JP7611556B2 - Pharmaceutical composition with excellent intake properties, stability, etc. - Google Patents

Description

The present invention relates to a pharmaceutical composition that contains an unpleasant-tasting drug as an active ingredient and has excellent swallowability, disintegration and dissolution properties, and storage stability.

For drugs that have unpleasant tastes such as bitterness or numbness, various formulation techniques are known for masking the unpleasant taste.
For example, Patent Document 1 discloses a fine granule preparation in which a core containing a bitter pharmacologically active ingredient is spray-coated with an aqueous suspension of ethyl cellulose and a water-soluble plasticizer as a bitterness suppressing layer.
For orally disintegrating tablets and chewable tablets, a masking technique using a sweetener as disclosed in Patent Document 2 and a method using a coating agent are also known.
Orally disintegrating tablets are more susceptible to problems such as delayed disintegration time due to moisture absorption and other factors than general tablets, and consideration must be given to ease of administration, such as avoiding unpleasant taste, while excellent disintegration and dissolution properties are also required.
In the oral administration formulation disclosed in Patent Document 3, the bitter taste of silodosin, a drug having a bitter taste, is masked by granulating or coating it with a coating agent containing a non-enteric polymer.
However, polymers such as non-enteric polymers have the property of softening when moistened or heated, which affects the disintegration properties of the preparation.
In particular, in polymers with low glass transition temperatures, the delay in disintegration time becomes more pronounced.
Therefore, in addition to improving ease of administration through masking technology, there is a demand for formulations that are excellent in disintegration, dissolution, and storage stability.

JP 2000-53563 A JP 2018-177706 A Patent No. 6392207

The present invention aims to provide a pharmaceutical composition that contains a drug with an unpleasant taste and has excellent swallowability, disintegration and dissolution properties, and storage stability.

The pharmaceutical composition according to the present invention is characterized by comprising a granule containing a drug having an unpleasant taste and a water-insoluble polymer.
Here, a drug having an unpleasant taste is a drug that has an unpleasant taste such as bitterness or numbness, and as will be described later, many drugs are subject to this.
Representative examples include eszopiclone, esomeprazole, silodosin, zonisamide, pitavastatin, vildagliptin, and ramelteon, preferably ramelteon.
The water-insoluble polymer is intended to exclude so-called water-soluble polymers that are easily soluble in water, and includes those generally expressed as gastrosoluble polymers, enteric polymers, sustained-release polymers, and the like.
In the present invention, the granulated material refers to a material obtained by using a binder or the like to turn a powdery raw material into granules having a particle size larger than that of the raw material.

The pharmaceutical composition according to the present invention includes an embodiment in which the composition is made of a granulated product that contains a drug having an unpleasant taste and a water-insoluble polymer and does not contain a lubricant such as talc.
It is particularly preferable that the granules do not contain talc, but other lubricants may be contained within the range that does not significantly affect the disintegration property, dissolution property, and storage stability.
Here, if the granules do not contain a lubricant such as talc, it is permissible for a lubricant to be contained in the subsequent formulation process.

The pharmaceutical composition according to the present invention also includes an embodiment comprising a sugar-coated granule comprising a granule containing a drug having an unpleasant taste and a water-insoluble polymer, and a sugar alcohol sprayed onto the granule.
In this case, examples of the sugar alcohol include D-mannitol, maltitol, erythritol, reduced isomaltulose, lactitol, and xylitol.
In this case too, it is preferable that the granules do not contain a lubricant such as talc.
In the present invention, the effect is achieved by spraying sugar alcohol onto the granulated material, and preferably, 1 to 50% by mass of sugar alcohol is sprayed onto the granulated material.

In the present invention, the water-insoluble polymer is preferably contained in an amount of 0.5 to 75% by mass relative to the granules, and the water-insoluble polymer is preferably one or more selected from the group consisting of aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer RL, and ethyl acrylate-methyl methacrylate copolymer dispersion.

The pharmaceutical composition according to the present invention, by incorporating a water-insoluble polymer in the granules, reduces unpleasant tastes such as bitterness and numbness that are associated with certain drugs.
Furthermore, by preventing the inclusion of a lubricant in the granules, delayed disintegration and dissolution of the pharmaceutical composition containing a water-insoluble polymer are suppressed, improving the storage stability of the pharmaceutical composition.
The granules used in the present invention can be further improved in disintegration property, dissolution property, etc. by coating the granules with sugar alcohol by spraying the granules with sugar after granulation.

The present invention relates to a pharmaceutical composition comprising a granule containing a drug having an unpleasant taste and a water-insoluble polymer.

In the present invention, the unpleasant taste refers to a taste that humans find unpleasant, such as bitterness, astringency, harshness, sourness, numbness, or roughness.
Among these, it is particularly preferable to apply it to drugs that have bitter or numbing effects.
Representative examples of drugs having an unpleasant taste include eszopiclone, esomeprazole, silodosin, zonisamide, pitavastatin, vildagliptin, and ramelteon, preferably ramelteon.
Drugs other than those mentioned above include acarbose, acyclovir, azithromycin hydrate, ascorbic acid, ascorbic acid/calcium pantothenate, aspirin/dialuminate, sodium azulenesulfonate hydrate, sodium azulenesulfonate hydrate/L-glutamine, acetaminophen, atenolol, atovaquone, atomoxetine hydrochloride, atorvastatin calcium hydrate, amiodarone hydrochloride, sodium amidotrizoate meglumine, ethyl aminobenzoate, aminophylline, amlodipine besylate, amoxicillin hydrate, aripiprazole, alimemazine tartrate, sodium alginate, albendazole, Antipyrine, ampicillin hydrate, ambroxol hydrochloride, isosorbide, itraconazole, ibuprofen, irbesartan, indomethacin, ecabet sodium hydrate, ethambutol hydrochloride, ethosuximide, ebastine, epinastine hydrochloride, epinephrine hydrochloride, epirizole, ephedrine hydrochloride, entecavir hydrate, oxycodone hydrochloride hydrate, oseltamivir phosphate, olanzapine, olmesartan medoxomil, olopatadine hydrochloride, ondansetron, kanamycin monosulfate, galantamine hydrobromide, calciferol combination drug, carteolol hydrochloride, carbocisteine, candesartan cilexeti le, guaifenesin, quetiapine fumarate, magnesium citrate, sodium ferrous citrate, ferrous ammonium citrate, granisetron hydrochloride, clavulanate potassium, clarithromycin, glimepiride, clemastine fumarate, clocapramine hydrochloride hydrate, chlorpheniramine maleate, ketotifen fumarate, ketoprofen, codeine phosphate, colistin sodium methanesulfonate, salbutamol sulfate, sarpogrelate hydrochloride, diclofenac sodium, sitafloxacin hydrate, dihydrocodeine phosphate, diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate Salt/Diprophylline, Dibucaine hydrochloride combination, Cyproheptadine hydrochloride hydrate, Dimethicone, Dimemorfan phosphate, Sildenafil citrate, Cilostazol, Simvastatin, Sucralfate hydrate, Stiripentol, Sumatriptan succinate, Sultamicillin tosilate hydrate, Sulpyrine, Cetirizine hydrochloride, Cetylpyridinium combination, Cetraxate hydrochloride, Cephalexin, Cefcapene pivoxil hydrochloride hydrate, Cefditoren pivoxil, Cefdinir, Cefteram pivoxil, Cefpodoxime proxetil, Selegiline hydrochloride, Zolpidem tartrate, Zolmitriptan, Tamsulosin hydrochloride, Taltirelin hydrate substances, tiaramide hydrochloride, tipepidine hibenzate, theophylline, tegafur/gimeracil/oteracil potassium combination drug, dextromethorphan hydrobromide, dexamethasone, telmisartan, docarpamine, doxazosin mesilate, tosufloxacin tosilate hydrate, donepezil hydrochloride, tranexamic acid, tramadol hydrochloride, triazolam, triamcinolone acetonide, trimetoquinol hydrochloride hydrate, droxidopa, troxipide, domperidone, sodium/potassium/ascorbic acid combination drug, sodium/potassium combination drug, naftopidil, naproxen, nalidixic acid, nifedipine, valacyclovir hydrochloride, para Diethylaminoethyl butylaminobenzoate hydrochloride, valsartan, sodium valproate, paroxetine hydrochloride hydrate, pioglitazone hydrochloride, bicalutamide, sodium picosulfate hydrate, vitamin A, hydroxyzine pamoate, hydrochlorothiazide, pipamperone hydrochloride, bifidobacterium preparation, pyrantel pamoate, famotidine, faropenem sodium hydrate, fexofenadine hydrochloride, phenacetin, phenylbutazone, phenylpropanolamine hydrochloride, phenobarbital, sodium fluoride, pranoprofen, pravastatin sodium, pranlukast hydrate, flecainide acetate, pregabalin, bromine Tizolam, procaterol hydrochloride, propranolol hydrochloride, bepotastine besilate, benzalkonium chloride, benzylpenicillin benzathine hydrate, benzbromarone, benzethonium chloride, pentazocine, pentoxyverine citrate, voglibose, fosfomycin calcium hydrate, bosentan hydrate, povidone-iodine, polaprezinc, polycarbophil calcium, polystyrene sulfonate calcium, miglitol, mycophenolate mofetil, mizoribine, mitiglinide calcium hydrate, mequitazine, methylephedrine hydrochloride, metoclopramide, metronidazole, mefenamic acid, mebendazole, meman cinnamon hydrochloride, meloxicam, mosapride citrate hydrate, morphine sulfate hydrate, montelukast sodium, potassium iodide, lactomin, lafutidine, ramosetron hydrochloride, lamotrigine, lansoprazole, rizatriptan benzoate, risperidone, lidocaine hydrochloride, ritonavir, rilmazafone hydrochloride hydrate, retinol, retinol palmitate, rebamipide, levetiracetam, levocarnitine, levocetirizine hydrochloride, levofloxacin hydrate, roxatidine acetate hydrochloride, loxoprofen sodium hydrate, rosuvastatin calcium, lopinavir, ropinirole hydrochloride, loratadine and the like.
These may be used alone or in combination of two or more.

The water-insoluble polymer in the present invention refers to polymers other than those generally called water-soluble polymers, such as gastro-soluble polymers, enteric polymers and sustained-release polymers.
Examples of the stomach-soluble polymer include polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) EPO, Eudragit (registered trademark) E100, etc.), which is an acrylic polymer compound.
Examples of enteric polymers include cellulose-based polymer compounds such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and carboxymethylethylcellulose, and acrylic polymer compounds such as methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S.
Examples of sustained-release polymers include cellulose acetate, ethyl cellulose, vinyl acetate resins, and the like, as well as acrylic polymer compounds such as ammonioalkyl methacrylate copolymer RS (Eudragit (registered trademark) RS100, Eudragit (registered trademark) RSPO, Eudragit (registered trademark) RS30D, etc.), ammonioalkyl methacrylate copolymer RL (Eudragit (registered trademark) RL, Eudragit (registered trademark) RLPO, Eudragit (registered trademark) RL30D, etc.), and ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit (registered trademark) NE30D, etc.).
In the present invention, the above water-insoluble polymers may be used alone or in combination of two or more kinds.
In the present invention, the water-insoluble polymer is contained in an amount of preferably 0.5 to 75% by mass, more preferably 1 to 50% by mass, and particularly preferably 2 to 25% by mass, based on the granules.
The water-insoluble polymer used in the present invention is preferably an acrylic polymer compound, and more preferably an acrylic polymer compound having a glass transition temperature of 70° C. or lower.
Examples of acrylic polymer compounds having a glass transition temperature of 70° C. or less include aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer RL, and ethyl acrylate-methyl methacrylate copolymer dispersion.

The granulation method used in the present invention can be any commonly used granulation method, such as a wet granulation method or a dry granulation method.
The granulator may be appropriately selected from known granulators such as a fluidized bed granulator, a tumbling fluidized bed granulator, a Wurster type granulator, an agitator granulator, etc.

Orally administrable dosage forms include solid preparations such as tablets (including plain tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, drops, film-coated tablets, sugar-coated tablets, caplets, and pills), troches, powders, fine granules, granules, dry syrup, and capsules (including soft capsules and hard capsules); semi-solid preparations such as jellies; and liquid preparations such as liquids, suspensions, and syrups. Among these dosage forms, solid preparations are preferred from the viewpoints of the stability and portability of the ingredients contained therein.
In the pharmaceutical composition of the present invention, solid preparations prepared via granulation include tablets, troches, granules, dry syrups, hard capsules, and the like.
Among these, tablets, particularly orally disintegrating tablets which are easy to take even for people with poor swallowing ability, are preferred.

It is preferable that the granules used in the present invention do not contain a lubricant. Examples of lubricants include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, sucrose fatty acid esters, and hardened oils, and it is particularly preferable that the granules do not contain talc.
Furthermore, if a lubricant is not included in the granules, it may be included in the subsequent formulation process.

In the pharmaceutical composition according to the present invention, the granules may be sugar-coated granules onto which a sugar alcohol is sprayed.
Examples of sugar alcohols include D-mannitol, maltitol, erythritol, reduced isomaltulose, lactitol, and xylitol, and in consideration of taste and the like, D-mannitol is particularly preferred.
In this case, the sugar-coated granules are preferably formed by spraying 1 to 50% by mass of sugar alcohol onto the granules, more preferably 5 to 40% by mass, and particularly preferably 10 to 30% by mass.
Although the present invention is characterized in that the sugar alcohol is sprayed onto the granulated material, there is no limitation to adding the sugar alcohol in other formulation steps, for example, as an additive contained in the granulated material or during the formulation process after granulation.

The pharmaceutical composition according to the present invention may contain additives commonly used in this field, such as excipients, disintegrants, flavoring agents, colorants, etc., in addition to the above-mentioned water-insoluble polymers, lubricants, and sugar alcohols.
The excipient is not particularly limited, and suitable combinations of corn starch, lactose hydrate, crystalline cellulose, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, anhydrous calcium hydrogen phosphate, calcium carbonate, etc. may be used.
The disintegrant is not particularly limited, but low-substituted hydroxypropyl cellulose, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, etc. can be used.
The flavoring agent is not particularly limited, but sucralose, cyclodextrin, citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, DL-alanine, etc. can be used.
The colorant is not particularly limited, but yellow ferric oxide, ferric oxide, edible tar dyes, natural dyes, and the like can be used.

The present invention will be specifically explained below using ramelteon as an example of the active ingredient or drug, but the present invention is not limited to these examples.

96 g of ramelteon, 80.04 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences), and 116.4 g of corn starch (manufactured by Nippon Shokuhin Kako) were placed in a fluidized bed granulator (manufactured by Powrex: MP-01), and a solution prepared by dissolving and dispersing 18 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Nutrition & Care) and 0.36 g of yellow ferric oxide (manufactured by Kishi Chemicals) in 360 g of ethanol and 90 g of purified water was sprayed onto the mixture, followed by granulation to obtain a granule containing ramelteon.
The resulting granules were dried and sieved through a 22 mesh sieve to obtain a sized product.
To 12.95 g of the obtained granules, 43.9 g of D-mannitol (manufactured by Freund Corporation), 4.55 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 2.9 g of crystalline cellulose (manufactured by Asahi Kasei Corporation), 0.05 g of yellow ferric oxide (manufactured by Kishi Chemical Industries, Ltd.), and 0.65 g of magnesium stearate (manufactured by NOF Corp.) were added and mixed in a polyethylene bag to prepare a mixture for tableting.
This mixture was compressed into tablets using a rotary tablet press (VELA5, manufactured by Kikusui Seisakusho) to obtain tablets.

Ramelteon (1,080 g), D-mannitol (Mitsubishi Corporation Life Sciences), 1,737.45 g, and corn starch (Nihon Shokuhin Kako), 540 g, were placed in a fluidized bed granulator (FLO-5M, Freund Corporation), and a solution prepared by dissolving and dispersing 135 g of aminoalkyl methacrylate copolymer E (Evonik Nutrition & Care), and 4.05 g of yellow ferric oxide (Kisi Kasei), in 2,700 g of ethanol and 675 g of purified water, was sprayed onto the mixture, and the mixture was granulated to obtain a granule containing ramelteon.
The resulting granules were dried and sieved through a 22 mesh sieve to obtain a sized product.
A solution of 550 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences) in 4950 g of purified water was sprayed onto 2849 g of the resulting sized product, followed by granulation to obtain sugar-coated granules.
The obtained sugar-coated granules were dried and sieved through a 22 mesh sieve to obtain sugar-coated sized particles.
To 2935.5 g of the obtained sugar-coated granules, 7384.35 g of D-mannitol (manufactured by Freund Corporation), 1235 g of low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 551 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.), 123.5 g of sucralose (manufactured by San-Ei Gen F.F.I.), 9.5 g of yellow ferric oxide (manufactured by Kishi Chemical Co., Ltd.), and 123.5 g of magnesium stearate (manufactured by NOF Corp.) were added and mixed in a diffusion mixer (manufactured by Tokuju Machinery Works, Ltd.: V-60 type) to prepare a mixture for tableting.
This mixture was compressed into tablets using a rotary tablet press (VIRGO, manufactured by Kikusui Seisakusho) to obtain tablets.

Reference Example

Ramelteon (1,080 g), D-mannitol (Mitsubishi Corporation Life Sciences) (967.95 g), and corn starch (Nihon Shokuhin Kako) (1,309.5 g) were placed in a fluidized bed granulator (FLO-5M, Freund Corporation), and a solution prepared by dissolving and dispersing 135 g of aminoalkyl methacrylate copolymer E (Evonik Nutrition & Care) and 4.05 g of yellow ferric oxide (Kishi Chemicals) in 2,700 g of ethanol and 675 g of purified water was sprayed onto the mixture, followed by granulation to obtain a granule containing ramelteon.
The resulting granules were dried and sieved through a 22 mesh sieve to obtain a sized product.
To 2,849 g of the obtained granules, 9,086 g of D-mannitol (manufactured by Freund Corporation), 1,430 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 638 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.), 143 g of sucralose (manufactured by San-Ei Gen F.F.I.), 11 g of yellow ferric oxide (manufactured by Kishi Chemical Co., Ltd.), and 143 g of magnesium stearate (manufactured by NOF Corp.) were added and mixed in a diffusion mixer (manufactured by Tokuju Machinery Works, Ltd.: V-60 type) to prepare a mixture for tableting.
This mixture was compressed into tablets using a rotary tablet press (VIRGO, manufactured by Kikusui Seisakusho) to obtain tablets.

Comparative Example 1

24 g of ramelteon, 269.91 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences), and 29.1 g of corn starch (manufactured by Nippon Shokuhin Kako) were placed in a fluidized bed granulator (Powrex: MP-01), and a solution prepared by dissolving and dispersing 12 g of hydroxypropyl cellulose (manufactured by Nippon Soda) and 0.39 g of yellow ferric oxide (manufactured by Kishi Chemicals) in 188 g of purified water was sprayed onto the mixture, followed by granulation to obtain a granule containing ramelteon.
The resulting granules were dried and sieved through a 22 mesh sieve to obtain a sized product.
To 55.9 g of the obtained sized product, 4.55 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 2.9 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.), 0.65 g of sucralose (manufactured by San-Ei Gen F.F.I.), and 1 g of sodium stearyl fumarate (manufactured by JRS Pharma) were added and mixed in a polyethylene bag to prepare a mixture for tableting.
This mixture was compressed into tablets using a rotary tablet press (VELA5, manufactured by Kikusui Seisakusho) to obtain tablets.

Comparative Example 2

88 g of ramelteon, 65.12 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences), and 106.7 g of corn starch (manufactured by Nippon Shokuhin Kako) were placed in a fluidized bed granulator (manufactured by Powrex: MP-01), and a solution prepared by dissolving and dispersing 16.5 g of aminoalkyl methacrylate copolymer E (manufactured by Evonik Nutrition & Care), 8.25 g of talc (manufactured by Matsumura Sangyo), and 0.33 g of yellow ferric oxide (manufactured by Kishi Kasei) in 330 g of ethanol and 82.5 g of purified water was sprayed onto the mixture, followed by granulation to obtain a granule containing ramelteon.
The resulting granules were dried and sieved through a 22 mesh sieve to obtain a sized product.
To 38.5 g of the obtained granules, 131.7 g of D-mannitol (manufactured by Freund Corporation), 13.65 g of low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 8.7 g of crystalline cellulose (manufactured by Asahi Kasei Corporation), 0.15 g of yellow ferric oxide (manufactured by Kishi Chemical Industries, Ltd.), and 1.95 g of magnesium stearate (manufactured by NOF Corp.) were added and mixed in a polyethylene bag to prepare a mixture for tableting.
This mixture was compressed into tablets using a rotary tablet press (VELA5, manufactured by Kikusui Seisakusho) to obtain tablets.

Formulation examples for comparative evaluation of the tablets in the above Examples 1 and 2 and Comparative Example 1 are shown in Table 1 below.

[Test Example 1] Sensory Test of Orally Disintegrating Tablets For the orally disintegrating tablets obtained in Examples 1 and 2 and Comparative Example 1 above, a sensory test was conducted in which 4 to 5 subjects placed one tablet of each type in their mouths and evaluated the bitterness, numbness, and overall taste on a scale of 1 to 5.
The time required for the tablet to disintegrate in the oral cavity was evaluated as the oral disintegration time.
The results are shown in Table 2.

The results in Table 2 show that, compared with Comparative Example 1 in which the granules did not contain aminoalkyl methacrylate copolymer E, Examples 1 and 2, which contained aminoalkyl methacrylate copolymer E, reduced the unpleasant taste derived from the active pharmaceutical ingredient.
The evaluations of the numbness and overall taste were particularly notable.
Moreover, the oral disintegration time was shorter than that of Comparative Example 1, and it was confirmed that the tablet was a good oral disintegrating tablet.

Formulation examples for comparative evaluation of the tablets in Example 1 and Comparative Example 2 are shown in Table 3 below.

[Test Example 2] Disintegration test and dissolution test (test liquid: water) 40°C, 75% RH, 1 month The orally disintegrating tablets obtained in Example 1 and Comparative Example 2 were stored in the open for 1 month at 40°C, 75% RH, and the disintegration property and dissolution property were evaluated.
The disintegration test was carried out according to the disintegration test method of the 17th edition of the Japanese Pharmacopoeia, and the disintegration time of the tablets was measured.
The dissolution test was performed according to the dissolution test method (paddle method) of the 17th Edition of the Japanese Pharmacopoeia, using water as the test liquid and measuring the dissolution rate at 50 rpm and 15 minutes.
The results are shown in Table 4.

The results in Table 4 show that in Comparative Example 2, in which talc as a lubricant was blended in the granules, delays in disintegration and dissolution were significant after one month of storage under open conditions at 40°C, 75% RH, whereas in Example 1, in which talc was not blended in the granules, changes in both disintegration time and dissolution rate were small.
Polymers such as aminoalkyl methacrylate copolymer E are easily softened by absorbing moisture or heating, and it is presumed that the softened polymer fills the gaps between particles, reducing the voids within the tablet, thereby reducing the water conductivity necessary for the tablet to disintegrate quickly.
Furthermore, the softened polymer has high adhesiveness, and the interparticle bonding force is strengthened, which is thought to delay the disintegration time of granules and tablets.
Generally, lubricants such as talc are used to prevent adhesion, and it is assumed that they suppress the above phenomenon.
However, not incorporating talc into the granules suppresses this delayed disintegration and dissolution, resulting in improved storage stability of the pharmaceutical composition.

Formulation examples for comparative evaluation of the tablets in Example 2 and Reference Example are shown in Table 5 below.

Test Example 3 Dissolution test (test liquid: water) at 40° C. and 75% RH for 10 days The orally disintegrating tablets obtained in Example 2 and Reference Example were stored in the open at 40° C. and 75% RH for 10 days, and the dissolution properties were evaluated.
The dissolution test was performed according to the dissolution test method (paddle method) of the 17th Edition of the Japanese Pharmacopoeia, using water as the test liquid and measuring the dissolution rate at 50 rpm and 15 minutes.
The results are shown in Table 6.

The reference examples shown in Table 5 are included in the scope of the examples of the present invention, but are presented as reference examples for comparison with Example 2 in order to compare the case where an aqueous solution of D-mannitol is sprayed onto the granulated material and additional granulation is performed with the case where a sugar alcohol such as D-mannitol is not sprayed and additional granulation is not performed.
Considering the results in Table 6 from this perspective, it can be seen that the dissolution property was further improved by spray coating with sugar alcohol.
It is believed that the additional granulation of D-mannitol covered the aminoalkyl methacrylate copolymer E exposed on the surface of the granules, thereby mitigating the effect on the formulation.

Claims (3)

The pharmaceutical composition comprises a sugar-coated granule comprising a drug having an unpleasant taste and an acrylic polymer compound , and not containing a lubricant, hydroxypropyl cellulose, ethyl cellulose or crystalline cellulose , and a sugar alcohol sprayed onto the granule. The pharmaceutical composition according to claim 1, wherein the acrylic polymer compound is one or more selected from the group consisting of aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer RL, and ethyl acrylate-methyl methacrylate copolymer dispersion . An orally disintegrating tablet comprising the pharmaceutical composition according to claim 1 or 2 .