JP6514757B2 - Nasal composition - Google Patents

Description

  The present invention comprises a beclomethasone propionate, at least one selected from the group consisting of cromoglycic acid and its salts, ketotifen and its salts, and a cellulose polymer, and may contain a monoterpene. It relates to a composition.

  Beclomethasone is a steroidal anti-inflammatory drug that became available for OTC in 2010. The compound is formulated into pharmaceuticals and the like in the form of propionate, but beclomethasone propionate is a water-insoluble drug, and is used as a suspension preparation when formulated into nasal drops. With respect to a suspension preparation, when stored for a certain period, secondary particles in which many particles are aggregated form a secondary particle to deteriorate redispersibility, and clogging of the nozzle of the container becomes a problem. As a result, there are problems such as that the discharge of the spray and the like can not be performed although the preparation remains, the preparation can not be discharged uniformly, and the effect is uneven.

  In order to improve them, a method of suppressing the adsorptivity between solid and liquid by blending a surfactant and a method of improving dispersibility by blending a thickener or the like are taken. However, when they are formulated in large amounts, foaming and stringing of the preparation occur, and new problems with inconvenience and discomfort occur at the time of use.

  Furthermore, if a suspension nasal drop containing a surfactant is used, it may cause discomfort in the mouth through the nasal mucosa due to the surfactant or the like, and in order to eliminate this or to provide a refreshing sensation, The nasal spray contains a wide range of refreshing agents such as menthol.

  For example, in Patent Document 1, the dispersibility is good, the feeling of use is good, and even if stored for a long period, there is no solidification or spray abnormality of the tip of the nozzle, the physical stability is also good, and the good dispersibility is impaired. An aqueous suspension containing a poorly water-soluble medicinal ingredient (eg, beclomethasone propionate), a polyhydric alcohol, crystalline cellulose carmellose sodium, and a refreshing agent is disclosed as an aqueous suspension which does not ing. The blending amount of the crystalline cellulose and carmellose sodium is 0.3 to 3.5% by weight.

  In addition, suspension preparations are generally used after light shaking to re-disperse the contents, but the contents of the preparation are contained in a container with low light permeability, for example, an opaque container, due to insufficient light stability. As it is filled, it is difficult to confirm with naked eyes whether the contents have been sufficiently redispersed even if it is shaken gently.

  By the way, in OTC medicines, in addition to the sustainability of the effect of the preparation, the feeling of effect (immediate effect immediately after using it) and the feeling of use tend to be emphasized, and it is more There is also a high need for preparations with the above-mentioned balance adjusted by the combination drug. Beclomethasone is excellent in sustainability but hard to feel the immediate effect, so users are likely to use it beyond the prescribed dose too much for the feeling of effectiveness, and there are concerns that unexpected side effects will occur .

  Here, in Patent Document 2, it is described that the immediate effect of the steroidal anti-inflammatory agent is enhanced by combining the menthol, which is conventionally used as a refreshing agent, with the steroidal anti-inflammatory agent. Sex is still inadequate. In Example 2 of Patent Document 2, 0.1% by mass of beclomethasone propionate, 0.01% by mass of 1-menthol, 1.0% by mass of sodium cromoglycate, and 2.0% by mass of crystalline cellulose are contained. Nasal drops have been prepared.

Unexamined-Japanese-Patent No. 2004-67614 JP 2005-97221 A

  It is an object of the present invention to provide a nasal composition which can be filled in a container which has good dispersibility even when stored for a long period of time, is excellent in feeling of effect, and can easily confirm redispersion with the naked eye. To aim.

  As mentioned above, if a steroid anti-inflammatory agent is formulated alone into the nasal drops, even if it is formulated together with menthol, the effect is insufficient because the immediate effect is insufficient, and the user exceeds the usage dose. There is a risk of using nasal sprays.

  In order to solve this problem, the inventor of the present invention blended the immediate-acting cromoglycic acid or ketotifen in addition to beclomethasone propionate, which is a steroidal anti-inflammatory agent, using the composition disclosed in Patent Document 1 It was also found that good dispersibility after storage for a long period of time was not achieved.

  Then, in order to solve the said problem, when the present inventors thoroughly investigated, in the nasal composition containing beclomethasone propionate and cromoglycic acid or ketotifen, the amount of cellulose which is considerably smaller than the compounding amount conventionally adopted is obtained. By blending a system polymer in a predetermined ratio to cromoglycic acid or the like, or blending a much smaller amount of a cellulose polymer and a monoterpene than the conventionally employed blending amount. Therefore, even after long-term storage, it has good dispersibility, excellent feeling of effect, and excellent light stability, and can be filled in a container that allows the user to easily confirm redispersion with the naked eye. It was found that a composition for the preparation was obtained, and the present invention was completed.

That is, the gist of the present invention is as follows.
<1> (A) Beclomethasone propionate,
(B) at least one selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof,
(C) containing 0.001 to 0.1 w / v% of a cellulose-based polymer,
(D) A composition for nasal drops characterized in that it may contain a monoterpene (However, in the case where the monoterpene (D) is not contained, the above composition is based on 1 part by weight of the (B) component) The cellulose polymer (C) is contained in an amount of 0.0001 to 0.05 parts by weight).

  <2> The cellulose polymer (C) is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC) and salts thereof, and crystalline cellulose The nasal composition according to <1>, which is at least one of

  <3> The composition for nasal drops contains the monoterpene (D), and the monoterpene (D) is menthol and / or camphor, described in <1> or <2>. Nasal composition.

  The composition for nasal drops in any one of <1>-<3> characterized by being a <4> suspension formulation.

  ADVANTAGE OF THE INVENTION According to this invention, the composition for nasal drops which can be filled in the container which is excellent in a dispersibility also after it preserve | saves for a long period of time, is excellent in a feeling of effect, and can confirm redispersion visually is further provided.

  Hereinafter, the characteristics of the components (A) to (C) which are essential components of the composition for nasal administration of the present invention, the component (D) which is an optional component, other components and the composition will be described in detail.

[Composition for nasal cavity]
<(A) Beclomethasone propionate>
Beclomethasone propionate (A) is a steroidal anti-inflammatory agent conventionally used. The nasal composition of the present invention is effective in one application because the anti-inflammatory effect is excellent in persistence although it is not immediately effective.

  In the nasal composition of the present invention, the content of beclomethasone propionate (A) is usually 0.001 to 0.2 w relative to the whole nasal composition from the viewpoint of its effect and good dispersibility. / V%, preferably 0.01 to 0.1 w / v%.

<(B) At least one selected from the group consisting of cromoglycic acid and salts thereof, ketotifen and salts thereof>
The nasal composition of the present invention contains at least one (B) selected from the group consisting of cromoglycic acid and its salts, ketotifen and its salts. Although these are anti-allergic agents which have been widely used conventionally, they are excellent in immediate effect and impart a good feeling of effect to the nasal composition of the present invention.

  The salts of cromoglycic acid are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As such salts, for example, salts with alkali metals such as sodium salts and potassium salts; salts with alkaline earth metals such as calcium salts and magnesium salts, etc. may be mentioned. Preferred is sodium cromoglycate.

  Chromoglic acid and / or salts thereof can also be used in the form of a hydrate, and these can be used alone or in combination of two or more.

  Next, pharmaceutically, pharmacologically or physiologically acceptable salts can be used as salts of the ketotifen. Such salts include organic acid salts [eg, monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polyvalent carboxylates (fumarates, maleates, etc. Acid salts), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate etc.), organic sulfonates (methane sulfonate, toluene sulfonate, tosylate etc) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, etc.) Salts with organic amines such as pyrrolidine, tripyridine, picoline, etc., salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium etc.) Alkaline earth metals (calcium, magnesium etc.) and salts with metals such as aluminum or the like].

  Among the salts of ketotifen, organic acid salts, in particular ketotifen fumarate, are preferred. These salts of ketotifen can be used alone or in combination of two or more. Ketotifen or a salt thereof can be used in the form of a hydrate.

  The content of the component (B) in the nasal composition of the present invention is usually 0.001 to 5 w / v%, preferably 0.01 to 2 w /% of the whole nasal composition from the viewpoint of solubility. It is v%, more preferably 0.05 to 1 w / v%.

<(C) Cellulose-based polymer>
The composition for nasal drops of the present invention contains 0.001 to 0.1 w / v% of a cellulosic polymer (C). Conventionally, a nasal drop containing beclomethasone propionate, which is a hardly soluble component, is blended with a polyhydric alcohol, 0.3 to 3.5 w / v% of crystalline cellulose and carmellose sodium, and a refreshing agent, Good dispersion of beclomethasone propionate was maintained.

  However, in the composition in which cromoglycic acid etc. is blended in addition to beclomethasone propionate as in the present invention, good dispersibility can not be achieved even if the composition as described above is adopted. Cellulose-based polymers such as crystalline cellulose are thickeners, which function as thickeners to enhance the dispersibility of poorly soluble components as described in the [Background Art] section. It is also surprisingly found that the dispersibility can be enhanced by reducing the content of the cellulose-based polymer (C) more than the conventional one, and furthermore, the light stability of the composition can be enhanced. The By being excellent in light stability, the composition for nasal drops of this invention can be filled also in a transparent container, In this case, it is obvious whether the contents re-dispersed when the container is shaken.

  In addition, the composition for nasal drops of this invention may contain a monoterpene (D) so that it may mention later, and when it contains the said component, content of a cellulose type polymer (C) is said point. As long as the range of 0.001 to 0.1 w / v% with respect to the entire nasal composition is satisfied, the composition is not further limited, and the blending ratio with other components may be any ratio.

  On the other hand, in the composition for nasal drops of the present invention, the monoterpene (D) is not necessarily an essential component, and the three components (A) to (C) have good dispersibility even after storage for a long time The composition for nasal drops which can be filled in a container which is excellent in feeling of effect and can confirm redispersion with the naked eye. When the monoterpene (D) is not contained, the blending amount of the cellulose-based polymer (C) is, in addition to the small amount as described above, 1 part by weight of the component (B), cellulose It is necessary that the proportion of the polymer (C) is 0.0001 to 0.05 parts by weight. Needless to say, the monoterpene (D) may further be contained in that case.

  Thus, from the viewpoint of achieving good dispersibility and the like without containing the monoterpene (D), the cellulose-based polymer (C) is a cellulose-based polymer (C) relative to 1 part by weight of the component (B). Is preferably contained in a proportion of 0.0005 to 0.05 parts by weight.

  The cellulose-based polymer (C) not only improves the dispersibility but also functions as a thickener, and can impart viscosity to the composition for nasal drops to prevent dripping after nasal drops. From the viewpoint of such various functions and dispersibility, the content of the cellulose-based polymer (C) in the composition for nasal drops of the present invention is preferably 0.001 to 0.1 w / v%, more preferably Is 0.001 to 0.05 w / v%.

  The cellulose-based polymer (C) is not particularly limited as long as it is generally used in pharmaceuticals, quasi-drugs and cosmetics, but specifically, methylcellulose, ethylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose (HEC), Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and salts thereof (eg, carmellose sodium, carmellose calcium, carmellose ammonium), stearoxyhydroxypropylmethylcellulose, crystalline cellulose and the like can be mentioned. .

  Among these, from the viewpoint of achieving good dispersibility and the like, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and salts thereof, and crystalline cellulose are preferable as the cellulose-based polymer (C).

  Moreover, cellulose type polymer (C) can also be used combining 1 type, or 2 or more types. In that case, it is desirable to adjust the blending ratio appropriately, in consideration of the feeling of use and the like of the nasal drop composition.

<(D) monoterpene>
The nasal composition of the present invention may contain a monoterpene (D).
When beclomethasone propionate (A) and component (B) are used in combination, good dispersibility is achieved in a composition containing a predetermined amount of crystalline cellulose and a refreshing agent as employed in Patent Document 1 It will not be done.

  In the present invention, a composition containing beclomethasone propionate (A) and (B) components by blending a predetermined amount of a cellulose-based polymer (C) in a smaller amount than that conventionally employed as described above Nevertheless, excellent dispersibility is achieved.

  Furthermore, when the composition for nasal drops of this invention does not contain a monoterpene (D), it is necessary for the content ratio of (B) component and a cellulosic polymer (C) to be a predetermined range as mentioned above. However, by containing the monoterpene (D), it is not necessary to satisfy the range of the content ratio, the freedom of the content of the cellulosic polymer (C) is increased, and the dispersibility and the light stability, In particular, the light stability is enhanced.

  Specific examples of monoterpenes (D) used in the present invention include menthol, borneol, camphor, geraniol, cineole, anethole, limonene and eugenol, and these monoterpenes may be used alone or in combination of two or more. You may use in combination. These are considered to contribute to the dispersibility, and also function as a refreshing agent, so that it is possible to give a composition for nasal use excellent in the feeling of use without causing discomfort.

  Among the above mentioned, at least one monoterpene selected from menthol, borneol, geraniol and camphor is preferable, and menthol and camphor are more preferable. These monoterpenes (D) may be any of d-form, l-form and dl-form, and may be used as essential oils containing such monoterpenes (peppermint oil, eucalyptus oil, bergamot oil, rose oil, etc.) The composition can be formulated into a nasal composition.

  The content of the monoterpene (D) in the nasal composition of the present invention is generally 0.0001 to 1 w / v%, preferably 0.001 to 1 w / v%, more preferably 0. It is 01 to 0.5 w / v%.

<PH of nasal composition>
The composition for nasal administration of the present invention can adjust the pH to make it difficult to cause unpleasant irritation when applied to the nasal cavity mucosa, and the pH is usually 4.0 to 9.0, preferably 4.0. It is -7.5, more preferably 4.5-7.0, and particularly preferably 4.5-6.5. As pH adjusters, boric acid, borax, phosphoric acid, acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, succinic acid, tartaric acid, malic acid, gluconolactone, ammonium acetate, hydrochloric acid Sulfuric acid, polyphosphoric acid, potassium carbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogenphosphate, sodium lactate, sodium citrate, potassium hydroxide, sodium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, diisopropanol An amine, triisopropanolamine etc. can be illustrated.

  In addition, a buffer may be used to adjust the pH of the composition for nasal administration of the present invention. Examples of the buffer include known borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, good buffers, etc. Preferably, good buffers, borate buffers, Phosphate buffer, carbonate buffer or citrate buffer, particularly preferably Good buffer, borate buffer, phosphate buffer or citrate buffer. "Good buffer" is a generic term for aminoethane sulfonic acid derivatives and aminopropane sulfonic acid derivatives of zwitterionic structure having buffer capacity, and is a buffer devised by Good et al. Good buffers include MES, MOPS (3-morpholinopropanesulfonic acid), PIPES, HEPES (2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid), BES, TES, etc. .

  Examples of the borate buffer include boric acid, borates such as alkali metal borates, alkaline earth metal borates, and combinations of boric acid and borate.

  Examples of the phosphate buffer include phosphates, phosphates such as phosphate alkali metal salts and alkaline earth metal phosphates, combinations of phosphate and phosphate, and the like.

  Examples of the citrate buffer include citric acid, an alkali metal citrate, a citrate such as an alkaline earth metal citrate, a combination of citric acid and a citrate, and the like.

  Also, as a borate buffer, a phosphate buffer or a citrate buffer, a borate, phosphate or citrate hydrate may be used. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate etc.) And carbonic acid or salts thereof (sodium hydrogen carbonate, sodium carbonate and the like), citric acid or salts thereof (monosodium citrate, trisodium citrate and the like) and the like.

  In the present invention, these pH adjusters and buffers may be used alone or in combination of two or more, to obtain a suitable pH range.

<Other ingredients>
Furthermore, in the composition for nasal administration of the present invention, as long as the effects of the present invention are not impaired, active ingredients, preservatives, nonionic surfactants, perfumes, etc. used for nasal drops if necessary. The species or two or more species can be used in combination.

  The active ingredients include vasoconstrictors such as epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and pseudoephedrine, antihistamines such as iproheptin, diphenhydramine and chlorpheniramine, acrinol, cetyl pyridinium, benzalkonium, benzethonium, chlorhexidine Disinfectants such as glycyrrhetinic acid, glycyrrhizinic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulene sulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice etc, anti-inflammatory agent, zinc flower, zinc lactate , Astringent agents such as zinc sulfate, indomethacin, ibuprofen, ibuprofen piconol, bufexamak, full Enamu butyl, bendazac, piroxicam, ketoprofen, felbinac, lithospermi radix, horse chestnut, and salts thereof, and the like.

  Examples of the preservative include sodium benzoate, parahydroxybenzoate, potassium sorbate, phenoxyethanol, hexanediol, boric acid, borax and the like.

  Examples of the nonionic surfactant include polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (for example, poloxamer 407, poloxamer 235, poloxamer 188, poloxamine etc.); monolaurate POE (20) sorbitan (polysorbate 20) POE sorbitan fatty acid esters such as monooleic acid POE (20) sorbitan (polysorbate 80); POE castor oil such as POE (60) castor oil, POE (60) hydrogenated castor oil or hydrogenated castor oil; POE (9) ) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE · POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonylphenyl ether Etc., and the like.

  Examples of the perfume include casinene, anesol, safrole, eugenol, cinnamaldehyde, estragol, patchouli alcohol, benzyl acetate, linalyl acetate, jasmon, indole, octanol, carvacrol, ethylfuran, farnesol, guaiol, santarol, cedrol, tyuopsen , Globrol, cedrene, epiglobrol, essential oils and the like.

<Light stability of nasal composition>
Since the composition for nasal drops of the present invention contains beclomethasone propionate, which is a hardly soluble component, it is usually used as a suspension preparation by blending a surfactant (for example, the above-mentioned nonionic surfactant).

  Suspension preparations are generally used after shaking the container at the time of use to re-disperse the contents, but since the container is opaque to prevent photodegradation of the contents, it is easy to determine whether the re-dispersion has been sufficiently performed conventionally. It was difficult to confirm.

  In the present invention, in the nasal composition containing beclomethasone propionate (A) and (B), the amount of the cellulose-based polymer (C) is smaller than that conventionally employed, and (B ) By blending a predetermined proportion of the component (B) or blending a small amount of a cellulose polymer (C) and a monoterpene (D), it is possible to maintain good dispersibility and yet have good light stability. Achieved.

  For this reason, the composition for nasal administration of the present invention can also be filled in a transparent container, and if filled in such a container, redispersion was sufficiently performed if the container was shaken at the time of use, or the user It can be easily confirmed.

<Formulation form of nasal composition>
The nasal composition of the present invention can take various formulation forms such as a spray-type preparation, a drop-type preparation, a coating-type preparation and the like. In addition, in the spray type preparation form, a manual pump type nasal drop with a mechanism for manually moving a pump attached to a container to eject a liquid, compressed gas (air, oxygen, nitrogen, carbonic acid, mixed gas And the like, and an aerosol-type nasal drop with a mechanism for automatically spouting a solution by moving a valve attached to the container by filling the container with a propellant.

<Dosage and administration of composition for nasal use>
The nasal composition of the present invention is administered in an appropriate manner according to the formulation form, and for example, the dose to each nasal cavity per dose is
Preferably, the amount of beclomethasone propionate (A) is 1 to 100 μg, more preferably 5 to 50 μg, still more preferably 10 to 25 μg,
Also, the daily dose to each nasal cavity is
The beclomethasone propionate (A) is preferably 10 to 1000 μg, more preferably 50 to 800 μg, and still more preferably 100 to 400 μg.
When ketotifen and / or its salts are used as component (B), the total amount is preferably about 0.01 to 15 mg,
When chromoglic acid and / or a salt thereof is used as component (B), it is preferably administered in an amount of 0.01 to 15 mg in total.

<Method of producing composition for nasal use>
The method for producing the nasal composition of the present invention is not particularly limited, and the composition can be produced by a known method. For example, the essential components (A) to (C) in the present invention described above and, if necessary, the component (D) and other components, etc., in water or warm water by an ordinary method, if necessary, in an oil base After dissolving / suspending, pH and osmotic pressure etc. may be appropriately adjusted to prepare a liquid preparation, sterile filtration may be carried out if necessary, and it may be filled into a nasal drop container.

  EXAMPLES The present invention will be described in more detail by the following examples, but the present invention is not limited thereto.

[Reference Example (Test preparation 1 to 3)]
Test formulations 1 to 3 were prepared by known methods according to the compositions in Table 1 below, and evaluated for their dispersibility. Specifically, the evaluation was performed by confirming the dispersibility of each test preparation before and after light irradiation as described below. In the following table, the unit of numerical value is "w / v%" unless otherwise stated.

7 mL of each test preparation was filled in a glass screw cap test tube, and allowed to stand for about 1 day at room temperature under light-shielded conditions. The turbidity at the start of the test was measured for this sample. Specifically, the sample container is shaken immediately before measurement, and the turbidity of the preparation in the vicinity of the center in the vertical direction of the container is measured to obtain “turbidity after preparation of the preparation” to further confirm the dispersibility. After the sample for which "the turbidity after preparation of the preparation" was measured was allowed to stand for 3 hours, the turbidity of the preparation located near the center in the vertical direction of the sample container was measured again to obtain "the turbidity after dispersion". Based on these measured values, the dispersibility at the start of the test was calculated by the following equation.
Dispersion at the start of the test (%) = (turbidity after dispersion) / (turbidity after preparation of the preparation) x 100

Next, the influence of light irradiation on the dispersibility was confirmed using a sample evaluated for “dispersion at the start of the test”. Specifically, each test preparation was irradiated with light at an irradiance of 765 W / m ² for 3 hours using a Sun Tester (SUNTEST XLS +; Toyo Seiki Seisakusho Co., Ltd.) that is a light irradiation device (total irradiation energy is 10000 kJ / M ² ). For this light-irradiated sample, the turbidity of the preparation in the vicinity of the center in the vertical direction of the sample container shaken immediately before the measurement was measured to obtain “turbidity after light irradiation”, and this “turbidity after light irradiation” The sample for which "was measured" was allowed to stand for 3 hours, and the turbidity of the preparation near the center in the vertical direction of the sample container was measured again to obtain "turbidity after dispersion after light irradiation". Based on these measured values, the dispersibility after light irradiation was calculated by the following equation.
Dispersion after light irradiation (%) = (turbidity after light irradiation dispersed) / (turbidity after light irradiation) x 100

  The above results are shown in Table 1 below. In the following table, "remaining amount" is an amount necessary to make the amount of the whole preparation 100 w / v%.

[Examples 1 to 4, Comparative Examples 1 to 4]
The test preparations of Examples 1 to 4 and Comparative Examples 1 to 4 are prepared by known methods according to the compositions in Table 2 below, and the dispersibility at the start of each test and the dispersibility after light irradiation are the same as in the above reference example. It was evaluated. The results are shown in Table 2 below.

  As shown in Table 2, preparations containing beclomethasone propionate and sodium cromoglycate have poor dispersibility (Comparative Examples 1 and 2). Even if carmellose sodium, which is conventionally used to improve dispersibility, and hydroxypropyl methylcellulose (HPMC), which is a cellulose-based polymer, are added to this, the dispersibility can not be improved (Comparative Example 3 and Comparative Example 3). 4). Also, in some comparative examples, the dispersibility is further deteriorated by light irradiation from the beginning of the test, but this is because the suspension (beclomethasone propionate) is aggregated or the viscosity change occurs by light irradiation. it is conceivable that.

  On the other hand, a cellulose-based polymer (HPMC or carmellose sodium) is blended in a smaller amount than the amount conventionally blended, and the blending amount of the cellulose-based polymer to 1 part by weight of sodium cromoglycate is within the range specified in the present invention By doing this, the dispersibility becomes good (Examples 1 and 3). Moreover, the dispersibility, in particular the dispersibility after light irradiation, is also improved by blending l-menthol which is a monoterpene in addition to the cellulose-based polymer (Examples 2 and 4).

[Example 5, Comparative Examples 5 to 8]
The test preparations of Example 5 and Comparative Examples 5 to 8 are prepared by known methods according to the compositions in Table 3 below, and the dispersibility at the start of each test and the dispersibility after light irradiation are the same as in the above reference example. evaluated. The results are shown in Table 3 below.

  As shown in Comparative Example 8, sodium cromoglycate (component (B) component) and crystals even when both beclomethasone propionate and sodium cromoglycate are blended and crystalline cellulose is further blended in a small amount specified in the present invention If the blending ratio of cellulose (component (C)) is not within the range defined in the present invention (in Comparative Example 8, 0.1 parts by weight of component (C) is contained with respect to 1 part by weight of component (B)) ), The dispersity is poor.

  On the other hand, as shown in Example 5, when L-menthol is further blended even in such a blend, the dispersibility becomes good regardless of the blend ratio of the (B) component and the (C) component.

[Examples 6 and 7, Comparative Example 9]
The test preparations of Examples 6 and 7 and Comparative Example 9 were prepared by known methods according to the compositions in Table 4 below, and the dispersibility at the start of each test was evaluated in the same manner as in the above reference example. The results are shown in Table 4 below.

  As shown in Comparative Example 9, even when all the components (A) to (D) defined in the present invention are contained, good dispersibility is achieved when the content of crystalline cellulose exceeds the range of the present invention. You can not do it.

[Formulation Example 1]
Purified water was added in a total amount of 100 ml to a weighed amount of each component described below and mixed to prepare a suspension (pH 5.5) to obtain a nasal composition of the present invention.
Beclomethasone propionate 25 mg (0.025 w / v%)
Sodium cromoglycate 1000 mg (1.0 w / v%)
Hydroxypropyl methylcellulose 1 mg (0.001 w / v%)
l-menthol 20 mg (0.02 w / v%)
Polysorbate 80 100 mg (0.1 w / v%)
Propylene glycol 20000 mg (20.0 w / v%)
Citric acid dosage sodium citrate dosage

[Formulation Example 2]
A total of 100 ml of purified water was added to a weighed amount of each component described below and mixed to prepare a suspension (pH 5.8) to obtain a nasal composition of the present invention.
Beclomethasone propionate 50 mg (0.05 w / v%)
Ketotifen fumarate 75.6 mg (0.0756 w / v%)
Naphazoline hydrochloride 25 mg (0.025 w / v%)
Hydroxypropyl methylcellulose 1 mg (0.001 w / v%)
l-menthol 10 mg (0.01 w / v%)
Polysorbate 80 100 mg (0.1 w / v%)
Propylene glycol 5000 mg (5.0 w / v%)
Citric acid dosage sodium citrate dosage

Claims (6)

In the nasal composition,
(A) beclomethasone propionate,
(B) at least one member selected from the group consisting of ketotifen and salts thereof,
A method of enhancing the dispersibility of the suspension composition as a suspension preparation after light irradiation, which comprises blending a non-ionic surfactant . Furthermore, (C) 0.001 to 0.1 w / v% of a cellulose-based polymer is blended,
The method of improving the dispersibility after light irradiation of the composition for nasal drops of Claim 1 which may mix | blend (D) monoterpene. (However, when the monoterpene (D) is not blended, 0.0001 to 0.05 parts by weight of the cellulose-based polymer (C) is blended with 1 part by weight of the component (B). ) The cellulose polymer (C) is at least one member selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC) and salts thereof, and crystalline cellulose. A method for enhancing the dispersibility of the nasal composition according to claim 2 after light irradiation according to claim 2 . The intranasal composition according to claim 2 or 3 , wherein the monoterpene (D) is blended in the intranasal composition, and the monoterpene (D) is menthol and / or camphor. To increase the dispersion after light irradiation . Said nasal composition, characterized by mixing a slow衝剤Furthermore, a method to improve the dispersibility of after irradiation of the nasal composition point of any of claims 1-4. The method according to any one of claims 1 to 5 , wherein the pH of the composition for nasal drops is 4.0 to 9.0, and the method for enhancing the dispersibility of the composition for nasal drops according to any one of claims 1 to 5 after light irradiation. .