KR20130030606A - PHARMACEUTICAL COMPOSITION COMPRISING CORTICOSTEROID, ANTIHISTAMINIC AGENT AND β-CYCLODEXTRIN WITH IMPROVED STABILITY - Google Patents

Abstract

PURPOSE: A pharmaceutical composition is provided to suppress insoluble foreign material generation and to be used as a nasal spray formulation for treating allergic inflammation. CONSTITUTION: A pharmaceutical composition contains corticosteroid or a salt thereof; an anti-histamine agent selected from olopatadine, azelastine, and a pharmaceutically acceptable salt thereof; and beta-cyclodextrin. A method for manufacturing the pharmaceutical composition comprises: a step of preparing a solution containing corticosteroid, beta-cyclodextrin, and a pharmaceutically acceptable additive; a step of preparing a solution containing the anti-histamine agent and a pharmaceutically acceptable additive; and a step of mixing the solutions.

Description

PHARMACEUTICAL COMPOSITION COMPRISING COMPOSING CORTICOSTEROID, ANTIHISTAMINIC AGENT AND β-CYCLODEXTRIN WITH IMPROVED STABILITY}, including corticosteroids, antihistamines and β-cyclodextrins

The present invention provides a corticosteroid or a pharmaceutically acceptable salt thereof; Antihistamines selected from the group consisting of olopatadine, azelastine and pharmaceutically acceptable salts thereof; And it relates to a pharmaceutical composition comprising β-cyclodextrin and a method for preparing the same.

In allergic rhinitis, allergens interact with surface IgE antibodies on mast cells and basophil cells and form crosslinks. When a mast cell-antibody-antigen complex is formed, cell-degranulation occurs, and histamine is secreted from mast cells or basophilic cells to cause an allergic reaction.

Histamine acting on the H1-receptor induces pruritis, vasodilation, hypotension, flushing, headache, tachycardia and bronchoconstriction, increases vascular permeability, and enhances pain. Thus, H1-antihistamines are clinically useful in the treatment of histamine-mediated allergic conditions such as allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, urticaria, angioedema, pruritus (atopic pruritus) . These antihistamines can be administered locally, such as skin, nose, and eyes, and can be administered systemically.

Antihistamines used mainly for the treatment and alleviation of symptoms of seasonal allergic rhinitis include azelastine, olopatadine, chlorpheniramine, loratadine and its isomers, fexofenadine ), Astemizole, terfenadine, diphenhydramine, cetirizine and isomers thereof, and pseudoephedrine. Drugs currently available to them, especially in the nasal inhalants has azelastine ^(Astepro?, MEDA pharm Co.) and Fatah OLLO Dean ^(Patanase?, Alcon, Inc.).

Corticosteroids are drugs closely related to cortisol, a naturally occurring hormone in the adrenal cortex, such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Deltasone, Triamcinolone, Mometasone, Fluticasone and the like.

Corticosteroids act to block the production of substances that cause allergic and inflammatory actions such as prostaglandins, but they disrupt foreign bodies and interfere with the function of white blood cells, which allows the immune system to function properly, Resulting in side effects such as increased susceptibility.

Corticosteroids can be used with other drugs and are prescribed for short-term and long-term use. However, long-term use of corticosteroids for systemic absorption causes side effects such as appetite and weight gain, accumulation of water and salt resulting in fat deposits, edema and species such as chest and face, hypertension, diabetes, osteoporosis, and cataracts . Therefore, when corticosteroids are used for the treatment of nasal diseases, such as rhinitis, they are usually administered in nasal spray and drop formulations that can reduce systemic absorption, and inhaler forms for the treatment of asthma or bronchial diseases. Dosing is possible. Currently available nasal spray products include mometasone, fluticasone, and budesonide.

The combination of antihistamines and corticosteroids in the nasal passages is expected to provide synergistic effects in the treatment of seasonal allergic rhinitis. Korean Patent Publication No. 2007-0121786 discloses a process for preparing corticosteroids and antihistamines in nanoparticle form, and in particular, various methods for preparing corticosteroids in nanoparticle form. U.S. Patent Publication No. 2006/0025391 also discloses a nasal application composition comprising corticosteroids and azelastine.

In general, corticosteroids are poorly water-soluble, so they do not melt, so that the nasal spray of corticosteroids contains dispersible microcrystalline cellulose (MCC) to prevent non-uniformity in the injection content that can occur when spraying. . Dispersible MCCs used in commercially available nasal spray products are dispersed in the liquid and present in the colloidal phase, using about 10% sodium carboxymethylcellulose (CMC) to prevent MCC from settling. However, when adding olopatadine hydrochloride or azelastine hydrochloride, CMC sodium and olopatadine hydrochloride or azelastine hydrochloride form an insoluble gel and consequently deteriorate the stability of corticosteroids. These insoluble gels are not soluble in water and have irregular sizes in nasal sprays, affecting the spray content of the drug when spraying and preventing the desired effect, as well as mechanically blocking the spray nozzles to prevent spraying. do.

Therefore, the present inventors earnestly researched to prevent insoluble foreign matter generation using various thickeners. When using β-cyclodextrin (β-CD), the insoluble foreign material generated when the dispersible MCC and the antihistamine are combined. The present invention was completed by discovering that β-cyclodextrin increases the solubility of the antihistamine and prevents olopatadine from precipitating in the liquid, as well as improving the stability in the liquid.

[Patent Document 1] Republic of Korea Patent Publication No. 2007-0121786

[Patent Document 2] US Patent Publication No. 2006/0025391

Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising a corticosteroid and an antihistamine, wherein the production of insoluble gel is inhibited and the solubility of the antihistamine is increased.

Another object of the present invention is to provide a method for preparing the pharmaceutical composition.

The present invention to achieve the above object is a corticosteroid or a pharmaceutically acceptable salt thereof; Antihistamines selected from the group consisting of olopatadine, azelastine and pharmaceutically acceptable salts thereof; And it provides a pharmaceutical composition comprising β-cyclodextrin.

The present invention to achieve the above other object

(1) preparing a solution comprising a corticosteroid, β-cyclodextrin and a pharmaceutically acceptable additive;

(2) preparing a solution comprising an antihistamine selected from the group consisting of olopatadine, azelastine and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable additive; And

(3) It provides a method for producing the pharmaceutical composition comprising the step of mixing the solution prepared in the step (1) and (2).

Since the pharmaceutical composition comprising corticosteroid, olopatadine or azelastine, and β-cyclodextrin according to the present invention is inhibited insoluble foreign matter production and the solubility of the antihistamine is increased, it is stable even without long term storage without precipitation of the active ingredient, It can be usefully used as a nasal spray preparation for the treatment of allergic inflammation.

Figure 1 shows a photograph of the liquid preparation of Comparative Example 10 (left) and Example 6 (right) performed according to Test Example 1.

The present invention provides a corticosteroid or a pharmaceutically acceptable salt thereof; Antihistamines selected from the group consisting of olopatadine, azelastine and pharmaceutically acceptable salts thereof; And it provides a pharmaceutical composition comprising β-cyclodextrin.

The composition of the present invention includes β-cyclodextrin, which can suppress the formation of insoluble foreign matter in pharmaceutical compositions including corticosteroids, antihistamines and dispersible MCCs, and increases the solubility of antihistamines in liquids. Not only can it prevent precipitation, but it can also improve stability in the liquid.

The pharmaceutical composition according to the present invention can be used for the prevention or treatment of perennial allergic rhinitis, seasonal allergic rhinitis, vasomotor rhinitis, allergic rhinitis, nasal polyps or acute rhinosinusitis.

Hereinafter, each component which comprises the pharmaceutical composition of this invention is demonstrated concretely.

(i) corticosteroids

Possible corticosteroid used in the invention is mometasone ^(Nasonex?, Schering Pulau), fluticasone (Flixsonase, ^Veramyst?, GSK), budesonide ^(Pulmicort?, AstraZeneca), or a pharmaceutically acceptable salt thereof or It may be a free salt, and preferably, mometasone or a pharmaceutically acceptable salt thereof may be used, and more preferably mometasone furoate may be used.

In one embodiment of the invention the mometasone used as a corticosteroid has the structure of Formula 1 and can be used in the form of anhydrides or hydrates:

In the present invention, the corticosteroid may be 0.01 to 1 w / v%, preferably 0.01 to 0.1 w / v%, more preferably 0.02 to 0.06 w / v%, based on the total weight of the composition. According to a preferred embodiment of the present invention, the corticosteroid can be used in an amount of 0.02 to 0.06 w / v% based on 1 ml of the nasal spray, which is a form of the pharmaceutical composition of the present invention.

(ii) antihistamines

The antihistamines usable in the present invention are antihistamines used for nasal spraying to treat and alleviate the symptoms of seasonal allergic rhinitis, and may use olopatadine, azelastine, or a pharmaceutically acceptable salt or free salt thereof. Can be.

In the present invention, the antihistamine may be 0.1 to 2 w / v%, preferably 0.5 to 1 w / v%, based on the total weight of the composition. According to a preferred embodiment of the present invention, the antihistamine may be used in an amount of 0.5 to 1 w / v% based on 1 ml of the nasal spray, which is a form of the pharmaceutical composition of the present invention.

(iii) β-cyclodextrin

Β-cyclodextrin (β-CD) used in the present invention is a polymer compound having a structure as shown in the following formula (2), a compound of the substituted form such as methyl β-CD or hydroxypropyl β-CD (HPβ-CD) And hydroxypropyl β-CD is preferred:

Β-cyclodextrin in the present invention can be used for the use of thickeners or precipitation inhibitors. According to an embodiment of the present invention, the β-cyclodextrin may inhibit the action of dispersing MCC which may be included in the pharmaceutical composition of the present invention to form an insoluble gel in combination with an antihistamine to reduce the stability of corticosteroids In addition, by increasing the solubility of the antihistamines can prevent the antihistamines from being precipitated in the liquid.

Β-cyclodextrin in the present invention may be 0.05 to 20 w / v%, preferably 0.1 to 10 w / v%, more preferably 1 to 5 w / v% based on the total weight of the composition. According to a preferred embodiment of the invention, β-cyclodextrin may be used in an amount of 1 to 5 w / v% based on 1 ml of nasal spray, which is one form of the pharmaceutical composition of the present invention.

The pharmaceutical composition of the present invention may comprise dispersible microcrystallin cellulose (MCC) and pharmaceutically acceptable additives such as pH adjusting agents, isotonic agents, preservatives and other excipients.

In the present invention, the dispersible MCC may use Avicel RC 591 (FMC biopolymer). The dispersible MCC may be used in an amount of 0.1 to 10 w / v%, preferably 1 to 5 w / v%, based on the total weight of the composition.

In the present invention, the pH adjusting agent may be citric acid hydrate or sodium citrate hydrate, and the pH of the composition according to the present invention may be adjusted to 3 to 5 by using the pH adjusting agent.

In the present invention, the humectant may use glycerin, propylene glycol, glycerin acetate, sorbitol, and the like, and preferably, glycerin may be used.

In the present invention, the preservative may be used benzalkonium chloride, sodium benzoate, boric acid, phenylethyl alcohol, and the like, preferably benzalkonium chloride.

In the present invention, the other excipients may be used, such as polysorbate.

The composition of the present invention is preferably in a form suitable for nasal administration, for example in the form of a liquid. The liquid may be administered in the form of a nasal spray or a nasal drop, and is preferably a nasal spray.

According to a preferred embodiment of the present invention, an aqueous solution comprising mometasone furoate, azelastine hydrochloride and hydroxypropyl β-cyclodextrin may be prepared, which may be administered in the form of a nasal spray solution.

According to a preferred embodiment of the present invention, an aqueous solution comprising mometasone furoate, olopatadine hydrochloride and hydroxypropyl β-cyclodextrin may be prepared, which may be administered in the form of a nasal spray solution. .

The nasal spray liquid may include dispersible microcrystalline cellulose (MCC) included in a conventional nasal spray liquid, the dispersible MCC is 0.1 to 10 w / v%, preferably based on the total weight of the composition It may be contained in 1 to 5 w / v%.

Nasal spray solutions may be produced, for example, using conventional spray-squeeze bottles or pump steam generators. Moreover, compressed gas aerosols may be used. The nasal spray solution according to the present invention preferably releases 0.1 to 1.0 mg of antihistamine and 0.01 to 0.05 mg of corticosteroid in one release.

The pharmaceutical composition according to the present invention comprises the steps of (1) preparing a solution comprising a corticosteroid, β-cyclodextrin and a pharmaceutically acceptable additive; (2) preparing a solution comprising olopatadine or azelastine and a pharmaceutically acceptable additive; And (3) it may be prepared by a manufacturing method comprising the step of mixing the solution prepared in steps (1) and (2).

Various processes involved in the preparation of the pharmaceutical composition according to the present invention can be carried out according to the conventional manufacturing process of the liquid, in step 1) it is possible to prepare a solution including dispersible microcrystalline cellulose (MCC). have.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Comparative Examples 1 to 9: Preparation of nasal spray solution containing no HPβ-CD- (1)

The nasal spray solution was prepared using the ingredients and contents (mg / ml) as described in Table 1 below. Specifically, a solution is prepared by dispersing and dissolving mometasone furoate anhydride, dispersible MCC, citric acid hydrate, sodium citrate hydrate, and benzalkonium chloride using an appropriate amount of purified water, and separately from olopatadine hydrochloride and the remaining pharmaceuticals. A solution in which acceptable additives were dissolved was prepared. The prepared solution for nasal spray was prepared by uniformly dispersing and mixing the mometasone-containing solution and olopatadine-containing solution prepared above using a homogeneous mixer.

In this case, corticosteroids and antihistamines are used as mometasone furoate anhydride (Cipla, India) and olopatadine hydrochloride (Dongwoo Syntech, South Korea), and as a dispersible MCC Avicel RC591 (Avicel RC591, FMC Biopolymer) The pH was adjusted to 4.5 using citric acid hydrate (Jungbunzlauer, Switzerland) and sodium citrate hydrate (Jungbunzlauer, Switzerland), and benzalkonium chloride (Dolder, Switzerland) was used as a preservative. Other excipients were glycerin (Seojin Chemical, Korea) and polysorbate (Croda Oleochemicals). Thickeners or precipitation inhibitors include: hydroxypropylmethylcellulose (HPMC, Shinetsu), polyvinylpyrrolidone (PVP, BASF), logger bean gum (CPkelco, USA), polyethylene glycol (PEG, Sanyo), Carbomer (Lubrizol Advanced Material) or guar gum (Haji Dossa, Japan) and the like were used. The amounts of raw materials indicated throughout Tables 1 to 3 represent mg of each component in 1 ml of purified water.

Comparative Example
One Comparative Example
2 Comparative Example
3 Comparative Example
4 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Comparative Example
9 Mometasone furoate 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 - Olopatadine Hydrochloride 6.65 6.65 6.65 6.65 6.65 6.65 6.65 - 6.65 Dissipative MCC 20 20 20 20 20 20 20 20 20 glycerin 21 21 21 21 21 21 21 21 21 Citric Acid Hydrate 2 2 2 2 2 2 2 2 2 Sodium citrate monohydrate 2.8 2.8 2.8 2.8 2.8 2.8 2.8 2.8 2.8 Polysorbate 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Benzalkonium chloride 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Purified water Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount Proper amount HPβ-CD - - - - - - - - - HPMC - 20 - - - - - - - PVP - - 20 - - - - - - Logurstonggum - - - 20 - - - - - PEG - - - - 20 - - - - Carbomer - - - - - 20 - - - Guar gum - - - - - - 20 - -

Examples 1 to 5: Preparation of nasal spray solution containing HPβ-CD- (1)

Ingredients and contents as shown in Table 2 below (mg / ml), except that HPβ-CD (Roquette) was used instead of HPMC, PVP, Rogersonggum, PEG, Carbomer or Guar Gum as a thickener or precipitation inhibitor. ) To prepare a nasal spray solution in the same manner as described in the comparative example.

Example 1 Example 2 Example 3 Example 4 Example 5 Mometasone furoate 0.25 0.25 0.25 0.25 0.25 Olopatadine Hydrochloride 6.65 6.65 6.65 6.65 6.65 Dissipative MCC 20 20 20 20 20 glycerin 21 21 21 21 21 Citric Acid Hydrate 2 2 2 2 2 Sodium citrate monohydrate 2.8 2.8 2.8 2.8 2.8 Polysorbate 0.1 0.1 0.1 0.1 0.1 Benzalkonium chloride 0.2 0.2 0.2 0.2 0.2 Purified water Proper amount Proper amount Proper amount Proper amount Proper amount HPβ-CD 10 20 40 100 200

Example 6 Preparation of Nasal Spray Solution Comprising HPβ-CD- (2)

Antihistaminic agent instead OLLO Zapata hydrochloride using the azelastine hydrochloride and is to such ingredients and contents shown in Table 3, except for using (h ^jeptin? Biaek, M auxiliary optical line Pharmaceutical Co.) (mg / ml) to the above-described embodiment A nasal spray solution was prepared in the same manner as described.

Comparative Example 10 Preparation of Solution for Nasal Spray Not Containing HPβ-CD- (2)

Except for using azelastine hydrochloride instead of olopatadine hydrochloride as an antihistamine and not using thickeners or anti-settling agents, the ingredients and contents (mg / ml) as shown in Table 3 below were used in the above examples. A nasal spray solution was prepared in the same manner as described.

Comparative Example 10 Example 6 Mometasone furoate 0.25 0.25 Azelastine hydrochloride One One Dissipative MCC 20 20 glycerin 21 21 Citric Acid Hydrate 2 2 Sodium citrate monohydrate 2.8 2.8 Polysorbate 0.1 0.1 Benzalkonium chloride 0.2 0.2 Purified water Proper amount Proper amount HPβ-CD - 20

Test Example 1: Short-term precipitation and content change test

The nasal spray solution prepared in Comparative Examples 1 to 9 and Examples 1 to 5 was placed in a transparent container such as a vial and then stored at room temperature for 24 hours to observe whether precipitates formed.

In addition, after 24 hours, the supernatant dispersed without precipitation was taken to check the contents of mometasone and olopatadine, and the difference from the initial content was measured. At this time, the content analysis of each component was analyzed according to the assay described in each USP monograph.

The results of Comparative Examples 1 to 9 are shown in Table 4 below, and the results of Examples 1 to 5 are shown in Table 5 below.

Comparative Example
One Comparative Example
2 Comparative Example
3 Comparative Example
4 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Comparative Example
9 Precipitation 24 hours after manufacture Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation
none Sedimentation
none Changes in Olopatadine Content 0.3% -0.50% 0.30% -0.20% 0.30% 0.40% 0.10% - -0.20% Change of Mometasone Content -94.2% -82.5% -86.2% -91.0% -89.2% -88.9% -90.2% -0.1% -

Example 1 Example 2 Example 3 Example 4 Example 5 Precipitation 24 hours after manufacture No precipitation No precipitation No precipitation No precipitation No precipitation Changes in Olopatadine Content 0.00% 0.10% -0.20% -0.10% 0.10% Change of Mometasone Content 0.20% 0.30% 0.00% -0.20% -0.10%

As shown in Tables 4 and 5, in Comparative Examples 2 to 7 without using HPβ-CD, all precipitates were formed after storage for 24 hours, and these precipitates were confirmed to be precipitated mometasone insoluble in water. In addition, in the liquid formulation of Comparative Example 8, in which olopatadine was not used, it was found that precipitation did not form. Thus, dispersing MCC did not play a role due to the addition of olopatadine, thereby causing precipitation of mometasone. . On the other hand, in Examples 1 to 5 using HPβ-CD, all of the precipitates were not formed, and thus the liquid formulation was found to be in a stable form without unbalanced content of the main components.

In addition, a precipitation confirmation test and a content change test were performed on the nasal spray solution prepared in Comparative Example 10 and Example 6, and the results are shown in Table 6.

Comparative Example 10 Example 6 Precipitation 24 hours after manufacture Sedimentation No precipitation Azelastine content change -0.10% -0.20% Mometasone Content Change -93.1% -0.5%

As shown in Table 6, even in the case of using azelastine hydrochloride as an antihistamine, the solution of Comparative Example 10, which did not use HPβ-CD, caused precipitation of mometasone after storage for 24 hours, whereas HPβ-CD was used. In the solution of Example 6, no precipitate was formed, indicating that the solution was stable for nasal spraying.

Test Example 2: Long-term precipitation and content change confirmation test

The nasal spray solution prepared in Comparative Examples 1 to 9 and Examples 1 to 5 was placed in a transparent container such as a vial and then stored for 3 months in a long-term storage (25 ° C., 65% RH) storage condition. It was observed to form.

Also, after 3 months, the supernatant dispersed without precipitation was taken to check the contents of mometasone and olopatadine, and the difference from the initial content was measured. At this time, the content analysis of each component was analyzed according to the assay described in each USP monograph.

The results of Comparative Examples 1 to 9 are shown in Table 7 below, and the results of Examples 1 to 5 are shown in Table 8 below.

Comparative Example
One Comparative Example
2 Comparative Example
3 Comparative Example
4 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Comparative Example
9 Long-term storage
Settle after 3 months Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation
none Sedimentation
(handful) Olopatadine
Change in content -13.2% -11.2% -10.2% -9.8% -11.2% -10.3% -11.9% - -11.4% Mometasone
Change in content -99.2% -94.5% -96.5% -94.1% -94.1% -92.8% -94.7% -3.1% -

Example 1 Example 2 Example 3 Example 4 Example 5 Long-term storage
Settle after 3 months No precipitation No precipitation No precipitation No precipitation No precipitation Changes in Olopatadine Content -0.40% -0.30% -0.50% -0.40% -0.30% Change of Mometasone Content -2.50% -1.00% -1.00% -0.70% -0.30%

As shown in Tables 7 and 8, precipitates were formed in all comparative examples except Comparative Example 8, and it was confirmed that the precipitates were precipitates of mometasone insoluble in water. However, a small amount of olopatadine precipitated in the nasal spray solution containing no mometasone as in Comparative Example 9, which is thought to have occurred due to the solubility problem of long-term storage of olopatadine. On the other hand, no precipitation was formed in the solutions of Examples 1 to 5 using HPβ-CD, and it was found that HPβ-CD had an effect of preventing precipitation of olopatadine.

Through the results of the test examples, HPβ-CD not only prevents the formation of olopatadine precipitates, but also increases the solubility of olopatadine itself has the effect of preventing the precipitation of olopatadine alone. Could.

Claims (14)

Corticosteroids or pharmaceutically acceptable salts; Antihistamines selected from the group consisting of Olopatadine, Azelastine and pharmaceutically acceptable salts thereof; And β-cyclodextrin. The method of claim 1,
Pharmaceutical composition, characterized in that the corticosteroid is mometasone (Mometasone), fluticasone, Budesonide, or a pharmaceutically acceptable salt or free salt thereof. The method of claim 1,
The pharmaceutical composition, characterized in that the corticosteroid is mometasone or a pharmaceutically acceptable salt thereof. The method of claim 1,
The pharmaceutical composition, characterized in that the corticosteroid is 0.01 to 1 w / v% based on the total weight of the composition. The method of claim 1,
The antihistamine is a pharmaceutical composition, characterized in that 0.1 to 2 w / v% based on the total weight of the composition. The method of claim 1,
The β-cyclodextrin is hydroxypropyl β-cyclodextrin, characterized in that the pharmaceutical composition. The method of claim 1,
The β-cyclodextrin is 0.05 to 20 w / v% based on the total weight of the composition, pharmaceutical composition. The method of claim 1,
Pharmaceutical composition, characterized in that the pharmaceutical composition is in the form of a liquid. The method of claim 8,
Pharmaceutical composition, characterized in that the pharmaceutical composition is a nasal spray solution. The method of claim 1,
A pharmaceutical composition, characterized in that the pharmaceutical composition comprises dispersible microcrystalline cellulose (MCC). 11. The method of claim 10,
The dispersible microcrystalline cellulose is characterized in that 0.1 to 10 w / v% based on the total weight of the composition, pharmaceutical composition. The method of claim 1,
The pharmaceutical composition is characterized in that the pH of the pharmaceutical composition is 3 to 5. (1) preparing a solution comprising a corticosteroid, β-cyclodextrin and a pharmaceutically acceptable additive;
(2) preparing a solution comprising an antihistamine selected from the group consisting of olopatadine, azelastine and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable additive; And
(3) A method for producing the pharmaceutical composition of claim 1, comprising the step of mixing the solutions prepared in steps (1) and (2). The method of claim 13,
In the step 1), dispersible microcrystalline cellulose (MCC) is added, characterized in that the manufacturing method.

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