阅读说明：本技术 粒状组合物及其制造方法 (Granular composition and process for producing the same ) 是由 增田清 榊原贤司 于 2019-08-08 设计创作，主要内容包括：本发明提供一种苦味受到抑制而易于服用的含有奥洛他定或其药学上允许的盐的粒状组合物、含有该粒状组合物的固体药物制剂、均质且高效地制造该粒状组合物的方法。(The present invention provides a granular composition containing olopatadine or a pharmaceutically acceptable salt thereof, which has suppressed bitterness and is easy to take, a solid pharmaceutical preparation containing the granular composition, and a method for homogeneously and efficiently producing the granular composition.)

1. A granular composition comprising olopatadine or a pharmaceutically acceptable salt thereof.

2. Granular composition according to claim 1, containing thaumatin and/or acesulfame potassium.

3. A granulated composition according to claim 1 or 2, which comprises white sugar and/or trehalose hydrate.

4. The granular composition according to any one of claims 1 to 3, wherein the binder contains dextrin and/or hydroxypropyl cellulose.

5. A granulated composition according to any of claims 1 to 4, wherein DL-malic acid is contained as a flavoring agent.

6. The granular composition according to any one of claims 1 to 5, which comprises sodium edetate hydrate and/or dibutylhydroxytoluene as a stabilizer.

7. A solid pharmaceutical preparation comprising the granular composition according to any one of claims 1 to 6.

8. The formulation of claim 7, wherein the solid pharmaceutical formulation is a granule, powder or dry syrup.

9. A process for producing a granular composition, characterized by comprising (d) a step of sieving with a sieve A and a sieve B, a step of mixing olopatadine or a pharmaceutically acceptable salt thereof with an additive and subjecting the resulting granules to wet granulation, (B) drying and (c) pulverization and size stabilization, a step of subjecting the residual granules A, which are retained on the sieve A having a large mesh size, and passing granules B, which have passed through the sieve B having a small mesh size, to the steps (c) and (d), respectively, and a step of subjecting the passing granules B to the steps (a) to (d), respectively.

10. A method for producing a granular composition containing 85 wt% or more of a granular composition having a particle size lower limit of 125 to 160 [ mu ] m and a particle size upper limit of 710 to 1000 [ mu ] m, based on 100 wt% of the total amount,

specifically disclosed is a method for producing granules, which comprises (a) mixing olopatadine or a pharmaceutically acceptable salt thereof with an additive, and subjecting the mixture to wet granulation, (B) drying, and (c) pulverization and size stabilization, wherein the method comprises (d) a step of sieving the mixture with a sieve A having a mesh size of 16-22 mesh and a sieve B having a mesh size of 93-119 mesh, and further comprises (c) and (d) steps for residual granules A remaining in the sieve A and passing granules B passing through the sieve B, and further comprises (a) to (d) steps for passing granules B.

11. The production method according to claim 9 or 10, further comprising a step of (a') wet-mass straightening, between the steps (a) and (b).

12. The production method according to claim 11, wherein the wet cake (a') is granulated into crushed granules.

13. The production method according to any one of claims 9 to 12, wherein the (c) pulverized pellets are oscillator-type pellets.

14. The production method according to any one of claims 9 to 13, wherein in the step (c), the second time after the first time and thereafter, the pulverization and the straightening are performed using a mesh having a small mesh size.

15. The production method according to claim 14, wherein, in the step (c), the primary use of a screen having a mesh size selected from any one of 12 to 18 mesh screens and the secondary and subsequent use of a screen having a mesh size selected from any one of 18 to 30 mesh screens and smaller than the primary screen are subjected to the pulverization and size adjustment.

16. The production method according to any one of claims 9 to 15, wherein the binder contained as the additive is hydroxypropylcellulose and/or dextrin.

17. A method for producing a solid pharmaceutical preparation, wherein the solid pharmaceutical preparation is produced using the granular composition produced by the production method according to any one of claims 9 to 16.

18. The method of manufacturing according to claim 17, wherein the solid pharmaceutical formulation is a granule, a powder, or a dry syrup.

19. The production method according to claim 17 or 18, wherein the solid pharmaceutical preparation is a packaged product.

20. The manufacturing method according to claim 19, wherein the packaging material of the subpackage is polyethylene composite cellophane, aluminum laminated film or aluminum vapor-deposited film.

21. Use of a granular composition produced by the production method according to any one of claims 9 to 16 for producing the solid pharmaceutical preparation.

22. The use according to claim 21, wherein the solid pharmaceutical formulation is a granule, powder or dry syrup.

Technical Field

The present invention relates to a granular composition containing olopatadine or a pharmaceutically acceptable salt thereof as an active ingredient, a method for producing the granular composition, a method for producing a preparation using the granular composition, and the like.

Background

In recent years, for the purpose of improving convenience for patients, development of new preparations has been carried out for various conventional drugs. Providing a formulation that meets the needs of the patient not only helps to increase the patient's satisfaction with the treatment, but also helps to reduce the burden on the person assisting the patient in taking the medication.

Solid pharmaceutical preparations include, in addition to tablets, capsules, granules, powders, dry syrups and the like, and are generally taken by oral administration. Oral administration is the simplest and highly versatile method of administration. However, a preparation to be taken with water or warm water is likely to have a taste of a drug or the like as an active ingredient in the oral cavity, and may be painful to take if the preparation has an unpleasant taste or a bitter taste. In particular, when children take preparations with strong bitterness, the children do not want to take the preparations, and parents who take the preparations in an auxiliary manner may feel troublesome. In order to reduce such problems, preparations having improved medication compliance by masking unpleasant taste and bitter taste have been generally made.

Among solid pharmaceutical preparations, dry syrup is a preparation designed mainly for young children and added with a sweetener and a flavor for easy administration. Generally, it is dissolved in water for oral administration, and the dosage form contains a larger amount of taste-improving agents such as sweeteners than granules. When the active ingredients and additives have unpleasant taste and bitter taste, the taste is masked and the sweetness is enhanced.

In fact, for example, in the case of bitter taste, even if the bitter taste is masked too much, it is difficult to completely eliminate the bitter taste. Nevertheless, it is determined that the compliance of taking medicine and the burden on the assistant of taking medicine vary depending on the degree of bitterness remaining after masking. Therefore, it is of great interest to the social demand to suppress bitterness as much as possible and to develop and provide an easily taken preparation.

In addition, the pharmaceutical preparation has a small volume for the person taking the preparation, and the burden is small. In particular, in the case of a dry syrup for infants, etc., when the dose is reduced as much as possible, compliance of the infant himself/herself who is not willing to take the medicine is generally improved, and the burden on the person assisting the medicine taking is also reduced, which is preferable.

Olopatadine has an antiallergic action and an anti-inflammatory action, and therefore, a preparation containing a hydrochloride thereof has been developed and widely used as a therapeutic agent for allergic rhinitis, urticaria, pruritus (eczema, dermatitis, prurigo, etc.) associated with skin diseases, and the like. As dosage forms of the conventional preparations, there are orally disintegrating tablets (OD tablets) and granules, in addition to tablets which were first approved. As for the granules, it is considered that children aged 2 years or more and less than 7 years old can be taken, but dry syrups more suitable for children to take than the granules are not yet commercially available, and they are expected to be on the market.

On the other hand, olopatadine is a drug having a special bitter taste, and therefore, in the case of powder, granules, dry syrup, OD tablets, and the like, it may be rapidly dissolved in the oral cavity to cause a bitter taste, and thus it is difficult to take the drug. Therefore, in designing these preparations, it is one of the important subjects to investigate masking of bitterness. As a method for masking bitterness, there is a method based on blending additives such as a sweetener, a taste corrigent, and a flavor corrigent, but there are cases where the additives used are poor in moldability and brittleness, and depending on the amount added, problems may occur in granulation and size control in the production process. Further, olopatadine itself has a problem of poor granulation properties. Therefore, a granular composition such as granules obtained by granulating the granulated substance generates a large amount of fine powder, and includes substances out of a predetermined particle size range. Various problems occur in granular compositions containing a large amount of fine powders, granules prepared by formulating the same, and the like. For example, this preparation may segregate due to differences in the density and particle size of the components, resulting in a preparation with an uneven content of the main drug. Further, since the fine powder is likely to generate static electricity, the flowability of the preparation is poor, and the workability is poor when the preparation is packaged into a bottle container or the like. Further, the preparation may have poor administration properties because fine powder remains in the oral cavity when the preparation is administered. In this regard, as a countermeasure for formulation design, it is conceivable to blend a large amount of binder. However, since a binder is excessively added to generate hard granules, the granulation time increases, the productivity is deteriorated, and the amount of fine powder and coarse particles generated further increases, it is necessary to sufficiently study the type and the amount of the binder. In addition, not only the formulation design but also the design for suppressing generation of fine powder and coarse particles is required in the production process.

Patent document 1 discloses a method for improving granulation properties by adding glycyrrhizic acid and/or a salt thereof to olopatadine hydrochloride to suppress fine powder. However, in detail, no document has been found which discloses a method for suppressing generation of fine particles or coarse particles by devising a production process thereof, as in the method for producing a granular composition containing olopatadine or a pharmaceutically acceptable salt thereof in the present invention described below.

Documents of the prior art

Patent document

Patent document 1: japanese patent laid-open publication No. 2016-222657

Disclosure of Invention

Problems to be solved by the invention

The present invention addresses the problem of providing a granular composition containing olopatadine or a pharmaceutically acceptable salt thereof, wherein bitterness is suppressed by formulation design without special handling, and a solid pharmaceutical preparation containing the granular composition. Another object of the present invention is to provide a method for producing a granular composition having a predetermined particle size distribution and high uniformity by suppressing generation of fine particles and coarse particles during granulation or the like in the production of the granular composition to improve the yield and reducing the ratio of the fine particles to the coarse particles in the granular composition.

Means for solving the problems

As a result of intensive studies to solve the above problems, the present inventors have completed the following invention by incorporating olopatadine or a pharmaceutically acceptable salt thereof in combination with an appropriate additive: a granular composition which is suppressed in bitterness, is easily dissolved in water, and forms a highly transparent solution when dissolved, and a method for efficiently and uniformly producing the granular composition. Furthermore, the present inventors have succeeded in achieving a concentration of the active ingredient of a preparation containing the granular composition of the present invention which is 2 times that of a conventional preparation (granule).

In the production of the granular composition of the present invention, the granular composition was trial-produced through a usual production process, that is, a process of mixing the active ingredient and the additive → wet granulation → drying → pulverization and size stabilization → classification in this order, and as a result, it was confirmed that: despite the classification, the resulting granular composition still contains a large amount of micropowder. Further, the following problems were confirmed: depending on the production conditions including the type and amount of additives, not only fine particles outside the predetermined particle size range but also a large amount of coarse particles are generated, and the yield may be deteriorated.

Accordingly, the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that: in the classification of the whole grain product obtained in the step of wet granulation → drying → fine grinding, the step of (1) performing the step of pulverizing the whole grain → classifying again with respect to the remaining grains sieved with the sieve having a large mesh size, and the step of (2) performing the step of wet granulation → drying → fine grinding, and classifying again with respect to the passing grains sieved with the sieve having a small mesh size can suppress the generation of the fine powder and the coarse particles, and can obtain a granulated composition having a grain diameter in a predetermined range with a reduced ratio of these particles. Further, it was found that in the above step, generation of fine powder and coarse particles was further suppressed by the step of granulating the wet granulated substance obtained by wet granulation, particularly, crushing and granulating the wet granulated substance. Further, it has been found that: by wet granulation with a predetermined amount of granulation liquid containing a part of the hydroxypropyl cellulose out of the total amount of hydroxypropyl cellulose as a binder, generation of fine powder and coarse particles is further suppressed, and the yield is improved. The present inventors have further studied based on the above findings, and have completed the present invention.

That is, the present invention includes, for example, the following embodiments. However, the present invention is not limited to these examples, and the present invention also includes embodiments that achieve the same object by substantially the same means.

(1) A granular composition comprising olopatadine or a pharmaceutically acceptable salt thereof.

(2) The granular composition according to the above (1), wherein the olopatadine or a pharmaceutically acceptable salt thereof is contained in an amount of 0.01 to 2 wt% based on 100 wt% of the granular composition.

(3) The granular composition according to the above (1) or (2), which contains thaumatin and/or acesulfame potassium.

(4) The granular composition according to the above (3), wherein the thaumatin is contained in an amount of 0.0005 to 0.02% by weight based on 100% by weight of the granular composition.

(5) The granular composition according to the above (3) or (4), wherein the acesulfame potassium is contained in an amount of 0.5 to 20% by weight based on 100% by weight of the granular composition.

(6) The granular composition according to any one of the above (1) to (5), which comprises white sugar and/or a trehalose hydrate.

(7) The granular composition according to the above (6), wherein the white sugar is contained in an amount of 30 to 90% by weight based on 100% by weight of the granular composition.

(8) The granular composition according to the above (6) or (7), wherein the trehalose hydrate is contained in an amount of 5 to 60% by weight based on 100% by weight of the granular composition.

(9) The granular composition according to any one of the above (1) to (8), wherein the binder contains dextrin and/or hydroxypropyl cellulose.

(10) The granular composition according to the above (9), wherein the dextrin is contained in an amount of 0.5 to 20% by weight based on 100% by weight of the granular composition.

(11) The granular composition according to the above (9) or (10), wherein the hydroxypropyl cellulose is contained in an amount of 0.5 to 15% by weight based on 100% by weight of the granular composition.

(12) The granular composition according to any one of the above (1) to (11), wherein the DL-malic acid is contained as a taste-masking agent.

(13) The granular composition according to the above (12), wherein the DL-malic acid is contained in an amount of 0.01 to 5% by weight based on 100% by weight of the granular composition.

(14) The granular composition according to any one of the above (1) to (13), which comprises sodium edetate hydrate and/or dibutylhydroxytoluene as a stabilizer.

(15) The granular composition according to the above (14), wherein the sodium edetate hydrate is contained in an amount of 0.05 to 1% by weight based on 100% by weight of the granular composition.

(16) The granular composition according to the above (14) or (15), wherein the dibutylhydroxytoluene is contained in an amount of 0.05 to 1 wt% based on 100 wt% of the granular composition.

(17) A solid pharmaceutical preparation comprising the granular composition according to any one of (1) to (16) above.

(18) The solid pharmaceutical preparation according to the item (17), wherein the olopatadine or a pharmaceutically acceptable salt thereof is contained in an amount of 0.01 to 2 wt% based on 100 wt% of the preparation.

(19) The solid pharmaceutical preparation according to the above (17) or (18), wherein thaumatin is contained in an amount of 0.0005 to 0.02% by weight based on 100% by weight of the preparation.

(20) The solid pharmaceutical preparation according to any one of the above (17) to (19), wherein the acesulfame potassium is contained in an amount of 0.5 to 20% by weight based on 100% by weight of the preparation.

(21) The solid pharmaceutical preparation according to any one of (17) to (20) above, wherein the white sugar is contained in an amount of 30 to 90% by weight based on 100% by weight of the preparation.

(22) The solid pharmaceutical preparation according to any one of (17) to (21), wherein the trehalose hydrate is contained in an amount of 5 to 60% by weight based on 100% by weight of the preparation.

(23) The solid pharmaceutical preparation according to any one of (17) to (22) above, wherein the dextrin is contained in an amount of 0.5 to 20% by weight based on 100% by weight of the preparation.

(24) The solid pharmaceutical preparation according to any one of the above (17) to (23), wherein the hydroxypropyl cellulose is contained in an amount of 0.5 to 15% by weight based on 100% by weight of the preparation.

(25) The solid pharmaceutical preparation according to any one of the above (17) to (24), wherein the DL-malic acid is contained in an amount of 0.01 to 5% by weight based on 100% by weight of the preparation.

(26) The solid pharmaceutical preparation according to any one of (17) to (25) above, wherein the sodium edetate hydrate is contained in an amount of 0.05 to 1% by weight based on 100% by weight of the preparation.

(27) The solid pharmaceutical preparation according to any one of the above (17) to (26), wherein the dibutyl hydroxytoluene is contained in an amount of 0.05 to 1 wt% based on 100 wt% of the preparation.

(28) The solid pharmaceutical preparation according to any one of the above (17) to (27), wherein the fluidizing agent is light anhydrous silicic acid.

(29) The solid pharmaceutical preparation according to the item (28), wherein the light anhydrous silicic acid is contained in an amount of 0.01 to 5 wt% based on 100 wt% of the preparation.

(30) The solid pharmaceutical preparation according to any one of the above (17) to (29), wherein the solid pharmaceutical preparation is a granule, a powder or a dry syrup.

(31) A process for producing a granular composition, characterized by comprising (d) a step of sieving with a sieve A and a sieve B, a step of mixing olopatadine or a pharmaceutically acceptable salt thereof and an additive, and subjecting the resulting granules to wet granulation, (B) drying, and (c) a step of pulverizing and granulating, a step of subjecting the residual granules A, which are retained on the sieve A having a large mesh size, and the passing granules B, which have passed through the sieve B having a small mesh size, to the steps (c) and (d), respectively, and a step of subjecting the passing granules B to the steps (a) to (d), respectively.

(32) A process for producing a granular composition comprising 85% by weight or more of a granular composition having a particle size lower limit of 125 to 160 μm and a particle size upper limit of 710 to 1000 μm based on 100% by weight of the total amount, the method is characterized in that a granulated substance obtained by mixing olopatadine or a pharmaceutically acceptable salt thereof and an additive and subjecting the mixture to the steps of (a) wet granulation, (B) drying and (c) crushing and granulating is subjected to (d) a step of sieving the mixture by using a sieve A with a mesh size of 16-22 meshes and a sieve B with a mesh size of 93-119 meshes, the steps of (c) and (d) are performed again on residual granules A remaining on the sieve A and passing granules B passing through the sieve B, respectively, and the steps of (a) to (d) are performed again on the passing granules B.

(33) A method for producing a granular composition containing 85% by weight or more of a granular composition having a lower limit particle size of 150 μm and an upper limit particle size of 850 μm, based on 100% by weight of the total, characterized by comprising (d) a step of sieving with a sieve A having an 18-mesh and a sieve B having a 100-mesh, a step of subjecting the residual granules A remaining in the sieve A and the passing granules B having passed through the sieve B to the above-described (c) and (d), respectively, and a step of subjecting the passing granules B to the above-described (a) to (d), with respect to a granulated product obtained by mixing olopatadine or a pharmaceutically acceptable salt thereof and an additive and subjecting the mixture to the respective steps of (a) wet granulation, (B) drying and (c) grinding.

(34) The production method according to any one of the above (31) to (33), further comprising a step of (a') shaping wet mass between the steps (a) and (b).

(35) The production method according to the above (34), wherein the wet mass sizing of the (a') is crushing sizing.

(36) The production method according to any one of the above (31) to (35), wherein the (c) grinding and sizing are oscillator-type sizing.

(37) The production method according to any one of the above (31) to (36), wherein in the step (c), the second and subsequent times after the first time are subjected to pulverization and size adjustment using a mesh having a small mesh size.

(38) The production method according to the above (37), wherein, in the step (c), the mesh having a mesh size selected from any one of 12 to 18 mesh is used for the first time, and the second time and thereafter, the grinding and sizing are performed using the mesh having a mesh size selected from any one of 18 to 30 mesh and smaller than the first time.

(39) The production method according to the above (38), wherein, in the above (c), the 16-mesh screen is used for the first time, and the 22-mesh screen is used for the second time and thereafter to perform the pulverization and size adjustment.

(40) The production method according to any one of the above (31) to (39), wherein the binder contained as an additive is hydroxypropylcellulose and/or dextrin.

(41) The production method according to the above (40), wherein the hydroxypropyl cellulose has a viscosity of 2 to 10 mPas in a 2% aqueous solution at 20 ℃.

(42) The production method according to any one of the above (31) to (41), wherein in the step (a), a granulation liquid containing hydroxypropyl cellulose is used.

(43) The production method according to the above (42), wherein the concentration of the hydroxypropyl cellulose in the granulating liquid is 7 to 11% by weight.

(44) The production method according to the item (42) or (43), wherein the granulated liquid is obtained by adding hydroxypropyl cellulose to water in a concentration of 7 to 11 wt% in an amount of 3.5 to 5.5 wt% based on 100 wt% of the total feed amount.

(45) The production method according to any one of the above (40) - (44), wherein the hydroxypropyl cellulose is added in an amount of 0.5-5 wt% based on 100 wt% of the total amount charged.

(46) The production method according to any one of the above (40) - (45), wherein the dextrin is added in an amount of 0.5-5 wt% based on 100 wt% of the total charged amount.

(47) A method for producing a solid pharmaceutical preparation, wherein the solid pharmaceutical preparation is produced using the granular composition produced by the production method according to any one of the above (31) to (46).

(48) The production method according to the above (47), wherein the solid pharmaceutical preparation is a granule, a powder or a dry syrup.

(49) The production method according to the above (47) or (48), wherein the solid pharmaceutical preparation is a packaged product.

(50) The production method according to the above (49), wherein the packaging material of the subpackage product is polyethylene composite cellophane (drawn paper of cellophane and polyethylene), cellophane, aluminum laminated film or aluminum evaporated film.

(51) Use of the granular composition produced by the production method according to any one of (31) to (50) above for producing a solid pharmaceutical preparation.

(52) The use of (51) above, wherein the solid pharmaceutical preparation is in the form of granules, powder or dry syrup.

ADVANTAGEOUS EFFECTS OF INVENTION

A solid pharmaceutical preparation (hereinafter, sometimes referred to as "the present preparation") containing the granular composition containing olopatadine or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "the present granular composition") according to the present invention is a preparation developed for the purpose of improving the medication compliance of infants and reducing the burden on the medication assistor, and is highly useful as a preparation which is reduced in bitterness and is easy to take. In addition, the preparation can be prepared by reducing the dose of the effective component to 2 times of the existing product. Furthermore, the preparation is easily soluble in water, and forms a colorless and highly transparent solution when dissolved, and therefore, has a feature of being easy to take in appearance.

Further, according to the production method of the present invention (hereinafter, sometimes referred to as "the present production method"), the present granular composition in which the ratio of fine particles to coarse particles is reduced can be produced in a good yield while suppressing the generation of fine particles and coarse particles in the production process. The granular composition and the preparations such as granules produced by using the granular composition are less likely to segregate, and therefore, the dispersion of the content of the active ingredient is small, and dust is less likely to be generated during use or dispensing, and the granular composition is extremely useful.

Drawings

FIG. 1 is a photograph showing a state in which 2.5mg of olopatadine hydrochloride was dissolved in 30mL of purified water. A. B and D are obtained by dissolving 0.5g of the particles of commercially available olopatadine hydrochloride granules (hereinafter referred to as "conventional preparations") in 30mL of purified water, and C is obtained by dissolving 0.25g of the present preparation in 30mL of purified water.

Fig. 2 shows an example of the manufacturing flow of the present manufacturing method.

Detailed Description

The present invention relates to a granular composition containing olopatadine or a pharmaceutically acceptable salt thereof as an active ingredient, particularly a granular composition containing thaumatin and/or acesulfame potassium, and a solid pharmaceutical preparation containing the granular composition and having suppressed bitterness and being easy to take. Furthermore, the present invention relates to an efficient manufacturing method of the granular composition. More specifically, the present invention relates to a method for producing a granular composition, which comprises (d) a step of sieving with a sieve a and a sieve B, a step of mixing olopatadine or a pharmaceutically acceptable salt thereof and an additive, and subjecting the resulting granules to each of (a) wet granulation, (B) drying, and (c) pulverization and size regulation, a step of subjecting the residual granules a remaining on the sieve a having a large mesh size and the passing granules B having passed through the sieve B having a small mesh size to the above-described steps (c) and (d), respectively, and a step of subjecting the passing granules B to the above-described steps (a) to (d).

The granular composition contains olopatadine or a pharmaceutically acceptable salt thereof as an active ingredient. Olopatadine also exhibits an action of inhibiting the liberation of chemical conductive substances such as histamine, thromboxane, leukotriene, Platelet Activating Factor (PAF) and the like, on the basis of the antihistamine action as a main action; inhibiting secretion of cytokine such as interleukin-6 (IL-6) and interleukin-8 (IL-8); has various and excellent allergic effects such as an effect of inhibiting the expression of cell adhesion molecules in vascular endothelial cells and an effect of inhibiting eosinophil moistening, and is a drug which can be used in a wide range of ages from young children to the elderly. Olopatadine as long as it is pharmaceutically acceptable acid addition salt, can be used without any particular limitation, for example, hydrochloride, sulfate, nitrate, phosphate, hydrogen fluoride, hydrogen bromide and other inorganic acid salts; organic acid salts such as acetic acid, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate. Particularly preferred is olopatadine hydrochloride which is commercially available as an antiallergic agent and widely used in clinical applications. In addition, stereoisomers, hydrates, and solvates of olopatadine are also included in olopatadine that can be an active ingredient of the present granular composition.

In the present invention, the amount of olopatadine or a pharmaceutically acceptable salt thereof to be blended is not particularly limited and can be appropriately selected. For example, in the case of olopatadine hydrochloride, the amount may be 0.01 to 2% by weight, preferably 0.3 to 1.8% by weight, and more preferably 0.5 to 1.5% by weight, based on 100% by weight of the present granular composition or the present preparation.

A preferable example of the granular composition is obtained by adding thaumatin and/or acesulfame potassium to olopatadine or a pharmaceutically acceptable salt thereof as an active ingredient. The granular composition may further contain an excipient such as white sugar or trehalose, and an additive such as a flavoring agent such as DL-malic acid. Thus, the preparation containing the granular composition (the preparation) has preferable characteristics in terms of administration, such as suppression of bitterness and easiness of administration, easy dissolution in water, and formation of a colorless and highly transparent solution upon dissolution. Hereinafter, the additives to be added to the present granular composition will be described in detail.

Among the substances that can be used as additives for the granular composition, examples of the additives called sweeteners include refined white sugar, saccharin sodium hydrate, D-mannitol, dextrin, erythritol, sucralose, xylitol, powdered reduced maltose syrup, thaumatin, acesulfame potassium, and the like, and combinations thereof. Among them, a combination of thaumatin and acesulfame potassium is preferable. Thaumatin, also known as thaumatin, is a sweet substance of protein line derived from seeds of kiwi (Thaumatococcus danielli Benth) which is a perennial plant, grown in the west africa belonging to the Marantaceae family (arrowaceae). The sweetness is 3000-8000 times that of granulated sugar, and the sweetness expression is slower and the sweetness is lasting compared with the granulated sugar. Acesulfame potassium is one of artificial sweeteners, which is said to have about 200 times the sweetness of sucrose, and is more often used in combination than when used alone. In addition, it is known to exhibit sweetness more rapidly than other sweeteners.

In the present invention, the amount of thaumatin to be blended is not particularly limited, and may be 0.0005 to 0.02 wt%, preferably 0.001 to 0.01 wt%, particularly preferably 0.002 to 0.008 wt%, and most preferably 0.0035 to 0.0044 wt% with respect to 100 wt% of the present granular composition or the present preparation. On the other hand, the amount of acesulfame potassium is not particularly limited, and may be 0.5 to 20% by weight, preferably 1 to 15% by weight, particularly preferably 2 to 8% by weight, and most preferably 4.5 to 5.4% by weight, based on 100% by weight of the present granular composition or the present preparation.

As the excipient which can be used as an additive of the present granular composition, corn starch, lactose hydrate, cellulose, dextrin, calcium silicate, silica (anhydrous silicic acid), microsilica, white sugar, trehalose hydrate, and the like, and combinations thereof can be used, and preferred examples thereof include a combination of white sugar and trehalose. White sugar is used as an additive for various foods, medicines, and the like, and commercially available products can be easily obtained, and those contained in the japanese pharmacopoeia (seventeenth revision) can be used. Trehalose is a disaccharide having 2 molecules of glucose bonded thereto. It is naturally widely distributed, and is contained in a large amount in mushrooms, and also in beans, seaweeds, and the like. Trehalose hydrate is also readily available as a commercial product, and those described in the japanese pharmacopoeia (seventeenth revision) can be used.

In the present invention, when white sugar is used as the excipient, it is not particularly limited, and it is preferably contained in an amount of 30 to 90% by weight, preferably 40 to 80% by weight, more preferably 40 to 75% by weight, based on 100% by weight of the granular composition or the preparation. When trehalose hydrate is used as the excipient, it is preferably contained in an amount of 5 to 60% by weight, preferably 10 to 45% by weight, more preferably 20 to 30% by weight, based on 100% by weight of the granular composition or the preparation.

Examples of the binder that can be used as an additive of the granular composition include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose, and carboxymethylcellulose; polyvinyl alcohol, polyvinyl pyrrolidone (povidone), a vinyl pyrrolidone copolymer (copovidone), an acrylic polymer, gelatin, gum arabic, prussian polysaccharide, agar, tragacanth, sodium alginate, propylene glycol alginate, partially pregelatinized starch, dextrin, sodium dioctylsulfosuccinate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, polyethylene glycol 6000, and the like, and combinations thereof. Preferred examples thereof include hydroxypropyl cellulose and/or dextrin. By compounding the binder, the present granular composition is more suitable because it forms particles having an appropriate particle size. However, since excessive mixing of the binder generates hard particles, which leads to an increase in the time for straightening the particles and an increase in the amount of fine powder generated, an appropriate mixing ratio is required. That is, in order to select a dry syrup as a formulation of the present preparation, appropriate dissolution property and stability are required, and when hydroxypropylcellulose and/or dextrin is selected as a binder, generation of fine powder in the production process of the present granular composition can be effectively suppressed.

In the present invention, the amount of hydroxypropyl cellulose to be blended is not particularly limited, and may be usually 0.5 to 10% by weight, preferably 0.8 to 5% by weight, and more preferably 1 to 3% by weight, based on 100% by weight of the present granular composition or the present preparation. The amount of dextrin to be blended is not particularly limited, and may be usually 0.5 to 10% by weight, preferably 0.8 to 5% by weight, and more preferably 1 to 3% by weight, based on 100% by weight of the present granular composition or the present preparation.

As the taste-improving agent which can be used as an additive of the present granular composition, DL-malic acid, sodium chloride, citric acid, glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, sodium L-glutamate, glycine and the like, and combinations thereof can be used, and preferred examples thereof include DL-malic acid. In the present invention, the amount of DL-malic acid to be blended is not particularly limited, and may be usually 0.01 to 5% by weight, preferably 0.05 to 2% by weight, and more preferably 0.1 to 1% by weight, based on 100% by weight of the particulate composition or the present preparation.

As the stabilizer which can be used as an additive of the present granular composition, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium citrate, sodium fumarate, povidone, sodium lauryl sulfate, glycerin fatty acid ester, dimethylpolysiloxane, sorbitan fatty acid ester, sucrose fatty acid ester, sorbitan sesquioleate, cetyl alcohol, gelatin, polysorbate 80, β -cyclodextrin, tocopherol (vitamin E), dextran, adipic acid, ascorbic acid (vitamin C), sodium edetate hydrate, dibutylhydroxytoluene, and the like, and a combination thereof can be used. The effect of edetate sodium hydrate and dibutylhydroxytoluene on improving the stability of olopatadine hydrochloride to light and heat was confirmed. Furthermore, the sodium edetate hydrate also has a function of adjusting the pH.

In the present invention, the amount of the sodium edetate hydrate to be blended is not particularly limited, and is usually 0.05 to 1% by weight, preferably 0.1 to 0.8% by weight, and more preferably 0.3 to 0.5% by weight, based on 100% by weight of the present granular composition or the present preparation. The amount of dibutylhydroxytoluene to be blended is not particularly limited, and is usually 0.05 to 1 wt%, preferably 0.1 to 0.8 wt%, and more preferably 0.3 to 0.5 wt% with respect to 100 wt% of the particulate composition or the preparation.

Examples of the fluidizing agent that can be used as an additive for the granular composition include light anhydrous silicic acid, hydrous silica, talc, and the like. The light anhydrous silicic acid is involved in the fluidity during granulation (mixing) and the suppression of fluidity/static electricity during final mixing. In the present invention, the amount of the light anhydrous silicic acid to be blended is not particularly limited, and is usually 0.01 to 5% by weight, preferably 0.05 to 3% by weight, and more preferably 0.1 to 1% by weight, based on 100% by weight of the present particulate composition or the present preparation.

The present granular composition may contain various additives for producing general formulations without impairing the effects of the invention, in addition to the above-mentioned substances. Examples of such additives include excipients, binders, flavoring agents, disintegrating agents, foaming agents, perfumes, lubricants, coloring agents, and the like other than those exemplified above, and they can be appropriately selected and added according to the purpose.

The present granular composition may be coated as necessary. By coating, the preparation is less likely to be damaged or abraded, and is sometimes advantageous for transportation and packaging.

The manufacturing method of the present invention is explained below based on the manufacturing flow shown in fig. 2. The following terms and symbols correspond to the terms and symbols described in the present manufacturing flow.

The present granular composition can be preferably produced by a wet granulation method. Specifically, a granular composition having a desired particle size distribution can be produced by mixing an additive into a powder of olopatadine or a pharmaceutically acceptable salt thereof, adding a binder (hereinafter, sometimes referred to as "granulation liquid") in a solution state to the powder, granulating (wet granulation), drying, sizing, classifying, pulverizing, sizing again for coarse particles, and performing wet granulation again for fine particles until classification (hereinafter, sometimes referred to as "re-granulation to classification"). The description is given for each step as follows.

(I) A step (a) of mixing an additive into a powder of olopatadine or a pharmaceutically acceptable salt thereof, and adding a binder (granulation liquid) in a solution state to perform wet granulation;

(II) if necessary, (a') wet-mass sizing the granulated product obtained in the step (I);

(III) a step of (b) drying the granulated substance or the whole granulated substance obtained in the step (I) or (II) and (c) pulverizing and granulating the dried substance or the whole granulated substance;

(IV) sieving the whole granules obtained in the step (III), (d) classifying the granules into coarse granules (residual granules a), a granular composition having a desired particle size (classified product), and fine powders (passing granules B);

(V) a step of (c) pulverizing and sizing the coarse particles (residual particles a) obtained in the step (IV) again, and sieving the obtained sized product, (d) a step of classifying the particles into coarse particles (residual particles a), a granular composition (classified product) having a desired particle size, and fine particles (passing particles B);

(VI) a step of performing wet granulation (a) again on the fine powder (passing particles B) obtained in the steps (IV) and (V) to perform the steps (II) to (IV); and

(VII) a step of mixing the granular composition (fraction) obtained in the above steps (IV), (V) and (VI).

In the step (VII), the lubricant and/or the fluidizing agent, and if necessary, other additives may be mixed in the form of powder without granulation into the granular composition, and the granular composition may be prepared into a preparation such as granules, powder, or dry syrup.

The steps (I) to (VII) are described in detail below.

(I) Mixing and granulating step

In the mixing step, olopatadine or a pharmaceutically acceptable salt as an active ingredient and an additive may be mixed by any method as long as the powder of the ingredients can be uniformly mixed, and the mixing method is not particularly limited. Examples of the mixing method include mixing using a container rotary mixer (e.g., a V-type mixer, a double cone-type mixer), a container fixed mixer (e.g., a stirring type mixer, a ribbon type mixer, a screw type mixer), a complex type mixer (e.g., a mixer having a stirring blade attached to a rotary type mixer), and the like. Further, a pin-and-chu mixer or the like may be used, which can mix and stir the raw material powder and can add the granulation liquid and perform kneading and granulation. The additive may be pulverized in advance by a pulverizer (pin mill, cutter mill, rotary mill, hammer mill, roll mill, shear mill, ball mill, jet mill, or the like) and classified as necessary.

Granulation can be performed by a method (wet granulation method) in which a binder in a solution state, preferably a binder in an aqueous solution, is added to the powder mixture prepared above and granulation is performed. In the present production method, the binder may be mixed separately from the binder in the form of a solution (granulation liquid) dissolved in water or the like in the granulation step, or may be mixed in the form of a powder in the mixing step, or an additive other than the binder may be mixed in the granulation liquid.

The granulation method is not particularly limited as long as it is a wet granulation method that is generally used, and examples thereof include the following methods: an extrusion granulation method in which a granulation liquid is added to a raw material powder mixture, and the mixture is kneaded, and the kneaded product is extruded from a screen, and formed and granulated; a crushing and pelletizing method in which a kneaded mass prepared by kneading by the above method is cut by a rotating blade of a pelletizer and ejected from a screw thread of a screw on the outer periphery by a centrifugal force; a tumbling granulation method in which a powder obtained by adding a granulation liquid to a raw material powder mixture and humidifying the mixture is subjected to a rotary motion or vibration to aggregate the powder, thereby obtaining approximately spherical particles; fluidized bed granulation, which is a method of fluidizing a raw material powder mixture from below by a hot air stream, spraying a granulation liquid on the fluidized material powder mixture, and granulating the fluidized material powder mixture; a stirring granulation method in which a raw material powder is put into a container, and water or a granulation liquid is added while stirring with a rotating blade to aggregate the raw material powder into a spherical shape; a mixing and stirring granulation method in which a granulation liquid is added to a raw material powder and granulation is performed while mixing and stirring.

The binder used as the granulation liquid is not particularly limited, and preferable examples thereof include hydroxypropyl cellulose. When hydroxypropyl cellulose is used, it is preferable to use a granulation liquid containing hydroxypropyl cellulose in a concentration of 7 to 11% by weight, preferably 7.5 to 8.5% by weight, in water in an amount of 3.5 to 5.5% by weight, preferably 4.5 to 5.5% by weight, based on 100% by weight of the total amount charged, and this granulation liquid is effective for suppressing the generation of fine powder and coarse particles in the present production method.

(II) Wet Block sizing step

In the process of the present production method, the wet granulation step may be followed by the wet granulation step and then the drying step, if necessary, to further exhibit the effects of the present invention. That is, it is possible to produce a granular composition containing olopatadine or a pharmaceutically acceptable salt having a reduced ratio of fine powder to coarse particles in a high yield while suppressing the generation of fine powder and coarse particles in the production process, and a pharmaceutical preparation using the granular composition.

The apparatus used in the wet mass sizing step is not particularly limited, and a commonly used granulator or granulator can be used, and a crushing granulator is particularly preferably used. "crushing" is an operation of refining particles by an action such as crushing by a rod-shaped rotating body (rotation speed: about 800rpm to 3000rpm) or the like, and as a treatment of refining particles in the same manner as "crushing", there is "crushing", but it is different in that a crusher utilizes a hammer or pin to refine powder particles by an action such as compression, impact, friction, shearing or the like. Examples of the crushing and sizing machine include a crushing and sizing machine having: the charged raw material powder is pressed against a cylindrical screen by centrifugal force of a rotating turbine (rotating blades) and crushed, and after the granulation is performed on the turbine, the granulated material is discharged from a plurality of openings provided in the screen. In the present production method, the diameter of the screen (the diameter of the screen opening) of the crushing and sizing machine is preferably set to 5mm to 20mm, more preferably 10mm to 15mm, and the rotation speed is preferably set to 800 to 2000rpm, more preferably 1000 to 1500 rpm.

(III) drying, pulverizing and sizing step

The granulated substance or the whole granulated substance produced in the step (I) or (II) may be dried by a common method, for example, a drying method using various drying apparatuses such as a parallel flow box type dryer, an air flow box type dryer, a fluidized bed dryer, and a vacuum type dryer.

The method of pulverizing and granulating is not particularly limited, and can be carried out using a granulator or granulator which is generally used in general granulating methods. The crushing and sizing device is not particularly limited, and examples thereof include an oscillator type granulator and a screen granulator. In this step, in order to prepare the granulated material obtained in the granulation step or the like into a granular composition having a predetermined particle size distribution, it is necessary to select the type of screen (mesh, punched hole or the like) of the sizing device, the mesh of the screen, the hole shape and size of the punched hole, and the like. For example, when a granular composition having a particle size of less than 1000 μm is to be obtained, a mesh having a mesh size of 1180 μm (14 mesh) or 1400 μm (12 mesh) may be used in the primary pulverizing/sizing step, and a mesh having a mesh size of 850 μm (18 mesh) or 710 μm (22 mesh) may be used in the secondary pulverizing/sizing step and the subsequent pulverizing/sizing step, respectively. In addition, when it is desired to obtain a granular composition having a particle size of less than 850 μm, a mesh having a mesh size of 1000 μm (16 mesh) or 1180 μm (14 mesh) may be used in the primary pulverizing/sizing step, and a mesh having a mesh size of 710 μm (22 mesh) or 600 μm (26 mesh) may be used in the secondary pulverizing/sizing step and the subsequent pulverizing/sizing step, respectively. In addition, when it is desired to obtain a granular composition having a particle size of less than 710 μm, a mesh having a mesh size of 850 μm (18 mesh) or 1000 μm (16 mesh) may be used in the primary pulverizing/sizing step, and a mesh having a mesh size of 600 μm (26 mesh) or 500 μm (30 mesh) may be used in the secondary pulverizing/sizing step and the subsequent pulverizing/sizing step, respectively. As described above, it is preferable to use a mesh having a mesh size slightly larger than the desired particle size in the first pulverizing/sizing step and to use a mesh having a mesh size slightly smaller than the desired particle size in the second and subsequent pulverizing/sizing steps, whereby generation of fine particles can be suppressed. In the present invention, it is preferable to use a screen having a mesh size selected from any of 12 to 18 mesh for the first time, and use a screen having a mesh size smaller than the first time selected from any of 18 to 30 mesh for the second time and thereafter, and it is further preferable to use a screen having a mesh size of 16 mesh for the first time, and use a screen having a mesh size of 22 mesh for the second time and thereafter. The mesh size in the present application is expressed based on table 1.

[ Table 1]

(IV) a classification step

In the classification operation, there are dry classification using a gas as a medium and wet classification using a liquid as a medium, but in the present production method, dry classification is preferably selected. Further, the dry fractionation includes the following methods: a screening method in which powder is placed on a mesh surface and particles are moved by a certain method to be classified; and a gas flow dispersion method using a difference in settling velocity based on particle size, and in the present production method, a screening method is preferably selected, and the apparatus thereof is not particularly limited. In this classification step, the target sieves in table 1 were selected according to the desired particle size distribution by using a sieving device such as a vibrating sieve, and the whole granules prepared in the step (III) were classified. For example, when a granular composition having a particle size of 150 to 850 μm is to be obtained by classification, the composition is classified into coarse particles by sieving the composition with an 18-mesh sieve (sieve a) and a 100-mesh sieve (sieve B): particles remaining in the 18-mesh sieve (remaining particles a), fraction: particles that pass through an 18-mesh sieve and remain in a 100-mesh sieve, and fine powder: particles passing through a 100 mesh screen (pass through particles B). In the present invention, when a granular composition having a particle size lower limit of 125 to 160 μm and a particle size upper limit of 710 to 1000 μm is obtained, it is preferable to sieve the granular composition by using a sieve A having a mesh size of 16 to 22 mesh and a sieve B having a mesh size of 93 to 119 mesh.

(V) Process of straightening and classifying again

In this step (V), the coarse particles (residual particles a) obtained in the step (IV) are subjected to the pulverizing and sizing step of the step (III) and the step (IV) again, and classified into coarse particles (residual particles a), classified products, and fine particles (passing particles B). Here, coarse particles (residual particles a) are discarded. In the step of pulverizing and sizing in step (V), a sieve having a mesh size smaller than that of the sieve used in the step of pulverizing and sizing in step (III) is preferably used. For example, when a granular composition having a particle size of less than 850 μm is to be obtained, it is preferable to use a mesh having a mesh size of 710 μm (22 mesh) or 600 μm (26 mesh) smaller than the mesh size of 1000 μm (16 mesh) or 1180 μm (14 mesh), which is a mesh size preferable in the step (III) in the present step (V). Thereby, a granular composition having a particle diameter of less than 850 μm more while suppressing generation of fine powder can be obtained.

(VI) Re-granulation to Classification Process

In the present step (V), the fine powder (passing particle B) obtained in the above steps (IV) and (V) is subjected to (a) wet granulation again, and the above steps (II) to (IV) are carried out to classify into a coarse particle (residual particle a), a classified product, and a fine powder (passing particle B). Here, coarse particles (residual particles a) and fine particles (passing particles B) are discarded. In the step of pulverizing and sizing in step (VI), similarly to step (V), a mesh sieve having a mesh size smaller than that used in the step of pulverizing and sizing in step (III) is preferably used.

(VII) mixing step

In the present step (VII), the fraction obtained in the above steps (IV), (V) and (VI) is not particularly limited, and may be put into a mixer such as a rotary mixer and mixed. In the step (VII), the lubricant and/or the fluidizing agent, and if necessary, other additives are added in the form of powder without granulation and mixed to prepare the present preparation such as granules, powder, or dry syrup.

Examples

The present invention will be described in detail with reference to examples, but the present invention is not limited thereto at all.

The formulation of olopatadine hydrochloride dry syrup prepared as an example of the present formulation is shown in table 2 in terms of the amount of each component contained in 1g (1000mg) of the formulation. The dry syrup can be produced by the production method described in the following examples.

[ Table 2]

Composition (I)	Amount (mg)
		Olopatadine hydrochloride	10
White sugar	648.16
		Trehalose hydrate	240
Acetylsulfanilic acid	50
		Dextrin	20
Hydroxypropyl cellulose	15
		Light anhydrous silicic acid	4.4
Edetate sodium hydrate	4.4
		DL-malic acid	4
Dibutylhydroxytoluene	4
		Thaumatin	0.04
Total up to	1000

Example 1: preparation of granular compositions and formulations

64.816 parts of white sugar, 0.4 part of DL-malic acid, 0.4 part of butylated hydroxytoluene, 24 parts of trehalose hydrate, 1 part of olopatadine hydrochloride, 5 parts of acesulfame potassium, 2 parts of dextrin, 0.25 part of light anhydrous silicic acid, 0.44 part of sodium edetate hydrate and 1.06 parts of hydroxypropyl cellulose (HPC) are put into a stirring granulator. A granulation liquid prepared by separately dissolving 0.44 parts of HPC and 0.004 parts of thaumatin in 5 parts of purified water was added thereto, and granulation was performed. After granulation, wet cake sizing was performed by a crushing and sizing machine, and drying was performed at 45 ℃ to obtain a granulated and dried product 1. The granulated and dried product 1 was put into a crushing and sizing machine having a screen mesh of 1000 μm, and sized to obtain a sized product 1. The whole grain product 1 was put into a vibrating screen and classified by a screen having a mesh size of 850 μm and a mesh size of 150 μm to obtain an unscreened product 1, a classified product 1 and a screened product 1.

The non-sieved product 1 was put into a crushing and sizing machine with a screen having a mesh opening of 710 μm, and sized to obtain a sized product 2. The whole grain product 2 was put into a vibrating screen and classified by a screen having a mesh size of 850 μm and a mesh size of 150 μm to obtain an unscreened product 2, a classified product 2 and a sieved product 2. The sieved product 1 and the sieved product 2 were put into a stirring granulator, and granulated with purified water (total sieved product × 0.08 parts). After granulation, wet granulation was performed using a crushing granulator, and the granules were dried at 45 ℃ to obtain a granulated dried product 2. Granulated and dried product 2 was put into a crushing and sizing machine having a screen mesh of 710 μm, and sized to obtain a sized product 3. The whole grain product 3 was put into a vibrating screen and classified by a screen having a mesh size of 850 μm and a mesh size of 150 μm to obtain an unscreened product 3, a classified product 3 and a sieved product 3. The classified products 1 to 3 and 0.19 part of light anhydrous silicic acid are put into a rotary mixer and mixed to obtain dry syrup.

Test example (1): taste Functions test 1

Taste functionality tests were performed with a total of 8 randomly selected men and women as panelists. The control product was a conventional product a (a granulated preparation corresponding to a in fig. 1), and the evaluation product was the present preparation obtained in example 1. First, 0.5g of a control (2.5 mg of olopatadine hydrochloride) was mixed/dissolved in about 50mL of water, and the total amount was held in the mouth and discharged after 30 seconds. Thereafter, 0.25g (2.5 mg as olopatadine hydrochloride) of the evaluation product was similarly mixed and dissolved in about 50mL of water, and the total amount was taken in the mouth and discharged after 30 seconds. The sweetness and bitterness of the evaluation product were evaluated based on the sweetness and bitterness of the control product.

The evaluation results are represented by five stages of "weak", "slightly weak", "constant", "slightly strong" and "strong". As a result, the evaluation product was "slightly stronger" than the control for the sweetness, and "stronger" was 4 persons. For bitterness, 8 people were "unchanged" between the evaluation and control.

Test example (2): taste functionality test 2

Taste functional tests were performed with 7 men and women randomly selected as panelists. The control product was designated as conventional product a, and the evaluation product was designated as the present preparation obtained in example 1. First, 0.5g of a control (2.5 mg of olopatadine hydrochloride) was mixed/dissolved in about 2mL of water, and the total amount was held in the mouth and discharged after 30 seconds. Thereafter, 0.25g (2.5 mg as olopatadine hydrochloride) of the evaluation product was similarly mixed and dissolved in about 2mL of water, and the total amount was taken in the mouth and discharged after 15 seconds. The sweetness and bitterness of the evaluation product were evaluated based on the sweetness and bitterness of the control product.

The evaluation results are shown in the same manner as in test example (1). For sweetness, the number of people who responded to the assessments "unchanged" compared to the control was 1, 2 for "slightly stronger", and 4 for "stronger". For bitterness, the evaluation product was "slightly weaker" than the control product, 2, "unchanged" and "slightly stronger" were 2, and "stronger" was 1.

Test example (3): transparency of the solution

0.5g of particles of three prior preparations containing 2.5mg of olopatadine hydrochloride (2.5 mg in terms of olopatadine hydrochloride) and 0.25g of the present preparation obtained in example 1 (2.5 mg in terms of olopatadine hydrochloride) were mixed into 30mL of purified water. The transparency of the solution is shown in FIG. 1 (photograph).

A. B and D are products obtained by mixing 0.5g (2.5 mg in terms of olopatadine hydrochloride in each case) of granules of the conventional preparation to 30mL of purified water, and C is a product obtained by mixing 0.25g (2.5 mg in terms of olopatadine hydrochloride) of the present preparation to 30mL of purified water. The conventional product a is a preparation containing yellow iron sesquioxide, titanium oxide, iron sesquioxide as a pigment, and exhibits a slightly yellow milky white color in a state of being mixed with water. The pigment contained in conventional product B (granule preparation corresponding to B in fig. 1) is unclear, but appears orange when mixed with water. C, which represents the results of the present formulation, appears as a colorless, almost transparent solution. The conventional product D (a granular preparation corresponding to D in fig. 1) is a preparation containing yellow iron sesquioxide, titanium oxide, and iron sesquioxide as pigments, and in a state of being mixed with water, it appears slightly milky white in color.

The conventional products A, B and D are colored when mixed with water and are opaque solutions in suspension, so that they give a feeling of inconvenience in taking (both are foreign substances in taking) and are particularly unpleasant for infants. On the other hand, C, which is a solution in which the present preparation is dissolved, is colorless and has high transparency, and therefore does not cause such an adverse impression. Therefore, there is an advantage that it is easy for children to take and the burden on the person assisting in taking the medicine is also reduced.

Test example (4)

In test examples 1 to 4 in which the same production process as in example 1, i.e., the process of re-granulating/re-granulating was performed to produce a granular composition, and comparative examples 1 to 4 in which the process of re-granulating/re-granulating was not performed to produce a granular composition, the proportions (wt%) of the obtained unsieved product (coarse grain) having a mesh size of 850 μm, the unsieved product (classified product) having a mesh size of 150 μm, and the sieved product (fine powder) having a mesh size of 150 μm with respect to the total amount thereof were calculated. Further, the ratio of the 150 μm unsieved product (classified product) to the total charged amount was calculated as the recovery rate (% by weight). An example of the results is shown in table 3.

[ Table 3]

As is clear from table 3: by performing the process of re-sizing and re-granulating, generation of coarse particles and fine particles can be suppressed, a granular composition having a desired particle size of 150 to 850 μm can be produced, and the recovery rate can be improved.

Test example (5)

The particle size distribution by sieving was measured for each of lots a to C of the dry syrup preparation obtained in the production process of example 1. An example of the results is shown in table 4.

[ Table 4]

The particle size distribution of the dry syrup prepared from the particle composition classified as a classified product having a particle size of 150 to 850 μm by classification in the production process was measured, and it was clearly confirmed from table 4 of the results of the measurements: the fraction having a particle size of 150 to 850 μm contains substantially 90% of particles having a particle size of 150 to 850 μm.

Test example (6)

The content (% by weight) of olopatadine hydrochloride as an active ingredient in 10 samples (1. upper left end, 2. upper center, 3. upper right end, 4. middle left end, 5. middle center, 6. upper right end, 7. lower left end, 8. lower center, 9. lower right end, and 10. middle inside) sampled from the mixer was measured for the dry syrup batches a to C obtained by the production process of example 1. An example of the results is shown in table 5.

[ Table 5]

It is clear from table 5 that: the dry syrup produced by the present production method has a small variation in the content of active ingredients and is free from segregation.

Test example (7)

The concentration of HPC in the granulation liquid used in example 1 and the amount of purified water (ratio to the total charged amount) used in preparing the granulation liquid were examined using 74.5 parts of white sugar, 24 parts of trehalose, and 1.5 parts of HPC. Further, whether or not the wet cake sizing in this step is necessary has also been examined. The test nos. (1) to (7) were performed under the conditions shown in table 6.

[ Table 6]

In this study, additives other than the effective ingredient having a small content ratio in the formulation and the above 3 ingredients were not blended, and the blending amount of these ingredients was replaced with the blending amount of white sugar for convenience. Evaluation was carried out by calculating the ratio of coarse particles having a particle size of 850 μm or more (unsieved product 1), classified product 1 having a particle size of 150 to 850 μm, and fine particles having a particle size of 150 μm (sieved product 1) in the classification operation of example 1. In the tests No. (1) and (3), No wet cake sizing was performed. An example of the results is shown in table 6.

[ Table 7]

It is clearly confirmed from table 7: in the present production step, from the viewpoint of suppressing the generation of fine particles and coarse particles of the product, purified water having a HPC concentration of 8 wt% in the granulation liquid and 5 wt% with respect to the total charged amount is preferably used, and further, the step of wet granulation is preferably performed.

Industrial applicability

As described above, the present granular composition and the present preparation containing olopatadine or a pharmaceutically acceptable salt thereof have the following characteristics: the bitter taste is suppressed and the product is easy to take, and compared with the existing product, the effective component concentration is 2 times and the dosage is reduced by half, the product is easy to dissolve in water, and if the product is dissolved, the solution is colorless and has high transparency, so the product is easy to take in appearance.

Further, according to the present production method, the production of fine particles and coarse particles in the production process is suppressed, and the present granular composition can be produced in a high yield. Further, the granular composition produced by the present production method and the present preparation are less likely to undergo segregation, and therefore have the following advantages: the dispersion of the content of the active ingredient is small, and dust is not easily generated at the time of use or dispensing.