KR20160036000A - Oral Spray Composition Comprising Water-Soluble Azulene and Alkylpyridinium Halide - Google Patents

Abstract

The present invention relates to oral spray compositions for the prevention or treatment of respiratory diseases. The oral spray composition according to the present invention improves adherence and compliance of the pharmacologically active ingredient, and has excellent taste and refreshing sensation. Also, stability and preservability are improved when stored for a long period of time, have.

Description

[0001] The present invention relates to an oral spray composition comprising water-soluble azulene and an alkylpyridinium halide,

The present invention relates to a water-soluble azulene (azulene), C ₁₃ -C ₁₇ alkyl pyridinium halides, and, prevention or treatment of the oral spray composition of the respiratory disease, including an emulsifier.

Sore throat is caused by inflammation of the pharynx or larynx due to infection with viruses or germs, usually caused by rapid temperature changes (dry environment), colds, fever, and overwork. In recent years, the number of patients suffering from sore throat such as fine dust or dust has continuously increased, and the market for preventing sore throat is increasing.

The agent for the treatment of sore throat mainly improves the therapeutic effect of sore throat through promotion of wound healing and anti-inflammatory effect, while the symptom relief agent of sore throat alleviates the bacterial growth and inflammation of throat through the antibacterial effect.

The azulene component extracted from chamomile belongs to non-benzene aromatic compounds, and has anti-inflammatory drugs with less side effects, such as oral anti-inflammatory drugs and anti-ulcer drugs. It is also used as an ointment to soothe skin and strengthen skin barrier to protect skin and prevent and treat skin diseases. It is also used for the treatment of children's diseases and allergies.

Cetylpyridinium chloride is a quaternary ammonium salt with antimicrobial activity and is used as a preservative and disinfectant as a cationic sterilizing material. As a conventional preservative, it is used at a low concentration of 0.1% or less, and at a high concentration of 0.1% or more as a bactericide.

When the water-soluble azulene and cetylpyridinium chloride are used together, the effect of treatment and symptom relief of sore throat is improved and the stability of water-soluble azulene is also improved.

Water-soluble azulene is a dark blue solid and becomes an aqueous solution of purple when dissolved in water. This color is attributed to the ring structure peculiar to azulene. In the acid state, the ring is decomposed and the purple color is faded, and the drug efficacy is lowered, but it is stable in the alkali state. However, it is tastingly not preferable that the ingredient to be applied to the oral cavity containing azulene has alkalinity.

Regarding medical treatment applications using azulene, Japanese Patent No. 4880477 discloses compositions for oral administration for the treatment of gastric mucosal diseases including L-glutamine and azulene derivatives.

The present inventors have made extensive efforts to develop a composition for oral spray improved in patient compliance and drug stability of azulene and alkylpyridinium halides as pharmacological components for the treatment of inflammatory or infectious diseases. As a result, the oral spray composition comprising the azulene, the alkylpyridinium halide and the emulsifier of a specific component in the composition not only improves adherence compliance but also maintains high preservation power and drug stability during long storage period, Can be used as an excellent pharmaceutical formulation for the treatment of various inflammatory or infectious diseases that occur.

It is an object of the present invention to provide an oral spray composition for the prevention or treatment of respiratory diseases.

In accordance with one aspect, the invention provides a water-soluble azulene (Azulene), C ₁₃ -C ₁₇ alkyl pyridinium halides, and mouth spray composition for the prevention and treatment of respiratory disease, including an emulsifier.

The oral spray composition of the present invention improves adherence and compliance of medicines due to the elimination of the fragrance unique to the active ingredient, has excellent taste and refreshing sensation, and greatly improves stability and preservability even when stored for a long period of time. .

FIG. 1 is a graph showing changes in contents when the samples prepared in Examples and Comparative Examples were stored under accelerated conditions. FIG.
2 shows the sensory evaluation scores of the respective samples prepared in Examples and Comparative Examples.

The present invention provides a water-soluble azulene (Azulene), C ₁₃ -C ₁₇ alkyl pyridinium halides, and mouth spray composition for the prevention and treatment of respiratory disease, including an emulsifier.

As used herein, the term "respiratory disease" refers to the function of the organs involved in gas exchange, such as upper respiratory tract, trachea, bronchi, alveoli, pleura, Of all pathological conditions that affect. According to the present invention, the oral spray composition of the present invention effectively delivers a therapeutically effective amount of the pharmacological components of azulene and alkylpyridinium halide to the lesion site, thereby preventing pain, swelling, discomfort, sore throat or stomatitis caused by neck inflammation, Can be used for treatment.

As used herein, the term " therapeutically effective amount " means an amount of the active ingredient sufficient to provide a therapeutic or prophylactic effect to the individual to whom the composition is to be administered, including a " prophylactically effective amount ".

As used herein, the term " treatment " includes (a) inhibiting the development of a disease, disorder or condition; (b) relief of the disease, disorder or condition; Or (c) eliminating the disease, disease or condition. The composition of the present invention has the role of suppressing, eliminating or alleviating the development of respiratory diseases or symptoms thereof. Thus, the composition of the present invention may itself be a therapeutic composition for respiratory diseases, or may be administered together with other pharmaceutical compositions and applied as a therapeutic adjuvant. Herein, the term " treatment " or " therapeutic agent " includes the meaning of " therapeutic aid "

As used herein, the term " prophylactic " means inhibiting the development of a disease or disease in a subject who has never been diagnosed as having a disease or disease, but is likely to suffer from such disease or disease.

According to a specific embodiment of the present invention, the respiratory diseases to be prevented or treated with the composition of the present invention are upper respiratory infections, and more specifically, pharyngitis or stomatitis.

The term "water-soluble azulene" as used herein means a water-soluble derivative of azulene having a solubility of 1% or more at 20 ± 5 ° C. The water-soluble azulene includes, for example, azulenesulfonate salts, but not limited to, azulene (bicyclo [5.3.0] decapentaene) all of which are substituted with a functional group imparting charge or polarity Lt; / RTI > derivatives. More specifically, the water-soluble azulene of the present invention is sodium azulene sulfonate, most specifically 7-isopropyl-1,4-dimethyl-3-sodium sulfonate agulene.

According to the present invention, the oral spray composition of the present invention contains water-soluble azulene in an amount of 0.005 to 0.2 w / v% based on the total amount of the composition. When the amount of water-soluble azulene is less than 0.005 w / v%, it is acidic and is not suitable as an oral spray, and the anti-inflammatory effect may be deteriorated. If it exceeds 0.2 w / v% There may be a sense of discomfort.

According to a specific embodiment of the present invention, the water-soluble azulene of the present invention is contained in an amount of 0.005 to 0.2 w / v%, more specifically 0.01 to 0.2 w / v%, based on the total amount of the composition.

As used herein, the term " alkylpyridinium " means a quaternary ammonium ion substituted by an alkyl group in the ring nitrogen of the heteroaromatic molecule pyridine, and the term " alkyl " means a straight chain saturated hydrocarbon group. Accordingly, C ₁₃ -C ₁₇ alkylpyridinium means a quaternary ammonium ion to which an alkyl group having an alkyl unit having 13 to 17 carbon atoms is bonded to nitrogen in the ring of pyridine.

According to the invention, the oral spray composition includes about 0.01 total composition of the invention include a 2.0 w / v% of a C ₁₃ -C ₁₇ alkyl pyridinium halides. When the amount of the alkylpyridinium halide is less than 0.01 w / v%, the effect on the antibacterial action is insignificant and the product is not worthy. When the amount exceeds 2.0 w / v%, the unique flavor is too strong, Can be greatly reduced.

According to a specific embodiment of the present invention, the C ₁₃ -C ₁₇ alkylpyridinium halide of the present invention is contained in an amount of 0.01 to 2.0 w / v%, more specifically 0.1 to 1.0 w / v%, based on the total amount of the composition do.

According to a specific embodiment of the present invention, the C ₁₃ -C ₁₇ alkylpyridinium halide of the present invention is cetylpyridinium (C ₁₅ alkylpyridinium) halide.

According to a more specific embodiment of the present invention, the cetylpyridinium halide is cetylpyridinium chloride or cetylpyridinium bromide, most specifically cetylpyridinium chloride.

As used herein, the term " emulsifier " refers to a substance that alters the nature of the interface in a mixture of two or more non-immiscible materials and uniformly mixes and homogenizes them, and thus has the same meaning as a surfactant Is used. In the present invention, the emulsifier is an additive that plays an important role in improving stability of the oral spray composition over time.

According to a specific embodiment of the present invention, the oral spray composition of the present invention contains 0.1 to 10.0 w / v% of the emulsifier, more specifically 0.5 to 5.0 w / v%, based on the total amount of the composition.

According to a specific embodiment of the present invention, the emulsifier of the present invention may be a polypropylene oxide-polyoxypropylene-polypropylene oxide copolymer; Polysorbate; Docusate; Polyethoxylated castor oil; Polyoxyethylene-sorbitan-fatty acid esters; Sorbitan fatty acid esters; Polyoxyethylene-polyoxypropylene block copolymers; And mixtures thereof.

According to a more specific embodiment of the present invention, the emulsifier of the present invention is polyethoxylated castor oil, polypropylene oxide-polyoxypropylene-polypropylene oxide copolymer or polysorbate. Polyethoxylated castor oil is also known as crmporo, and there are various types of polyoxyl n-hardened castor oil (n is 30-60), depending on the oxyethylene unit. Polysorbate has various kinds of polysorbate n (n is 20-80) depending on degree of polyoxyethylene sorbitan fatty acid esterification. Poloxamer has various kinds depending on the number of side chains of the polypropylene oxide-polyoxypropylene-polypropylene oxide constituting the copolymer as a nonionic surfactant.

More specifically, the polyethoxylated castor oil is a polyoxyl 40 hydrogenated castor oil, the polypropylene oxide-polyoxypropylene-polypropylene oxide copolymer is Poloxamer 407, the poly Sorbate is Polysorbate 80 (Tween 80).

The emulsifier used in the present invention improves constellation stability by maintaining the pH at a constant level over time in an oral spray composition containing water-soluble azulene and C ₁₃ -C ₁₇ alkylpyridinium halide. Thus, the oral spray composition of the present invention maintains a pH of 4.0 to 7.0, more specifically, a pH of 5.0 to 6.0, and most particularly, a pH of 5.5 to 6.0.

According to a more specific embodiment of the present invention, the weight ratio of water-soluble azulene and C ₁₃ -C ₁₇ alkylpyridinium halide in the composition of the present invention is from 1: 2 to 1:20, more specifically from 1: 5 to 1: 15.

According to specific embodiments of the present invention, the composition of the invention for the composition the total amount of water-soluble azulene 0.005 - contains 2.0 w / v%, where - 0.2 w / v% and the C ₁₃ -C ₁₇ alkyl pyridinium halides 0.01 The weight ratio of the water-soluble azulene and the C ₁₃ -C ₁₇ alkylpyridinium halide is from 1: 2 to 1:20.

The oral spray composition of the present invention can be applied to an oral cavity such as an alcohol, a sweetener, a buffer, a fragrance, and a flavoring agent in order to maintain transparency over time and to improve flavor, fragrance and refreshing sensation, Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable additive.

As the alcohols, for example, concentrated glycerin or propylene glycol may be used, but not limited thereto, various kinds of alcohols used as food or pharmaceutical additives can be used. Alcohols not only improve the stability of water-soluble azulene, but also can act as an increasing agent. The alcohols may be contained in an amount of 1.0 to 30.0 w / v%, specifically 5 to 20 w / v%, based on the total amount of the composition. The inclusion of alcohols has an advantage of improving the whitening effect of water-soluble azulene, but when used in an amount exceeding 30 w / v%, the viscosity increases and uniform spraying is not attained, making administration difficult.

As used herein, the term " sweetener " means an additive added for the purpose of improving the compliance with medicines by imparting sweetness to the pharmaceutical composition for food or oral administration. The sweetening agent included in the composition of the present invention may be, for example, sugar, fructooligosaccharide, xylitol, maltodextrin, sucralose, stevioside, aspartame, oligosaccharide, sorbitol, fructose, honey, malt, Starch, tartaric acid, sodium tartrate, lactic acid, adipic acid, fumaric acid, sodium fumarate, potato extract (pyrozolic acid), glycyrrhetenic acid But are not limited to, food or medicinal products including, but not limited to, corn starch, monelin, thaumatin, acesulfame, dicin, cyclamate sodium, glucitol, A variety of known sweeteners may be used. The sweetening agent may be used in an amount of 0.1 to 90 w / v%, specifically 0.2 to 75 w / v%, based on the total amount of the composition.

As used herein, the term " buffering agent " refers to a substance that minimizes changes in the pH of a preparation to prevent changes in properties and stability depending on the pH. For example, sodium hydrogen phosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, At least one substance selected from sodium, citric acid and sodium citrate may be used. The buffer may be used in an amount of 0.1 to 2.0 w / v%, specifically 0.2 to 1.0 w / v%, based on the total amount of the composition.

The term " fragrant agent " and " flavoring agent " as used herein mean a substance that improves compliance by allowing a person to feel the fragrance when taking a food or oral administration pharmaceutical composition. Examples thereof include L-menthol, DL- , Eucalyptol, and peppermint oil may be used. The perfume and flavoring agent may be used in an amount of 0.001 to 10 w / v%, specifically 0.004 to 7 w / v%, based on the total amount of the composition.

A suitable dose of the pharmaceutical composition of the present invention to be administered orally to the oral cavity may vary depending on factors such as the patient's age, weight, sex, pathological condition, food, time of administration, route of administration, excretion rate and responsiveness It can be prescribed. The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

According to a specific embodiment of the present invention, the water-soluble azulene and the C ₁₃ -C ₁₇ alkylpyridinium halide in the composition of the present invention have an initial content of 90- It has a content of 100%.

The water-soluble azulene and alkylpyridinium halide contents in the composition according to the invention are measured under relative humidity of 50-80%, more particularly 60-80%, most particularly about 75%. The content of water-soluble azulene and alkylpyridinium halide in the composition according to the present invention is measured based on a period of initial ~ 2 months. As used herein, the term " initial " means a point within 10 days after the liquid preparation composition of the present invention is manufactured, more specifically, a point within 7 days, and most specifically, a point within 5 days do.

According to another aspect of the present invention, the present invention provides a method for preparing an oral spray composition for the prevention or treatment of respiratory diseases, comprising the steps of:

(a) adding to the purified water one or more pharmaceutically acceptable additives selected from the group consisting of buffers, sweeteners, and alcohols and stirring to prepare solution 1;

(b) preparing a second solution by adding a water-soluble azulene, and C ₁₃ -C ₁₇ alkyl pyridinium halide in the solution is 1; And

(c) adding to the ethanol at least one pharmaceutically acceptable additive selected from the group consisting of fragrances and flavors, followed by stirring to prepare solution 3; And

(d) mixing Solution 3 with Solution 2, adding an emulsifier, and stirring.

The water-soluble azulene, the alkylpyridinium halide and the emulsifier used in the production method of the present invention have already been described above with respect to the composition, so that the description thereof is omitted in order to avoid excessive overlapping.

According to a specific embodiment of the present invention, step (a) of the present invention may be carried out by adding any one of buffers, sweeteners and alcohols to the purified water, or by adding two or more additives, When more than one additive is added, each additive may be subjected to a process of addition and stirring sequentially, or may be added simultaneously and stirred. According to a more specific embodiment, when two or more additives are added, each additive is added and stirred sequentially.

According to a specific embodiment of the present invention, the method of the present invention further comprises the step of adding the purified water to the solution obtained in step (d) after the step (d) to adjust the concentration (step (e)).

Exemplary embodiments of the present invention include, but are not limited to, the following, which can be manufactured under various production conditions used in the art:

I) sterilized purified water is added to the preparation tank and heated to 70-95 ° C, specifically about 80 ° C, and then cooled to 30 ° C or lower, specifically, 15-30 ° C, followed by addition of a buffer and stirring;

Ii) adding the sweetening agent to the solution obtained in step i) and stirring;

Iii) adding alcohol to the solution obtained in step ii) and stirring;

Ⅳ) comprising: stirring a water-soluble azulene, and C ₁₃ -C ₁₇ alkyl pyridinium halide in the solution obtained in the step ⅲ);

v) simultaneously adding ethanol to another preparation tank, adding a fragrance and a flavoring agent, and then stirring;

Vi) adding the solution obtained in step v) to the solution obtained in step iv), adding an emulsifying agent and stirring the solution;

(Iii) adding sterilized purified water to the solution obtained in step (vi) above to the desired final volume and stirring; And

Ⅷ) Filtering the final mixture obtained through step 상기) with 1 ㎛ filter and storing in a storage container.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention more specifically and that the scope of the present invention is not limited by these embodiments.

Example

Example  1: water soluble Azulene  And chloride Cetylpyridinium  Manufacture of oral spray formulations containing

Approximately 50 mL of sterile purified water was added to the preparation tank, and the mixture was heated to 80 ° C. After cooling to about 25 ° C with slow stirring, 0.15 g of sodium hydrogenphosphate hydrate, 0.25 g of citric acid hydrate and 0.75 g of sodium citrate hydrate were added and dissolved Solution. While keeping the temperature of the preparation tank, 0.05 g of sucralose was added and stirred, and 20 g and 10 g of concentrated glycerin and propylene glycol were added, respectively, to prepare a solution. 0.02 g of water-soluble azulene and 0.3 g of cetylpyridinium chloride were added thereto and stirred to prepare solution 1. At the same time, 0.04 g of L-menthol, 0.004 g of DL-camphor and 0.1 g of eucalyptol were added to 3 g of ethanol and stirred. Then, 5 g of peppermint oil was added to prepare solution 2. Solution 1 and solution 2 were combined and stirred with 1 g of polyoxyl 40 hardened castor oil and finally sterile purified water was added to make a final volume of 100 mL solution. The resulting final mixture was filtered with a 1 [mu] m filter to prepare a transparent purple oral mouth spray formulation.

Example  2 to 6: water-soluble Azulene  And chloride Cetylpyridinium  Manufacture of oral spray formulations containing

As shown in the following Table 1, an oral spray formulation was prepared in the same manner as in Example 1 except that each constituent component or its content was changed.

Composition of Oral Spray Formulations of the Examples Additive substance (g) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Water-soluble azulene 0.02 0.02 0.02 0.02 0.02 0.02 Cetylpyridinium chloride 0.3 0.3 0.3 0.3 0.3 0.3 Concentrated glycerin 20.0 20.0 20.0 20.0 20.0 20.0 Propylene glycol 10.0 10.0 10.0 10.0 10.0 10.0 Sucralose 0.05 0.05 0.05 0.05 0.05 0.05 Sodium hydrogen phosphate hydrate 0.15 0.15 0.15 0.15 0.15 0.15 Citric acid hydrate 0.25 0.25 0.25 0.25 0.25 0.25 Sodium citrate hydrate 0.75 0.75 0.75 0.75 0.75 0.75 L-menthol 0.04 0.04 0.04 0.04 0.04 0.04 DL-Campa 0.004 0.004 0.004 0.004 0.004 0.004 Eucalyptol 0.1 0.1 0.1 0.1 0.1 0.1 Peppermint oil 5.0 5.0 5.0 5.0 5.0 5.0 Polyoxyl 40
Hardened castor oil 1.0 0.1 10.0 - - - Poloxamer 407 - - - 1.0 - - Sodium lauryl sulfate - - - - 1.0 - Polysorbate 80 - - - - - 1.0 ethanol 3.0 3.0 3.0 3.0 3.0 3.0 Purified water Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Total volume (ml) 100 100 100 100 100 100

Comparative Example  1: Comparison oral spray

Stona of SATO Pharmaceutical Co., Ltd., currently available on the market, was used as Comparative Example 1.

Comparative Example  2 to 7: Preparation of Comparative Oral Spray Formulations

As shown in the following Table 2, an oral spray formulation was prepared in the same manner as in Example 1, except that each component or its content was changed.

Composition of comparative oral spray formulation Additive substance (g) Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Water-soluble azulene 0.02 0.02 0.02 0.02 0.02 0.02 Cetylpyridinium chloride 0.3 0.3 0.3 0.3 0.3 - Concentrated glycerin 20.0 20.0 20.0 20.0 20.0 20.0 Propylene glycol 10.0 10.0 10.0 10.0 10.0 10.0 Sucralose 0.05 0.05 0.05 0.05 0.05 0.05 Sodium hydrogen phosphate hydrate 0.15 0.15 0.15 0.15 0.15 0.15 Citric acid hydrate 0.25 0.25 0.25 0.25 0.25 0.25 Sodium citrate hydrate 0.75 0.75 0.75 0.75 0.75 0.75 L-menthol 0.04 0.04 0.04 0.04 0.04 0.04 DL-Campa 0.004 0.004 0.004 0.004 0.004 0.004 Eucalyptol 0.1 0.1 0.1 0.1 0.1 0.1 Peppermint oil 5.0 5.0 5.0 5.0 5.0 5.0 Polyoxyl 40
Hardened castor oil - 0.05 11.0 - - 1.0 Castor oil - - - 1.0 - - Polyethylene glycol - - - - 1.0 - ethanol 3.0 3.0 3.0 3.0 3.0 3.0 Purified water Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount Total volume (ml) 100 100 100 100 100 100

Experimental Example  1: pH measurement of oral spray formulations

The pH of the oral spray preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 7 was measured with a pH meter, and the results are shown in Table 3.

The pH of the oral spray formulations of the Examples and Comparative Examples Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 pH 5.62 5.62 5.61 5.59 5.80 5.72 5.65 5.69 5.64 5.67 5.64 5.67 8.24

As a result of pH checking of the preparations of Examples 1 to 6 and Comparative Examples 1 to 7, it was confirmed that the pH of the preparation of Comparative Example 7 containing no cetylpyridinium chloride deviates from pH 4 to 7. The preparations of the remaining examples and comparative examples showed an appropriate pH range.

Experimental Example  2: Characterization of Oral Spray Formulation

The oral spray preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 7 were stored in HDPE bottles at room temperature for 7 days and visually observed for layer separation and clouding, and the results are shown in Table 4.

Isolating and clouding of oral spray formulations of Examples and Comparative Examples division Layer separation and property evaluation Whether the layer is separated Cloudiness Example 1 - - Example 2 - - Example 3 - - Example 4 - - Example 5 - - Example 6 - - Comparative Example 1 - - Comparative Example 2 + - Comparative Example 3 + - Comparative Example 4 - + Comparative Example 5 + - Comparative Example 6 + - Comparative Example 7 - + -: no delamination, transparency, +: delamination, opacity

When the formulations of Examples 1 to 6 and Comparative Examples 1 to 7 were examined at the time of storage at room temperature on the 7th day of storage, it was found that in the case of the preparations of Comparative Example 2 and Comparative Example 3 in which the emulsifier was not contained or out of the acceptable range, Was generated. Also, in the formulations in which the emulsifier was added in an excessive amount, or the preparations containing no cetylpyridinium chloride, that is, the preparations of Comparative Example 4 and Comparative Example 7, water-soluble azulene was decomposed to exhibit clouding phenomenon.

Experimental Example  3: Observation of content of oral spray formulation

The oral spray preparations of Examples 1 to 6 and Comparative Examples 1 to 7 were stored in an HDPE bottle under accelerated conditions (40 DEG C, 75% RH) for 2 months, analyzed by liquid chromatography under the following conditions, 5 and Fig.

<Accelerated Storage Conditions>

Storage conditions: 40 캜 and relative humidity 75%, light-shielded sealed glass containers

Testing time: Initial, 1 month, 2 months

Analysis: Water-soluble azulene and cetylpyridinium chloride content

&Lt; Conditions for simultaneous analysis of water-soluble azulene and cetylpyridinium chloride content >

Column: A column (Inertsil CN-3, 25 cm X 4.6 mm, 5 m) packed with cyanated silica gel for liquid chromatography having a particle size of 5 占 퐉 was inserted into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm.

Mobile phase: 1 mM tetrabutylammonium phosphate solution (pH 6.0; 10 mM sodium hydroxide solution)

Detector: Ultraviolet absorptiometer (measuring wavelength 260 nm)

Flow rate: 1.0 mL / min

Column temperature: 25 ° C

The contents of the oral spray preparations of Examples and Comparative Examples at each storage point sample Early 1 month 2 months receptivity
Azulene Chloride
Cetylpyridinium receptivity
Azulene Chloride
Cetylpyridinium receptivity
Azulene Chloride
Cetylpyridinium Example 1 100.0% 100.0% 99.4% 99.5% 99.2% 99.0% Example 2 100.0% 100.0% 99.5% 99.8% 99.6% 99.5% Example 3 100.0% 100.0% 99.6% 99.9% 99.0% 100.0% Example 4 100.0% 100.0% 99.6% 99.4% 99.4% 99.6% Example 5 100.0% 100.0% 99.5% 99.6% 99.5% 99.6% Example 6 100.0% 100.0% 99.7% 99.7% 99.5% 99.7% Comparative Example 1 100.0% 100.0% 99.6% 98.2% 99.2% 96.2% Comparative Example 2 100.0% 100.0% 98.6% 99.3% 96.0% 99.2% Comparative Example 3 100.0% 100.0% 98.3% 99.0% 97.8% 99.5% Comparative Example 4 100.0% 100.0% 60.3% 98.0% 40.1% 98.6% Comparative Example 5 100.0% 100.0% 92.6% 97.6% 90.4% 94.2% Comparative Example 6 100.0% 100.0% 92.4% 94.7% 89.6% 90.6% Comparative Example 7 100.0% - 50.6% - 20.6% -

The contents of the preparations of Examples 1 to 6 and Comparative Examples 1 to 7 were checked at the initial stage and at the 2-month storage of the accelerated condition. As a result, Comparative Example 4 in which an emulsifier was added in an excess amount and Comparative Example 7 in which cetylpyridinium chloride was not contained , The stability of the water-soluble azulene was lowered, and the content of the water-soluble azulene rapidly decreased. On the other hand, although the content of water-soluble azulene in the preparations of Examples 1 to 6 and Comparative Examples 1 to 3, 5 and 6 was somewhat lowered, the amount of water-soluble azulene contained in the raw material containing 90 to 110% The test report criteria were appropriate.

Experimental Example  4: Sensory Evaluation of Oral Spray Formulations

To confirm the cooling sensation and the degree of taste and flavor of the oral spray preparations prepared in Examples 1 to 6 and Comparative Examples 1 to 7, each formulation was sprayed into mouths of 30 adult men in a spray container, , And the sensory evaluation was carried out with the evaluation items in Table 6. The results are shown in Table 7 and Fig.

Sensory evaluation item Degree of evaluation After spraying, feeling One There is no sense of coolness and it is very bitter. 2 There is a little feeling of coolness, a little bit 3 It's refreshing and tasty. 4 Good cooling sensation, slightly sweet 5 Very cool and sweet.

Sensory evaluation scores of the oral spray preparations of Examples and Comparative Examples sample After spraying, feeling rating (average) Example 1 4.9 Example 2 4.6 Example 3 4.7 Example 4 4.5 Example 5 4.0 Example 6 4.2 Comparative Example 1 3.4 Comparative Example 2 3.7 Comparative Example 3 3.4 Comparative Example 4 2.1 Comparative Example 5 2.5 Comparative Example 6 3.6 Comparative Example 7 3.8

As shown in Table 6, the difference in the degree of taste and flavor during spraying was divided into five scores, and the average of the results obtained by summing the scores was shown in Table 7. As a result of the sensory evaluation, it was confirmed that the preparation of Comparative Example 4 in which the emulsifier was added in an excessive amount and the preparation of Comparative Example 5 in which the castor oil was added were unsatisfactory due to the unique fragrance. In addition, the preparation of Comparative Example 7 did not contain cetylpyridinium chloride, and it was confirmed that the specific fragrance disappeared and satisfaction was satisfied.

Experimental Example  5: Water-Soluble in Oral Spray Formulations Azulene  Determine optimal content

Experiments were conducted to confirm the proper content of water-soluble azulene in the preparation of oral spray formulations of the present invention.

First, an oral spray formulation containing water-soluble azulene and cetylpyridinium chloride in an amount of 0.001 to 0.3 w / v% and 0.005 to 4.0 w / v% was mixed with the same ingredients and the same amount of cetylpyridinium chloride except for water-soluble azulene and cetylpyridinium chloride . The results are shown in Table 1. &lt; tb &gt; &lt; TABLE &gt; The specific amounts of water-soluble azulene and cetylpyridinium chloride of the prepared oral spray preparation are shown in Table 8 below.

Determination of optimal content of water-soluble azulene in oral spray preparations Comparative Example 8 Example 7 Example 8 Example 9 Example 10 Example 11 Comparative Example 9 Addition amount
(g) receptivity
Azulene 0.001 0.005 0.01 0.05 0.1 0.2 0.3 Cetylpyridinium chloride 0.005 0.01 0.1 0.3 0.5 1.0 4.0 Acceleration
2 months
After storage
content(%) receptivity
Azulene 70.6 95.6 99.3 99.5 100.0 99.3 99.7 Cetylpyridinium chloride 99.6 99.9 99.5 99.4 100.0 99.6 99.1 Sensory evaluation result Color
Pale - - - - - When spraying, strong feeling

In addition, the content of water-soluble azulene and cetylpyridinium chloride was confirmed at the two-month time point of accelerated storage in the same manner as in Experimental Example 3 using the oral spray preparations prepared above. As shown in Table 8, the preparations of Examples 7 to 11 kept the content of water-soluble azulene and cetylpyridinium chloride high. On the other hand, in the case of the preparation of Comparative Example 8 in which water-soluble azulene was added in an amount of 0.001 w / v%, the content of water-soluble azulene was drastically decreased. In addition, it was confirmed that the color of the preparation of Comparative Example 8 became thin when visually confirmed. The water-soluble azulene is stable in a basic state and has an inherent color bluish purple color. In the case of the preparation of Comparative Example 8, the color becomes weak, and the pH of the preparation is acidic. Therefore, it can be seen that the composition is unsuitable as an oral spray preparation. On the other hand, in the case of the preparation of Comparative Example 9 in which water-soluble azulene was added in an amount of 0.3 w / v%, the content of water-soluble azulene was somewhat lowered. However, the content of water-soluble azulene was so high that the color was turbid and too dense. In the sensory evaluation conducted in the same manner as in Experimental Example 4, the high content of cetylpyridinium chloride gave a strong arine sensation, Could not be shielded.

Claims (18)

Water-soluble azulene (azulene), C ₁₃ -C ₁₇ alkyl pyridinium halides, and mouth spray composition for the prevention and treatment of respiratory disease, including an emulsifier.
The composition according to claim 1, wherein the water-soluble azulene is included in an amount of 0.005 to 0.2 w / v% based on the total amount of the composition.
The composition according to claim 2, wherein the water-soluble azulene is contained in an amount of 0.01 to 0.2 w / v% based on the total amount of the composition.
The composition according to claim 1 or 2, wherein the C ₁₃ -C ₁₇ alkylpyridinium halide is present in an amount of 0.01 to 2.0 w / v% based on the total amount of the composition.
The method of claim 4, wherein the C ₁₃ -C ₁₇ alkyl pyridinium halide is 0.1 for the total composition - a composition, characterized in that contained as 1.0 w / v%.
The composition of claim 1, wherein the C ₁₃ -C ₁₇ alkylpyridinium halide is a cetylpyridinium halide.
7. The composition of claim 6, wherein the cetylpyridinium halide is cetylpyridinium chloride or cetylpyridinium bromide.
The composition according to claim 1, wherein the emulsifier is present in an amount of 0.1 to 10.0 w / v% based on the total amount of the composition.
The composition of claim 1, wherein the emulsifier is selected from the group consisting of polypropylene oxide-polyoxypropylene-polypropylene oxide copolymer; Polysorbate; Docusate; Polyethoxylated castor oil; Polyoxyethylene-sorbitan-fatty acid esters; Sorbitan fatty acid esters; Polyoxyethylene-polyoxypropylene block copolymers; &Lt; / RTI &gt; and mixtures thereof.
10. The composition of claim 9, wherein the emulsifier is a polyethoxylated castor oil, polypropylene oxide-polyoxypropylene-polypropylene oxide copolymer or polysorbate.
11. The composition of claim 10, wherein the polyethoxylated castor oil is a polyoxyl 40 hydrogenated castor oil.
The composition of claim 1, wherein the weight ratio of water-soluble azulene and C ₁₃ -C ₁₇ alkylpyridinium halide in the composition is from 1: 2 to 1:20.
The composition of claim 1, wherein the weight ratio of water-soluble azulene and C ₁₃ -C ₁₇ alkylpyridinium halide in the composition is from 1: 5 to 1:15.
The composition according to claim 1, wherein the total amount of the composition comprises 0.002 to 0.2 w / v% of water-soluble azulene and 0.01 to 2.0 w / v% of C ₁₃ -C ₁₇ alkylpyridinium halide, the weight ratio of ₁₃ -C ₁₇ alkyl pyridinium halide is from 1: composition, characterized in that 2 to 1:20.
The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable additives selected from the group consisting of alcohols, sweeteners, buffering agents, fragrances, and flavoring agents.
The process according to claim 1, wherein the water-soluble azulene and the C ₁₃ -C ₁₇ alkylpyridinium halide in the composition have a content of 90-100% of the initial content at 2 months after storage under accelerated conditions of 40 ° C and 75% relative humidity &Lt; / RTI &gt;
The composition of claim 1, wherein the respiratory disease is an upper respiratory tract infection.
18. The composition of claim 17, wherein the upper respiratory tract infection is sore throat or stomatitis.

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