Fluticasone pharmaceutical composition and pharmaceutical preparation

Abstract

The invention relates to a fluticasone pharmaceutical composition and a pharmaceutical preparation thereof. The pharmaceutical composition comprises fluticasone and pharmaceutically acceptable salts thereof, a surfactant, a cosolvent and a thickening agent. In another aspect, the invention provides a pharmaceutical formulation comprising a pharmaceutical composition of the invention. On the other hand, the invention further provides application of the pharmaceutical composition or the pharmaceutical preparation in preparation of drugs for preventing or treating asthma, allergic rhinitis, chronic infarction pneumonia or atopic dermatitis.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a fluticasone pharmaceutical composition and a pharmaceutical preparation. Background Art

[0002] Fluticasone, with the chemical name of (6α,11β,16α,17α)-S-(fluoromethyl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioate, is a corticosteroid that has the effects of inhibiting mast cells, eosinophils and mucosal reactions, and stabilizing the nasal mucosal epithelial and vascular endothelial barriers. It has been applied in the treatment of asthma, allergic rhinitis, chronic obstructive pneumonia, atopic dermatitis, etc. Its structural formula is as follows:

[0003]

[0004] Fluticasone is a kind of off-white crystalline powder, poorly soluble in water (usually less than 1 μg / mL), easily soluble in dimethylformamide, and slightly soluble in acetone, dichloromethane, and 96% ethanol. According to the biopharmaceutics classification system, it belongs to BCS class II compounds. Such compounds pose various challenges in terms of water solubility when prepared into pharmaceutical compositions or preparations. In the commercially available fluticasone propionate nasal spray fluticasone propionate exists in the form of a suspension. CN1098680C discloses the preparation of a fluticasone propionate suspension preparation by micronizing fluticasone propionate. CN103588846B uses a solvent and antisolvent system to precipitate fluticasone propionate microparticles to form a suspension with smaller particle size. Summary of the Invention

[0005] In view of this, the object of the present invention is to provide a fluticasone pharmaceutical composition that overcomes the above-mentioned defects of the prior art.

[0006] In one aspect, the present invention provides a pharmaceutical composition comprising fluticasone or a pharmaceutically acceptable salt thereof, a surfactant, and a cosolvent, and the pharmaceutical composition is a solution.

[0007] In one embodiment, the surfactant is a non-ionic surfactant. In a preferred embodiment, the surfactant is one or more selected from tyloxapol, vitamin E polyethylene glycol succinate (TPGS), sorbitan fatty ester, and polyoxyethylene sorbitan fatty acid ester.

[0008] In another embodiment, the co-solvent is an alcohol compound. In a preferred embodiment, the co-solvent is one or more selected from ethanol, isopropanol, propylene glycol, glycerol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, and polyvinyl alcohol.

[0009] In one embodiment, the weight ratio of the active ingredient to the surfactant is about 1:100 to about 1:500; and / or the weight ratio of the active ingredient to the co-solvent is about 1:30 to about 1:300; and / or the weight ratio of the surfactant to the co-solvent is about 0.5:1 to about 6:1.

[0010] In a further embodiment, the pharmaceutical composition of the present invention further comprises a thickening agent. In one embodiment, the thickening agent is a cellulose thickening agent, preferably one or more selected from microcrystalline cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl methyl cellulose, and cross-linked carboxymethyl cellulose.

[0011] On the other hand, the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition of the present invention.

[0012] In yet another aspect, the present invention also provides the use of the pharmaceutical composition or pharmaceutical preparation of the present invention in the preparation of a drug for preventing or treating asthma, allergic rhinitis, chronic obstructive pneumonia, or atopic dermatitis. Specific Embodiments

[0013] The present invention will be further described in detail below. Such description is for illustrative purposes only and is not intended to limit the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention. Unless otherwise specified or obviously inappropriate, the ratios (including percentages) used herein are by weight.

[0014] General terms and definitions

[0015] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety if not otherwise indicated.

[0016] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. In case of conflict, the definitions provided in this application shall prevail.

[0017] When a quantity, concentration, or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood as equivalently disclosing any range formed by combining any upper range limit or preferred numerical value with any lower range limit or preferred numerical value, regardless of whether the range is specifically disclosed. Unless otherwise specified, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. The scope of the present invention is not limited to the specific numerical values cited when defining the range. The terms "about" and "approximately", when used in conjunction with numerical variables, generally refer to the numerical value of the variable and all numerical values of the variable within the experimental error (e.g., within the 95% confidence interval for the mean value) or within ±10% of the specified numerical value, or within a wider range.

[0018] The term "comprising" or similar terms synonymous therewith, such as "including", "containing", "having", and "involving", are inclusive or open-ended and do not exclude additional unenumerated elements, steps, or components. The expression "consisting essentially of" refers to a range limited to the specified elements, steps, or components, plus optionally present elements, steps, or components that do not substantially affect the basic and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0019] The term "measurement ratio" means that various substances are proportioned by a certain weight. For example, in the present invention, the active ingredient (fluticasone or its pharmaceutically acceptable salt) is proportioned with a surfactant, a co-solvent, a thickener, and optionally present pharmaceutically acceptable excipients in a certain weight ratio.

[0020] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the occurrence and non-occurrence of the described event or situation.

[0021] The term "selected from..." means one or more elements independently selected from the group listed hereinafter, and may include combinations of two or more elements. The term "one or more" or "at least one" as used herein means one, two, three, four, five, or more. Unless otherwise specified, the terms "combinations thereof" and "mixtures thereof" refer to multi-component mixtures of the various elements, such as two, three, four, and up to the maximum possible multi-component mixtures.

[0022] The term "surfactant" refers to a substance that can lower the surface tension of a target solution. It has fixed hydrophilic and lipophilic groups and can be oriented on the surface of the solution. It is usually divided into ionic surfactants (including cationic surfactants and anionic surfactants), non-ionic surfactants, amphoteric surfactants, compound surfactants, other surfactants, etc. Surfactants are usually metabolizable (such as biodegradable) and biocompatible, and thus are suitable for use as pharmaceutically acceptable excipients. In the present invention, the surfactant is preferably a non-ionic surfactant.

[0023] The term "non-ionic surfactant" refers to a class of surfactants whose molecules do not ionize after being dissolved in water. According to the structure of the hydrophilic group, non-ionic surfactants can be divided into polyoxyethylene type, polyol type, alkanolamide type, polyether type, and amine oxide type. Examples include but are not limited to fatty alcohol polyoxyethylene ethers, alkylphenol polyoxyethylene ethers, fatty acid polyoxyethylene esters, polyoxyethylene alkylamines, polyoxyethylene alkylamides, and polyether alcohols.

[0024] The term "cosolvent" refers to a substance that can increase the solubility of a poorly soluble active substance in a solvent.

[0025] The term "fluticasone" encompasses its various forms of salts, esters, prodrugs, derivatives, solvates (such as hydrates), isomers (such as enantiomers), polymorphs, complexes, and any mixtures thereof. Preferably, these forms are pharmaceutically acceptable. The terms "pharmaceutically active ingredient", "active ingredient" refer to a chemical entity that can effectively treat or prevent a target disease or disorder.

[0026] The term "pharmaceutically acceptable" means applicable to contact with a patient's tissue within the scope of normal medical judgment without undue toxicity, irritation, allergic reaction, etc., having a reasonable benefit-risk ratio, and being effective for its intended use.

[0027] The term "pharmaceutically acceptable salt" includes salts of the active ingredient prepared with relatively non-toxic acids or bases. Exemplary pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfide, hydroiodic acid, or phosphorous acid, etc., and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid salts, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are amino acid salts, such as arginine salts, etc., and organic acid salts, such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge et al., Journal of Pharmaceutical Science, 66:1-19 (1977)). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0028] The term "thickening agent" refers to substances that can increase the viscosity or consistency of a product. According to their composition and mechanism of action, thickening agents can be classified into cellulose thickening agents, inorganic thickening agents, polyurethane thickening agents, acrylic thickening agents, and alkali-swellable thickening agents. In the present invention, the thickening agent is preferably a cellulose thickening agent, which associates with surrounding water molecules through hydrogen bonds via its hydrophobic backbone, increases the fluid volume of the polymer itself, and reduces the space for free movement of particles, thereby further increasing the viscosity of the system.

[0029] The term "pharmaceutically acceptable excipient" refers to those carrier substances that have no obvious irritating effect on the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, pH regulators, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0030] The term "solution" refers to a homogeneous and stable mixture formed by dissolving one or more substances in another substance. In the present invention, this term can refer to a solution in which fluticasone or its pharmaceutically acceptable salt is dissolved in an aqueous solution containing a surfactant, a cosolvent, a thickening agent, and optionally a pharmaceutically acceptable excipient. In the present invention, the pharmaceutical composition in solution form (such as an aqueous solution) contains the active ingredient fluticasone, and thus it can also be referred to as a fluticasone (drug) composition.

[0031] The terms "clear" and "clear solution" are used to describe that the clarity of the pharmaceutical composition of the present application can be evaluated, for example, by the human eye, and refer to the obtained pharmaceutical composition being transparent and without visible particles and / or precipitates (e.g., without obvious turbidity, cloudiness, or non-uniformity).

[0032] Pharmaceutical compositions and their pharmaceutical preparations

[0033] In one aspect, the present invention relates to a pharmaceutical composition comprising fluticasone or a pharmaceutically acceptable salt thereof as an active ingredient, a surfactant, and a cosolvent.

[0034] Considering the deficiencies of existing suspensions, especially the problems in formulation stability and use, the pharmaceutical composition of the present invention is preferably in the form of a solution. For example, the pharmaceutical composition of the present invention can be an aqueous solution. In this case, the pharmaceutical composition of the present invention contains water as a solvent.

[0035] In the pharmaceutical composition of the present invention, a stable product can be obtained by including a surfactant and a cosolvent.

[0036] Active ingredient

[0037] In the pharmaceutical composition of the present invention, the active ingredient is fluticasone or a pharmaceutically acceptable salt thereof, especially fluticasone propionate.

[0038] In one embodiment, the active ingredient is about 0.005 - about 0.1% by weight, preferably about 0.005% - about 0.06% by weight, based on the total weight of the pharmaceutical composition (or the total weight of the active ingredient, surfactant, and cosolvent), such as about 0.005% by weight, about 0.006% by weight, about 0.007% by weight, about 0.008% by weight, about 0.009% by weight, about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, and any range composed of these values, and particularly preferably 0.005 - 0.02%.

[0039] Surfactant

[0040] In one embodiment, the surfactant used in the pharmaceutical composition of the present invention can be a nonionic surfactant.

[0041] In one embodiment, the surfactant can be one or more selected from the following: (i) alkylaryl polyether alcohols, such as tyloxapol (a polymer of 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde, also known as superione, triton or tyloxapol); (ii) polyoxyethylene sorbitan fatty acid esters (commonly known as Tween, Tween or polysorbate), such as Tween 20 (polyoxyethylene ether (20) sorbitan laurate), Tween 40 (polyoxyethylene ether (20) sorbitan palmitate), Tween 60 (polyoxyethylene ether (20) sorbitan stearate), Tween 65 (polyoxyethylene ether (20) sorbitan tristearate), Tween 80 (polyoxyethylene ether (20) sorbitan oleate); (iii) sorbitan fatty esters (commonly known as Span, Span), such as Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan stearate), Span 65 (sorbitan tristearate), Span 80 (sorbitan oleate) and Span 85 (sorbitan trioleate); (iv) vitamin E derivatives, such as vitamin E polyethylene glycol succinate (D-α-tocopherol polyethylene glycol 1000 succinate, TPGS, Vitamin E TPGS, Tocophersolan); (v) polyoxyethylene fatty ether surfactants derived from lauryl alcohol, cetyl alcohol, stearyl alcohol and oleyl alcohol, such as polyoxyethylene-4-lauryl ether (30, 104P), polyoxyethylene-9-lauryl ether and polyoxyethylene 12 cetyl / stearyl ether (B 1, cetostearyl alcohol polyether-12 or polyoxyethylene cetostearyl ether); (vi) copolymers of ethylene oxide (EO), propylene oxide (PO) and / or butylene oxide (BO), sold under the trade names DOWFAX TM , Pluronic TM (e.g., grades F68, F127 or L121) or Synperonic TM , such as linear EO / PO block copolymers, such as poloxamer 407, poloxamer 401 and poloxamer 188; (vii) octylphenol polyethers, the number of repeating ethoxy (oxy-1,2-ethanediyl) groups of which can vary, such as octylphenol polyether-9 (Triton X 100, or tert-octylphenoxy polyethoxyethanol). (viii) (octylphenoxy) polyethoxyethanol (IGEPAL CA-630 / NP-40).

[0042] In one embodiment, a single surfactant or a combination of surfactants can be used.

[0043] In one embodiment, the surfactant is one or more selected from the following: polyether alcohol, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, water-soluble derivative of vitamin E. In a preferred embodiment, the surfactant is one or more selected from tyloxapol, TPGS, Tween 80, and Span 20.

[0044] The polyoxyethylene sorbitan fatty acid ester that can be used in the present invention is Tween 80, which acts as a solubilizer as a surfactant in the pharmaceutical composition of the present invention. An example of Tween 80 that can be used in the present invention is the commercially available product Tween TM 80 pharma, but not limited thereto.

[0045] The alkylaryl polyether alcohol that can be used in the present invention is tyloxapol, which acts as a solubilizer as a surfactant in the pharmaceutical composition of the present invention. An example of tyloxapol that can be used in the present invention is the commercially available product Tyloxapol from Gangwal Healthcare, but not limited thereto.

[0046] The sorbitan fatty acid ester that can be used in the present invention is Span 20, which acts as a solubilizer as a surfactant in the pharmaceutical composition of the present invention. An example of Span 20 that can be used in the present invention is the commercially available product Span TM 20 pharma, but not limited thereto.

[0047] In a more preferred embodiment, the surfactant is TPGS.

[0048] The applicable TPGS in the present invention is a water-soluble derivative of vitamin E, which is esterified from vitamin E succinate (VES) and polyethylene glycol (PEG) 1000, with a relative molecular weight of about 1513 and has been included in the United States Pharmacopeia. TPGS acts as a solubilizer as a surfactant in the pharmaceutical composition of the present invention. An example of TPGS that can be used in the present invention is the commercially available product Vitamin E TPGS NF from PMC Isochem, but not limited thereto. In one embodiment, the TPGS is VitaminE TPGS NF.

[0049] In one embodiment, the surfactant is present in an amount of about 1% to about 20% by weight based on the total weight of the pharmaceutical composition. For example, the surfactant is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20% by weight based on the total weight of the pharmaceutical composition, and any range composed of these values. In a preferred embodiment, the surfactant is about 1% to about 12% by weight based on the total weight of the pharmaceutical composition, more preferably about 2% to about 12% by weight, further preferably about 3%, about 5%, about 8%, about 10%, about 12% by weight, and any range composed of these values, and particularly preferably about 3% by weight.

[0050] In one embodiment, the weight ratio of the active ingredient to the surfactant is about 1:100 to about 1:500. For example, the weight ratio of the active ingredient to the surfactant is about 1:100, about 1:200, about 1:300, about 1:400, about 1:500. In a preferred embodiment, the weight ratio of the active ingredient to the surfactant is about 1:100 to about 1:400, more preferably about 1:200 to about 1:400, further preferably about 1:200, about 1:300, and particularly preferably about 1:300.

[0051] Cosolvent

[0052] In one embodiment, the co-solvent used in the pharmaceutical composition of the present invention is an alcohol compound.

[0053] In one embodiment, the co-solvent is one or more selected from ethanol, isopropanol, propylene glycol, glycerol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, and polyvinyl alcohol.

[0054] In a preferred embodiment, the co-solvent is one or more selected from propylene glycol, ethanol, and polyethylene glycol. In one embodiment, the co-solvent is ethanol. In one embodiment, the co-solvent is propylene glycol. In one embodiment, the co-solvent is polyethylene glycol.

[0055] To reduce the potential irritation of the pharmaceutical composition, the co-solvent used in the pharmaceutical composition of the present invention can be propylene glycol.

[0056] In one embodiment, the co-solvent is present in an amount of about 1% to about 10% by weight based on the total weight of the pharmaceutical composition. For example, the co-solvent is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% by weight based on the total weight of the pharmaceutical composition, and any range composed of these values. In a preferred embodiment, the co-solvent is about 1% to about 8% by weight based on the total weight of the pharmaceutical composition, and more preferably about 2% to about 6% by weight.

[0057] In one embodiment, the co-solvent ethanol is present in an amount of about 1% to about 10% by weight based on the total weight of the pharmaceutical composition, preferably about 1% to about 5% by weight, more preferably about 2% to about 5% by weight, more preferably about 2%, about 3%, about 4% by weight, and any range composed of these values, and particularly preferably about 3% by weight.

[0058] In one embodiment, the co-solvent propylene glycol is present in an amount of about 1% to about 10% by weight based on the total weight of the pharmaceutical composition, preferably about 1% to about 6% by weight, more preferably about 2% to about 5% by weight, more preferably about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5% by weight, and any range composed of these values, and particularly preferably about 2.5%, about 3%, about 4%, about 5% by weight.

[0059] In one embodiment, the co-solvent polyethylene glycol is present in an amount of about 1% to about 10% by weight based on the total weight of the pharmaceutical composition, preferably about 1% to about 7% by weight, more preferably about 3% to about 7% by weight, more preferably about 3%, about 4%, about 5%, about 6% by weight, particularly preferably about 4%, about 5% by weight, and any range composed of these values.

[0060] In a preferred embodiment, the surfactant is TPGS, and the co-solvent is one or more selected from propylene glycol, ethanol, and polyethylene glycol. In a more preferred embodiment, the surfactant is TPGS, and the co-solvent is propylene glycol.

[0061] In one embodiment, the weight ratio of the active ingredient to the co-solvent is about 1:30 to about 1:500, preferably about 1:50 to about 1:300, more preferably about 1:60 to 1:250, such as about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, and any range composed of these ratios.

[0062] In one embodiment, the weight ratio of the active ingredient to ethanol is about 1:30 to about 1:500, preferably about 1:30 to about 1:200, more preferably about 1:40 to about 1:100, more preferably about 1:50 to about 1:100, and particularly preferably about 1:60.

[0063] In one embodiment, the weight ratio of the active ingredient to propylene glycol is about 1:30 to about 1:500, preferably about 1:30 to about 1:300, more preferably about 1:40 to about 1:300, more preferably about 1:50 to about 1:300, and particularly preferably about 1:60, about 1:80, about 1:100, about 1:250.

[0064] In one embodiment, the weight ratio of the active ingredient to polyethylene glycol is about 1:30 to about 1:500, preferably about 1:50 to about 1:500, more preferably about 1:50 to about 1:300, more preferably about 1:60 to about 1:300, and particularly preferably about 1:80, about 1:100.

[0065] In one embodiment, the weight ratio of the surfactant to the co-solvent is about 0.5:1 to about 6:1, for example, about 0.5:1, about 0.8:1, about 1:1, about 1.2:1, about 1.25:1, about 1.75:1, about 2:1, about 2.5:1, about 3:1, about 4:1, about 5:1, about 6:1, and any range composed of these ratios. In a preferred embodiment, the weight ratio of the surfactant to the co-solvent is about 0.5:1 to about 4:1, more preferably about 1:1 to about 4:1, further preferably about 1.2:1, about 1.25:1, about 2:1, about 2.5:1, about 3:1 and any range composed of these ratios, and particularly preferably about 1.2:1.

[0066] By selecting appropriate contents of the respective components, a pharmaceutical composition having excellent properties (such as stability) can be obtained.

[0067] Thickener

[0068] As described above and as well known in the art, when applied to a composition, a thickening agent can increase the viscosity or consistency of the product. However, the inventors unexpectedly found that when a thickening agent is further added to the pharmaceutical composition of the present invention, the mucosal irritation can be effectively reduced, thereby reducing the local irritation and further improving the safety.

[0069] In one embodiment, the thickening agent used in the pharmaceutical composition of the present invention is a cellulose thickening agent.

[0070] In one embodiment, the thickener is one or more selected from microcrystalline cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, ethyl methylcellulose, and crosslinked carboxymethylcellulose.

[0071] In a preferred embodiment, the thickener is one or more of hydroxypropyl methylcellulose, carboxymethylcellulose, and its derivatives.

[0072] In a preferred embodiment, the thickener is one or more selected from hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMCAS), hypromellose trimellitate (HPMCT), hypromellose phthalate (HPMCP), hypromellose succinate (HPMCS), hypromellose trimellitate (HPMCT), hypromellose acetate phthalate (HPMCAP), and hypromellose acetate maleate (HPMCAM), sodium carboxymethylcellulose (CMC-Na), and sodium methylcellulose (MC). In a more preferred embodiment, the thickener is HPMC.

[0073] Generally, HPMC can be characterized according to viscosity. For example, low-viscosity polymers include those having a viscosity of less than about 1000 mPas (in a 2% w / w aqueous solution at 25 °C), medium viscosity (1000 mPas to about 10,000 mPas), and high viscosity (greater than about 10,000 mPas). In the present invention, HPMC can comprise materials having different viscosities and average molecular weights, or can include a combination of two or more different forms of HPMC. The above viscosity ranges include all values and sub-ranges therebetween, including 1, 5, 10, 20, 50, 70, 100, 125, 250, 500, 750, 800, 900, and 950 mPas (for low-viscosity polymers); 1,000, 1,100, 2,000, 4,000, 5,000, 7,000, 9,000, 9,500, 9,750, and 10,000 mPas (for medium-viscosity polymers); and 10,250, 10,500, 11,000, 12,000, 15,000, 19,000, 20,000, 50,000, 75,000, 90,000, 100,000, 125,000, 250,000, and 500,000 mPas (for high-viscosity polymers). The HPMC of different viscosity grades used in the present invention can be purchased from commercially available products including but not limited to METHOCEL from Dow Chemical Co. TM and METOLOSE from Shin Etsu TM, a commercially available product of AQUALON, NATROSOL, and / or a commercially available product of Amerchol Corporation, CELLOSIZE), but not limited thereto, including, for example, METHOCEL TM E3LV, METHOCEL TM E5LV, METHOCEL TM E50 and METHOCEL TM K100, etc.

[0074] In one embodiment, the thickener is one or more selected from hydroxypropyl methylcellulose E5LV (HPMC E5LV), hydroxypropyl methylcellulose E4M (HPMC E4M).

[0075] In a specific embodiment, the thickener is HPMC E5LV. The HPMC E5LV that can be used in the present invention is a low-viscosity HPMC. Examples of HPMC E5LV that can be used in the present invention include the commercially available product METHOCEL of Dow Chemical Co. TM E5LV, but not limited thereto. In one embodiment, HPMC E5LV is preferably METHOCEL TM E5LV.

[0076] In a specific embodiment, the thickener is HPMC E4M. Examples of HPMC E4M that can be used in the present invention include the commercially available product METHOCEL of Dow Chemical Co. TM E4M, but not limited thereto.

[0077] In a specific embodiment, the thickener is sodium carboxymethylcellulose (CMC Na). Examples of CMC Na that can be used in the present invention include the commercially available product Aqualon of Ashland TM TM , but not limited thereto.

[0078] In a specific embodiment, the thickener is one or more of HPMC E5LV, HPMC E4M, and CMC Na.

[0079] In a preferred embodiment, the surfactant is TPGS, the co-solvent is propylene glycol, and the thickener is HPMCE5LV.

[0080] In a preferred embodiment, the surfactant is TPGS, the co-solvent is propylene glycol, and the thickener is HPMCE4M.

[0081] In a preferred embodiment, the surfactant is TPGS, the cosolvent is propylene glycol, and the thickener is CMC Na.

[0082] In one embodiment, the thickener is present in an amount of about 0.01 - about 10% by weight, preferably about 0.01% - about 8% by weight, such as about 0.01% by weight, about 0.05% by weight, about 0.1% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, and any range composed of these values, based on the total weight of the pharmaceutical composition (or the total weight of the active ingredient, surfactant, cosolvent, and thickener).

[0083] In one embodiment, the pH of the pharmaceutical composition is from about 5.0 to about 8.0, preferably from about 5.5 to about 8.0, more preferably from about 5.5 to about 7.5.

[0084] Other excipients

[0085] If desired, the pharmaceutical composition may also optionally contain other pharmaceutically acceptable excipients. Examples of excipients include, but are not limited to, humectants, stabilizers, chelating agents, antioxidants, tonicity modifiers, diluents, disintegrants, glidants, lubricants, preservatives, pH regulators, antibacterial agents, antiviral agents, and antifungal agents, dyes / colorants, flavoring agents, surfactants, dispersants, solvents, or emulsifiers, or one or more of other additives known in the art. The concentration of the excipients can be adjusted according to the use of different pharmaceutical preparations, and the presence or absence of the excipients or their concentration is not an essential feature of the present invention.

[0086] It should be noted that the above-listed pharmaceutically acceptable excipients are only illustrative and representative. Therefore, the pharmaceutical preparations of the present invention are not limited to containing only the excipients listed above. Those skilled in the art can make various changes, adjustments, or equivalent substitutions to the above excipients according to conventional techniques, all of which do not exceed the protection scope of the present invention.

[0087] On the other hand, the present invention also provides a pharmaceutical preparation comprising the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention can be further combined with pharmaceutically acceptable medicinal excipients as needed to form various dosage forms.

[0088] In one embodiment, the dosage form of the pharmaceutical preparation is a solution, and its administration routes include, but are not limited to, nasal spray, inhalation, ophthalmic, otic, injection, oral, topical.

[0089] Use

[0090] The pharmaceutical composition or pharmaceutical preparation of the present invention can be used to treat or prevent a disease. Therefore, in another aspect, the present invention relates to the use of the pharmaceutical composition or pharmaceutical preparation of the present invention in the preparation of a medicament for treating or preventing a disease. The present invention also relates to a method for treating or preventing a disease, comprising administering the pharmaceutical composition or pharmaceutical preparation of the present invention to a subject in need thereof. In one embodiment, the disease comprises asthma, allergic rhinitis, chronic obstructive pneumonia or atopic dermatitis.

[0091] Beneficial effects

[0092] In the field of pharmaceutical preparations, the active ingredients in suspensions need to be dissolved before they can be absorbed, and different drug particle size distributions will also affect the drug exposure, drug deposition site and stability, etc. In addition, most of these dosage forms contain more organic solvents, resulting in large side effects, and the preparation process is complex, with high mechanical crushing costs and low yields.

[0093] Compared with the prior art, the pharmaceutical composition of the present invention is in the form of a solution, and the active ingredient has a large dispersion, fast absorption, and good bioavailability; the dosage can be further reduced and side effects can be reduced; the solution has good uniformity, the dosage size is easy to adjust and control, and can be accurately measured and used, and the route of administration is not restricted, and no special equipment is required for administration, and no special production equipment such as pressure-resistant containers is required during the production process. The pharmaceutical preparation in which fluticasone or a pharmaceutically acceptable salt thereof is dissolved in the surfactant or cosolvent can be prepared by stirring and dissolving, and the preparation process is simple, the quality is stable and controllable, and the production capacity is improved. In addition, the pharmaceutical composition and pharmaceutical preparation of the present invention also have excellent stability.

[0094] In addition, the inventors of the present invention have unexpectedly discovered that further adding a thickener to the pharmaceutical composition can effectively reduce mucosal irritation, thereby reducing local irritation and further improving safety and patient comfort.

[0095] Examples

[0096] The scheme of the present invention is further described in detail below in conjunction with specific examples. Unless otherwise specified, the instruments, equipment and reagents used herein are all commercially available. Unless otherwise specified, the determination methods used for evaluating the physicochemical properties in each example are briefly described as follows:

[0097] 1. Determination of supernatant content: The test substance (Fluticasone (reference preparation) and the drug-loaded composition (i.e., the pharmaceutical composition of the present invention) were centrifuged at 10000 rpm for 10 min, 100 μL of the supernatant was mixed with 900 μL of 0.001 M hydrochloric acid, and the content of fluticasone propionate in the supernatant was determined using an Agilent 1260 high performance liquid chromatograph. The analysis parameters are as follows:

[0098]

[0099] 2. Related Substances: Precisely pipette 0.50 mL of the test substance (Fluticasone Propionate Nasal Spray (reference preparation), drug-loaded composition (i.e., the pharmaceutical composition of the present invention)), add 0.50 mL of diluent, mix well, and use it as the related substances sample solution. Use an Agilent 1260 high performance liquid chromatograph for content determination. Analytical method:

[0100] Chromatographic column Waters Spherisorb ODS1 4.6×250mm, 5μm Mobile phase [Methanol - acetonitrile (77:23)] - pH 3.4 buffer solution (55:45) Flow rate 1.5 mL / min Column temperature 40℃ Detection wavelength 239 nm Injection volume 50 μL

[0101] 3. Osmotic Pressure: After shaking the test substance (Fluticasone Propionate Nasal Spray (reference preparation), drug-loaded composition (i.e., the pharmaceutical composition of the present invention)), use the freezing point depression method to test the osmotic pressure (OSMOMAT-030 freezing point osmometer manufactured by GONOTEC).

[0102] Example 1 Preparation and Evaluation of Fluticasone Surfactant / Cosolvent Composition

[0103] 1. Preparation:

[0104] Prepare the fluticasone surfactant / cosolvent composition according to the specific composition and dosage in Table 1-1.

[0105] Preparation of the active ingredient concentrate: Dissolve fluticasone propionate in a mixed solvent containing different types of surfactants (Tween 80, tyloxapol, TPGS, span 20) and the cosolvent propylene glycol to obtain a concentrate of fluticasone propionate.

[0106] Preparation of the pharmaceutical composition: Under stirring conditions, dilute the concentrate of fluticasone propionate with purified water to 100 g to obtain the fluticasone surfactant / cosolvent composition.

[0107] According to the above method, Compositions 1-1 to 1-4 of the present invention were prepared, and the appearance state of the compositions was observed. The results are shown in Table 1-1.

[0108] Table 1-1 Composition and Dosage of Each Component of Fluticasone Surfactant / Cosolvent Composition (g)

[0109]

[0110] As can be seen from the appearance state in Table 1-1, in the presence of a cosolvent, adding a surfactant can dissolve fluticasone propionate to form a clear solution. The composition 1-3 formed by TPGS will not precipitate white crystals after forming a clear solution, achieving a stable physical state. The results show that using a mixed solvent of surfactant / cosolvent can dissolve fluticasone propionate and form a stable solution, and using TPGS can obtain a fluticasone propionate composition with a stable physical state.

[0111] 2. Physicochemical Property Evaluation

[0112] 2.1 Determination of Supernatant Content

[0113] Determine the content of fluticasone propionate in the supernatant of each composition after dissolution, and the results are shown in Table 1-2.

[0114] Table 1-2 Supernatant Content of Fluticasone Compositions and Reference Preparations

[0115]

[0116] As can be seen from Table 1-2, compared with the reference preparation (Fluticasone Propionate Nasal Spray), the content of fluticasone propionate in Compositions 1-1, 1-2, and 1-3 has increased, indicating that surfactants Tween 80, tyloxapol, and TPGS can improve the solubility of fluticasone propionate. In particular, the content of fluticasone propionate in the supernatant of Composition 1-3 is about 25 times or more that of the reference preparation, indicating that TPGS can significantly improve the solubility of fluticasone propionate.

[0117] Preparation and Evaluation of Fluticasone Solubilizer Compositions in Example 2

[0118] 1. Preparation:

[0119] Prepare the fluticasone solubilizer compositions according to the specific composition and dosage in Table 2-1.

[0120] Preparation of the active ingredient concentrate: Dissolve fluticasone propionate in a mixed solvent containing surfactant TPGS and different solubilizers to obtain a concentrate of fluticasone propionate.

[0121] Preparation of the pharmaceutical composition: Under stirring conditions, dilute the concentrate of fluticasone propionate with purified water to 100 g to obtain the fluticasone solubilizer composition.

[0122] According to the above method, Compositions 2-1 to 2-7 of the present invention are prepared, and the appearance states of the compositions are observed, and the results are shown in Table 2-1.

[0123] Table 2-1 Composition and Dosage of Each Component of Fluticasone Solubilizer Composition (g)

[0124]

[0125] As can be seen from the appearance status in Table 2-1, fluticasone propionate in Composition 2-1 without cosolvent was not completely dissolved. Compared with Composition 2-1, a clear solution (corresponding to Composition 2-5) could be obtained by adding ethanol (about 3% of the total weight of the solution). When using about 3% by weight of propylene glycol, the active ingredient was not completely dissolved, and a clear solution could be obtained by increasing the dosage to more than about 4% by weight (corresponding to Composition 2-3). When using about 4% by weight of polyethylene glycol 400, the active ingredient was not completely dissolved, and a clear solution could be obtained by increasing the dosage to more than about 5% by weight (corresponding to Composition 2-7). The above results indicate that different cosolvents have different solubilization effects on the active ingredient, and the solubility of the active ingredient can be increased by increasing the dosage of the cosolvent.

[0126] It can be seen that in the presence of a surfactant, the solubility of fluticasone propionate can be improved by using a certain amount of cosolvent to form a clear solution.

[0127] 2. Physicochemical Property Evaluation

[0128] 2.1 Determination of Supernatant Content

[0129] The test results are shown in Table 2-2 in detail.

[0130] Table 2-2 Supernatant Content of Fluticasone Cosolvent Composition and Reference Preparation

[0131]

[0132] As can be seen from Table 2-2, compared with the reference preparation, the content of fluticasone propionate in the supernatant of Compositions 2-3, 2-4, 2-5, and 2-7 was significantly increased, indicating that the addition of cosolvent can significantly improve the solubility of fluticasone propionate.

[0133] Preparation and Evaluation of Fluticasone Compositions with Different Proportions of Surfactant and Cosolvent in Example 3

[0134] 1. Preparation:

[0135] Prepare fluticasone compositions with different proportions of surfactant and cosolvent according to the specific composition and dosage in Table 3-1.

[0136] Preparation of Active Ingredient Concentrate: Dissolve fluticasone propionate in a mixed solvent containing different dosages of surfactant TPGS and cosolvent propylene glycol to obtain a concentrate of fluticasone propionate.

[0137] Preparation of Pharmaceutical Composition: Under stirring conditions, dilute the concentrate of fluticasone propionate with purified water to 100 g to obtain fluticasone compositions with different proportions of surfactant and cosolvent.

[0138] According to the above method, the compositions 3-1 to 3-4 of the present invention were prepared, and the appearance states of the compositions were observed. The results are shown in Table 3-1.

[0139] Table 3-1 Composition and dosage of each component of the fluticasone composition (g)

[0140]

[0141]

[0142] As can be seen from the appearance states in Table 3-1, when propylene glycol is about 4% by weight relative to the total weight of the pharmaceutical composition, a clear solution can be obtained by using TPGS of about 8% by weight or more relative to the total weight of the pharmaceutical composition. When the dosage of TPGS is about 5% by weight relative to the total weight of the pharmaceutical composition, the active ingredient is not completely dissolved (corresponding to Composition 3-1). When the weight percentage is increased to more than about 8% on the basis of Composition 3-1, the obtained compositions all show clear solutions. It shows that the solubility of the active ingredient in the composition can be further improved by adjusting the ratio of TPGS and propylene glycol.

[0143] 2. Physicochemical property evaluation

[0144] 2.1 Determination of supernatant content

[0145] The test results are shown in Table 3-2.

[0146] Table 3-2 Supernatant content of the fluticasone composition and the reference preparation

[0147]

[0148] As can be seen from Table 3-2, compared with the reference preparation, the content of fluticasone propionate in the supernatants of Compositions 3-1, 3-2, 3-3, and 3-4 has increased. Specifically, Compositions 3-2, 3-3, and 3-4 can significantly improve the solubility of fluticasone propionate. The ratio of the surfactant to the cosolvent is about 1.25:1, 2:1, 2.5:1, 3:1.

[0149] Example 4 Preparation and evaluation of the fluticasone composition

[0150] 1. Preparation

[0151] Prepare fluticasone compositions containing different thickeners according to the specific composition and dosage in Table 4-1.

[0152] Preparation of the active ingredient concentrate: Dissolve fluticasone propionate in a mixed solvent containing the surfactant TPGS and the cosolvent propylene glycol to obtain a concentrate of fluticasone propionate.

[0153] Preparation of thickener aqueous solution: Different thickeners were dissolved in purified water to obtain thickener aqueous solutions.

[0154] Preparation of pharmaceutical composition: Under stirring conditions, the concentrated solution of fluticasone propionate was diluted with the thickener aqueous solution, and the pH of the solution was adjusted to about 5.5 - 7.5 with sodium hydroxide solution, and then made up to 100 g with purified water to obtain the fluticasone composition.

[0155] According to the above method, the compositions 4 - 1 to 4 - 8 of the present invention were prepared, and the appearance states of the compositions were observed. The results are shown in Table 4 - 1.

[0156] Table 4 - 1 Composition and dosage of each component of fluticasone composition (g)

[0157]

[0158] It can be seen from the appearance states in Table 4 - 1 that the compositions 4 - 1 to 4 - 8 are all clear solutions.

[0159] 2. Evaluation of physicochemical properties

[0160] 2.1 Detection of supernatant content

[0161] The test results are shown in Table 4 - 2.

[0162] Table 4 - 2 Supernatant content of fluticasone composition

[0163]

[0164] It can be seen from Table 4 - 2 that compared with the composition without thickener (corresponding to composition 4 - 1), the content of fluticasone propionate in the supernatant of compositions 4 - 2 to 4 - 8 is close, indicating that adding thickener does not affect the solubility of fluticasone propionate.

[0165] 2.2 Osmotic pressure detection

[0166] The test results are shown in Table 4 - 3.

[0167] Table 4 - 3 Osmotic pressure of fluticasone composition

[0168]

[0169] Since the osmotic pressure of nasal epithelial cells is 280 mOsm·kg -1 , therefore, it is generally considered that the osmotic pressure of the preparation within the range of 200 - 400 mOsm·kg -1 has the least irritation and damage to nasal epithelial cells.

[0170] It can be seen from Table 4 - 3 that the osmotic pressures of compositions 4 - 1, 4 - 2, 4 - 3, 4 - 5, 4 - 6, 4 - 7 are all 400 mOsm·kg-1 Nearby, the compositions 4-8 are slightly higher than 400 mOsm·kg -1 , indicating that the pharmaceutical composition of the present invention will not cause irritation and damage to nasal epithelial cells.

[0171] 2.3 Stability testing

[0172] During the storage process, the pharmaceutical composition is susceptible to the influence of the external environment (such as temperature, humidity, etc.), and phenomena such as crystallization and growth of related substances are likely to occur, resulting in unqualified product quality. To evaluate the stability of the fluticasone pharmaceutical composition, the stability under the accelerated conditions of 40°C / 75% RH was tested in this example. The specific test method is as follows:

[0173] Load the pharmaceutical composition into an HDPE bottle and place the HDPE bottle in a stability chamber. Take out the pharmaceutical composition at the specified time points for testing. Set the observation time to 3 months, and record the appearance state of the composition and the maximum single impurity and total impurities before and after the start of the stability experiment.

[0174] The stability test results of the composition are shown in Table 4-4.

[0175] Table 4-4 Accelerated stability of fluticasone composition

[0176]

[0177] As can be seen from Table 4-4, the pharmaceutical compositions 4-1 to 4-8 are clear before and after the accelerated experiment. After testing, after being placed under accelerated conditions for 3 months, the maximum single impurity of the related substances is ≤0.22%, which is consistent with the maximum single impurity of the starting solution, and the total impurities are close before and after the accelerated experiment.

[0178] Thus, it can be seen that the composition has not produced precipitation or crystallization, and the active ingredient has not been significantly degraded, indicating that the composition has excellent stability.

[0179] 2.4 Irritation testing

[0180] Test grouping: Randomly divide 24 rabbits (Hangzhou Yuhang Kelian Rabbit Industry Professional Cooperative) with a body weight of 2.5 ± 0.3 kg into 4 groups, with 6 rabbits in each group. They are the normal control group, test article group 1 (composition 4-1), test article group 2 (composition 4-3), and test article group 3 (composition 4-6).

[0181] Experimental treatment and analysis:

[0182] 1) No treatment is given to the normal control group. For each experimental animal in test article groups 1-3, administer the drug intranasally once a day at a dosage of 120 μg / kg for 7 consecutive days.

[0183] 2) Observe the general conditions of the experimental animals (such as respiration, circulation, central nervous system) and local irritation symptoms (such as asthma, cough, vomiting, asphyxia, etc.) after each administration, and score and evaluate the irritation intensity according to the "Grading Criteria for Local Mucosal Irritation Reaction in Table 4-8 (see Wang Beiying, Li Yikui. Techniques and Methods for the Research and Development of New Chinese Medicines. Shanghai Scientific and Technical Publishers, 2001: 815)".

[0184] 3) Sacrifice some experimental animals 24 hours after the last administration, observe whether there is congestion, redness, etc. in the mucosal tissues of the local respiratory tract (nose, larynx, trachea, bronchus), and perform staining and pathological examinations on the nasal mucosal epithelial cells.

[0185] The results of the irritation test are shown in Table 4-9.

[0186] Table 4-8 Grading Criteria for Local Irritation Reaction

[0187] Morphological change Graded score No change or no obvious change 0 Mild congestion, small amount of secretion 1 Moderate congestion, more secretion 2 Severe congestion, edema, a lot of secretion, mucosal degeneration 3

[0188] The average score is between 0.00 and 0.40, indicating no irritation.

[0189] The average score is between 0.41 and 4.50, indicating mild irritation.

[0190] The average score is between 1.51 and 2.50, indicating moderate irritation.

[0191] The average score > 2.50, indicating severe irritation.

[0192] Table 4-9 Results of the Local Irritation Experiment of Fluticasone Compositions

[0193]

[0194]

[0195] As can be seen from the results in Table 4-9, compared with the normal control group, the experimental animals in the test article group 1 all showed congestion of the nasal mucosal epithelial cells, and some mild chronic inflammation occurred, indicating that Composition 4-1 has mild irritation to the experimental animals. In contrast, the degree of congestion of the nasal mucosal epithelial cells in the experimental animals of the test article group 2 and the test article group 3 was lower or no abnormality was observed, and no inflammatory cell infiltration was seen, and the score was non-irritating. It shows that Composition 4-3 and Composition 4-6 (especially Composition 4-3) have no local irritation to the experimental animals. By comparing the components of the compositions, it can be seen that Composition 4-3 and Composition 4-6 are added with thickeners on the basis of Composition 4-1, indicating that the thickener can effectively reduce the mucosal irritation of the composition.

Claims

1. A fluticasone pharmaceutical composition, which is a solution and contains fluticasone or a pharmaceutically acceptable salt thereof as an active ingredient, a surfactant, and a cosolvent.

2. The pharmaceutical composition according to claim 1, wherein the active ingredient is fluticasone propionate.

3. The pharmaceutical composition according to claim 1 or 2, wherein the surfactant is a nonionic surfactant, preferably one or more selected from tyloxapol, vitamin E polyethylene glycol succinate (TPGS), sorbitan fatty esters, polyoxyethylene sorbitan fatty acid esters, and particularly preferably vitamin E polyethylene glycol succinate (TPGS); and / or the cosolvent is an alcohol compound, preferably one or more selected from ethanol, isopropanol, propylene glycol, glycerol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, and polyoxyethylene alcohol, and more preferably one or more selected from ethanol, propylene glycol, and polyethylene glycol.

4. The pharmaceutical composition according to any one of claims 1-3, wherein based on the total weight of the pharmaceutical composition, the active ingredient is present in an amount of about 0.005-0.1% by weight; and / or the surfactant is present in an amount of about 1-20% by weight; and / or the cosolvent is present in an amount of about 1-10% by weight.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the weight ratio of the active ingredient to the surfactant is about 1:100 - about 1:500; and / or the weight ratio of the active ingredient to the cosolvent is about 1:30 - about 1:300; and / or the weight ratio of the surfactant to the cosolvent is about 0.5:1 - about 6:

1.

6. The pharmaceutical composition according to any one of claims 1-5, which further comprises a thickening agent.

7. The pharmaceutical composition according to claim 6, wherein, the thickening agent is a cellulose thickening agent, preferably one or more selected from microcrystalline cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl methyl cellulose, and crosslinked carboxymethyl cellulose, and more preferably one or more selected from hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose.

8. The pharmaceutical composition according to claim 6 or 7, wherein based on the total weight of the pharmaceutical composition, the thickening agent is present in an amount of about 0.01-10% by weight.

9. The pharmaceutical composition according to any one of claims 6-8, wherein the weight ratio of the active ingredient to the thickening agent is about 1:5 - about 1:1000; and / or the weight ratio of the thickening agent to the surfactant is about 1:0.1 - about 1:

60.

10. A pharmaceutical preparation, which comprises the pharmaceutical composition according to any one of claims 1-9.

11. Use of the pharmaceutical composition according to any one of claims 1-9 or the pharmaceutical preparation according to claim 10 in the preparation of a drug for preventing or treating asthma, allergic rhinitis, chronic obstructive pneumonia, or atopic dermatitis.

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