Pharmaceutical composition

Abstract

To provide a pharmaceutical composition which exhibits reduced bitterness derived from an active ingredient and demonstrates improved swallowability.SOLUTION: A pharmaceutical composition according to one embodiment of the present invention comprises: an active ingredient having bitterness; and two or more sweeteners in a total content of 13 pts.mass or more when the weight of the active ingredient having bitterness is 100 pts.mass. The pharmaceutical composition further contains a specific amount of an acidulant depending on the type of the active ingredient having bitterness.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition. The present invention also relates to a method for producing the pharmaceutical composition. The present invention further relates to a method for suppressing the bitterness of the pharmaceutical composition.

Background Art

[0002] When the active ingredient contained in a pharmaceutical composition is a bitter substance, it is known to blend a sweetening agent and / or an acidulant to suppress the bitterness of the pharmaceutical composition. For example, Patent Document 1 discloses an oral pharmaceutical composition containing a pharmaceutical active ingredient having an unpleasant taste, two or more high-intensity sweeteners (sweetness intensity of 150 or more), and a substance exhibiting acidity.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, in the pharmaceutical compositions tested in the above-described prior art, the blending amount of the substance exhibiting acidity with respect to the content of the pharmaceutical active ingredient is large. In this case, although the bitterness of the active ingredient can be suppressed, it may result in an unpleasant taste such as too strong acidity, and there is room for improvement from the viewpoint of swallowability.

[0005] One aspect of the present invention aims to realize a pharmaceutical composition in which the bitterness derived from the active ingredient is suppressed and the swallowability is improved.

Means for Solving the Problems

[0006] As a result of intensive studies to solve the above problems, the inventors of the present invention have found for the first time that by including a specific amount of two or more sweeteners, or a specific amount of two or more sweeteners and an acidulant, the bitterness derived from the active ingredient can be suppressed and the swallowability can be improved, thus completing the present invention. That is, one aspect of the present invention includes the following configurations. <1>An active ingredient having bitterness, Two or more sweeteners having a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having bitterness, An acidulant having a total content of more than 0 part by weight and 30 parts by weight or less based on 100 parts by weight of the total content of the sweeteners, A pharmaceutical composition. <2>An active ingredient having bitterness, Two or more sweeteners having a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having bitterness, An acidulant having a total content of more than 0 part by weight and 30 parts by weight or less based on 100 parts by weight of the weight of the active ingredient having bitterness, A pharmaceutical composition. <3>An active ingredient having bitterness, Two or more sweeteners having a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having bitterness, Not containing an acidulant, The active ingredient having bitterness is lacosamide or oseltamivir phosphate, A pharmaceutical composition. <4>A method for producing a pharmaceutical composition containing an active ingredient having bitterness, A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more with respect to 100 parts by weight of the active ingredient having bitterness, and A step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less based on 100 parts by weight of the total content of the sweeteners, A method. <5>A method for producing a pharmaceutical composition containing an active ingredient having bitterness, A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more per 100 parts by weight of the active ingredient having the bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less per 100 parts by weight of the active ingredient having the bitterness, A method. A method for producing a pharmaceutical composition containing an active ingredient having bitterness and not containing an acidulant, including a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more per 100 parts by weight of the active ingredient having the bitterness, wherein the active ingredient having the bitterness is lacosamide or oseltamivir phosphate, A method. A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness, including a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more per 100 parts by weight of the active ingredient having the bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less with respect to 100 parts by weight of the total content of the sweeteners, A method. <8>A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness, including a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more per 100 parts by weight of the active ingredient having the bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less per 100 parts by weight of the active ingredient having the bitterness, A method. <9>A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness and not containing an acidulant, including a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more per 100 parts by weight of the active ingredient having the bitterness, wherein the active ingredient having the bitterness is lacosamide or oseltamivir phosphate, A method. <10>The pharmaceutical composition according to any one of <1> to <3>, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight with respect to 100 parts by weight of the weight of the active ingredient having bitterness. <11>The method for producing a pharmaceutical composition according to any one of <4> to <6>, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight with respect to 100 parts by weight of the weight of the active ingredient having bitterness. <12>The method for suppressing the bitterness of a pharmaceutical composition according to any one of <7> to <9>, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight with respect to 100 parts by weight of the weight of the active ingredient having bitterness.

Advantages of the Invention

[0007] According to one aspect of the present invention, it is possible to provide a pharmaceutical composition in which the bitterness derived from the active ingredient is suppressed and the swallowability is improved.

Modes for Carrying Out the Invention

[0008] An embodiment of the present invention will be described below, but the present invention is not limited thereto. In the present specification, unless otherwise specified, "A to B" representing a numerical range means "A or more and B or less".

[0009] 〔1. Outline of the Present Invention〕 When the active ingredient contained in the pharmaceutical composition is a substance having bitterness, in order to suppress the bitterness of the pharmaceutical composition, as described above, it is known to blend a sweetener and / or an acidulant. It is considered that the larger the blending amount of the sweetener and the acidulant, the more the bitterness derived from the active ingredient having bitterness can be suppressed. However, when the blending amount of the sweetener and the acidulant is too large, unpleasant tastes such as being too sweet or too sour may occur. Pharmaceutical compositions are often required to be taken continuously, and it is required to be excellent in swallowability such as ease of drinking.

[0010] The pharmaceutical composition described in the above Patent Document 1 contains a very large amount of acidulant with respect to the pharmaceutical active ingredient, and the resulting pharmaceutical composition is considered to be sour. Therefore, there was room for improvement from the viewpoint of swallowability. As a result of intensive studies by the present inventors, it was discovered that there is an optimal amount for the contents of sweetener and acidulant in the pharmaceutical composition.

[0011] [2. Pharmaceutical Composition] The pharmaceutical composition according to one embodiment of the present invention contains an active ingredient having bitterness (hereinafter simply referred to as "active ingredient" in the present specification). The active ingredient having bitterness is not particularly limited as long as it has bitterness and there is concern about deterioration in swallowability. Specifically, examples of the active ingredient having bitterness include lacosamide, oseltamivir phosphate, desloratadine, vilastine, sitagliptin phosphate hydrate, sitagliptin phosphate, linagliptin, empagliflozin, vonoprazan fumarate, and the like. The active ingredient having bitterness may be blended alone or in combination of two or more. The active ingredient may be in the form of a free acid or free base, its salt form, or a solvate thereof.

[0012] The oseltamivir phosphate contained in the pharmaceutical composition according to one embodiment of the present invention can be used in any crystal form. For example, crystal form A described in International Publication No. 2009 / 087062 can be preferably used. The lacosamide contained in the pharmaceutical composition according to one embodiment of the present invention can be used in any crystal form. For example, the polymorphic form (I) (also referred to as crystal form I in the present application) described in International Publication No. 2012 / 072256 can be preferably used.

[0013] The pharmaceutical composition according to an embodiment of the present invention contains two or more sweeteners. The sweetener is not particularly limited as long as it can suppress the bitterness of the active ingredient contained in the pharmaceutical composition, but a sweetener having a sweetness degree of 70 or more is preferable, a sweetener having a sweetness degree of 100 or more is more preferable, and a sweetener having a sweetness degree of 150 or more is even more preferable. The "sweetness degree" in the present specification is a value determined from the ratio of the concentration showing the same sweetness intensity as sucrose at an arbitrary concentration or the ratio to the threshold value of sucrose determined under the same conditions, using sucrose as a standard substance (Kenji Maebashi, "Basic Knowledge of Sweetness", Brewing Association (2011) No. 106, No. 12, p818-825). That is, the "sweetness degree" in the present specification is a numerical value obtained by quantifying the relative sweetness when the sweetness degree of sucrose is set to 1.

[0014] Specific examples of the sweetener include erythritol, xylitol, sucralose, stevia extract, stevia extraction purified product, purified stevia extract, aspartame, thaumatin, glycyrrhizic acid, glycyrrhizin, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, monopotassium glycyrrhizinate, ammonium glycyrrhizinate, acesulfame potassium, monellin, neotame, advantame, saccharin, sodium saccharin, sodium saccharin hydrate, calcium saccharin, and the like.

[0015] The lower limit of the total content of the sweetener is 13 parts by weight or more, preferably 14 parts by weight or more, and more preferably 14.5 parts by weight or more, based on 100 parts by weight of the active ingredient. The upper limit of the total content of the sweetener is preferably 50 parts by weight or less, more preferably 45 parts by weight or less, and even more preferably 40 parts by weight or less, based on 100 parts by weight of the active ingredient. If the total content of the sweetener is within the above range, the resulting pharmaceutical composition can suppress the bitterness derived from the active ingredient and does not cause an unpleasant taste due to the sweetener.

[0016] When the active ingredient having a bitter taste is not either lacosamide or oseltamivir phosphate, the pharmaceutical composition according to an embodiment of the present invention contains an acidulant. When the active ingredient having a bitter taste is either lacosamide or oseltamivir phosphate, the pharmaceutical composition may or may not contain an acidulant. The acidulant is not particularly limited as long as it can suppress the bitter taste of the active ingredient contained in the pharmaceutical composition, and it may be an organic acid or an inorganic acid, but an organic acid is preferred.

[0017] As the acidulant, an acidulant having a lower limit value of the acidity of 30 or more is preferred, an acidulant having 45 or more is more preferred, and an acidulant having 90 or more is even more preferred. Also, an acidulant having an upper limit value of the acidity of 160 or less is preferred, and an acidulant having 150 or less is more preferred. The "acidity" in the present specification is a value obtained by quantifying the relative acidity strength when the acidity strength of citric acid is set to 100. As a calculation method, when the amount of citric acid used is 100, the amount of the acidulant used that has the same acidity strength as citric acid (from Hideko Furukawa et al., "On the Taste of Organic Acids (First Report) P.S.E. Measurement of 9 Kinds of Food-Added Organic Acids", Journal of the Japan Society of Food Engineering, Vol. 16, No. 2, February 1969, p63-68 (especially Table 7)) is used, and it can be calculated by the following formula. Acidity = (A / B) × 100 〔In the above formula, A is 100 (the amount of citric acid used), and B is the amount of the acidulant used that has the same acidity strength as citric acid when the amount of citric acid used is 100〕 Specific examples of the acidulant include ascorbic acid, adipic acid, anhydrous citric acid, citric acid hydrate, gluconic acid, tartaric acid, D-tartaric acid, DL-malic acid, L-malic acid, fumaric acid, succinic acid, lactic acid, and the like. The acidulant may be used alone or in combination of two or more.

[0018] When formulating an acidulant, the total content of the acidulant can be expressed based on the content of either the active ingredient or the sweetener. When based on the content of the active ingredient, the lower limit of the total content of the acidulant is more than 0 part by weight and preferably 0.1 part by weight or more, with the weight of the active ingredient being 100 parts by weight. The upper limit of the total content of the acidulant in this case is 30 parts by weight or less, preferably 20 parts by weight or less, more preferably 15 parts by weight or less, and even more preferably 5 parts by weight or less, with the weight of the active ingredient being 100 parts by weight.

[0019] When expressing the total content of the acidulant based on the content of the sweetener, the lower limit of the total content of the acidulant is more than 0 part by weight and preferably 0.2 part by weight or more, more preferably 0.4 part by weight or more, with the total content of the sweetener being 100 parts by weight. The upper limit of the total content of the acidulant in this case is 30 parts by weight or less, preferably 28 parts by weight or less, more preferably 26 parts by weight or less. If the total content of the acidulant is within the above range, the bitterness derived from the active ingredient in the resulting pharmaceutical composition can be suppressed, and an unpleasant taste caused by the acidulant does not occur.

[0020] The pharmaceutical composition according to an embodiment of the present invention may optionally contain a pharmaceutically acceptable pharmaceutical additive. Examples of such pharmaceutical additives include binders, excipients, stabilizers, lubricants, disintegrants, fluidizing agents, lubricants, and the like.

[0021] The binder is not particularly limited, and examples thereof include water-soluble polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. Only one type of binder may be used, or two or more types may be used in combination.

[0022] Examples of excipients include starches, celluloses, saccharides, sugar alcohols, etc. Examples of starches include partially pregelatinized starch, corn starch, etc. Examples of celluloses include crystalline cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, etc. Examples of saccharides include lactose hydrate, sucrose, powdered reduced maltose syrup, etc. Examples of sugar alcohols include D-sorbitol, D-mannitol, etc. The excipient may be used alone or in combination of two or more kinds.

[0023] Examples of stabilizers include calcium chloride, calcium chloride hydrate, calcium chloride dihydrate, dibutylhydroxytoluene, alanine, sodium chloride, etc. The stabilizer may be used alone or in combination of two or more kinds.

[0024] Examples of lubricants include talc, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, etc. The lubricant may be used alone or in combination of two or more kinds.

[0025] Examples of disintegrants include crospovidone, calcium carmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, corn starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium starch glycolate, adipic acid, sodium hydrogen carbonate, sucrose, dextrin, lactose, crospovidone, croscarmellose sodium, etc. The disintegrant may be used alone or in combination of two or more kinds.

[0026] Examples of fluidizing agents include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, talc, etc. The fluidizing agent may be used alone or in combination of two or more kinds.

[0027] Examples of the wetting agent include sodium lauryl sulfate, lauromacrogol, macrogol, and propylene glycol. As the macrogol, grades with an appropriate degree of polymerization can be used as appropriate. For example, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 4000, macrogol 6000, etc. can be mentioned.

[0028] The content of the pharmaceutical additive is not particularly limited and is appropriately set based on conventionally known techniques.

[0029] The form (dosage form) of the pharmaceutical composition according to an embodiment of the present invention is not particularly limited. For example, tablets, OD tablets (Orally Disintegrating Tablets), capsules, powders, granules, dry syrups, syrups, internal liquids, jelly agents, etc. can be mentioned. Among these, granules or dry syrups are preferred.

[0030] The dry syrup may contain other particles in addition to the particles containing the active ingredient. For example, lactose hydrate, powdered reduced maltose syrup, partially pregelatinized starch, light anhydrous silicic acid, sodium hydrogen carbonate, talc, xanthan gum, and strawberry micron may be mixed. The other particles may contain known pharmaceutical compounds (such as antibiotics and antipyretic, analgesic and anti-inflammatory agents) that can be combined with the active ingredient as necessary. By including other particles, the odor and taste of the dry syrup and the dosage of the dry syrup can be changed without changing the composition of the particles containing the active ingredient. Also, by including an excipient for volume increase, etc. in the other particles, it is possible to prevent the particles containing the active ingredient from becoming too large.

[0031] The dry syrup may further contain a pharmaceutically acceptable fragrance as needed. Examples of the fragrance include strawberry micron, peppermint micron, peach micron, lychee micron, banana micron, and pineapple micron. The blending amount of the fragrance is not particularly limited and can be appropriately determined by those skilled in the art. The content of the fragrance may be, for example, 1% by weight or less based on the total mass of the dry syrup being 100% by weight.

[0032] Tablets and capsules may be packaged by PTP packaging, bottle filling, aluminum packaging, etc. as needed. Examples of the materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, and metals such as aluminum. These materials may be used alone or in combination of multiple types. Examples of the combination include, for example, laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. Tablets or capsules can be put into the formed pockets of a resin sheet formed from the above resin by a known method and covered with an aluminum foil to be packaged.

[0033] The PTP packaging may be further packaged with an aluminum pillow. The aluminum pillow may further contain a desiccant or an oxygen scavenger. Examples of the desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, or zeolite. Examples of the oxygen scavenger include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, or catechol. These desiccants and decarburizers may be used alone or in combination of multiple types, or a desiccant and an oxygen scavenger may be used in combination. Examples of the product combining a desiccant and an oxygen scavenger include "Farmakeep (registered trademark)" of Mitsubishi Gas Chemical Company, Inc.

[0034] Dry syrups and granules may be filled in glass bottles or plastic bottles as required, or may be sub-packaged for each single dose by aluminum packaging. As the material for the plastic bottle, the resin for PTP packaging described above may be mentioned. The aluminum packaging may be further packaged with an aluminum pillow. These glass bottles, plastic bottles, and aluminum pillows may further contain the desiccant and deoxidizer described above.

[0035] [3. Method for manufacturing pharmaceutical composition] The method for manufacturing a pharmaceutical composition according to an embodiment of the present invention includes a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more with respect to 100 parts by weight of the active ingredient having bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less with respect to 100 parts by weight of the total content of the sweeteners.

[0036] Further, the method for manufacturing a pharmaceutical composition according to an embodiment of the present invention includes a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more with respect to 100 parts by weight of the active ingredient having bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less with respect to 100 parts by weight of the active ingredient having bitterness.

[0037] Furthermore, the method for manufacturing a pharmaceutical composition according to an embodiment of the present invention includes a step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more with respect to 100 parts by weight of the active ingredient having bitterness, and the active ingredient having bitterness is lacosamide or oseltamivir phosphate.

[0038] In the method for producing a pharmaceutical composition according to an embodiment of the present invention, the step of blending a sweetening agent and the step of blending an acidulant may be performed simultaneously or sequentially. When performed sequentially, the order is not particularly limited. Further, in the method for producing a pharmaceutical composition according to an embodiment of the present invention, the descriptions of the respective components such as the sweetening agent and the acidulant are incorporated by reference to those described in [2. Pharmaceutical composition]. The above-described production method of the present invention is not particularly limited as long as the pharmaceutical composition obtained by the production method according to an embodiment of the present invention has the configuration described in [2. Pharmaceutical composition], and any method known in the art can be adopted. The production method of the present invention is performed, for example, by the method described in the examples.

[0039] [4. Method for Suppressing Bitterness of a Pharmaceutical Composition Containing an Active Ingredient Having Bitterness] In one embodiment of the present invention, there is provided a method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness (also simply referred to as "method for suppressing bitterness"), which comprises a step of blending two or more sweetening agents in an amount such that the total content of the sweetening agents is 13 parts by weight or more per 100 parts by weight of the active ingredient having bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less based on 100 parts by weight of the total content of the sweetening agents.

[0040] Also, in one embodiment of the present invention, there is provided a method for suppressing bitterness, which comprises a step of blending two or more sweetening agents in an amount such that the total content of the sweetening agents is 13 parts by weight or more per 100 parts by weight of the active ingredient having bitterness, and a step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and 30 parts by weight or less per 100 parts by weight of the active ingredient having bitterness.

[0041] Furthermore, in one embodiment of the present invention, there is provided a method for suppressing bitterness, which comprises a step of blending two or more sweetening agents in an amount such that the total content of the sweetening agents is 13 parts by weight or more per 100 parts by weight of the active ingredient having bitterness, and wherein the active ingredient having bitterness is lacosamide or oseltamivir phosphate.

[0042] In addition, in the method for suppressing bitterness according to an embodiment of the present invention, the step of blending a sweetening agent and the step of blending an acidifying agent may be performed simultaneously or sequentially. When performed sequentially, the order is not particularly limited. Further, in the method for suppressing bitterness according to an embodiment of the present invention, the descriptions of the respective components such as the sweetening agent and the acidifying agent are incorporated by reference to those described in [2. Pharmaceutical Composition].

[0043] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

Example

[0044] An example of the present invention will be described below.

[0045] 〔Materials used in the example〕 ● Active ingredient having bitterness · Lacosamide (crystalline form I) · Oseltamivir phosphate (crystalline form A) ● Sweetening agent · Sucralose: Sucralose (P) (manufactured by San-Ei Gen F.F.I., Inc.) · Purified stevia extract: Stevia MZ (manufactured by Maruzen Pharmaceutical Co., Ltd.) · Aspartame: manufactured by Ajinomoto Co., Inc. ● Acidifying agent · Citric acid hydrate: manufactured by Satsuma Kako Co., Ltd. · DL-Malic acid: Malic acid fusou M (manufactured by Fuso Chemical Industry Co., Ltd.) ● Pharmaceutical additives, fragrances · Binder Hydroxypropyl cellulose: HPC-SSL (manufactured by Nippon Soda Co., Ltd.) · Excipient Powdered reduced maltose syrup: manufactured by Mitsubishi Corporation Life Sciences D-Mannitol: PEARLITOL 50C (manufactured by ROQUETTE) · Lubricant Talc: Talcan Hayashi (manufactured by Hayashi Chemical Co., Ltd.) · Disintegrant Crospovidone: Kollidon CL-F (manufactured by BASF Japan Ltd.) Croscarmellose Sodium: Ac-Di-Sol (manufactured by DuPont Nutrition USA Inc.) · Fluidizing agent Light anhydrous silicic acid: Adsolider-101 (manufactured by Fuji Silysia Chemical Ltd.) · Wetting agent Sodium lauryl sulfate: SLS (manufactured by Nippon Surfactant Industry Co., Ltd.) · Flavor Banana micron: Banana micron ZD-2760 (manufactured by Takasago International Corporation) Peach micron: Peach micron H-80450 (manufactured by Takasago International Corporation) The method for measuring the cumulative volume-based 50% particle size according to an embodiment of the present invention can be appropriately selected. For example, the particle size distribution is measured by a dry method or a wet method using a laser diffraction particle size distribution measuring device, and calculated from the distribution.

[0046] The method for measuring the moisture content according to an embodiment of the present invention can be appropriately selected. For example, it can be measured by the loss on drying method.

[0047] <Sensory tests for bitterness, sourness, and sweetness> [Comparative Example 1] (1) 9 g of hydroxypropyl cellulose was dissolved in 36 g of purified water. (2) 441.9 g of powdered reduced maltose syrup, 7.5 g of crospovidone, 10 g of croscarmellose sodium, 1 g of sucralose, 0.5 g of purified stevia extract, 0.15 g of citric acid hydrate, and 0.25 g of DL-malic acid were put into a wet high-shear granulator and mixed. Then, the entire amount of the solution obtained in (1) was added and kneaded. The obtained product was designated as kneaded I powder. (3) 19.7 g of oseltamivir phosphate with a cumulative volume-based 50% particle size of 96 μm and 10 g of talc were added to the wet high-shear granulator containing the kneaded I powder and further kneaded. (4) The product obtained in (3) was passed through a dry granulator (screen diameter: 6350 μm) and crushed. This was designated as blended powder II. (5) Blended powder II was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (6) The dried product obtained in (5) was sized through a dry granulator (screen diameter: 1575 μm). (7) The sized powder obtained in (6) and 0.5 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.1%. The amounts of components contained per dose are shown in Table 1.

[0048] [Comparative Example 2] (1) 9 g of hydroxypropyl cellulose was dissolved in 36 g of purified water. (2) 428.8 g of powdered reduced maltose syrup, 7.5 g of crospovidone, 10 g of croscarmellose sodium, 6.5 g of sucralose, 1 g of purified stevia extract, 2.81 g of citric acid hydrate, and 4.69 g of DL - malic acid were put into a wet high - shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was added and blended. The product obtained was designated as blended powder I. (3) 19.7 g of oseltamivir phosphate with a cumulative volume - based particle diameter of 96 μm and 10 g of talc were added to the wet high - shear granulator containing blended powder I and further blended. (4) The product obtained in (3) was passed through a dry granulator (screen diameter: 6350 μm) and crushed. This was designated as blended powder II. (5) Blended powder II was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (6) The dried product obtained in (5) was sized through a dry granulator (screen diameter: 1575 μm). (7) The sized powder obtained in (6) and 0.5 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.2%. The amounts of components contained per dose are shown in Table 1.

[0049] [Comparative Example 3] (1) 9 g of hydroxypropyl cellulose was dissolved in 36 g of purified water. (2) 434.8 g of powdered reduced maltose syrup, 7.5 g of crospovidone, 10 g of croscarmellose sodium, 1 g of sucralose, 0.5 g of purified stevia extract, 2.81 g of citric acid hydrate, and 4.69 g of DL-malic acid were charged into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was charged and kneaded. The resulting product was designated as kneaded I powder. (3) 19.7 g of oseltamivir phosphate with a cumulative 50% particle diameter of 96 μm based on volume and 10 g of talc were charged into the wet high-shear granulator containing the kneaded I powder and further kneaded. (4) The product obtained in (3) was passed through a dry granulator (screen diameter 6350 μm) and crushed. This was designated as kneaded powder II. (5) The kneaded powder II was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (6) The dried product obtained in (5) was sized by passing it through a dry granulator (screen diameter 1575 μm). (7) The sized powder obtained in (6) and 0.5 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture value of the obtained dry syrup agent was 0.1%. The amounts of components contained per dose are shown in Table 1.

[0050] 〔Comparative Example 4〕 (1) 9 g of hydroxypropyl cellulose was dissolved in 36 g of purified water. (2) 435.9 g of powdered reduced maltose syrup, 7.5 g of crospovidone, 10 g of croscarmellose sodium, 7.5 g of sucralose, 0.15 g of citric acid hydrate, and 0.25 g of DL-malic acid were charged into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was charged and kneaded. The resulting product was designated as kneaded I powder. (3) 19.7 g of oseltamivir phosphate with a cumulative 50% particle diameter of 96 μm based on volume and 10 g of talc were charged into the wet high-shear granulator containing the kneaded I powder and further kneaded. (4) The product obtained in (3) was passed through a dry granulator (screen diameter: 6350 μm) for crushing. This was designated as the blended powder II. (5) The blended powder II was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (6) The dried product obtained in (5) was sized by passing it through a dry granulator (screen diameter: 1575 μm). (7) The sized powder obtained in (6) and 0.5 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.4%. The amounts of components contained per dose are shown in Table 1.

[0051] [Comparative Example 5] (1) 9 g of hydroxypropyl cellulose was dissolved in 36 g of purified water. (2) 436.3 g of powdered reduced maltose syrup, 7.5 g of crospovidone, 10 g of croscarmellose sodium, and 7.5 g of sucralose were put into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was added and kneaded. The product obtained was designated as the blended powder I. (3) 19.7 g of oseltamivir phosphate with a cumulative volume-based particle diameter of 96 μm and 10 g of talc were added to the wet high-shear granulator containing the blended powder I and further kneaded. (4) The product obtained in (3) was passed through a dry granulator (screen diameter: 6350 μm) for crushing. This was designated as the blended powder II. (5) The blended powder II was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (6) The dried product obtained in (5) was sized by passing it through a dry granulator (screen diameter: 1575 μm). (7) The sized powder obtained in (6) and 0.5 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.2%. The amounts of components contained per dose are shown in Table 1.

[0052] [Example 1] (1) 945 g of hydroxypropyl cellulose was dissolved in 3680 g of purified water. (2) 45,770 g of powdered reduced maltose syrup, 827.5 g of talc, 787.5 g of crospovidone, 1,050 g of croscarmellose sodium, 682.5 g of sucralose, 105 g of purified stevia extract, 15.75 g of citric acid hydrate, and 26.25 g of DL - malic acid were charged into a wet high - shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was charged and kneaded. The resulting product was designated as kneaded I powder. (3) 2,069 g of oseltamivir phosphate with a cumulative volume - based particle diameter of 96 μm and 222.5 g of talc were charged into the wet high - shear granulator containing the kneaded I powder and further kneaded. (4) The product obtained in (3) was passed through a dry sieving machine (screen diameter 6,350 μm) and crushed. This was designated as kneaded powder II. (5) The kneaded powder II was put into an extrusion granulator, granulated, and then dried in a fluidized - bed dryer. (6) The dried product obtained in (5) was passed through a dry sieving machine (screen diameter 1,575 μm) for sieving. (7) The sieved powder obtained in (6) and 1.3 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.5%, and the pH when 10 mg of the preparation was dispersed in 40 ml of water was 5.0. The amount of components contained per dose is shown in Table 1.

[0053] 〔Evaluation method〕 The evaluation of the bitterness, sourness, and sweetness intensities of the dry syrup agents of the comparative examples and Example 1 was carried out by conducting a sensory test using 13 subjects. In this sensory test, the bitterness, sourness, and sweetness of the dry syrup agents of each comparative example and example were quantified and evaluated. The detailed procedures and evaluation criteria are shown below. (1) 5.0 g of the dry syrup agent obtained in the comparative examples and examples was dissolved in 20 mL of water, and stirred well so that the dry syrup agent was uniformly dispersed to obtain Solution 1. (2) The subjects put 2 mL of Solution 1 obtained in (1) into their mouths, held it in the mouth for 10 seconds and then spat it out, and evaluated the bitterness, sourness, and sweetness according to the criteria shown below. The average scores of the 13 subjects are shown in Table 1. (Evaluation of Bitterness) 0 points: Not bitter at all 1 point: Hardly bitter 2 points: Slightly bitter 3 points: Bitter 4 points: Very bitter Here, when the average score of the subjects is 1.5 or less, it can be said that the bitterness is suppressed. In Table 1, A and B respectively mean the following. A: The average score of the subjects is 1.5 or less, and the bitterness is suppressed B: The average score of the subjects is more than 1.5, and the bitterness is not suppressed (Evaluation of Sourness) 0 points: Not sour at all 1 point: Hardly sour 2 points: Slightly sour 3 points: Sour 4 points: Very sour Here, when the average score of the subjects is 2.0 or more, it can be said that the sourness is too strong and thus it is an unpleasant taste. In Table 1, A and B respectively mean the following. A: The average score of the subjects is less than 2.0, and the unpleasant taste due to sourness does not occur B: The average score of the subjects is 2.0 or more, and the unpleasant taste due to sourness occurs (Evaluation of Sweetness) 0 points: Not sweet at all 1 point: Hardly sweet 2 points: Slightly sweet 3 points: Sweet 4 points: Very sweet

[0054]

Table 1

[0055] From the results of Comparative Example 1, it was confirmed that when the weight of the active ingredient having bitterness was 100 parts by weight and the total content of the sweetener was less than 13 parts by weight, the bitterness derived from the active ingredient could not be suppressed. Further, from the results of Comparative Examples 4 and 5, it was also confirmed that when only one type of sweetener was blended, the bitterness derived from the active ingredient could not be suppressed. Furthermore, from the results of Comparative Example 3, when an acidulant was blended, when the total content of the acidulant exceeded 30 parts by weight with the weight of the active ingredient having bitterness or the total content of the sweetener being 100 parts by weight, an unpleasant taste was caused by the excessive sourness and the swallowability was not improved. On the other hand, in Example 1, it was confirmed that the bitterness derived from the active ingredient was suppressed and no unpleasant taste due to sourness occurred. From these results, it became clear that when the number of types and blending amounts of the sweeteners to be blended and the blending amount of the acidulant are within the scope of the present invention, the bitterness derived from the active ingredient is suppressed and the swallowability is improved.

[0056] [Example 2] (1) 23.4 g of hydroxypropylcellulose was dissolved in 221 g of purified water. (2) 51.22 g of oseltamivir phosphate with a volume-based cumulative 50% particle size of 96 μm, 1073.6 g of powdered reduced maltose syrup, 26 g of light anhydrous silicic acid, 52 g of crospovidone, 52 g of croscarmellose sodium, 16.9 g of sucralose, 2.6 g of purified stevia extract, 0.975 g of citric acid hydrate, and 1.3 g of DL-malic acid were put into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (1) was added and kneaded. (3) The product obtained in (2) was passed through a dry granulator (screen diameter 6350 μm) and crushed. This was used as the kneaded powder. (4) The kneaded powder was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was sized through a dry granulator (screen diameter 1575 μm). (6) The sized powder obtained in (5) and 1.3 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture value of the obtained dry syrup agent was 0.8%. The amount of components contained per dose is shown in Table 2.

[0057] [Example 3] (1) 23.4 g of hydroxypropyl cellulose was dissolved in 195 g of purified water. (2) 51.22 g of oseltamivir phosphate with a cumulative 50% particle size of 96 μm based on volume, 1062.9 g of powdered reduced maltose syrup, 52 g of talc, 39 g of crospovidone, 52 g of croscarmellose sodium, 16.9 g of sucralose, and 2.6 g of purified stevia extract were put into a wet high-shear granulator and mixed. Subsequently, the entire amount of the solution obtained in (1) was added and kneaded. (3) The product obtained in (2) was passed through a dry granulator (screen diameter 6350 μm) and crushed. This was used as the kneaded powder. (4) The kneaded powder was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was passed through a dry granulator (screen diameter 1575 μm) for sizing. (6) The sized powder obtained in (5) and 1.3 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.7%. The amounts of components contained per dose are shown in Table 2.

[0058] [Example 4] (1) 23.4 g of hydroxypropyl cellulose was dissolved in 195 g of purified water. (2) 51.22 g of oseltamivir phosphate with a cumulative 50% particle size of 96 μm based on volume, 1061.8 g of powdered reduced maltose syrup, 52 g of talc, 39 g of crospovidone, 52 g of croscarmellose sodium, 16.9 g of sucralose, 2.6 g of purified stevia extract, 0.39 g of citric acid hydrate, and 0.65 g of DL-malic acid were put into a wet high-shear granulator and mixed. Subsequently, the entire amount of the solution obtained in (1) was added and kneaded. (3) The product obtained in (2) was passed through a dry granulator (screen diameter 6350 μm) and crushed. This was used as the kneaded powder. (4) The kneaded powder was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was granulated by passing it through a dry granulator (screen diameter: 1575 μm). (6) The granulated powder obtained in (5) and 1.3 g of banana micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.6%. The amounts of components contained per dose are shown in Table 2.

[0059] [Example 5] (1) 957.3 g of D-mannitol was crushed by passing it through a dry granulator (screen diameter: 1575 μm). (2) 22.5 g of hydroxypropyl cellulose was dissolved in 356 g of purified water. (3) 125 g of lacosamide with a cumulative volume-based 50% particle diameter of 8 μm, the D-mannitol obtained in (1), 50 g of crospovidone, 25 g of light anhydrous silicic acid, 50 g of croscarmellose sodium, 16.25 g of sucralose, 3.75 g of purified stevia extract, and 0.25 g of sodium lauryl sulfate were put into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (2) was added and kneaded. The obtained product was used as the kneaded powder. (4) The kneaded powder obtained in (3) was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was granulated by passing it through a screen with a diameter of 1575 μm. (6) The granulated powder obtained in (5) and 1.25 g of peach micron were mixed in a diffusion mixer to obtain a dry syrup agent. The amounts of components contained per dose are shown in Table 2.

[0060] [Example 6] (1) 957.1 g of D-mannitol was crushed by passing it through a dry granulator (screen diameter: 1575 μm). (2) 22.5 g of hydroxypropyl cellulose was dissolved in 356 g of purified water. (3) Lacosamide 125 g with a volume-based cumulative 50% particle size of 8 μm, D-mannitol obtained in (1), crospovidone 50 g, light anhydrous silicic acid 25 g, croscarmellose sodium 50 g, sucralose 16.25 g, purified stevia extract 3.75 g, citric acid hydrate 0.063 g, DL-malic acid 0.063 g, and sodium lauryl sulfate 0.25 g were charged into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (2) was charged and kneaded. The resulting product was used as the kneaded powder. (4) The kneaded powder obtained in (3) was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was sized by passing through a dry sieving machine (screen diameter 1575 μm). The volume-based cumulative 50% particle size of the sized powder obtained was 0.4 μm. (6) The sized powder obtained in (5) and 1.25 g of peach micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.2%. The amounts of components contained per dose are shown in Table 2.

[0061] 〔Example 7〕 (1) 957 g of D-mannitol was crushed by passing through a dry sieving machine (screen diameter 1575 μm). (2) 22.5 g of hydroxypropyl cellulose was dissolved in 356 g of purified water. (3) Lacosamide 125 g with a volume-based cumulative 50% particle size of 8 μm, D-mannitol obtained in (1), crospovidone 50 g, light anhydrous silicic acid 25 g, croscarmellose sodium 50 g, sucralose 16.25 g, purified stevia extract 3.75 g, citric acid hydrate 0.125 g, DL-malic acid 0.125 g, and sodium lauryl sulfate 0.25 g were charged into a wet high-shear granulator and mixed. Next, the entire amount of the solution obtained in (2) was charged and kneaded. The resulting product was used as the kneaded powder. (4) The kneaded powder obtained in (3) was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was sized by passing through a dry sieving machine (screen diameter 1575 μm). (6) The whole grains and 1.25 g of peach micron obtained in (5) were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.8%. The amounts of components contained per dose are shown in Table 2.

[0062] [Example 8] (1) 957 g of D-mannitol was crushed by passing through a dry granulator (screen diameter 1575 μm). (2) 22.5 g of hydroxypropyl cellulose was dissolved in 356 g of purified water. (3) 125 g of lacosamide with a cumulative volume-based particle size of 50% of 8 μm, the D-mannitol obtained in (1), 50 g of crospovidone, 25 g of light anhydrous silicic acid, 50 g of croscarmellose sodium, 16.25 g of sucralose, 3.75 g of purified stevia extract, 0.250 g of DL-malic acid, and 0.25 g of sodium lauryl sulfate were put into a wet high-shear granulator and mixed. Then, the entire amount of the solution obtained in (2) was added and kneaded. The obtained product was used as the kneaded powder. (4) The kneaded powder obtained in (3) was put into an extrusion granulator, granulated, and then dried in a fluidized bed dryer. (5) The dried product obtained in (4) was sized by passing through a dry granulator (screen diameter 1575 μm). (6) The sized powder obtained in (5) and 1.25 g of peach micron were mixed in a diffusion mixer to obtain a dry syrup agent. The moisture content of the obtained dry syrup agent was 0.6%. The amounts of components contained per dose are shown in Table 2.

[0063] [Evaluation Method] The evaluation of the examples was carried out by conducting a sensory test using 11 subjects for Examples 2 to 4 and 10 subjects for Examples 5 to 8. In the sensory test, the degree to which the dry syrup agent of the examples of the present application masked bitterness (masking effect) was quantified and compared with the active ingredient. The detailed procedures and evaluation criteria are shown below. (Examples 2 to 4) (1) As the active ingredient, 200 mg of lacosamide was dissolved in 20 mL of water, and the mixture was stirred well to ensure that the lacosamide was uniformly dispersed, obtaining Solution 1. (2) 2.0 g of the dry syrup agent obtained in the example was dissolved in 20 mL of water, and the mixture was stirred well to ensure that the dry syrup agent was uniformly dispersed, obtaining Solution 2. (3) The subject took 2 mL of Solution 1 obtained in (1) above into the mouth, held it in the mouth for 10 seconds, and then spat it out. After rinsing the mouth with water until the taste of Solution 1 was no longer felt, 2 mL of Solution 2 obtained in (2) above was taken into the mouth, held it in the mouth for 10 seconds, and then spat it out, and the evaluation was carried out according to the following criteria (masking effect score). The average score of 11 subjects is shown in Table 2. (Examples 5 to 8) (1) As the active ingredient, 197 mg of oseltamivir phosphate was dissolved in 20 mL of water, and the mixture was stirred well to ensure that the oseltamivir phosphate was uniformly dispersed, obtaining Solution 1. (2) 5.0 g of the dry syrup agent obtained in the example was dissolved in 20 mL of water, and the mixture was stirred well to ensure that the dry syrup agent was uniformly dispersed, obtaining Solution 2. (3) The subject took 2 mL of Solution 1 obtained in (1) above into the mouth, held it in the mouth for 10 seconds, and then spat it out. After rinsing the mouth with water until the taste of Solution 1 was no longer felt, 2 mL of Solution 2 obtained in (2) above was taken into the mouth, held it in the mouth for 10 seconds, and then spat it out, and the evaluation was carried out according to the following criteria (masking effect score). The average score of 10 subjects is shown in Table 2. In Table 2, A means that the bitter taste can be masked. (Masking effect score) 4 points: There is a very strong masking effect 3 points: There is a masking effect 2 points: There is a slight masking effect 1 point: There is a slight masking effect 0 point: There is no masking effect at all

[0064]

Table 2

[0065] From Table 2, in all of Examples 2 to 8, the masking effect score was 3 or more, confirming the presence of a masking effect. That is, also from the results of Examples 2 to 8, it was confirmed that for the pharmaceutical composition according to one embodiment of the present invention, the bitterness derived from the active ingredient can be suppressed. Further, also for Examples 2 to 8, as in Example 1, since the contents of the sweetening agent and / or acidulant are appropriate amounts, it does not result in an unpleasant taste and is considered to be excellent also from the viewpoint of ease of administration.

[0066] 〔Formulation Example〕 The pharmaceutical composition according to one embodiment of the present invention may be manufactured according to the following formulation example.

[0067] 〔Formulation Example 1〕 (1) Pass 945.4 g of D-mannitol through a dry granulator (screen diameter 1575 μm) and crush it. (2) Dissolve 22.5 g of hydroxypropylcellulose in 187.5 g of purified water and 125 g of ethanol. (3) Charge 125 g of lacosamide with a cumulative volume-based particle size of 50% of 8 μm, the D-mannitol obtained in (1), 93.8 g of crospovidone, 31.25 g of light anhydrous silicic acid, 12.5 g of sucralose, 3.75 g of purified stevia extract, 12.5 g of aspartame, 1.25 g of citric acid hydrate, 1.875 g of DL-malic acid, and 0.25 g of sodium lauryl sulfate into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (2) and knead. The resulting product is used as kneaded powder. (4) Put the kneaded powder obtained in (3) into an extrusion granulator, granulate, and then dry it in a fluidized bed dryer. (5) Pass the dried product obtained in (4) through a dry granulator (screen diameter 1575 μm) for sizing. (6) Mix the sized powder obtained in (5) and 1.25 g of peach micron in a diffusion mixer. The amounts of components contained per dose are shown in Table 3.

[0068] 〔Formulation Example 2〕 (1) Pass 944.8 g of D-mannitol through a dry granulator (screen diameter 1575 μm) and crush it. (2) Dissolve 22.5 g of hydroxypropyl cellulose in 187.5 g of purified water and 187.5 g of ethanol. (3) Put 125 g of lacosamide with a cumulative volume-based 50% particle size of 8 μm, the D-mannitol obtained in (1), 93.8 g of crospovidone, 31.25 g of light anhydrous silicic acid, 12.5 g of sucralose, 3.75 g of purified stevia extract, 13.125 g of aspartame, 1.25 g of citric acid hydrate, 1.875 g of DL-malic acid, and 0.25 g of sodium lauryl sulfate into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (2) and knead. The resulting product is taken as the kneaded powder. (4) Put the kneaded powder obtained in (3) into an extrusion granulator, granulate, and then dry it in a fluidized bed dryer. (5) Screen the dried product obtained in (4) through a dry granulator (screen diameter 1575 μm) for sizing. (6) Mix the sized powder obtained in (5) and 1.25 g of peach micron in a diffusion mixer. The amounts of components contained per dose are shown in Table 3.

[0069] [Formulation Example 3] (1) Pass 954.1 g of D-mannitol through a dry granulator (screen diameter 1575 μm) for crushing. (2) Dissolve 22.5 g of hydroxypropyl cellulose in 100 g of purified water and 200 g of ethanol. (3) Put 125 g of lacosamide with a cumulative volume-based 50% particle size of 8 μm, the D-mannitol obtained in (1), 93.8 g of crospovidone, 31.25 g of light anhydrous silicic acid, 15 g of sucralose, 3.75 g of purified stevia extract, 1.875 g of citric acid hydrate, 2.5 g of DL-malic acid, and 0.25 g of sodium lauryl sulfate into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (2) and knead. The resulting product is taken as the kneaded powder. (4) Put the kneaded powder obtained in (3) into an extrusion granulator, granulate, and then dry it in a fluidized bed dryer. (5) Screen the dried product obtained in (4) through a dry granulator (screen diameter 1575 μm) for sizing. (6) Mix the whole granules obtained in (5) and 1.25 g of peach micron with a diffusion mixer. The amounts of ingredients contained per dose are shown in Table 3.

[0070] 〔Formulation Example 4〕 (1) Pass 952.9 g of D-mannitol through a dry granulator (screen diameter 1575 μm) and crush it. (2) Dissolve 22.5 g of hydroxypropyl cellulose in 215 g of purified water. (3) Put 125 g of lacosamide with a cumulative volume-based 50% particle size of 8 μm, the D-mannitol obtained in (1), 93.8 g of crospovidone, 31.25 g of light anhydrous silicic acid, 16.25 g of sucralose, 3.75 g of purified stevia extract, 1.875 g of citric acid hydrate, 2.5 g of DL-malic acid, and 0.25 g of sodium lauryl sulfate into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (2) and knead. The resulting product is defined as the kneaded powder. (4) Put the kneaded powder obtained in (3) into an extrusion granulator, granulate it, and then dry it with a fluidized bed dryer. (5) Pass the dried product obtained in (4) through a dry granulator (screen diameter 1575 μm) for sizing. (6) Mix the sized powder obtained in (5) and 1.25 g of peach micron with a diffusion mixer. The amounts of ingredients contained per dose are shown in Table 3.

[0071] 〔Formulation Example 5〕 (1) Dissolve 945 g of hydroxypropyl cellulose in 7880 g of purified water. (2) Put 2069 g of oseltamivir phosphate with a cumulative volume-based 50% particle size of 96 μm, 42740 g of powder-reduced maltose syrup, 2100 g of talc, 1575 g of crospovidone, 2100 g of croscarmellose sodium, 682.5 g of sucralose, 105 g of purified stevia extract, 78.75 g of citric acid hydrate, and 105 g of DL-malic acid into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (1) and knead. (3) Pass the product obtained in (2) through a dry granulator (screen diameter: 6350 μm) for crushing. This is used as the blended powder. (4) Put the blended powder into an extrusion granulator, granulate it, and then dry it in a fluidized bed dryer. (5) Pass the dried product obtained in (4) through a dry granulator (screen diameter: 1575 μm) for sizing. (6) Mix the sized powder obtained in (5) and 52.5 g of banana micron in a diffusion mixer. The amounts of components contained per dose are shown in Table 3.

[0072] [Formulation Example 6] (1) Dissolve 23.4 g of hydroxypropyl cellulose in 195 g of purified water. (2) Charge 51.22 g of oseltamivir phosphate with a cumulative volume-based 50% particle diameter of 96 μm, 1061.3 g of powdered reduced maltose syrup, 52 g of talc, 39 g of crospovidone, 52 g of croscarmellose sodium, 16.9 g of sucralose, 2.6 g of purified stevia extract, 0.65 g of citric acid hydrate, and 0.91 g of DL-malic acid into a wet high-shear granulator and mix. Then, add the entire amount of the solution obtained in (1) and knead. (3) Pass the product obtained in (2) through a dry granulator (screen diameter: 6350 μm) for crushing. This is used as the blended powder. (4) Put the blended powder into an extrusion granulator, granulate it, and then dry it in a fluidized bed dryer. (5) Pass the dried product obtained in (4) through a dry granulator (screen diameter: 1575 μm) for sizing. (6) Mix the sized powder obtained in (5) and 1.3 g of banana micron in a diffusion mixer. The amounts of components contained per dose are shown in Table 3.

[0073] [Table 3] [Industrial Applicability]

[0074] One aspect of the present invention can be used in pharmaceutical compositions containing an active ingredient having bitterness, etc.

Claims

1. An active ingredient having a bitter taste, Two or more sweeteners with a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having a bitter taste, An acidulant with a total content of more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the total content of the sweeteners, and A pharmaceutical composition.

2. An active ingredient having a bitter taste, Two or more sweeteners with a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having a bitter taste, An acidulant with a total content of more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the weight of the active ingredient having a bitter taste, and A pharmaceutical composition.

3. An active ingredient having a bitter taste, Containing two or more sweeteners with a total content of 13 parts by weight or more based on 100 parts by weight of the weight of the active ingredient having a bitter taste, Without containing an acidulant, The active ingredient having a bitter taste is lacosamide or oseltamivir phosphate, A pharmaceutical composition.

4. A method for producing a pharmaceutical composition containing an active ingredient having a bitter taste, comprising: A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more based on 100 parts by weight of the active ingredient having a bitter taste, and A step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the total content of the sweeteners, A method.

5. A method for producing a pharmaceutical composition containing an active ingredient having a bitter taste, comprising: A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more based on 100 parts by weight of the active ingredient having a bitter taste, and A step of blending an acidulant in an amount such that the total content of the acidulant is more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the active ingredient having a bitter taste, A method.

6. A method for producing a pharmaceutical composition containing an active ingredient having a bitter taste and not containing an acidulant, comprising: A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more based on 100 parts by weight of the active ingredient having a bitter taste, and The active ingredient having a bitter taste is lacosamide or oseltamivir phosphate, A method.

7. A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having a bitter taste, comprising: A step of blending two or more sweeteners in an amount such that the total content of the sweeteners is 13 parts by weight or more based on 100 parts by weight of the active ingredient having a bitter taste, and A step of blending an acidulant in an amount of more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the total content of the sweetener, Method.

8. A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness, comprising: A step of blending two or more sweeteners in an amount of 13 parts by weight or more based on 100 parts by weight of the active ingredient having bitterness, and A step of blending an acidulant in an amount of more than 0 part by weight and not more than 30 parts by weight based on 100 parts by weight of the active ingredient having bitterness, Method.

9. A method for suppressing the bitterness of a pharmaceutical composition containing an active ingredient having bitterness and not containing an acidulant, comprising: A step of blending two or more sweeteners in an amount of 13 parts by weight or more based on 100 parts by weight of the active ingredient having bitterness, The active ingredient having bitterness is lacosamide or oseltamivir phosphate, Method.

10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight based on 100 parts by weight of the active ingredient having bitterness.

11. The method for producing a pharmaceutical composition according to any one of claims 4 to 6, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight based on 100 parts by weight of the active ingredient having bitterness.

12. The method for suppressing the bitterness of a pharmaceutical composition according to any one of claims 7 to 9, wherein the total content of the two or more sweeteners is 13 to 50 parts by weight based on 100 parts by weight of the active ingredient having bitterness.

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