Pharmaceutical emulsion composition

Abstract

Provided is a pharmaceutical emulsion composition having a small average particle diameter. The pharmaceutical emulsion composition contains (A) a surfactant, (B) water, and (C) the auxiliary agent, the auxiliary agent having an octanol / water partition coefficient Log P of 4.5 or more.

Description

Pharmaceutical Emulsion Composition

[0001] The present disclosure relates to a pharmaceutical emulsion composition.

[0002] As a therapeutic agent for chronic obstructive pulmonary disease (COPD) and asthma, the powder described in Patent Document 1 is used. In order to quickly reach the lungs and absorb the drug substance, it has a porous structure, and in order to form this porous structure, processing aids are currently used in pharmaceutical production. As the processing aid, a compound with low volatility (low vapor pressure) is preferred. Patent Documents 1 to 4 disclose perfluorooctyl bromide C ８ F １７ Br (PFOB), dichloroperfluorooctane C ８ F １６ Cl ２ 、perfluoroethyloctane C ８ F １７ C ２ H ５ 、perfluorodecyl bromide C １０ F ２１ Br, and perfluorobutylethane C ４ F ９ C ２ H ５ are exemplified.

[0003] U.S. Patent Application Publication No. 2002 / 0037316, U.S. Patent Application Publication 2012 / 0039952, International Publication No. 2010 / 138862, U.S. Patent Application Publication 2011 / 0023876

[0004] A pharmaceutical emulsion composition may be required to have a small average particle size of the particles in the composition. However, it has been difficult for conventional medical emulsion compositions to reduce the average particle size.

[0005] An object of the present disclosure is to provide a pharmaceutical emulsion composition having a small average particle size.

[0006] This disclosure includes the following embodiments: [Clause 1] A pharmaceutical emulsified composition comprising (A) a surfactant, (B) water, and (C) an auxiliary agent, wherein the octanol / water partition coefficient LogP of the auxiliary agent is 4.5 or greater. [Clause 2] The pharmaceutical emulsified composition according to Claim 1, wherein (C) the auxiliary agent is a compound containing one or more halogen atoms. [Clause 3] The pharmaceutical emulsified composition according to Claim 1 or 2, wherein (C) the auxiliary agent is a compound that is a fluorine-containing alkene. [Clause 4] The auxiliary agent is -C ａ F ｂ H ｃ A fluorine-containing compound that does not have a group represented by - (wherein a is an integer of 6 or more, b is an integer of 2a - c, and c is an integer of 4 or less), according to any one of claims 1 to 3. [Claim 5] (C) The auxiliary agent has the following structure: Formula: - (CF ２ ) ｎ A pharmaceutical emulsified composition according to any one of claims 1 to 4, wherein the compound is a fluorine-containing compound that does not have - (wherein n is an integer of 7 or more). [Claim 6] A pharmaceutical emulsified composition according to any one of claims 1 to 5, wherein (C) the auxiliary agent is a fluorine-containing ether or a perfluoroalkene. [Claim 7] The fluorine-containing ether is methyl nonafluoroisobutyl ether, perfluoropolyether, CF ３ CHFCF ２ OCH ２ CH ２ OCF ２ CHFCF ３ , 1,1,1,2,3,4,4,5,5,5-decafluoro-3-methoxy-2-(trifluoromethyl)pentane, or CF ３ CF ２ CF=CFCFOMeCF ２ CF ３ The pharmaceutical emulsified composition according to item 6. [Item 8] The pharmaceutical emulsified composition according to item 6 or item 7, wherein the number of carbon atoms of the perfluoroalkene is 6 or more and 15 or less. [Item 9] The pharmaceutical emulsified composition according to item 8, wherein the perfluoroalkene is a hexafluoropropene trimer. [Item 10] The hexafluoropropene trimer is a hexafluoropropene trimer of the following formulas (I) to (III): A pharmaceutical emulsified composition according to claim 9, wherein the compound represented by formula (I) is contained in an amount of 1% by mass or more and 99% by mass or less relative to the total amount of the compounds represented by formulas (I) to (III), according to claim 10. [Claim 12] A pharmaceutical emulsified composition according to claim 1, 2, 4, or 5, wherein the (C) auxiliary is a perfluorotrialkylamine. [Claim 13] A pharmaceutical emulsified composition according to claim 12, wherein the perfluorotrialkylamine is at least one selected from the group consisting of perfluorotributylamine, perfluorotripropylamine, and perfluorodibutylmethylamine. [Claim 14] A pharmaceutical emulsified composition according to claim 1, 2, or 5, wherein the (C) auxiliary is a perfluoroalkane. [Claim 15] A pharmaceutical emulsified composition according to claim 14, wherein the perfluoroalkane is perfluorohexane. [Clause 16] (C) The GWP of the auxiliary agent is 2000 or less, the pharmaceutical emulsified composition according to any one of Clauses 1 to 15. [Clause 17] (A) The surfactant is a saturated or unsaturated lipid, a nonionic surfactant, a nonionic block copolymer, or an ionic surfactant, the pharmaceutical emulsified composition according to any one of Clauses 1 to 16. [Clause 18] (A) The surfactant is a phospholipid, the pharmaceutical emulsified composition according to any one of Clauses 1 to 17. [Claim 19] The pharmaceutical emulsified composition according to claim 18, wherein the phospholipid is dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short-chain phosphatidylcholine, long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, and long-chain saturated phosphatidylinositol. [Claim 20] The pharmaceutical emulsified composition according to any one of claims 1 to 19, further comprising calcium chloride.

[0007] According to this disclosure, a pharmaceutical emulsifying composition with excellent dispersibility is provided, which uses an auxiliary agent for low-temperature effect.

[0008] As used herein, "hydrocarbon group" means a group containing carbon and hydrogen, obtained by removing a hydrogen atom from a hydrocarbon. Such hydrocarbon groups are not particularly limited, but include C １－２０ Examples of hydrocarbon groups include aliphatic hydrocarbon groups and aromatic hydrocarbon groups. The above-mentioned "aliphatic hydrocarbon group" may be linear, branched, or cyclic, and may be saturated or unsaturated. The hydrocarbon group may also contain one or more ring structures. The hydrocarbon group may be substituted with one or more substituents.

[0009] In the use herein, the substituents of the "hydrocarbon group" are not particularly limited, but may be, for example, a halogen atom, or one or more halogen atoms. １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ Cycloalkyl groups, C ３－１０ Unsaturated cycloalkyl group, 5-10 membered heterocyclyl group, 5-10 membered unsaturated heterocyclyl group, C ６－１０ Examples include one or more groups selected from aryl groups and heteroaryl groups with 5 to 10 members.

[0010] This disclosure provides a pharmaceutical emulsified composition comprising (A) a surfactant, (B) water, and (C) an auxiliary agent. In the pharmaceutical emulsified composition of this disclosure, the octanol / water partition coefficient LogP of the auxiliary agent is 4.5 or higher.

[0011] The pharmaceutical emulsifying composition of this disclosure has good dispersibility, and the powder obtained after evaporation of the solvent may be porous particles with a small average particle size.

[0012] (Component (A)) The pharmaceutical emulsifying composition of this disclosure contains (A) a surfactant. The pharmaceutical emulsifying composition of this disclosure suppresses particle aggregation by containing a surfactant.

[0013] A surfactant is any substance that preferentially adsorbs to the interface between immiscible phases. Examples of interfaces between immiscible phases include the interface between water and an organic polymer solution, the water / air interface, or the organic solvent / air interface.

[0014] The surfactant may preferably be saturated and unsaturated lipids (e.g., phospholipids), nonionic surfactants, nonionic block copolymers, or ionic surfactants, or combinations thereof. The surfactant is more preferably a phospholipid.

[0015] The phospholipids may be dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short-chain phosphatidylcholine, long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, or long-chain saturated phosphatidylinositol.

[0016] In the pharmaceutical emulsified composition of this disclosure, the content of (A) surfactant may be preferably 0.1 to 20% by mass, more preferably 1.0 to 13% by mass, and even more preferably 2.0 to 8% by mass, based on the total of (A) surfactant, (B) water, and (C) auxiliary agent.

[0017] (Component (B)) The pharmaceutical emulsifying composition of this disclosure comprises (B) water. Water functions as a dispersion medium in the pharmaceutical emulsifying composition.

[0018] As for the water, purified water such as distilled water or ion-exchanged water can be used.

[0019] (Component (C)) The pharmaceutical emulsifying composition of this disclosure contains (C) an auxiliary agent.

[0020] The octanol / water partition coefficient (LogP) of the above-mentioned auxiliary agent is 4.5 or higher. By using such an auxiliary agent, a highly dispersible pharmaceutical emulsified composition is provided.

[0021] The octanol / water partition coefficient LogP of the auxiliary agent is preferably 5 or higher, more preferably 5.2 or higher, even more preferably 5.4 or higher, even more preferably 5.6 or higher, and most preferably 5.8 or higher. The upper limit of the octanol / water partition coefficient LogP of the auxiliary agent is not particularly limited, but may be 20 or less, or 10 or less.

[0022] The octanol / water partition coefficient LogP can generally be measured by the flask immersion method described in JIS (Japanese Industrial Standard) Z7260-107 (2000). Alternatively, LogP can be estimated using computational chemistry methods or empirical methods instead of experimental measurement. The method for calculating LogP described in J. Pharma. Sci, 2009, 98, 861 can be used. For example, CLogP, MiLogP, PLogP derived from substructures, XLogP derived from atom-specific contributions, MLogP, and ALogPS using compound characteristics can be used. Furthermore, LogP can be computationally determined using the quantum scientific computing software TURBOMOLE, by using the optimized energy in vacuum of the target compound and the optimized energy in solution obtained by the COSMO-RS method, and performing calculations in COSMOtherm. Note that in this specification, Chem. Pharma. If MLogP is listed in Bull, 1994, 42, 976, the MLogP listed in Chem. Pharma. Bull, 1994, 42, 976 was used as the octanol / water partition coefficient LogP. If MLogP is not listed in Chem. Pharma. Bull, 1994, 42, 976, an estimated value was calculated using the computational science method described above, and this estimated value was used as the octanol / water partition coefficient LogP.

[0023] The Global Warming Potential (GWP) of the additive may preferably be 2000 or less, more preferably 1000 or less, even more preferably 800 or less, even more preferably 600 or less, particularly preferably 500 or less, and most preferably 400 or less. The lower limit of the GWP of the additive is not particularly limited, but may be, for example, 0 or more, 1 or more, or 10 or more.

[0024] Conventional processing aids for pharmaceuticals (hereinafter also referred to as "aids") have high global warming potentials (GWP), raising concerns about ozone depletion. Aids with low GWP, i.e., aids with a low-temperature effect, are preferable, but currently no such aids are known. The present inventors have found an aid with a low GWP and provide a pharmaceutical emulsifying composition using this "aid with a low GWP."

[0025] GWP measures the global warming effect of a compound over a certain period of time as CO2 ２ This represents a numerical comparison of the warming effect over a given period, with the warming effect set to 1. In this specification, GWP values ​​are used for a 100-year period. GWP is determined from the greenhouse effect and atmospheric lifetime of a compound; the greenhouse effect is derived from the absorption intensity of the infrared absorption spectrum, and the atmospheric lifetime is derived from the reaction rate evaluation with OH radicals. GWP can also be predicted by calculation. For example, GWP can be estimated by calculating the infrared absorption spectrum from structural optimization using molecular orbital calculations to determine the greenhouse effect, and then deriving the activation energy and frequency factor from the reaction transition state with OH radicals to determine the atmospheric lifetime. In this specification, estimated GWP values ​​were used for substances not listed in the literature.

[0026] The additive is preferably a compound with a boiling point higher than that of water. The boiling point of the additive is preferably 105°C or higher, for example, 110°C or higher, 120°C or higher, 130°C or higher, 140°C or higher, or 150°C or higher. The boiling point of the additive is not particularly limited, but may be 200°C or lower, 180°C or lower, 160°C or lower, 150°C or lower, 140°C or lower, 130°C or lower, or 120°C or lower.

[0027] The auxiliary agent is preferably a compound containing one or more halogen atoms.

[0028] The halogen atom is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, more preferably a fluorine atom, a chlorine atom, or a bromine atom, and even more preferably a fluorine atom. A chlorine atom or a bromine atom directly bonded to the double bond is also preferred.

[0029] A compound containing one or more halogen atoms may be a perfluoro compound in which all hydrogen atoms on the compound are replaced with fluorine atoms, or it may be a fluoro compound in which some of the hydrogen atoms are replaced.

[0030] In one embodiment, the auxiliary agent may be a fluorine-containing alkyl group.

[0031] In another embodiment, the auxiliary agent may be a fluorine-containing alkene or a fluorine-containing alkyne.

[0032] Fluorine-containing alkyls, fluorine-containing alkenes, and fluorine-containing alkynes may be perfluoro compounds in which all hydrogen atoms on the compound are replaced with fluorine atoms, or they may be fluoro compounds in which some hydrogen atoms are replaced.

[0033] Fluorine-containing alkyls, fluorine-containing alkenes, and fluorine-containing alkynes may have substituents other than fluorine atoms. For example, fluorine-containing alkenes may be substituted with chlorine, bromine, iodine, oxygen, or nitrogen, preferably chlorine, bromine, or iodine, more preferably chlorine or bromine.

[0034] In a preferred embodiment, the fluorinated alkyl, fluorinated alkene, and fluorinated alkyne are free of substituents other than fluorine atoms.

[0035] The fluorine-containing alkyl may preferably have 1 to 20 carbon atoms, more preferably 1 to 12, and even more preferably 2 to 6 carbon atoms.

[0036] Fluorine-containing alkenes and fluorine-containing alkynes may preferably have 3 to 20 carbon atoms, more preferably 5 to 15, even more preferably 6 to 12, and specifically 9 carbon atoms.

[0037] Fluorine-containing alkyls, fluorine-containing alkenes, and fluorine-containing alkynes may be cyclic or linear. If linear, fluorine-containing alkyls, fluorine-containing alkenes, and fluorine-containing alkynes may be linear or branched. In one embodiment, fluorine-containing alkyls and fluorine-containing alkenes are cyclic. In another embodiment, fluorine-containing alkyls and fluorine-containing alkenes are linear.

[0038] The number of double bonds in a fluorine-containing alkene is not particularly limited and may be, for example, 1 to 5, 1 to 3, preferably 1 to 2.

[0039] The number of triple bonds in a fluorine-containing alkyne is not particularly limited and may be, for example, 1 to 3, preferably 1 to 2.

[0040] In one embodiment, the auxiliary agent may be a compound having nitrogen or oxygen.

[0041] Compounds containing nitrogen may, for example, be substituted amine compounds.

[0042] The above substituted amine compounds are given by the following formula: NR １ ｎ R ２ ３－ｎ [In the formula, R １ and R ２ Each of these is an independently hydrocarbon group which may be substituted with a halogen, and R ２ n may be a hydrogen atom. n is an integer from 1 to 3. It may be a compound represented by [ ].

[0043] R １ and R ２ The hydrocarbon group in is preferably C １－６ Alkyl alkyl group, comfort C １－４ Alkyl alkyl groups, more preferably C ２－４ It may be an alkyl group, such as a butyl group.

[0044] The alkyl group described above may be linear or branched. In one embodiment, the alkyl group is linear. In another embodiment, the alkyl group is branched.

[0045] The halogen atom is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, more preferably a fluorine atom, a chlorine atom, or a bromine atom, even more preferably a fluorine atom or a bromine atom, and particularly preferably a fluorine atom.

[0046] n is an integer between 1 and 3, preferably 2 or 3, and more preferably 3. In one embodiment, n may be 2.

[0047] Compounds containing oxygen may, for example, be ether compounds.

[0048] The above-mentioned ether compound may be a linear ether compound or a cyclic ether compound.

[0049] The above ether compound is given by the following formula: [In the formula, R ３ R is an alkyl group which may be substituted with a halogen, ４ R is an alkyl group which may be substituted with a halogen, ５ Each is independently a hydrogen atom, a halogen, or an alkyl group which may be substituted with a halogen, and R ６ Each of these is independently a hydrogen atom, a halogen, or an alkyl group which may be substituted with a halogen, and m is an integer from 1 to 6. The compound may be represented by [ ].

[0050] R ３ and R ４ The alkyl group in is preferably C １－６ Alkyl alkyl group, comfort C １－４ Alkyl alkyl groups, more preferably C １－３ It can be an alkyl group.

[0051] R ５ and R ６ The alkyl group in is preferably C １－６ Alkyl alkyl group, comfort C １－４ It can be an alkyl group.

[0052] In a preferred embodiment, R ５ Each of these is an alkyl group which may be independently substituted with a fluorine atom or a halogen. In one embodiment, R ５ is a fluorine atom. In another embodiment, one R ５ R is a fluorine atom, and the other R is ５ is an alkyl group which may be substituted with a halogen. Such alkyl group which may be substituted with a halogen is preferably C １－６ Fluoroalkyl, more preferably C１－６ It may be a perfluoroalkyl group, such as perfluoro-n-butyl.

[0053] In a preferred embodiment, R ６ Each of these atoms is independently a hydrogen atom or a fluorine atom, and is preferably a fluorine atom.

[0054] The halogen atom is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, more preferably a fluorine atom, a chlorine atom, or a bromine atom, even more preferably a fluorine atom or a bromine atom, and particularly preferably a fluorine atom.

[0055] m is preferably an integer from 1 to 4, more preferably 3 or 4, for example, 3.

[0056] In one embodiment, the auxiliary agent has the following structure: Formula: -C ａ F ｂ H ｃ - (wherein a is an integer greater than or equal to 6, b is an integer of 2a - c, and c is an integer less than or equal to 4.) This is a fluorine-containing compound that does not have a group represented by this formula.

[0057] In one embodiment, the auxiliary agent has the following structure: Formula: -(CF ２ ) ｎ It may be a compound that does not have - (wherein n is an integer of 7 or more).

[0058] In a preferred embodiment, the auxiliary agent has the following structure: Formula: -(CF ２ ) ｎ It may be a fluorine-containing compound that does not have - (wherein n is an integer of 7 or more).

[0059] In one embodiment, the auxiliary agent may be a fluorine-containing ether or a perfluoroalkene. Fluorine-containing ethers include methyl nonafluoroisobutyl ether, perfluoropolyether, CF ３ CHFCF ２ OCH ２ CH ２ OCF ２ CHFCF ３ , 1,1,1,2,3,4,4,5,5,5-decafluoro-3-methoxy-2-(trifluoromethyl)pentane, or CF ３ CF２ CF=CFCFOMeCF ２ CF ３ It is possible that the number of carbon atoms in a perfluoroalkene can be between 6 and 15, between 7 and 14, or between 8 and 12. The perfluoroalkene can be a hexafluoropropene trimer. The perfluoroalkene can be a perfluoroheptene.

[0060] In one embodiment, the auxiliary agent may be a perfluorotrialkylamine. The perfluorotrialkylamine may be at least one selected from the group consisting of perfluorotributylamine, perfluorotripropylamine, and perfluorodibutylmethylamine.

[0061] In one embodiment, the auxiliary agent may be a perfluoroalkane. The number of carbon atoms in the perfluoroalkane may be 4 to 18, 4 to 10, 5 to 9, or 6 to 8. The perfluoroalkane may be a perfluorohexane.

[0062] In a preferred embodiment, the auxiliary agent is a hexafluoropropene trimer, 1,2-bis(perfluorodibutyl)ethylene, 1-perfluorobutyl-3,3,4,4,5,5-hexafluorocyclopentene, perfluorotributylamine, perfluoro-2-butyltetrahydrofuran, or perfluoro-1,6-dibromohexane, and more preferably a hexafluoropropene trimer.

[0063] The hexafluoropropene trimer is preferably of the following formulas (I) to (III): These are (E / Z) perfluoro-2,4-dimethyl-3-heptene (I), perfluoro-3-isopropyl-4-methyl-2-pentene (II), and perfluoro-3-isopropyl-2-methyl-2-pentene (III), represented by formulas (I) to (III). The hexafluoropropene trimer may contain only one of the compounds represented by the above formulas (I) to (III), or it may be a mixture containing two or three of these compounds.

[0064] In this specification, unless otherwise specified, the compound represented by formula (I) above includes both the geometric isomers E and Z.

[0065] The compounds represented by formulas (I) to (III) above may be produced by conventional methods, for example, by the method described in International Publication No. 2018 / 172919, and are not limited thereto. They may also be obtained by trimerization using hexafluoropropene as a starting material, and are not limited thereto; they may be obtained by employing a wide range of known methods.

[0066] The compound represented by formula (I) is preferably present in an amount of 1% by mass or more and 99% by mass or less, preferably 10% by mass or more and less than 90% by mass, relative to the total amount of the compounds represented by formulas (I) to (III).

[0067] In the pharmaceutical emulsified composition of this disclosure, the content of (C) auxiliary agent may be preferably 1.0 to 50% by volume, more preferably 5.0 to 40% by volume, and even more preferably 10 to 30% by volume, based on the total of (A) surfactant, (B) water, and (C) auxiliary agent.

[0068] The pharmaceutical emulsifying compositions of this disclosure may further contain calcium chloride. Calcium chloride has the effect of stabilizing the particles after the pharmaceutical emulsifying composition has been spray-dried, as described in U.S. Patent Application Publication No. 2002 / 0037316.

[0069] In the pharmaceutical emulsified composition of this disclosure, the content of calcium chloride may preferably be 0.05 to 3.0% by mass, more preferably 0.1 to 1.0% by mass, relative to the total of (A) surfactant, (B) water, and (C) auxiliary agent.

[0070] The pharmaceutical emulsified composition of this disclosure can be mixed with an active ingredient and dried to form drug particles containing the active ingredient (hereinafter also referred to as "drug particles").

[0071] The method for obtaining drug particles using the pharmaceutical emulsified composition of this disclosure is not particularly limited, but one example is a method of mixing the pharmaceutical emulsified composition with an active ingredient, homogenizing it with a homogenizer or the like, and then spray-drying it.

[0072] The above active ingredients are not particularly limited, but include short-acting β-agonists such as bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, limiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, ipratropium, and epinephrine; and long-acting β2 adrenergic receptors. Agonists ("LABA"), e.g., vanbuterol, clenbuterol, formoterol, salmeterol; ultra-long-acting β2 adrenergic receptor agonists, e.g., carmoterol, milveterol, indacaterol, and adamantyl-inducing β2 agonists containing saligenin or indole; corticosteroids, e.g., beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone , prednisone and triamcinolone; anti-inflammatory drugs, e.g., fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisolone, dexamethasone, betamethasone or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamo Examples include ru, albuterol, salmeterol, terbutaline; and muscarinic antagonists (such as long-acting muscarinic antagonists ("LAMA")), such as glycopyrrolate, dexipyrronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, acridinium, trospium, ipratropium, atropine, benztropine, or oxytropium.

[0073] The active ingredient may be in the form of a salt (e.g., an alkali metal salt or amine salt, or an acid addition salt), or in the form of an ester, solvate (e.g., a hydrate), derivative, or free base. The active ingredient may also be in any crystalline form, or in the form of an isomer or mixture of isomers, such as a pure enantiomer, a mixture of enantiomers, or a racemic compound.

[0074] The drug particles can be delivered to the lungs or via the nose. Preferably, the drug particles are delivered by a metered-dose inhaler (MDI).

[0075] In one embodiment, drug particles may be used to treat the following conditions: asthma, chronic obstructive pulmonary disease (COPD), exacerbations of airway hyperreactivity resulting from other drug therapies, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and any other respiratory disease that may respond to administration of LAMA, LABA, corticosteroids, or drug particles (whether alone or in combination with other therapies). Hereinafter, “COPD” and “chronic obstructive pulmonary disease” encompass chronic obstructive pulmonary disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL), and chronic obstructive respiratory disease (CORD), and include chronic bronchitis, bronchiectasis, and emphysema. "Asthma" encompasses all types or origins of asthma, such as endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced following bacterial infection.

[0076] The purification method of this disclosure will be described in more detail below through the following examples, but this disclosure is not limited to these examples.

[0077] Example 1 A pharmaceutical emulsifying composition was prepared with reference to U.S. Patent Application Publication 2012 / 0039952 and U.S. Patent Application Publication 2011 / 023876. 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) (1.8 g), calcium chloride (0.15 g), and water (25 mL) were added to a 50 mL glass container and stirred at 50°C for 1 hour. Perfluoro-2,4-dimethyl-3-heptene (compound (I)) (6.3 mL, octanol / water partition coefficient LogP = 5.9, GWP = 100 (estimated value)) was added as an auxiliary agent, and the mixture was homogenized using an ultrasonic homogenizer for 30 minutes (3 minutes x 10 times) while cooling the glass container in an ice bath to obtain an emulsion.

[0078] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 366 nm, and the turbidity was 11.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0079] Example 2 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluoro-3-isopropyl-4-methyl-2-pentene (compound (II)) (6.3 mL, octanol / water partition coefficient LogP = 5.9, GWP = 100 (estimated value)).

[0080] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 380 nm, and the turbidity was 12.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0081] Example 3 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluoro-3-isopropyl-2-methyl-2-pentene (Compound (III)) (6.3 mL, octanol / water partition coefficient LogP = 5.9, GWP = 200 (estimated value)).

[0082] 1 mL of the obtained emulsion was collected, and 19 mL of water was added to obtain a diluted solution. The average particle diameter of the particles in the diluted solution was measured by the dynamic light scattering method using a particle size analyzer (FPAR-1000 manufactured by Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200 manufactured by Mitsubishi Chemical Corporation). The average particle diameter was 372 nm, and the turbidity was 11.3 ppm. Also, there was no sedimentation of the particles even after standing for one week.

[0083] Example 4 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to 1,2-bis(perfluorodibutyl)ethylene C ４ F ９ CH=CHC ４ F ９ (6.3 mL, octanol / water partition coefficient LogP = 6.1, GWP = 50 (estimated value)).

[0084] 1 mL of the obtained emulsion was collected, and 19 mL of water was added to obtain a diluted solution. The average particle diameter of the particles in the diluted solution was measured by the dynamic light scattering method using a particle size analyzer (FPAR-1000 manufactured by Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200 manufactured by Mitsubishi Chemical Corporation). The average particle diameter was 214 nm, and the turbidity was 10.5 ppm. Also, there was no sedimentation of the particles even after standing for one week.

[0085] Example 5 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to 1-perfluorobutyl-3,3,4,4,5,5-hexafluorocyclopentene cyc(-C(C ４ F ９ )=CHC ３ F ６ -) (6.3 mL, octanol / water partition coefficient LogP = 5.1, GWP = 50 (estimated value)).

[0086] 1 mL of the obtained emulsion was collected, and 19 mL of water was added thereto to obtain a dilution. The average particle diameter of the particles in the dilution was measured by the dynamic light scattering method using a particle size analyzer (FPAR-1000 manufactured by Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200 manufactured by Mitsubishi Chemical Corporation). The average particle diameter was 214 nm, and the turbidity was 10.5 ppm. Also, there was no sedimentation of the particles even after standing for one week.

[0087] Example 6 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to hexafluoropropene trimer (Compound (I): Compound (II): Compound (III) = 55:23:22, 6.3 mL, octanol / water partition coefficient LogP = 5.9, GWP = 120 (estimated value)).

[0088] 1 mL of the obtained emulsion was collected, and 19 mL of water was added thereto to obtain a dilution. The average particle diameter of the particles in the dilution was measured by the dynamic light scattering method using a particle size analyzer (FPAR-1000 manufactured by Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200 manufactured by Mitsubishi Chemical Corporation). The average particle diameter was 408 nm, and the turbidity was 30.1 ppm. Also, there was no sedimentation of the particles even after standing for one week.

[0089] Example 7 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluorooctyl bromide (6.3 mL, octanol / water partition coefficient LogP = 6.0, GWP = 8,000 (estimated value)).

[0090] 1 mL of the obtained emulsion was collected, and 19 mL of water was added thereto to obtain a dilution. The average particle diameter of the particles in the dilution was measured by the dynamic light scattering method using a particle size analyzer (FPAR-1000 manufactured by Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200 manufactured by Mitsubishi Chemical Corporation). The average particle diameter was 165 nm, and the turbidity was 17.0 ppm. Also, there was no sedimentation of the particles even after standing for one week.

[0091] Example 8 The auxiliary agent was changed to perfluoro-2-butyltetrahydrofuran cyc(-OCF(C ４ F ９ C ３ F６ An emulsion was obtained in the same manner as in Example 1, except that the volume was changed to (6.3 mL, octanol / water partition coefficient LogP = 5.4, GWP = 15,000 (estimated value)).

[0092] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 313 nm, and the turbidity was 19.7 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0093] Example 9: The auxiliary agent is perfluorotributylamine N(C) ４ F ９ ) ３ An emulsion was obtained in the same manner as in Example 1, except that the volume was changed to (6.3 mL, octanol / water partition coefficient LogP = 6.6, GWP = 9,000).

[0094] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 153 nm, and the turbidity was 9.8 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0095] Example 10: Additive agent is perfluoro-1,6-dibromohexaneBrC ６ F １２ An emulsion was obtained in the same manner as in Example 1, except that Br (6.3 mL, octanol / water partition coefficient LogP = 5.2, GWP = 5,000 (estimated value)) was used.

[0096] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 408 nm, and the turbidity was 30.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0097] Example 11 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluorotributylamine (6.3 mL, octanol / water partition coefficient LogP = 7 (estimated value), GWP = 5,000 (estimated value)).

[0098] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 379 nm, and the turbidity was 24.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0099] Example 12 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluorohexane (6.3 mL, octanol / water partition coefficient LogP = 6 (estimated value), GWP = 5,000 (estimated value)).

[0100] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 398 nm, and the turbidity was 25.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0101] Example 13 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to methyl nonafluoroisobutyl ether (6.3 mL, octanol / water partition coefficient LogP = 6 (estimated value), GWP = 297).

[0102] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 438 nm, and the turbidity was 26.6 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0103] Example 14 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to 1,1,1,2,3,4,4,5,5,5-decafluoro-3-methoxy-2-(trifluoromethyl)pentane (6.3 mL, octanol / water partition coefficient LogP = 5 (estimated value), GWP = 310).

[0104] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 398 nm, and the turbidity was 26.9 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0105] Example 15 Additive (CF ２ CFCF ３ CF ２ O) ｎ An emulsion was obtained in the same manner as in Example 1, except that the solvent was changed to (Solvay HT135) (6.3 mL, octanol / water partition coefficient LogP = 6 (estimated value), GWP = 9000 (estimated value)).

[0106] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 388 nm, and the turbidity was 25.1 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0107] Example 16: Additive agent (CF ２ CFCF ３ CF ２ O) ｎ An emulsion was obtained in the same manner as in Example 1, except that the solvent was changed to (Solvay HT200) (6.3 mL, octanol / water partition coefficient LogP = 6 (estimated value), GWP = 10000 (estimated value)).

[0108] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 378 nm, and the turbidity was 25.7 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0109] Example 17 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to a mixture of perfluorotributylamine and perfluorodibutylmethylamine (FC40, manufactured by 3M) (6.3 mL, octanol / water partition coefficient LogP = 7 (estimated value), GWP = 10000 (estimated value)).

[0110] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 389 nm, and the turbidity was 24.7 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0111] Example 18 An emulsion was obtained in the same manner as in Example 1, except that the auxiliary agent was changed to perfluoroheptene (Opteon SF70, Chemours) (6.3 mL, octanol / water partition coefficient LogP = 5 (estimated value), GWP = 100 (estimated value)).

[0112] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 408 nm, and the turbidity was 26.7 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0113] Example 19: Additive agent is used in CF ３ CF ２ CF=CFCFOMeCF ２ CF ３ An emulsion was obtained in the same manner as in Example 1, except that it was changed to (Opteon SF10 manufactured by Chemours) (6.3 mL, octanol / water partition coefficient LogP = 5 (estimated value), GWP = 2).

[0114] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 428 nm, and the turbidity was 28.7 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0115] Example 20: Additive agent is used in CF ３ CHFCF ２ OCH ２ CH ２ OCF ２ CHFCF ３ An emulsion was obtained in the same manner as in Example 1, except that the volume was changed to (6.3 mL, octanol / water partition coefficient LogP = 4.5 (estimated value), GWP = 100 (estimated value)).

[0116] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 448 nm, and the turbidity was 29.5 ppm. Furthermore, no particle sedimentation occurred even after standing for one week.

[0117] Comparative Example 1: The auxiliary agent is 1H,1H,5H-octafluoropentyl 1,1,2,2-tetrafluoroethyl ether HCl ４ F ８ CH ２ OC ２ F ４ An emulsion was obtained in the same manner as in Example 1, except that H (6.3 mL, octanol / water partition coefficient LogP = 3.7, GWP = 200 (estimated value)) was used.

[0118] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 757 nm, and the turbidity was 794 ppm. Particle sedimentation was observed the following day.

[0119] Comparative Example 2: Using 1,4-dichlorobutane ClC as an auxiliary agent. ４ H ８ An emulsion was obtained in the same manner as in Example 1, except that Cl (6.3 mL, octanol / water partition coefficient LogP = 2.6, GWP = 1 (estimated value)) was used.

[0120] The resulting emulsion (1 mL) was collected and diluted with water (19 mL) to obtain a diluted solution. The average particle size of the particles in the diluted solution was measured by dynamic light scattering using a particle size analyzer (FPAR-1000, Otsuka Electronics Co., Ltd.), and the turbidity was measured using an integrating sphere turbidimeter (PT-200, Mitsubishi Chemical Corporation). The average particle size was 767 nm, and the turbidity was 2776 ppm. Particle sedimentation was observed the following day.

[0121] The pharmaceutical emulsifiers disclosed herein are useful in the manufacture of pharmaceuticals, particularly powdered pharmaceuticals.

Claims

1. A pharmaceutical emulsifying composition comprising (A) a surfactant, (B) water, and (C) an auxiliary agent, wherein the octanol / water partition coefficient LogP of the auxiliary agent is 4.5 or higher.

2. (C) The pharmaceutical emulsifying composition according to claim 1, wherein the auxiliary agent is a compound containing one or more halogen atoms.

3. (C) The pharmaceutical emulsifying composition according to claim 1 or claim 2, wherein the auxiliary agent is a compound that is a fluorine-containing alkene.

4. (C) The auxiliary agent is -C ａ F ｂ H ｃ A fluorine-containing compound that does not have a group represented by the formula - (wherein a is an integer of 6 or more, b is an integer of 2a - c, and c is an integer of 4 or less). A pharmaceutical emulsifying composition according to any one of claims 1 to 3.

5. (C) The auxiliary agent has the following structure: Formula: -(CF ２ ) ｎ A pharmaceutical emulsifying composition according to any one of claims 1 to 4, wherein the compound is a fluorine-containing compound that does not have - (wherein n is an integer of 7 or more).

6. (C) The pharmaceutically emulsifying composition according to any one of claims 1 to 5, wherein the auxiliary agent is a fluorine-containing ether or a perfluoroalkene.

7. The fluorine-containing ether is methyl nonafluoroisobutyl ether, perfluoropolyether, CF ３ CHFCF ２ OCH ２ CH ２ OCF ２ CHFCF ３ , 1,1,1,2,3,4,4,5,5,5 - decafluoro - 3 - methoxy - 2 - (trifluoromethyl) pentane, or CF ３ CF ２ CF = CF C FOMeCF ２ CF ３ The pharmaceutical emulsion composition according to claim 6.

8. The pharmaceutical emulsifying composition according to claim 6 or claim 7, wherein the number of carbon atoms in the perfluoroalkene is 6 or more and 15 or less.

9. The pharmaceutical emulsifying composition according to claim 8, wherein the perfluoroalkene is a hexafluoropropene trimer.

10. The hexafluoropropene trimer is given by the following formulas (I) to (III): A pharmaceutical emulsifying composition according to claim 9, wherein the compound is represented by [formula].

11. The pharmaceutical emulsified composition according to claim 10, wherein the compound represented by formula (I) is contained in an amount of 1% by mass or more and 99% by mass or less relative to the total amount of the compounds represented by formulas (I) to (III).

12. (C) The pharmaceutically emulsifying composition according to claim 1, claim 2, claim 4, or claim 5, wherein the auxiliary agent is a perfluorotrialkylamine.

13. The pharmaceutical emulsifying composition according to claim 12, wherein the perfluorotrialkylamine is at least one selected from the group consisting of perfluorotributylamine, perfluorotripropylamine, and perfluorodibutylmethylamine.

14. (C) The pharmaceutically emulsifying composition according to claim 1, claim 2, or claim 5, wherein the auxiliary agent is a perfluoroalkane.

15. The pharmaceutical emulsifying composition according to claim 14, wherein the perfluoroalkane is perfluorohexane.

16. (C) The GWP of the auxiliary agent is 2000 or less, the pharmaceutical emulsifying composition according to any one of claims 1 to 15.

17. (A) The pharmaceutical emulsifying composition according to any one of claims 1 to 16, wherein the surfactant is a saturated or unsaturated lipid, a nonionic surfactant, a nonionic block copolymer, or an ionic surfactant.

18. (A) The surfactant is a phospholipid, the pharmaceutical emulsifying composition according to any one of claims 1 to 17.

19. The pharmaceutical emulsifying composition according to claim 18, wherein the phospholipid is dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short-chain phosphatidylcholine, long-chain saturated phosphatidylethanolamine, long-chain saturated phosphatidylserine, long-chain saturated phosphatidylglycerol, and long-chain saturated phosphatidylinositol.

20. A pharmaceutical emulsifying composition according to any one of claims 1 to 19, further comprising calcium chloride.

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