Pharmaceutical composition comprising steroid compound and olopatadine

Abstract

The present invention relates to a pharmaceutical composition comprising a steroid compound and olopatadine, which is a homogeneous composition wherein the steroid compound is stably in suspension state and olopatadine is stably in solution state, and a process for preparing the composition.

Description

[Technical Field]

[0001] This invention relates to a composition containing a steroid compound and olopatadine, and a method for manufacturing the same, wherein the composition is a homogeneous composition in which the steroid compound is in a suspended state and olopatadine is stably present in a dissolved state. Furthermore, this invention can be used for the treatment of allergic rhinitis. [Previous Technology]

[0002] Steroid compounds with anti-inflammatory effects are widely used in the treatment of inflammatory diseases such as dermatitis, asthma, and rhinitis. For example, beclomethasone propionate, fluticasone propionate, mometasone furanylcarboxylate, and fluticasone furanylcarboxylate, which are glucocorticoid steroid compounds used topically to reduce inflammation of the skin or respiratory tract, are commercially available as nasal drops for allergic rhinitis (Patent Document 1).

[0003] These steroid compounds are extremely poorly soluble in water. When preparing nasal drops for the treatment of allergic rhinitis, it is difficult to contain a large amount of organic solvent from the point of view of irritation, if considering administration to the delicate nasal mucosa. Furthermore, even when considering other dissolving agents, there are certain limitations in choosing safe dissolving agents with low mucosal irritation. As a result, for nasal drops, aqueous suspensions with a weakly acidic pH range of 4.5 to 6.5 have been developed and are commercially available.

[0004] However, there are many issues in forming stable suspensions. Even when using crystalline cellulose and sodium carboxymethyl cellulose (carmellose Na), which are widely used as suspending agents, their suspension and dispersibility may not be stable. Generally, it is necessary to remind users to shake well before use.

[0005] On the other hand, europetrazol has been used as an antihistamine for the treatment of allergic rhinitis or allergic conjunctivitis. Patent Documents 2 and 3 disclose nasal drops containing its hydrochloride salt. Specifically, they disclose an invention relating to a topical preparation for the treatment and / or prevention of allergic or inflammatory disorders of the nose. The topical preparation is a formulation of europetrazol, characterized by containing 0.54 to 0.62% (w / v) of europetrazol free base and adjusted to a pH of 3.6 to 3.8.

[0006] Regarding the product according to Patent Document 2, PATANASE (registered trademark) (Europalate nasal solution) 0.6% is currently the only commercially available Europalate nasal drop product for nasal use. According to its label information, it contains Europalate hydrochloride equivalent to 0.6% Europalate, 0.01% benzalkonium chloride, and unspecified amounts of sodium dibasic phosphate, sodium edetate hydrate, sodium chloride, hydrochloric acid and / or sodium hydroxide (for pH adjustment) and purified water; however, the pH is adjusted to approximately 3.7, which is quite irritating to the nasal mucosa.

[0007] Also, there is a commercially available product called PATANOL (registered trademark), which has the same composition as PATANASE (registered trademark) and is an ophthalmic solution with a pH adjusted to about 7. However, since Europalate is poorly soluble near neutral, its concentration, when converted to Europalate free base, is a low value of 0.1%.

[0008] The poor solubility of Europalate is discussed in detail in Patent Document 2, which shows two "pH-solubility profiles of Europalate". When the pH exceeds 5, it shows that it cannot be dissolved, which is equivalent to more than 0.2% Europalate based on the free base of Europalate.

[0009] Therefore, even if steroid compounds are combined with europetrol to form a nasal spray, each component has the characteristics of solubility or suspension, making it difficult to obtain the physiologically most suitable pH, the most suitable concentration, and to satisfy the solubility or suspension requirements.

[0009] [Previous Technical Documents]

[0009] [Patent Documents]

[0010] [Patent Document 1] Japanese Patent No. 4838493

[0010] [Patent Document 2] Japanese Patent No. 5149308

[0010] [Patent Document 3] Japanese Patent No. 6203967

[0011] The object of the present invention is to develop a physiologically low-irritation pH range, preferably from pH 4.0 to 7.0, more preferably from pH 4.5 to 6.5, and even more preferably from pH 5.0 to 6.0, in which the steroid compound is in a stable suspension state and the steroid compound remains in a dissolved state even at high concentrations, especially in aqueous spray nasal spray formulations.

[0012] In view of the above-mentioned problems, the inventors have repeatedly and diligently studied the results and found that in the nasal drop composition containing steroid compounds and europetidine, without the presence of conventional solvents or dissolving aids and without suspending agents, by using carboxyethylene polymers, even in the pH range of 5.0 to 6.0, the steroid compounds can be in an extremely stable suspended dispersion state that has never been seen before, and europetidine maintains a stable dissolved state at an unprecedentedly high concentration, thereby completing the present invention.

[0013] The present invention is as follows.

[0014] [Item 1] A pharmaceutical composition comprising a steroid compound and europetidine or a pharmaceutically permissible salt thereof.

[0015] [Item 2] The pharmaceutical composition described in Item 1 contains a steroid compound and europetrazol hydrochloride.

[0016] [Item 3] The pharmaceutical composition described in item 1 or item 2 contains a carboxyethylene polymer as a thickener.

[0017] [Item 4] The pharmaceutical composition described in any one of items 1 to 3 is a composition comprising a steroid compound, europetidine or a pharmaceutically permissible salt thereof, and a carboxyethylene polymer, wherein the pH of the composition is adjusted to 4.0 to 7.0 (preferably 4.5 to 6.5, more preferably 5.0 to 6.0).

[0018] [Item 5] The pharmaceutical composition described in any one of items 1 to 4, wherein europetidine or a pharmaceutically permissible salt thereof is europetidine hydrochloride, the concentration of europetidine hydrochloride is 0.2% (w / w) or more, and europetidine exists in the composition in a dissolved state.

[0019] [Item 6] The pharmaceutical composition described in any one of items 1 to 5, wherein the concentration of the steroid compound is 0.005 to 1% (by weight), and the steroid compound exists in the composition in a stable dispersed state.

[0020] [Item 7] The pharmaceutical composition described in any one of items 1 to 6, wherein the steroid compound is any one of becquerel propionate, fluticasone propionate, mometasone furanylcarboxylate, or fluticasone furanylcarboxylate.

[0021] [Item 8] The pharmaceutical composition as described in Item 7, wherein the steroid compound is fluticasone furan carboxylic acid ester.

[0022] [Item 9] The pharmaceutical composition described in any one of items 1 to 8, wherein the carboxyethylene polymer is present at a concentration of 0.1% to 2% (by weight).

[0023] [Item 10] The pharmaceutical composition described in any of items 4 to 9 uses sodium hydroxide and / or hydrochloric acid as a pH adjuster in order to adjust the pH.

[0024] [Item 11] The pharmaceutical composition described in any of items 4 to 10 uses L-arginine as a neutralizing agent to adjust pH.

[0025] [Item 12] The pharmaceutical composition described in any of the items 1 to 11 further includes one or more suspensions.

[0026] [Item 13] The pharmaceutical composition as described in Item 12, wherein the suspension comprises polysorbate 80.

[0027] [Item 14] The pharmaceutical composition described in any of the items 1 to 13 further includes one or more preservatives.

[0027] [Item 15] The pharmaceutical composition of Item 14, wherein the preservative comprises benzyl alkyl ammonium chloride.

[0028] [Item 16] The pharmaceutical composition described in any of items 1 to 15 further includes one or more stabilizers.

[0029] [Item 17] The pharmaceutical composition described in Item 16, wherein the stabilizer comprises sodium edetate hydrate.

[0030] [Item 18] The pharmaceutical composition described in any of items 1 to 17 further includes one or more isotonic agents.

[0031] [Item 19] The pharmaceutical composition as described in Item 18, wherein the isotonic agent comprises sodium chloride and / or glycerin.

[0032] [Item 20] The pharmaceutical composition as described in item 18 or 19, wherein the isotonic agent is present at a concentration of 0.1 to 10% (by weight).

[0033] [Item 21] Any of the pharmaceutical ingredients described in any of the items 1 to 20 are isotropic.

[0034] [Item 22] The pharmaceutical composition described in any one of items 1 to 21 has a viscosity of 250 to 2500 mPa·s (preferably 500 to 1500 mPa·s).

[0035] [Item 23] The pharmaceutical composition described in any of items 1 to 22 has an average droplet diameter of 30 to 100 μm when sprayed.

[0036] [Item 24] The pharmaceutical composition described in any one of items 21 to 23, wherein the pH adjuster is sodium hydroxide, the neutralizer is L-arginine, the suspending agent is polysorbate 80, the preservative is benzyl ammonium chloride, the stabilizer is sodium edetate hydrate, and the isotonic agent is glycerol and sodium chloride.

[0037] [Item 25] The pharmaceutical composition described in any of items 1 to 24, wherein the pharmaceutical composition is an aqueous nasal spray.

[0038] [Item 26] A nasal spray formulation comprising any one of the pharmaceutical ingredients described in items 1 to 25.

[0039] [Item 27] ​​A pharmaceutical composition prepared simultaneously by the following methods: a method for dissolving europetidine in the range of pH 5.0 to 6.0 by adding a carboxyethylene polymer, and a method for stabilizing the suspension of an aqueous suspension containing fluticasone furan carboxylate.

[0040] According to the present invention, in a spray-type nasal spray containing europetrazol or a pharmaceutically permissible salt thereof and a steroid compound, europetrazol is dissolved, and the suspension of the steroid compound is extremely stable, so it does not need to be shaken before use. Furthermore, for nasal sprays, adjusting the pH to a physiologically more tolerable level of 5.0 to 6.0 allows the spray to easily remain in the nasal cavity after administration, and from a pharmacological perspective, a sustained and effective improvement in efficacy can be expected.

Implementation Method

[0041] The steroid compound is not particularly limited as long as it has anti-inflammatory effects. Examples include becquerel propionate, fluticasone propionate, memetazidine furanylcarboxylate, and fluticasone furanylcarboxylate, with fluticasone furanylcarboxylate being preferred. Fluticasone furanylcarboxylate is a furan-2-carboxylic acid 6α,9-difluoro-17β-[(fluoromethylhydrothio)carbonyl]-11β-hydroxy-16α-methyl-3-sideoxyandrosta-1,4-diene-17α-yl ester, having the following structure, and is widely used in the treatment of allergic rhinitis. The concentration of the steroid compound contained in the formulation of the present invention is 0.005 to 1% (w / w), preferably 0.01 to 0.1%.

[0041]

[0042] Europalatine is a compound having the following structure:

[0042] It has been used as an antihistamine for the treatment of allergic rhinitis or allergic conjunctivitis.

[0043] Regarding europetrazol, although europetrazol or its salts can be used to prepare the nasal drop formulation, it is preferable to use europetrazol hydrochloride. The concentration of europetrazol contained in the formulation of the present invention, for europetrazol hydrochloride, is 0.2% (w / w) or more, preferably 0.4 to 0.8% (w / w), and more preferably 0.4 to 0.7% (w / w).

[0044] When "pharmaceutically permissible salts" are used in humans or animals, there are no special restrictions as long as they do not cause adverse effects such as toxicity. Examples of acid addition salts include: hydrochloride, citrate, succinic acid, hydrobromide, ascorbate, furoate, sulfate, acetate, valerate, oleate, palmitate, laurate, stearate, hydrogen sulfate, borate, benzoate, lactate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, gluconate, lactobionate, and lauryl sulfate, etc.; examples of salts formed with alkalis include sodium, potassium, and other alkali metal salts; calcium, magnesium, and other alkaline earth metal salts.

[0045] The pharmaceutical composition system of the present invention can be formulated, for example, into oral, non-oral or topical administration, especially for topical administration.

[0045] The topical administration methods used in this specification can be applied by means of application, gas delivery, and inhalation. Examples of topical administration formulations include: ointments, lotions, creams, gels, sprays, aerosols, suppositories, eye drops, ear drops, nasal drops, and intranasal spray formulations.

[0045] In particular, the nasal drop composition for local intranasal administration includes nasal drops and intranasal spray formulations. Here, "nasal drop composition" is an aqueous liquid for nasal application and is in a suspended state.

[0046] There are no particular restrictions on the use of carboxyethylene polymers as long as they are commonly used in formulations. It is preferable to apply shear force externally to the carboxyethylene polymer to adjust its viscosity; the method and effects of this are described in WO 2007 / 123193. Specifically, well-known devices for applying shear force, such as high-speed rotary emulsifiers, colloid mill emulsifiers, high-pressure emulsifiers, roller mill emulsifiers, ultrasonic emulsifiers, and film emulsifiers, can be used. In particular, high-speed rotary emulsifiers of the homogenizing, comb-type, and intermittent jet-generating types are preferred. The concentration of the carboxyethylene polymer is 0.1 to 2% (w / w), preferably 0.25 to 1.0%.

[0047] Examples of suspending agents used in this invention include: polysorbate 80, polyoxyl stearate 40, and / or polyoxyethylated cured castor oil 60, with polysorbate 80 being preferred. The concentration of the suspending agent is 0.01 to 1% (by weight), preferably 0.025 to 0.5%.

[0048] Examples of preservatives used in this invention include: benzalkonium chloride, benzethonium chloride, and chlorobutanol, with benzalkonium chloride being preferred. Here, the concentration of the preservative is 0.005 to 1% (by weight), preferably 0.01 to 0.1%.

[0049] Examples of stabilizers used in this invention include sodium edetate hydrate. Here, the concentration of the stabilizer is 0.005 to 1% (w / w), preferably 0.01 to 0.1%.

[0050] The aqueous nasal drop composition of the present invention is preferably isotonic or close to isotonic. Isotonicity can be adjusted using isotonic agents such as sodium chloride, boric acid, glycerin and / or glucose. Here, the concentration of the isotonic agent is 0.1 to 10% (w / w), preferably 0.1 to 1.0%.

[0051] The pH of the aqueous nasal drop composition of the present invention must be adjusted to 4.0 to 7.0 (preferably 4.5 to 6.5, and even more preferably 5.0 to 6.0). Sodium hydroxide, potassium hydroxide, hydrochloric acid, etc. can be used as pH adjusters for pH adjustment, and sodium hydroxide is preferred.

[0052] The pH adjustment of the present invention further utilizes L-arginine as a neutralizing agent.

[0053] The viscosity of the aqueous nasal drop composition of the present invention is generally 250 to 2500 mPa·s, preferably 500 to 1500 mPa·s.

[0054] In this invention, "dissolved state" means a state in which the target pharmaceutical ingredient is completely dissolved, and "dispersed state" means a state in which the target pharmaceutical ingredient is suspended uniformly without crystallizing.

[0055] The droplet diameter of the aqueous nasal spray composition of the present invention refers to the particle size of the droplets during spraying, and the average droplet diameter is preferably 30 to 100 μm, and more preferably 40 to 80 μm.

[0056] "Nasal spray" means a spray that is administered into the nasal cavity via a spray device or similar means. "Nasal spray composition" means a liquid preparation that is administered into the nasal cavity via a spray.

[0056] The nasal spray preparation of the present invention is intended to be a conventional nasal spray, or a nasal preparation filled in an airless spray container with pressure relief as described in WO 2007 / 123193 and WO 2007 / 123207.

[0056] [Example]

[0057] Hereinafter, examples, comparative examples, and stability tests are provided to illustrate the present invention in more detail; however, these are not intended to limit the invention. Unless otherwise stated, the evaluation of the examples and comparative examples and the evaluation of the stability tests described below are based on the Japanese Pharmacopoeia.

[0058] The viscosity was determined according to the Japanese Pharmacopoeia / General Test Method / Viscosity Determination Method Rotation Viscometer Method. The details of the determination method are as follows.

[0058] [Determination Method]

[0058] To minimize the introduction of air bubbles, 1.1 mL of the test sample (test preparation) was placed into the sample cup of a cone-plate type rotational viscometer (cone plate type) pre-set to 20°C and left for 5 minutes. The viscosity value was then measured under the following conditions when a shear force was applied for 3 minutes.

[0058] [Measurement Conditions]

[0058] Machine used: TVE-25 viscometer from Toki Industrial Co., Ltd.

[0058] Measurement range: R (full-scale torque 1437.4 μN‧m)

[0058] Shearing speed: 9.575s-1 (2.5 revolutions per minute)

[0058] Rotor: 1°34'×R24

[0059] The droplet size (average droplet size: 10 to 100 μm (%)) was determined using a laser diffraction particle size distribution measuring device.

[0059] [Measurement Conditions]

[0059] Machine used: Malvern Spray Tech

[0059] Reading distance: 30mm

[0059] Spray angle: 40°

[0059] Extrusion speed: 100mm / s

[0060] The confirmation of crystallization is determined using a digital microscope.

[0060] [Measurement Conditions]

[0060] Machine used: Kenyence VHX-7000 digital microscope, Inc.

[0060] Multiplier: 500x

[0061] Example 1

[0061] (Prescription)

[0061]

[0061] (Manufacturing Method)

[0061] After dissolving L-arginine, sodium edetate hydrate, and europetrazol hydrochloride in purified water, the mixture was placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkyl ammonium chloride and half the amount of polysorbate 80 was then added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was added. These were then stirred in a vacuum stirring apparatus. Additionally, fluticasone furanyl ester was wetted in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in a vacuum stirring apparatus. As needed, the pH was adjusted to pH 5.5 with sodium hydroxide solution or dilute hydrochloric acid, and then further stirred under high-speed shear until the viscosity reached 1000 mPa·s, resulting in a homogeneous nasal dosing composition.

[0062] (Evaluation)

[0062] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0062]

[0063] Example 2 (Prescription)

[0063]

[0063] (Manufacturing method)

[0063] After dissolving L-arginine, sodium edetate hydrate, and europetrazol hydrochloride in purified water, the mixture was placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkyl ammonium chloride and half the amount of polysorbate 80 was then added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was added. These were then stirred in a vacuum stirring apparatus. Additionally, fluticasone furanyl ester was wetted in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in a vacuum stirring apparatus. The pH was adjusted to 5.5 with sodium hydroxide solution or dilute hydrochloric acid as needed, and then further stirred under high-speed shear until the viscosity reached 1250 mPa·s, thus preparing a homogeneous nasal spray composition.

[0064] (Evaluation)

[0064] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0064]

[0065] Example 3

[0065] (Prescription)

[0065]

[0065] (Manufacturing Method)

[0065] L-arginine, sodium edetate hydrate, and europetrazol hydrochloride were dissolved in purified water. The resulting mixture was then placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkylate chloride and half the amount of polysorbate 80 was added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was added. These were then stirred in a vacuum stirring apparatus. Fluticasone furanyl ester was moistened in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in a vacuum stirring apparatus. The pH was adjusted to 5.5 with sodium hydroxide solution or dilute hydrochloric acid as needed. The mixture was then further stirred under high-speed shear until the viscosity reached 1000 mPa·s. Finally, ethanol was added and stirred to prepare a homogeneous nasal spray formulation.

[0066] (Evaluation)

[0066] The evaluation results of the contents of the obtained nasal spray are shown below.

[0066]

[0067] Example 4

[0067] (Prescription)

[0067]

[0067] (Manufacturing Method)

[0067] L-arginine, sodium edetate hydrate, and europetrazol hydrochloride were dissolved in purified water. The resulting mixture was then placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkyl ammonium chloride and half the amount of polysorbate 80 was added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was then added. These were stirred together in the vacuum stirring apparatus. Separately, baconazole propionate was wetted in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in the vacuum stirring apparatus. The pH was adjusted to 6.0 as needed using sodium hydroxide solution or dilute hydrochloric acid, and the mixture was further stirred under high-speed shear until the viscosity reached 1500 mPa·s, thus producing a homogeneous nasal spray composition.

[0068] (Evaluation)

[0068] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0068]

[0069] Example 5

[0069] (Prescription)

[0069]

[0069] (Manufacturing Method)

[0069] After dissolving L-arginine, sodium edetate hydrate, and europetrazol hydrochloride in purified water, the mixture was placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkyl ammonium chloride and half the amount of polysorbate 80 was then added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was added. These were then stirred in a vacuum stirring apparatus. Additionally, fluticasone furanyl ester was wetted in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in a vacuum stirring apparatus. The pH was adjusted to pH 5.0 as needed using sodium hydroxide solution or dilute hydrochloric acid. The mixture was then further stirred under high-speed shear until the viscosity reached 1000 mPa·s. Finally, ethanol was added and stirred to prepare a homogeneous nasal spray formulation.

[0070] (Evaluation)

[0070] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0070]

[0071] Example 6

[0071] (Prescription)

[0071]

[0071] (Manufacturing Method)

[0071] L-arginine, sodium edetate hydrate, and europetrazol hydrochloride were dissolved in purified water. The resulting mixture was then placed in a vacuum stirring apparatus. A liquid containing dissolved benzyl alkylate chloride and half the amount of polysorbate 80 was added to the purified water and stirred. A liquid containing a pre-dissolved carboxyethylene polymer in purified water was added. These were then stirred in a vacuum stirring apparatus. Separately, momethasone furanyl ester was wetted in concentrated glycerol, and the remaining half of the polysorbate 80 and purified water were added and stirred thoroughly. This mixture was then added to the previously stirred mixture and stirred in a vacuum stirring apparatus. The pH was adjusted to 5.0 as needed using sodium hydroxide solution or dilute hydrochloric acid. The mixture was then further stirred under high-speed shear until the viscosity reached 1000 mPa·s. Finally, ethanol was added and stirred to prepare a homogeneous nasal spray formulation.

[0072] (Evaluation)

[0072] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0072]

[0073] Comparative Example 1

[0073] [Example 1 as described in Japanese Patent No. 4838493]

[0073] (Prescription)

[0073]

[0073] *: A mixture of crystalline cellulose and sodium carboxymethyl cellulose.

[0073] (Manufacturing Method)

[0073] A glucose solution was prepared by dissolving glucose in purified water. Sodium edetate hydrate was then dissolved in the solution, and Avicel RC591 was added while stirring to combine the hydrates and form suspension A. Separately, polysorbate 80 was dissolved in purified water at 50-60°C to wet fluticasone furanyl carboxylate. The remaining half of the polysorbate 80 and purified water were added to form suspension B. Suspension A and suspension B were combined and stirred. Benzyl ammonium chloride dissolved in purified water was added and stirred. The pH was adjusted to 6.0 with 1N hydrochloric acid, and purified water was added to correct the weight.

[0074] (Evaluation)

[0074] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0074]

[0075] Comparative Example 2

[0075] [Additional formulation of Europalate hydrochloride in Example 1 as described in Japanese Patent No. 4838493]

[0075] (Prescription)

[0075]

[0075] *: A mixture of crystalline cellulose and sodium carboxymethyl cellulose.

[0075] (Manufacturing Method)

[0075] A glucose solution was prepared by dissolving glucose in purified water. Sodium edetate hydrate and europetrazol hydrochloride were dissolved in the solution, and Avicel RC591 was added while stirring to hydrate it and form suspension A. Meanwhile, polysorbate 80 was dissolved in purified water at 50-60°C to wet fluticasone furanyl carboxylate, and the remaining half of polysorbate 80 and purified water were added to form suspension B. Suspensions A and B were combined, stirred, and benzyl alkyl ammonium chloride dissolved in purified water was added and stirred. The pH was adjusted to 6.0 with 1N hydrochloric acid, purified water was added, and the weight was corrected.

[0076] (Evaluation)

[0076] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0076]

[0077] Comparative Example 3

[0077] [Example 1 as described in Japanese Patent No. 5149308]

[0077] (Prescription)

[0077]

[0077] (Manufacturing Method)

[0077] While stirring the purified water, add anhydrous disodium hydrogen phosphate, sodium chloride, sodium edetate hydrate, benzyl ammonium chloride, and europetrazol hydrochloride. To ensure the dissolution of each component, schedule appropriate times and add dilute hydrochloric acid as needed. Add purified water, measure the pH, and adjust it to 3.7 as required using hydrochloric acid and sodium hydroxide. Then add purified water and correct the weight.

[0078] (Evaluation)

[0078] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0078]

[0079] Examples 7 to 8, Comparative Examples 4 to 7

[0079] Following the same method as Examples 1 to 6 and Comparative Examples 1 to 3, the following nasal drop compositions were prepared.

[0079]

[0080] (Evaluation)

[0080] The evaluation results of the contents of the obtained nasal spray composition are shown below.

[0080]

[0080]

[0081] [Europalate Indole Dissolution Stability Test]

[0081] Comparative test liquid sample

[0081] (1) Patanase™ (Batch No.: 7FPS1A) [Concentration pH 3.8]

[0081] The contents of the product container are removed and transferred to a glass container as a sample.

[0081] (2) Dissolve Europalate hydrochloride in purified water to adjust the concentration of Europalate to 0.6% (w / w), and then adjust the pH to 3.8 using L-arginine to form a liquid (stored in a glass container).

[0081] (3) Dissolve Europalate hydrochloride in purified water, adjust the concentration of Europalate to 0.6% (w / w), and then adjust the pH to 3.8 with sodium hydroxide to form a liquid (stored in a glass container).

[0081] (4) Dissolve Europalate hydrochloride in purified water, adjust the concentration of Europalate to 0.6% (w / w), and then adjust the pH to 5.5 using L-arginine (store in a glass container).

[0081] (5) Dissolve Europalate hydrochloride in purified water, adjust the concentration of Europalate to 0.6% (w / w), and then adjust the pH to 5.5 with sodium hydroxide (store in a glass container).

[0082] (Evaluation Method)

[0082] In addition to (1) to (5), the preparations of Examples 1 to 8 and Comparative Examples 1 to 7 were also filled into glass containers as specimens for the dissolution stability test.

[0082] (i) Visual inspection. Confirm that the crystals are large europetidine crystals, which are different from the finely dispersed suspension crystals of steroids. In cases where it is difficult to determine, heat the crystals to cause changes such as dissolution, and then determine that the crystals are europetidine.

[0082] ○: For (1) to (5) which do not contain steroid compounds and Comparative Example 3, they were confirmed to be in a clear dissolved state. For Examples 1 to 8 and Comparative Examples 1 to 2, 4 to 7 which contain steroid compounds, they were confirmed to be in a uniform suspension state without crystallization.

[0082] ×: Crystallization has been confirmed.

[0082] (ii) When using a digital microscope (VHX-7000) at 500x magnification, confirm whether there are any precipitated crystals larger than 50 μm other than steroids. In cases where crystalline cellulose sodium carboxymethyl cellulose is present and it is difficult to determine whether it is europetidine crystals, if heating causes changes such as dissolution of the crystals, then the crystals are determined to be europetidine.

[0082] ◎: Confirmed that there are no crystals other than steroids and no crystals precipitate, it is determined to be the dissolution of Europalate.

[0082] ◆: Crystallizations of 50 μm or larger confirmed outside of steroids are identified as Europalate precipitation.

[0083] (Experimental Results)

[0083]

[0084] [Fluticasone furan carboxylate suspension stability test]

[0084] The following tests were conducted using Example 7, Comparative Example 4, Comparative Example 5, and Comparative Example 6.

[0084] (Test Method)

[0084] Each test sample (test preparation) is thoroughly mixed and stirred to maintain a homogeneous state. The content of fluticasone furanyl ester in each test sample is determined by high performance liquid chromatography as the initial homogeneity result (quantitative result A).

[0084] Next, 12g of each test sample in a homogeneous state was filled into a 13.5mL glass spiral tube and shaken thoroughly again to achieve a homogeneous state. In addition, the test sample was centrifuged (5000rpm, 10 minutes).

[0084] The appearance and content of fluticasone furoate were confirmed and determined for test samples before and after filling and shaking the spiral tube, after 24 hours of standing at room temperature, after 1 week of standing, and after centrifugation. For content determination, each test sample was first divided into an upper layer (3g), a middle layer (4g), and a remaining lower layer (3g). 2g of the test sample was precisely separated from the upper and lower layers, and the content of fluticasone furoate was determined by high-performance liquid chromatography (quantitative result B). Suspension stability was evaluated by calculating the suspension stability ratio according to the following formula.

[0084] Suspension stability ratio (%) = [(Quantitative result B) / (Quantitative result A)] × 100

[0085] (Test Results: Appearance Changes)

[0085]

[0085] The crystallization of Europite ingots was confirmed to be in a state where it was completely attached to the wall of a glass spiral tube.

[0086] (Test Results: Suspension Stability)

[0086]

[0086] [Industrial Applicability]

[0087] According to the present invention, a pharmaceutical composition is prepared by mixing a steroid compound with a free base of europetrazol or an equivalent amount of a pharmaceutically permissible salt of europetrazol at a physiologically tolerable pH. This composition, especially for nasal sprays, stably dissolves europetrazol and is highly viscous, thus ensuring extremely stable suspension of the steroid compound and eliminating the need for shaking before use. Furthermore, after the spray is administered into the nasal cavity, it tends to remain there, and from a pharmacological point of view, a sustained and effective improvement can be expected.

Claims

1. A pharmaceutical composition comprising a steroid compound and europetidine or a pharmaceutically permissible salt thereof.

2. The pharmaceutical composition as described in claim 1 comprises a steroid compound and europetrazol hydrochloride.

3. The pharmaceutical composition as described in claim 1 or claim 2 contains a carboxyethylene polymer as a thickener.

4. The pharmaceutical composition described in any one of claims 1 to 3 is a composition comprising a steroid compound, europetrazol or a pharmaceutically permissible salt thereof, and a carboxyethylene polymer, wherein the pH of the composition is adjusted to be between 4.0 and 7.

0.

5. The pharmaceutical composition as described in any one of claims 1 to 4, wherein, Europalate or its pharmaceutically permissible salt is Europalate hydrochloride, wherein the concentration of Europalate hydrochloride is 0.2% (w / w) or more, and Europalate exists in the composition in a dissolved state.

6. A pharmaceutical composition as described in any one of claims 1 to 5, wherein, The concentration of the steroid compound is 0.005 to 1% (by weight), and the steroid compound exists in the composition in a stable dispersed state.

7. A pharmaceutical composition as described in any one of claims 1 to 6, wherein, The steroid compound is any one of becquerel propionate, fluticasone propionate, mometasone furan carboxylate, or fluticasone furan carboxylate.

8. The pharmaceutical composition as described in claim 7, wherein, The steroid compound is fluticasone furan carboxylate.

9. A pharmaceutical composition as described in any one of claims 1 to 8, wherein, The carboxyethylene polymer system exists at a concentration of 0.1% to 2% (by weight).

10. The pharmaceutical composition described in any one of claims 4 to 9 uses sodium hydroxide and / or hydrochloric acid as a pH adjuster for pH adjustment.

11. The pharmaceutical composition described in any one of claims 4 to 10 uses L-arginine as a neutralizing agent to adjust the pH.

12. The pharmaceutical composition described in any one of claims 1 to 11 further comprises one or more suspending agents.

13. The pharmaceutical composition as described in claim 12, wherein, The suspending agent contains polysorbate 80.

14. The pharmaceutical composition described in any one of claims 1 to 13 further comprises one or more preservatives.

15. The pharmaceutical composition as described in claim 14, wherein, The preservative contains benzyl alkyl ammonium chloride.

16. The pharmaceutical composition described in any one of claims 1 to 15 further comprises one or more stabilizers.

17. The pharmaceutical composition as described in claim 16, wherein, The stabilizer contains sodium edetate hydrate.

18. The pharmaceutical composition described in any one of claims 1 to 17 further comprises one or more isotonic agents.

19. The pharmaceutical composition as described in claim 18, wherein, Isotonic agents contain sodium chloride and / or glycerol.

20. The pharmaceutical composition as described in claim 18 or 19, wherein, The isotropic agent exists at a concentration of 0.1% to 10% (by weight).

21. The pharmaceutical composition described in any of claims 1 to 20 is isotropic.

22. A pharmaceutical composition as described in any one of claims 1 to 21, wherein, The viscosity is 250 to 2500 mPa‧s.

23. The pharmaceutical composition described in any one of claims 1 to 22 has an average droplet diameter of 30 to 100 μm when sprayed.

24. A pharmaceutical composition as described in any one of claims 21 to 23, wherein, The pH adjuster is sodium hydroxide, the neutralizer is L-arginine, the suspending agent is polysorbate 80, the preservative is benzyl ammonium chloride, the stabilizer is sodium edetate hydrate, and the isotropic agents are glycerol and sodium chloride.

25. A pharmaceutical composition as described in any one of claims 4 to 24, wherein, The pH should be adjusted to 4.5 to 6.

5.

26. A pharmaceutical composition as described in any one of claims 4 to 25, wherein, The pH should be adjusted to 5.0 to 6.

0.

27. A pharmaceutical composition as described in any one of claims 1 to 26, wherein, The pharmaceutical ingredient is an aqueous solution for nasal application.

28. A nasal spray formulation comprising any one of the pharmaceutical ingredients described in claims 1 to 27.

29. A pharmaceutical composition prepared by simultaneously using the following methods: adjusting europetidine to pH 5.0 by adding a carboxyethylene polymer. Methods for dissolving within the range of 6.0, and methods for stabilizing the suspension of aqueous suspensions containing fluticasone furan carboxylate.