005), whose content is based on the total weight of the final solution (% composition). 〇〇0 5% to 0 · 0 2 4% w / v, preferably 0.00 1% to 0.016% 16% w / v 'and the content of the phosphoric acid is equivalent to 0 based on the total weight of the final solution (composition) · 0.01 to 0.004 0% w / w, more preferably 0.001 to 0.0 3 0% w / w 'more preferably 0.002 to 0.027% w / w of 15M-33-200529882 (5) phosphoric acid. 2 3. The method according to item 22 of the scope of patent application, which is equipped with a metering valve equipped with a sealing ring and / or gasket, wherein the sealing ring and / or gasket is made of a butyl rubber and a butyl rubber. A cross-linking agent and a sulfide of an elastomer composition of the accelerator used in the cross-linking agent, wherein the accelerator includes a polysulfide compound derived from # ~ @ substituted dithiocarbonic acid or a derivative thereof. -34- 200529882 Qiwuming said that the simple and simple itutu symbol is the definitive figure finger table: the descriptive figure book, the table, and the one or two fingers. If the case can be the most revealing, you can learn: