KR20160145396A - Pharmaceutical composition for nasal spray and a process for the preparation thereof - Google Patents

Abstract

An aspect of the present invention provides a pharmaceutical composition for nasal spray, comprising xylomethazoline or a pharmaceutically acceptable salt thereof as active ingredient and chlorpenilamine or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for nasal spray and a process for preparing the same,

The present invention relates to a pharmaceutical composition for nasal spray containing a complex active ingredient effective for the treatment or prevention of rhinitis, nasal cold, or sinusitis, and a method for producing the same.

Rhinitis is an inflammatory disease of the nasal mucosa associated with one or more symptoms of nasal discharge, sneezing, itching and nasal obstruction. Rhinitis is often caused by a combination of various causes and pathophysiology. Depending on the clinical features of rhinitis, acute rhinitis, chronic rhinitis, and atrophic rhinitis are also roughly divided into. Acute rhinitis is infectious rhinitis, which is often called cold. Chronic rhinitis is largely classified as infectious and noninfective depending on the cause. In particular, acute rhinitis (nose cold) has symptoms such as nasal congestion, runny nose, sneezing, and hairiness, and there is a growing demand for compound nasal spray formulations to effectively alleviate such acute rhinitis (nose cold) symptoms.

Rhinitis, sinusitis, and the like are continuously increasing in modern society. Therefore, it is necessary to develop a complex nasal spray pharmaceutical composition for preventing or treating rhinitis or sinusitis, which is more effective and has improved side effects.

In general, antihistamines are known to help in the treatment of rhinitis, nasal cold, or sinusitis. Antihistamines Is a drug that inhibits the activation of histidine decarboxylase, which inhibits histamine receptor uptake and inhibits the action of histamine or promotes the conversion of histidine to histamine. Antihistamines are usually used to alleviate allergies caused by over-the-body reactions to proteins. When histamine is secreted, it increases the permeability of the blood vessels, causing body fluids to escape from the capillaries into the tissues, creating typical symptoms of allergic reactions such as runny nose and tears. Histamine also promotes angiogenesis. Antihistamines block the histamine receptors present in nerves, vascular smooth muscle, glandular tissues, endothelium, and mast cells to inhibit skin swelling (swelling) and vascular swelling due to histamine action. They work against histamine. Blocking histamine H1 receptors in the nasal sensory nerve can prevent itching and sneezing and is known to help treat rhinitis, nosebleeds, or sinusitis.

Antihistamines acting on H1-receptors include azelastine, olopatadine, chlorpheniramine, loratadine and its isomers, fexofenadine, aastemizole, terfenadine, Drugs such as Terfenadine, Diphenhydramine, Cetirizine and its isomers, and Pseudoephedrine.

Nasal decongestant shrinks nasal vessels and improves nasal congestion. Topical sympathomimetic excitatory decongestants such as imidazoline alpha-adrenergic antagonists (vasoconstrictors), for example, xylomethazoline, may be used to reduce nasal congestion and prevent nasal sprays or nasal sprays nose-drop). A commercial drug containing xylomethazoline is Zymelin (TM), a nasal spray. Other topical nasal decongestants include phenyl urephenol, oxymetazoline, napazoline, tetrahydralazine, ephedrine, etphedrine, clonazolines, dimethophenone, phenoxazoline and indanazoline (WO 2003- 024433).

Since the local nasal decongestant has a strong effect within 5 minutes of nasal spray, it can rapidly improve the nasal congestion, and recently it has been known that it is used in combination with antihistamines for more effective treatment of rhinitis. The topical nasal decongestant may be selected from the group consisting of phenylephrine as a short-acting agent (up to 4 hours), tetrahydralazine as a major hepatic agonist (4-6 hours), napazolin, long-acting agonists Methazoline and the like are known.

It is an object of the present invention to provide a novel combination of pharmaceutical compositions for nasal spray for nebulization effective for the treatment of rhinitis, nosebleeds, or sinusitis and the like.

Another object of the present invention is to provide the above-mentioned pharmaceutical composition for nasal spray composition which is excellent in pharmaceutical aspects such as property and content stability.

It is still another object of the present invention to provide a method for preparing a pharmaceutical composition for nasal spray, which is excellent in pharmaceutical aspects such as stability and content stability.

One aspect of the present invention is

There is provided a pharmaceutical composition for nasal spray comprising xylomethazoline as the active ingredient or a pharmaceutically acceptable salt thereof and chlorpenilamine or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention,

A pharmaceutical composition comprising xylomethazoline or a pharmaceutically acceptable salt thereof as an active ingredient and chlorpenilamine or a pharmaceutically acceptable salt thereof, wherein the composition comprises an emulsifier, a pH buffering agent, an isotonic agent, a flavoring agent, a sweetener, ≪ / RTI > or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention,

A solution 1 preparation step in which a pH buffering agent and an isotonic agent are added to purified water and stirred;

A solution 2 preparation step in which an emulsifier is added to the solution 1 and stirred;

Adding the active ingredient to the solution 2, adding purified water to the solution 2, and stirring the solution 2, according to an embodiment of the present invention.

The pharmaceutical composition for nasal spray according to one aspect of the present invention comprises xylomethazoline or a pharmaceutically acceptable salt thereof and chlorpenilamine or a pharmaceutically acceptable salt thereof so that nasal congestion caused by nasal decongestant It is advantageous to have an enlarged indications which broadly encompass the nose cold, rhinitis and sinusitis by the combined action of rhinitis such as runny nose, nasal congestion, sneezing or the effect of antihistamines on the symptoms of nose cold . In addition, since xylomethazoline can act for a long period of time in a non-decongestant, it is included as a complex component together with chlorpheniramine having a long half-life, and has an advantage that an antihistamine effect and nasal decongestant removal effect can be maintained for a long time. Accordingly, the pharmaceutical composition for nasal spray according to one aspect of the present invention not only has an enlarged indications but also can increase the administration interval by a long time action, so that the number of times of spraying is reduced compared to the conventional antihistamine and nasal decongestant combination agents, Can be increased.

In addition, the pharmaceutical composition for nasal spray according to one aspect of the present invention can be provided as a nasal spray agent which is very preferable in terms of pharmaceuticals including a new complex active ingredient, and also including stability and content stability, sensory preference and the like.

1 is a graph showing the results of measuring the pH of a pharmaceutical composition for nasal spray according to an embodiment of the present invention with a pH meter.
FIG. 2 is a graph showing the results of confirming the content of the active ingredient in the HDPE bottle according to an embodiment of the present invention after storage for 2 months under accelerated conditions (40 ° C, 75% RH) .

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

There is provided a pharmaceutical composition for nasal spray comprising xylomethazoline as the active ingredient or a pharmaceutically acceptable salt thereof and chlorpenilamine or a pharmaceutically acceptable salt thereof.

The xylomethazoline corresponds to an imidazole a-sympathetic stimulant having vasoconstrictor activity, which is used locally to relieve congestion of the nasal mucosa, and its chemical name is 2- (4- tert -butyl-2, Dimethylbenzyl) -4,5-dihydro-1-H-imidazole.

In one embodiment, the xylomethazoline is in the form of a pharmaceutically acceptable salt. Free bases that are xylomethasone have limited stability to hydrolysis in aqueous solutions during formulation.

The pharmaceutically acceptable salts of xylomethazoline may be acid addition salts or base addition salts, for example, xylomethazoline hydrochloride, xylomethazoline sodium, xylomethazoline potassium, xylomethazoline strontium, But are not limited to, xylomethazoline calcium, xylomethazoline magnesium, xylomethazoline ammonium, xylomethazoline maleic acid, and any combination thereof.

In one embodiment, the pharmaceutically acceptable salt of xylomethazoline is xylomethazoline hydrochloride.

The xylomethazoline or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition at such a concentration as to render it administrable in an effective amount when administered topically to the nasal cavity, and may be administered, for example, as a xylomethazoline free base at a concentration of about 0.01 to 1.0 w / v%, specifically 0.01 to 0.5 w / v%, more specifically 0.05 to 0.1 w / v%.

The chlorpheniramine is a first generation antihistamine effective against runny nose, nasal stuffing, sneezing and the like, and its chemical name is 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin- Amine. Chlorpheniramine functions to inhibit the activation of histidine decarboxylase, which inhibits histamine receptor uptake and promotes the inhibition of histamine action or the conversion of histidine to histamine.

In one embodiment, the chlorpenilamine may be used as a pharmaceutically acceptable salt of chlorpenilamine, for example, chlorpenilamine hydrochloride, chlorpheniramine sodium, chlorpheniramine potassium, chlorpheniramine strontium, chlorpenilamine calcium, chlorpheniramine magnesium, But are not limited to, chlorpheniramine ammonium, chlorpheniramine maleic acid, and any combination thereof.

In one embodiment, the pharmaceutically acceptable salt of chlorpenilamine is chlorpenilamine maleic acid.

The chlorpenilamine or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition at a concentration that enables administration in a dose effective for topical nasal administration and may be, for example, from 0.05 to 1.5 w / v% as a chlorpenilamine free base, More specifically from 0.1 to 1.0 w / v%, more specifically from 0.1 to 0.5 w / v%.

In one embodiment, the compounding ratio of xylomethazoline or a pharmaceutically acceptable salt thereof: chlorpenilamine or a pharmaceutically acceptable salt thereof is about 1.0: 2.0 to 1.0: 3.0, more specifically about 1.0: 2.2 ~ 1.0: 2.7.

The above-mentioned chlorpenilamine has an excellent antihistaminic effect and has a long half-life characteristic. Therefore, it can be advantageously used in combination with xylomethazoline to have an enlarged indications covering a wide range of nose cold and rhinitis. In addition, since xylomethazoline can act for a long period of time in a non-decongestant, it is included as a complex component together with chlorpheniramine having a long half-life, and has an advantage that an antihistamine effect and nasal decongestant removal effect can be maintained for a long time. Accordingly, the pharmaceutical composition for nasal spray according to one aspect of the present invention not only has an enlarged indications but also can increase the administration interval by a long time action, so that the number of times of spraying is reduced compared to the conventional antihistamine and nasal decongestant combination agents, Can be increased.

Another aspect of the present invention relates to a pharmaceutical composition comprising xylomethazoline or a pharmaceutically acceptable salt thereof as an active ingredient and chlorpenilamine or a pharmaceutically acceptable salt thereof and which contains an emulsifier, a buffer, an isotonic agent, Wherein the pharmaceutical composition is in the form of a liquid comprising at least one pharmaceutical additive selected from the group consisting of sweeteners, sweeteners, and preservatives.

The details of the pharmaceutical composition according to this aspect may be applied to the description of the pharmaceutical composition according to one aspect of the present invention.

The pharmaceutical composition may have a pharmaceutical form suitable for nasal spray having excellent stability, content stability, sensory preference, and / or shelf stability by having a liquid form containing the one or more pharmaceutical additives.

As used herein, the term "emulsifier " refers to a material that alters the nature of the interface in a mixture of two or more non-immiscible materials and acts to uniformly mix and homogenize them, Used in the same sense. The emulsifier can significantly increase the stability over time and stability of the active ingredient of the pharmaceutical composition for nasal spray. The pharmaceutical composition for nasal spray may contain water-insoluble fragrance components such as menthol, eucalyptol and the like in order to improve the feeling of emolliency and increase the holding time of the refreshing feeling. The emulsifier may be added to the nasal spray composition And can be mixed homogeneously without showing. Therefore, the emulsifier can play various roles such as improving the properties of the pharmaceutical composition for nasal spray, increasing stability over time, increasing sensory preference by increasing the refreshing sensation, increasing the stability of the active ingredient over time, and increasing the preservative power.

In one embodiment, the emulsifier may be any pharmaceutically suitable emulsifier, for example, polypropylene oxides-polyoxypropylene-polypropylene oxide copolymer; Polysorbate; Docusate; Polyethoxylated castor oil; Polyoxyethylene-sorbitan-fatty acid esters; Sorbitan fatty acid esters; Polyoxyethylene-polyoxypropylene block copolymers; ethanol; And any mixture thereof, but is not limited thereto.

In one embodiment, the emulsifier may be present at a ratio of about 0.1 to 10 w / v%, more specifically about 0.5 to 5 w / v%, based on the total amount of the pharmaceutical composition for nasal spray.

In one embodiment, the emulsifier is polyethoxylated castor oil, polysorbate, or any combination thereof. The polyethoxylated castor oil is also referred to as Kremporo, and there are various types of polyoxyl n-hardened castor oil (n is 30 to 60) depending on the oxyethylene unit. The polysorbate has various kinds of polysorbate n (n is 20 to 80).

In the case of using the polyoxyl hydrogenated castor oil or polysorbate as the emulsifier, the pharmaceutical composition for nasal spray is remarkably improved in stability of the ingredient and stability of the content of the active ingredient compared to the case of using other emulsifiers Lt; / RTI > In addition, the pharmaceutical composition for nasal spray is significantly superior in sensory preference in the case of using polyoxylated castor oil or polysorbate, in the absence of emulsifier or in the presence of other emulsifiers.

In one embodiment, the polyethoxylated castor oil is polyoxyl 40 hydrogenated castor oil and the polysorbate is polysorbate 80 (tween 80).

The buffer may be any pharmaceutically acceptable pH buffer, and in one embodiment, the buffer is an inorganic buffer. Such inorganic buffers include, for example, buffers of alkali metal phosphates or alkali metal borates, specifically sodium or potassium phosphate or borate buffers.

In one embodiment, the buffer is a sodium phosphate buffer, a potassium phosphate buffer, or a combination thereof.

In one embodiment, the buffer is monosodium di-di-sodium monohydrate, monopotassium di-di-potassium monohydrate, or combinations thereof.

In one embodiment, the buffer may be used so that the pH of the pharmaceutical composition for nasal spray is at a pH of from 5.0 to 7.5, more specifically from 5.0 to 7.0, more specifically from 6.0 to 7.0. The pharmaceutical composition for nasal spray has a significantly higher sensory preference than other pH ranges in sensory evaluation such as sensation of nasal mucosa, specific odor, and refreshing sensation in the range of pH in the actual human being. In addition, the pharmaceutical composition for nasal spray has high preservation ability against microorganisms in the pH range.

As used herein, the term " isotonic agent " means an additive for adjusting the osmotic pressure of the pharmaceutical composition for nasal spray to an equivalent or similar level to the osmotic pressure of the nasal cavity. The isotonicity agent may be any pharmaceutically acceptable isotonicity agent and may be, for example, sorbitol, glycerol, xylitol, sodium chloride, glucose, or any combination thereof.

The isotonic agent may be present in an amount such that the osmotic pressure of the pharmaceutical composition for nasal spray is about 250-300 mOsmol / kg. If the osmotic pressure is outside the above range, it may cause pain by stimulating the nasal mucosa. If the osmotic pressure is too low, the liquid agent may flow to the nasal cavity after spraying.

In one embodiment, the isotonic agent is D-sorbitol.

D-sorbitol not only acts as an isotonic agent but also improves the solubility of the active ingredient in the solvent and increases the tackiness of the active ingredient to the nasal mucosa, which is advantageous for the delivery of the active ingredient, and on the other hand, Lt; / RTI > In addition, sorbitol also masks the bitter taste of the active ingredient.

The D-sorbitol may be present in an amount of about 1 to 20 w / v%, specifically about 1 to 10 w / v%, more specifically about 1 to 5 w / v%, based on the total amount of the nasal spray pharmaceutical composition.

As used herein, the term "preservative" means an additive for suppressing changes in properties, flavor, taste, content, and microbial propagation of the pharmaceutical composition for nasal spray. The preservative may be any pharmaceutically acceptable preservative and may be, for example, benzalkonium chloride, benzyl alcohol or any combination thereof. The content of the preservative may be an amount required to inhibit changes in properties, flavor, taste, content, and microbial propagation of the pharmaceutical composition for nasal spray, and may vary depending on the specific species.

In one embodiment, the preservative is a benzalkonium chloride, and about 0.005-0.02 w / v%, especially about 0.01 w / v%, based on the total amount of the pharmaceutical composition for nasal spray may be used.

As used herein, the term "fragrance" means an additive that improves compliance by allowing the user to feel the fragrance during food or oral administration, taking or spraying the pharmaceutical composition for nasal spray. The perfume can be any pharmaceutically acceptable directional agent and can be, for example, a material selected from, for example, l-menthol, DL-camphor, eucalyptol, peppermint oil, and any combination thereof. The content of the fragrance may be any amount necessary to improve the compliance of the pharmaceutical composition for nasal spray, and may vary depending on the specific kind.

In one embodiment, the fragrance is a combination of 1-menthol and eucalyptol. The combination of 1-menthol and eucalyptol may be used in an amount of 0.01 to 5 w / v%, specifically 0.02 to 1.0 w / v%, based on the total amount of the pharmaceutical composition for nasal spray.

As used herein, the term "sweetener " means an additive added for the purpose of improving the compliance with the medicines by imparting sweetness to food, oral administration, or nasal administration. The sweetener may be any pharmaceutically acceptable sweetener and may be selected from the group consisting of sugar, sucralose, fructooligosaccharide, xylitol, maltodextrin, stevioside, aspartame, oligosaccharides, sorbitol, fructose , Glycyrrhetinic acid (citric acid), citric acid, tartaric acid, sodium tartrate, adipic acid, fumaric acid, sodium fumarate, potato extract (glycyrrhetinic acid), glycyrrhetinic acid but are not limited to, ascorbic acid, monellin, thaumatin, acesulfame, dicin, cyclamate sodium, and any combination thereof. .

The content of the sweetener may be an arbitrary amount necessary for improving the compliance of the pharmaceutical composition for nasal spray, and may vary depending on the specific type. For example, the content of the sweetener may be about 0.001 w / v% 1 w / v%, more specifically from about 0.01 w / v% to 0.1 w / v%.

As used herein, the term "solvent" means a liquid medium which dissolves both the active ingredient and the additive of the pharmaceutical composition for nasal spray and makes it usable as a preparation for nasal spray. The solvent refers to any pharmaceutically acceptable solvent that can be applied to the nasal spray, for example, water or a water / ethanol mixture.

In one embodiment, the solvent is water, more specifically purified water, more specifically sterile purified water.

In one embodiment, the pharmaceutical composition for nasal spray contains xylomethazoline hydrochloride and chlorpenilamine maleate as active ingredients, and at about 2 months after storage at 40 < 0 > C under accelerated conditions of 75% relative humidity, Each active ingredient may have an amount of about 90-100% of the original content.

The pharmaceutical composition for nasal spray is in the form of a nasal spray liquor and may be formulated as a nasal spray formulation by filling the nasal spray composition with a conventional nasal spray container, for example a spray-squeeze bottle or pump steam generator, . In addition, the pharmaceutical composition for nasal spray may be prepared as a compressed gas aerosol preparation.

In one embodiment, the pharmaceutical composition for nasal spray may be such that about 0.1 to 1.0 mg of xylomethazoline and 0.1 to 1.0 mg of chlorpenilamine are released upon a single release.

One embodiment of the present invention is a pharmaceutical composition comprising sorbitol as an isotonic agent and having a pH of 5.0 to 7.5 in a liquid form.

In the above pharmaceutical composition, sorbitol not only acts as an isotonic agent but also can increase the viscosity of the nasal mucosa to increase the rate of adherence of the active ingredient in the nasal mucosa, . In addition, the above-mentioned pharmaceutical composition has a range of the above-described pH, so that sensory evaluation such as sensation of nasal mucus on the nasal mucosa when sprayed on actual human nasal cavity, sensory evaluation such as refreshing sensation is remarkably superior to other pH range, It has the advantage of being able to function as a hypotensive preservative because of its high preservation ability against microorganisms in the range.

In another aspect of the present invention,

A solution 1 in which a buffer and an isotonic agent are added to water and stirred;

A solution 2 preparation step in which an emulsifier is added to the solution 1 and stirred;

Adding the active ingredient to the solution 2, adding water thereto, and stirring the solution 2, according to all aspects of the present invention.

 The details of the method for preparing a pharmaceutical composition according to this aspect may be applied to the description of the pharmaceutical composition according to all aspects of the present invention.

In one embodiment, a fragrance may be added in the solution 2 preparation step, and in the stirring step, a sweetener and / or a preservative may be added together with the active ingredient.

When two or more additives are to be added in one step in the above production method, a plurality of components may be sequentially added and stirred, or simultaneous addition and stirring may be performed. In one embodiment, when two or more additives are added, each additive is subjected to sequential addition and stirring.

The specific conditions of the above production method may be prepared according to the method for producing any composition for nasal administration known in the art and may be produced under various production conditions used in the art.

In one embodiment,

I) adding sterilized purified water to the preparation tank and heating to about 70-95 ° C, specifically about 80 ° C, followed by addition of a buffering agent and an isotonic agent, and stirring;

Ii) cooling the solution obtained in step i) to about 50 캜, adding a fragrance and an emulsifier, and stirring;

Iii) cooling the solution obtained in step ii) to about 30 캜, stirring the mixture with xylometazoline hydrochloride, chlorpenilamine maleate, preservative, and sweetening agent;

Iv) adding sterile purified water to the solution obtained in step iii) to a final volume to be prepared, and then stirring; And

V) filtering the final mixture obtained through step iv) with a 1 탆 filter, and filling the resulting filtrate into a nasal spray container.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1: Preparation of a pharmaceutical composition for nasal spray containing xylomethazoline hydrochloride and chlorpheniramine maleate

Add 50 mL of sterile purified water to the preparation tank, add 200 mg of sodium dihydrogenphosphate and sodium hydrogen phosphate, while heating to 80 ° C., add 470 mg of sodium chloride, 50 mg of sodium edetate and 2,000 mg of D-sorbitol and dissolve by stirring. After cooling to 50 ° C, 25 mg of 1-menthol, 60 mg of eucalyptol and 500 mg of castor oil, hardened castor oil are added and dissolved by stirring. After cooling to 25 ° C, 100 mg of xylomethazoline maleate, 250 mg of chlorpenilamine maleate, 10 mg of benzalkonium chloride, and 10 mg of sucralose were dissolved and made into 100 mL of purified water. The liquid preparation thus obtained exhibited a transparent property.

Examples 2 to 7: Preparation of pharmaceutical composition for nasal spray comprising xylomethazoline hydrochloride and chlorpenilamine maleate

A liquid formulation was prepared in the same manner as in Example 1, except that the ingredients and their contents were listed in Table 1 below.

Comparative Examples 1 to 3 and Examples 8 to 11: Preparation of pharmaceutical composition for nasal spray

A liquid formulation was prepared in the same manner as in Example 1, except that the ingredients and the contents thereof were listed in Table 2 below.

Experimental Example 1: pH measurement of pharmaceutical composition for nasal spray

The pH of the nasal spray formulations prepared in Examples 1 to 11 and Comparative Examples 1 to 5 was measured with a pH meter, and the results are shown in Table 3 and FIG.

As a result of pH confirmation of Examples 1 to 11 and Comparative Examples 1 to 5, weak acidity results of about pH 6 were obtained except for Examples 5, 8 and 9 in which the ratio of the buffer was different.

Experimental Example 2: Osmotic pressure measurement of pharmaceutical composition for nasal spray

The osmotic pressure of the nasal spray formulations prepared in Examples 1 to 11 and Comparative Examples 1 to 5 was measured with an osmotic pressure measuring device and the results are shown in Table 4.

As a result of the osmotic pressure measurements of Examples 1 to 11 and Comparative Examples 1 to 5, the osmotic pressure of the experimental group except for Examples 10 and 11 showed an osmotic pressure of not more than 300 mOsmol / kg.

Experimental Example 3: Stability test of pharmaceutical composition for nasal spray

The nasal spray formulations prepared in Examples 1 to 11 and Comparative Examples 1 to 5 were stored in an HDPE bottle at room temperature for 7 days, visually separated and visually observed for transparency, and the results are shown in Table 5.

As a result of confirming the growth of the preparations of Examples 1 to 11 and Comparative Examples 1 to 5 at room temperature 7 days after storage, if the polyoxyl-hardened castor oil or polysorbate was not contained, the layer separation occurred and became an opaque liquid agent, Other emulsifiers such as polyethylene glycol, ethanol, poloxamer 407 and sodium lauryl sulfate were used, but no transparency of the liquid agent was obtained, although layer separation did not occur.

Experimental Example 3: Content stability test of pharmaceutical composition for nasal spray

The nasal spray formulations of Examples 1 to 11 and Comparative Examples 1 to 5 were stored in an HDPE bottle under accelerated conditions (40 DEG C, 75% RH) for 2 months and confirmed by liquid chromatography under the following conditions. Respectively.

<Accelerated Storage Conditions>

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

Testing time: Initial, 1 month, 2 months

Analyzes: xylomethazoline hydrochloride and chlorpenilamine maleate content

&Lt; Conditions for analysis of xylometazoline hydrochloride content >

Column: A column or a similar column (Inertsil ODS-2, 25 cm x 4.6 mm, 5 m) filled with silica gel for liquid chromatography having a particle diameter of 5 m was inserted into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm,

Mobile phase: 0.1% TEA: ACN = 65: 35 (pH 2.5; 5% acetic acid)

Detector: Ultraviolet absorptiometer (measuring wavelength 220 nm)

Flow rate: 1.0 mL / min

Column temperature: 30 ° C

<Chlorpheniramine maleate content analysis condition>

Column: A column or a similar column (Waters C18 30 cm x 3.9 mm, 10 m) filled with silica gel for liquid chromatography having a particle size of 10 mu m and having a diameter of about 3.9 mm and a length of 30 cm was filled,

(PH 5.0; 5% acetic acid) in a mobile phase: 0.01 mol / L Dioctyl Sulfosuccinate: ACN = 50:50

Detector: Ultraviolet absorptiometer (measuring wavelength 250 nm)

Flow rate: 1.0 mL / min

Column temperature: 30 ° C

The content ratios of the preparations of Examples 1 to 11 and Comparative Examples 1 to 5 were checked at the initial stage and the accelerated storage stage at 2 months and as a result, it was found that the content of Comparative Examples 1 to 5 exhibiting layer separation or exhibiting an opaque property sharply decreased Respectively. Also, it was found that the change of pH and osmotic pressure did not affect the content of main component.

Experimental Example 4: Sensory evaluation of pharmaceutical composition for nasal spray

30 adults were examined in order to check the sensation (nasal, olfactory, taste, etc.) sensed until the nasal cavity contacted with the nasal cavity and absorbed during spraying of the nasal spray formulations prepared in Examples 1 to 11 and Comparative Examples 1 to 5 As the evaluation items in Table 7, the sensory evaluation was carried out once by spraying, and the results are shown in Table 8. [

As shown in Table 8, the difference in the degree of flavor and aroma during spraying is divided into five scores, and the average of the results obtained by summing the scores is shown in Table 8. As a result of the sensory evaluation, overall satisfaction was high, but in Comparative Examples 1 to 5, in which no emulsifier was added, or when an emulsifier other than polyoxyl-hardened castor oil or polysorbate was used, satisfaction was lowered. Also, in the case of Examples 8 and 9 having a pH of 4 or 8, there was a tendency that the feeling of arness in spraying was increased and a specific odor was generated and the satisfaction was lowered. Example 10 showed that the spraying of the liquid agent was strong after spraying, which was due to the osmotic pressure being too low, and it was also scored low due to insufficient blocking of bitter taste through sorbitol. Example 11 resulted in low scores due to pain during spraying, which appears to be due to too high osmotic pressure and high viscosity.

Experimental Example 5: Conservation test of pharmaceutical composition for nasal spray

The liquid preparations of Examples 1 and 5 and Examples 8 and 9 were applied to Bitish Pharmacopoeia 2012 (Appendix XVI C. Efficacy of Antimicrobial Preservation) to observe the number of bacteria on day 14. The results are shown in Table 9.

As shown in Table 9, the preservation ability of Examples 1 and 5, in which the pH of the solution was 6 to 7, was confirmed. However, it was found that the preservation power was difficult to obtain in Examples 8 and 9 in which the pH was 4 or 8.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (14)

A pharmaceutical composition for nasal spray, comprising xylomethazoline as the active ingredient or a pharmaceutically acceptable salt thereof and chlorpenilamine or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in a liquid form comprising at least one pharmaceutical additive selected from the group consisting of an emulsifier, a buffer, an isotonic agent, a fragrance, a sweetener, and a preservative in a solvent. 3. The pharmaceutical composition according to claim 2, wherein the emulsifier is a polyoxylated castor oil, polysorbate or any combination thereof. The pharmaceutical composition according to claim 3, wherein the emulsifier is polyoxyl 40 hardened castor oil or polysorbate 80. 4. The pharmaceutical composition according to claim 3, wherein the emulsifier is present in an amount of 0.1 to 10 w / v% based on the total weight of the composition. 3. The pharmaceutical composition according to claim 2, wherein the pH of the composition is 5-7. 3. The pharmaceutical composition of claim 2 wherein the buffer is a sodium phosphate buffer, a potassium phosphate buffer, or a combination thereof. 8. The pharmaceutical composition according to claim 7, wherein the buffer is monosodium dihydrogen-disodium monohydrate phosphate buffer, monopotassium dihydrogenphosphate monohydrate phosphate buffer, or a combination thereof. The pharmaceutical composition according to claim 2, wherein the osmotic pressure is from 250 to 350 mOsmol / kg. 3. The pharmaceutical composition according to claim 2, wherein the isotonic agent is sorbitol, glycerol, xylitol, sodium chloride, glucose, or any combination thereof. 3. The pharmaceutical composition according to claim 2, wherein the isotonic agent is sorbitol, in an amount of 1 to 5 w / v% based on the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the active ingredient is contained in an amount of 0.01 to 1.0 w / v% as xylomethazoline free base, and 0.05 to 1.5 w / v% as chlorpenilamine free base. The pharmaceutical composition according to claim 1 for the prophylaxis or treatment of rhinitis, nasal flu, or sinusitis. A solution 1 in which a buffer and an isotonic agent are added to water and stirred;
A solution 2 preparation step in which an emulsifier is added to the solution 1 and stirred;
13. A method for producing a pharmaceutical composition according to any one of claims 1 to 13, which comprises the step of adding the active ingredient to the solution 2, adding water and stirring.

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