Inhibitor of eosinophil infiltration into the nasal cavity

Abstract

To provide novel formulations that can inhibit intranasal eosinophil infiltration.SOLUTION: A composition containing (A) an inorganic salt selected from the group consisting of alkali metal chlorides and alkali metal carbonates, (B) polyoxyethylene sorbitan fatty acid ester, and (C) quaternary ammonium salt is effective as an intranasal eosinophil infiltration inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for inhibiting eosinophil infiltration into the nasal cavity. [Background technology]

[0002] The nasal mucosa is an epithelial tissue directly exposed to the outside world and sensitive to external stimuli. It is known that adhesion of foreign substances, such as pollen, microorganisms, and house dust, to the nasal mucosa can cause discomfort and lead to the development of various diseases, including allergies and infectious diseases. Removing foreign substances from the mucosa using a rinsing solution (so-called nasal irrigation) is considered effective in preventing or alleviating such nasal mucosal symptoms. Nasal rinses have appropriately adjusted salt concentrations and pH to achieve a desired cleansing effect while reducing irritation in the nasal cavity. Examples of nasal rinses include a nasal rinse containing citric acid and sodium citrate, with the sodium citrate content ranging from 0.02% to 0.2% by weight (Patent Document 1), and a solution obtained by mixing purified water, sodium chloride, glycerin, a fragrance, and benzalkonium chloride (Patent Document 2).

[0003] When eosinophils increase in the mucosa of the nasal cavity and infiltrate into the mucosa, it leads to eosinophilic sinusitis, a chronic sinusitis prone to recurrence. Eosinophilic sinusitis presents with lesions mainly in the ethmoid sinus, with multiple nasal polyps in the nasal cavity, and is accompanied by olfactory disturbance. Antibiotics are ineffective for eosinophilic sinusitis, and it responds only to oral steroids (Non-Patent Document 1). For this reason, long-term oral steroids and endoscopic sinus surgery are the main treatments for eosinophilic sinusitis (Non-Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-001317 [Patent Document 2] Japanese Patent Application Laid-Open No. 2017-213280 [Non-patent literature]

[0005] [Non-Patent Document 1] “Eosinophilic sinusitis (designated intractable disease 306),” [online], October 2020, Intractable Disease Information Center, [searched June 16, 2021], Internet<URL: https: / / www.nanbyou.or.jp / entry / 4538> [Non-patent document 2] Jpn Otorhinolaryngology 117: 96-102, 2014 Summary of the Invention [Problem to be solved by the invention]

[0006] Symptoms associated with eosinophil infiltration in the nasal mucosa are difficult to treat, and unlike common sinusitis, antibiotics are no longer an appropriate treatment. However, current treatments have problems with side effects, such as long-term steroid use, and invasiveness, such as endoscopic sinus surgery. Therefore, a new, simple method for suppressing eosinophil infiltration in the nasal mucosa is desired.

[0007] Therefore, an object of the present invention is to provide a new preparation capable of suppressing eosinophil infiltration into the nasal cavity. [Means for solving the problem]

[0008] As a result of extensive research, the present inventors have unexpectedly found that a composition containing an inorganic salt selected from the group consisting of alkali metal chlorides and alkali metal carbonates, a polyoxyethylene sorbitan fatty acid ester, and a quaternary ammonium salt can suppress eosinophil infiltration into the nasal cavity. The present invention was completed through further research based on this finding.

[0009] That is, the present invention provides the following aspects. Item 1. An agent for inhibiting eosinophil infiltration into the nasal cavity, comprising (A) an inorganic salt selected from the group consisting of alkali metal chlorides and alkali metal carbonates, (B) a polyoxyethylene sorbitan fatty acid ester, and (C) a quaternary ammonium salt. Item 2. The intranasal eosinophil infiltration inhibitor according to Item 1, further comprising (D) a monoterpene compound. Item 3. The agent for suppressing eosinophil infiltration into the nasal cavity according to Item 2, wherein the component (D) is contained in the form of peppermint oil containing the component (D). Item 4. The agent for suppressing eosinophil infiltration into the nasal cavity according to any one of Items 1 to 3, which is a composition for nasal irrigation. [Effects of the Invention]

[0010] According to the present invention, a new preparation capable of suppressing eosinophil infiltration into the nasal cavity is provided. DETAILED DESCRIPTION OF THE INVENTION

[0011] The agent for inhibiting eosinophil infiltration into the nasal cavity of the present invention is characterized by comprising (A) an inorganic salt selected from the group consisting of alkali metal chlorides and alkali metal carbonates (hereinafter also referred to as "component (A)"), (B) a polyoxyethylene sorbitan fatty acid ester (hereinafter also referred to as "component (B)"), and (C) a quaternary ammonium salt (hereinafter also referred to as "component (C)"). The agent for inhibiting eosinophil infiltration into the nasal cavity of the present invention will be described in detail below.

[0012] (A) Inorganic salts The agent for inhibiting eosinophil infiltration into the nasal cavity of the present invention contains a predetermined inorganic salt as component (A).

[0013] The inorganic salt is selected from the group consisting of alkali metal chlorides and alkali metal carbonates. Examples of alkali metal chlorides include sodium chloride and potassium chloride. Examples of alkali metal carbonates include sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate. These inorganic salts may be used alone or in combination of two or more.

[0014] Among these inorganic salts, sodium chloride and / or sodium bicarbonate are preferred from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect.

[0015] The content of component (A) in the intranasal eosinophil infiltration inhibitor of the present invention is not particularly limited and can be appropriately determined by those skilled in the art, taking into consideration avoiding irritation to the nasal mucosa. Specifically, the content of component (A) in the intranasal eosinophil infiltration inhibitor of the present invention is, for example, 0.6 to 1.04 wt %, preferably 0.65 to 0.9 wt %.

[0016] (B) Polyoxyethylene sorbitan fatty acid ester The agent for suppressing eosinophil infiltration into the nasal cavity of the present invention can contain a polyoxyethylene sorbitan fatty acid ester as component (B).

[0017] The polyoxyethylene sorbitan fatty acid ester used in the present invention is not particularly limited, but examples thereof include polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate.

[0018] The average number of moles of ethylene oxide (EO) added in the polyoxyethylene sorbitan fatty acid ester is not particularly limited, but may be, for example, 5 to 40 moles.

[0019] These polyoxyethylene sorbitan fatty acid esters may be used alone or in combination of two or more.

[0020] Among the above polyoxyethylene sorbitan fatty acid esters, from the viewpoint of further enhancing the effect of inhibiting eosinophil infiltration, preferred are polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate, and more preferred are polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan monostearate.

[0021] Furthermore, among the above polyoxyethylene sorbitan fatty acid esters, from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, those having an added mole number of ethylene oxide (EO) of preferably 10 to 30 moles, more preferably 15 to 25 moles, and even more preferably 18 to 22 moles are mentioned.

[0022] Specifically, among the above polyoxyethylene sorbitan fatty acid esters, particularly preferred are polyoxyethylene sorbitan monooleate (polyoxyethylene (18-22) sorbitan monooleate) having 18 to 22 moles of added ethylene oxide (EO) and polyoxyethylene sorbitan monostearate (polyoxyethylene (18-22) sorbitan monostearate) having 18 to 22 moles of added ethylene oxide (EO), from the viewpoint of further enhancing the effect of suppressing eosinophil infiltration.

[0023] The content of component (B) in the intranasal eosinophil infiltration inhibitor of the present invention is not particularly limited, but may be, for example, 0.01 to 0.1% by weight, or more by weight, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.03 to 0.07% by weight, more preferably 0.04 to 0.07% by weight.

[0024] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (A) to component (B) is determined by the content of each of the above components, and the content of component (B) per 1 weight part of component (A) is, for example, 0.01 to 0.12 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.03 to 0.12 weight parts, more preferably 0.05 to 0.11 weight parts.

[0025] (C) Quaternary ammonium The intranasal eosinophil infiltration inhibitor of the present invention contains a quaternary ammonium as component (C). Quaternary ammonium is a type of antibacterial agent, and although antibacterial agents have been recognized as ineffective against the symptoms of eosinophil infiltration, when combined with components (A) and (B), it can effectively inhibit the infiltration of acid-fast bacteria.

[0026] The quaternary ammonium used in the present invention is not particularly limited, but examples thereof include cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, dequalinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbenzethonium chloride, lauroylcholaminoformylmethylpyridinium chloride, etc. These antibacterial or disinfecting agents may be used alone or in combination of two or more.

[0027] Among these quaternary ammonium salts, from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, benzethonium chloride, benzalkonium chloride and cetylpyridinium chloride are preferred, and benzalkonium chloride is more preferred.

[0028] The content of component (C) in the intranasal eosinophil infiltration inhibitor of the present invention is not particularly limited, but may be, for example, 0.0001 to 0.01% by weight, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.0005 to 0.01% by weight, more preferably 0.001 to 0.008% by weight, and even more preferably 0.001 to 0.005% by weight.

[0029] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (A) to component (C) is determined by the content of each of the above components, and the content of component (C) per 1 weight part of component (A) is, for example, 0.001 to 0.05 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.001 to 0.01 weight parts, more preferably 0.002 to 0.007 weight parts.

[0030] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (B) to component (C) is determined by the content of each of the above components, but the content of component (C) per 1 weight part of component (B) is, for example, 0.01 to 0.1 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.02 to 0.08 weight parts, more preferably 0.04 to 0.08 weight parts.

[0031] (D) Monoterpene compounds The agent for inhibiting eosinophil infiltration into the nasal cavity of the present invention may further contain a monoterpene compound as component (D) for the purpose of further enhancing the effect of inhibiting eosinophil infiltration. The monoterpene compound is a C monoterpene compound consisting of two isoprene units. 10 H 16 It is a compound having a hydrocarbon skeleton as the basic skeleton.

[0032] Specific examples of the monoterpene compounds used in the present invention include alcohol monoterpenes such as menthol, neomenthol, neoisomenthol, isomenthol, terpineol, transturanol, linalool, isopulegol, thymol, geraniol, and borneol; aldehyde monoterpenes such as citral, citronellal, perillaldehyde, and safranal; hydrocarbon monoterpenes such as pinene, sabinene, myrcene, terpinene, paracymene, limonene, cis-ocimene, and terpinolene; ketone monoterpenes such as menthone, isomenthone, pulegone, piperitone, carbomenthone, ionone, and camphor; ether terpenes such as cineole; monoterpene esters such as menthyl acetate; and furan monoterpenes such as menthofuran.

[0033] When optical isomers of these monoterpene compounds exist, they may be any of d-, l-, and dl-isomers. These monoterpenes may be used singly or in combination of two or more.

[0034] Among these monoterpene compounds, from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, alcohol monoterpenes and / or ketone monoterpenes are preferred, and menthol and / or menthone are more preferred.

[0035] In addition, these monoterpene compounds may be contained in the form of essential oils containing monoterpene compounds.The essential oils containing monoterpene compounds can be appropriately selected from known ones and used, for example, peppermint oil, peppermint oil, spearmint oil, etc.Among these essential oils, from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, peppermint and peppermint oil are preferred, and peppermint oil is more preferred.

[0036] When the intranasal eosinophil infiltration inhibitor of the present invention contains component (D), the content of component (D) is not particularly limited, but may be, for example, 0.001 to 1.7% by weight. From the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, the content of component (D) is preferably 0.005 to 1.6% by weight, more preferably 0.008 to 1.5% by weight, and even more preferably 0.01 to 1.4% by weight, 0.01 to 1% by weight, 0.01 to 0.7% by weight, 0.01 to 0.5% by weight, 0.01 to 0.3% by weight, 0.01 to 0.1% by weight, 0.01 to 0.05% by weight, or 0.01 to 0.03% by weight.

[0037] Furthermore, when the intranasal eosinophil infiltration inhibitor of the present invention contains menthol as component (D), the content of menthol is, for example, 0.001 to 1.7% by weight, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, the content of menthol is preferably 0.005 to 1.6% by weight, more preferably 0.008 to 1.5% by weight, and even more preferably 0.01 to 1.4% by weight, 0.01 to 1% by weight, 0.01 to 0.7% by weight, 0.01 to 0.5% by weight, 0.01 to 0.3% by weight, 0.01 to 0.1% by weight, 0.01 to 0.05% by weight, or 0.01 to 0.03% by weight.

[0038] Furthermore, when the intranasal eosinophil infiltration inhibitor of the present invention contains menthone as component (D), the content of menthone may be set appropriately depending on the refreshing feeling that the intranasal eosinophil infiltration inhibitor should provide, or the concentration rate of the intranasal eosinophil infiltration inhibitor, etc., and may be, for example, 0.002 to 1.7 wt.%, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, the content is preferably 0.01 to 1.6 wt.%, more preferably 0.015 to 1.5 wt.%, 0.015 to 1 wt.%, 0.015 to 0.7 wt.%, 0.015 to 0.5 wt.%, 0.015 to 0.3 wt.%, 0.015 to 0.1 wt.%, 0.015 to 0.05 wt.%, or 0.015 to 0.03 wt.%.

[0039] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (A) to component (D) is determined by the content of each of the above components, and the content of component (D) per 1 weight part of component (A) is, for example, 0.001 to 0.2 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.005 to 0.15 weight parts, more preferably 0.01 to 0.1 weight parts.

[0040] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (B) to component (D) is determined by the content of each of the above components, and the content of component (D) per 1 weight part of component (B) is, for example, 0.05 to 3 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 0.1 to 2 weight parts, more preferably 0.2 to 1.2 weight parts.

[0041] In the intranasal eosinophil infiltration inhibitor of the present invention, the ratio of component (C) to component (D) is determined by the content of each of the above components, and the content of component (D) per 1 weight part of component (C) is, for example, 0.5 to 50 weight parts, and from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect, preferably 1 to 25 weight parts, more preferably 3 to 20 weight parts.

[0042] Other ingredients In addition to the above-mentioned components, the agent for inhibiting nasal eosinophil infiltration of the present invention may contain other bases and additives required for formulation, etc., as long as they do not impair the effects of the present invention. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, and examples include additives such as water, aqueous bases of monohydric lower alcohols and polyhydric alcohols, surfactants, preservatives, colorants, thickeners, pH adjusters, humectants, preservatives, stabilizers, antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, and preservatives. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives can be appropriately determined depending on the formulation, etc.

[0043] Among these bases and additives, polyhydric alcohols are preferred from the viewpoint of further enhancing the eosinophil infiltration inhibitory effect. Examples of polyhydric alcohols include dihydric alcohols (e.g., alkylene diols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and isoprene glycol, and polyalkylene ether diols such as diethylene glycol and dipropylene glycol, preferably alkylene diols, and more preferably propylene glycol) and trihydric alcohols (e.g., glycerin, etc.), preferably propylene glycol and glycerin. When the intranasal eosinophil infiltration inhibitor of the present invention contains a polyhydric alcohol, the content of the polyhydric alcohol is, for example, 0.2 to 0.5 wt %, preferably 0.3 to 0.5 wt %.

[0044] In addition to the above-mentioned components, the agent for inhibiting eosinophil infiltration into the nasal cavity of the present invention may contain other pharmacological ingredients as needed, provided that the effects of the present invention are not impaired. Examples of such pharmacological ingredients include vitamins, antihistamines, local anesthetics, anti-inflammatory agents, mucosal protective agents, blood circulation promoting ingredients, cooling agents, mucopolysaccharides, etc. These pharmacological ingredients may be used alone or in combination of two or more. When these pharmacological ingredients are contained, the content thereof may be appropriately determined depending on the type of pharmacological ingredient used, the desired effect, etc.

[0045] form The form of the intranasal eosinophil infiltration inhibitor of the present invention is not particularly limited as long as it is a form that can be applied to the nasal mucosa, and examples include liquids and semi-solids (ointments, gels, etc.), preferably liquids.

[0046] Purpose The intranasal eosinophil infiltration inhibitor of the present invention is used by applying it to the mucous membrane in the nasal cavity. The specific application form is not particularly limited as long as it is a form in which the intranasal eosinophil infiltration inhibitor of the present invention comes into contact with the intranasal mucous membrane, and examples thereof include washing, spraying, and application, with washing being preferred. Therefore, the intranasal eosinophil infiltration inhibitor of the present invention is preferably used as a nasal washing composition.

[0047] The specific method of using the nasal eosinophil infiltration inhibitor of the present invention is not particularly limited as long as the effect of application is achieved, but examples include a method of directly pouring it into the nasal cavity for irrigation, a method of spraying it onto the mucosa with a spray or the like, and a method of directly applying it to the mucosa using a jig, etc., and preferably a method of directly pouring it into the nasal cavity for irrigation. More specifically, the method of directly pouring it into the nasal cavity for irrigation includes a method of pouring the nasal eosinophil infiltration inhibitor prepared as a nasal irrigation composition into the nasal cavity and expelling it from a port, and a method of pouring the nasal eosinophil infiltration inhibitor prepared as a nasal irrigation composition into one nostril and expelling it from the other nostril, etc. [Example]

[0048] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0049] Test Example Test samples were prepared with the compositions shown in Table 1. The test samples were prepared in the form of nasal rinsing compositions. The peppermint oil used contained 94.5% by weight of monoterpenes, of which 32.7% by weight was menthol and 27.5% by weight was menthone.

[0050] Four 6-week-old guinea pigs with confirmed eosinophil infiltration in the nasal cavity were used as test animals. After urethane anesthesia, the guinea pigs were catheterized in both nostrils. The test sample was administered into the nasal cavity by injecting it into one nostril under negative pressure (nasal irrigation). This nasal irrigation procedure was performed once daily for two days. The nasal cavities of the guinea pigs were then excised, blocked with paraffin, and sliced ​​to prepare tissue sections. The tissue sections were stained for eosinophils using Congo-Red staining to evaluate the presence or absence of infiltration. The degree of effect of inhibiting eosinophil infiltration in the nasal cavity was scored according to the following criteria. If infiltration was observed in up to one of four cases, it was considered to have the desired effect of inhibiting eosinophil infiltration. The results are shown in Table 1.

[0051] ++: No infiltration was observed in any of the four cases. +: One of four cases was infiltrated -: 2 out of 4 cases were infiltrated --: 3 out of 4 cases were infiltrated ---: Infiltration in all four cases

[0052] [Table 1]

[0053] As shown in Table 1, infiltration was observed in all cases without treatment (Reference Example 1), and washing with a solution containing only component (A) did not result in a substantial effect of inhibiting infiltration (Comparative Example 1). However, washing with a solution containing components (A), (B), and (C) resulted in the desired effect of inhibiting infiltration (Examples 1 to 3). Furthermore, when component (D) was added in addition to components (A), (B), and (C), the effect of inhibiting infiltration was further enhanced (Examples 4 to 8).

[0054] Prescription example Test samples were prepared with the compositions shown in Table 2. The test samples were prepared in the form of nasal irrigation compositions. The eosinophil infiltration inhibitory effect of each test sample was confirmed in the same manner as in the Examples. The test sample of Formulation Example 1 was found to have an infiltration inhibitory effect similar to that of Examples 1 to 3, and the test samples of Formulation Examples 2 to 10 were found to have an infiltration inhibitory effect similar to that of Examples 4 to 8.

[0055] [Table 2]

Claims

1. An agent for inhibiting eosinophil infiltration into the nasal cavity, comprising: (A) an inorganic salt selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate; (B) a polyoxyethylene sorbitan fatty acid ester; and (C) benzalkonium chloride and / or cetylpyridinium chloride.

2. The intranasal eosinophil infiltration inhibitor according to claim 1, further comprising (D) a monoterpene compound.

3. The agent for suppressing eosinophil infiltration into the nasal cavity according to claim 2, wherein the component (D) is contained in the form of peppermint oil containing the component (D).

4. The agent for inhibiting eosinophil infiltration into the nasal cavity according to any one of claims 1 to 3, which is a composition for nasal irrigation.

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