Film preparation

Abstract

To provide a film preparation in which bitterness of loperamide or a salt thereof is reduced by identifying a bitterness-masking agent highly effective for loperamide or a salt thereof and formulating the bitterness-masking agent into a base of the film preparation so as to lessen unpleasant sensations during oral administration.SOLUTION: A film preparation is formed mainly from a base and loperamide or a pharmaceutically acceptable salt of loperamide incorporated into the base, and a bitterness-masking agent. As the bitterness-masking agent, β-cyclodextrin, ι-carrageenan, λ-carrageenan, or calcium lactate can be used.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a film preparation, and in particular to a film preparation in which the bitterness of loperamide is reduced. [Background technology]

[0002] Loperamide and pharmaceutically acceptable salts of loperamide have been known as active ingredients in antidiarrheal agents. However, loperamide and loperamide salts have a very strong bitter taste, which can cause discomfort when administered orally. Therefore, it is desirable to mask the bitter taste to make them easier to take. For example, Patent Document 1 describes the application of loperamide hydrochloride to a film preparation that dissolves or disintegrates in the oral cavity, and the formation of a coating layer on both sides of the film preparation to mask the bitter taste. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent No. 5624472 Summary of the Invention [Problem to be solved by the invention]

[0004] In conventional film preparations in which the bitter taste of loperamide hydrochloride is masked by a coating layer as described above, the bitter taste may become more noticeable as the film preparation dissolves or disintegrates due to the extremely strong bitter taste of loperamide hydrochloride and the film preparation's tendency to dissolve or disintegrate. Thus, masking the bitter taste with a coating layer may not be sufficient to suppress the bitter taste.

[0005] The present invention has been made to solve the above-mentioned problems, and aims to provide a film preparation that is less likely to cause discomfort when orally administered by discovering a bitterness-masking agent that is particularly effective for loperamide or loperamide salts, and incorporating the bitterness-masking agent into the base of a film preparation to suppress the bitterness of loperamide or loperamide salts. [Means for solving the problem]

[0006] In order to achieve the above object, the first invention is a film formulation comprising a base, loperamide or a pharmaceutically acceptable salt of loperamide, and a bitterness-masking agent, wherein the bitterness-masking agent is any one of β-cyclodextrin, ι-carrageenan, λ-carrageenan, and calcium lactate.

[0007] When configured in this manner, the bitterness of loperamide or a salt of loperamide is suppressed by the bitterness masking agent, resulting in a film preparation that is less likely to cause discomfort when orally administered.

[0008] The second invention is a film formulation according to the first invention, wherein the bitterness-masking agent is β-cyclodextrin, and the content of β-cyclodextrin is 254 times or more and 600 mg or less of the amount of loperamide or a pharmaceutically acceptable salt of loperamide.

[0009] When configured in this manner, the bitter taste of loperamide or a salt of loperamide is more effectively suppressed by β-cyclodextrin, resulting in a film preparation that is less likely to cause discomfort when orally administered.

[0010] The third invention is a film formulation according to the first invention, wherein the bitterness masking agent is ι-carrageenan and the content of ι-carrageenan is 0.0036 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide and 300 mg or less.

[0011] With this configuration, the bitter taste of loperamide or loperamide salt is more effectively suppressed by ι-carrageenan, resulting in a film preparation that is less likely to cause discomfort when orally administered.

[0012] A fourth invention is a film formulation according to the first invention, wherein the bitterness masking agent is λ-carrageenan and the content of λ-carrageenan is 0.073 times or more and 600 mg or less of the amount of loperamide or a pharmaceutically acceptable salt of loperamide.

[0013] When configured in this manner, the bitter taste of loperamide or a salt of loperamide is more effectively suppressed by λ-carrageenan, resulting in a film preparation that is less likely to cause discomfort when orally administered.

[0014] A fifth invention is a film preparation according to the first invention, wherein the bitterness-masking agent is calcium lactate, and the content of calcium lactate is 18.9 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide but 330 mg or less.

[0015] With this configuration, the bitter taste of loperamide or a salt of loperamide is more effectively suppressed by calcium lactate, resulting in a film preparation that is less likely to cause discomfort when orally administered.

[0016] A sixth invention is the film preparation of the first invention, wherein the CPA output value measured with a BTO sensor is −7 mV or less.

[0017] When configured in this manner, the bitterness of loperamide or a salt of loperamide is suppressed by the bitterness masking agent, resulting in a film preparation that is less likely to cause discomfort when orally administered. [Effects of the Invention]

[0018] According to this invention, a film preparation in which the bitterness of loperamide is suppressed can be obtained. DETAILED DESCRIPTION OF THE INVENTION

[0019] The film preparation according to one embodiment of the present invention is in the form of a thin film, for example, 80 μm to 500 μm thick. The film preparation is mainly formed from a base, loperamide or a pharmaceutically acceptable salt of loperamide blended into the base, and a bitterness-masking agent. Some film preparations dissolve or disintegrate in the oral cavity, while others are digested in the stomach or intestines after swallowing. Furthermore, the film preparation can contain various materials depending on the purpose. For example, flavoring agents, binders, excipients, disintegrants, wetting agents, colorants, and emulsifiers are included.

[0020] The base is the main material used to form the film formulation. It can be an edible powder or an edible liquid used to solidify the powder used together with the base to form a solid. Examples of edible powders include edible organic compounds or edible inorganic compounds. Examples of edible organic compounds include edible carbohydrates, edible proteins, and edible fats. Examples of edible carbohydrates include edible disaccharides, edible polysaccharides, edible sugar alcohols, and edible dietary fiber. Examples of edible polysaccharides include alginic acid, sodium alginate, pregelatinized starch, carrageenan, agar, xanthan gum, potato starch, cellulose, and pullulan. Examples of edible dietary fiber include pectin and cellulose. Examples of edible disaccharides include refined sucrose. Examples of edible sugar alcohols include sorbitol. Examples of edible proteins include gelatin. Examples of edible organic compounds other than carbohydrates, proteins, and fats include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP (povidone)), polyethylene oxide, and macrogol (polyethylene glycol). Their edible derivatives include carbohydrate derivatives, cellulose derivatives, polyvinyl alcohol derivatives, and sorbitol derivatives. Examples of carbohydrate derivatives include sucrose fatty acid esters. Cellulose derivatives include ethyl cellulose, carmellose (CMC), carmellose sodium, and hypromellose (HPMC). Sorbitol derivatives include sorbitan and sorbitan fatty acid esters (polysorbates). Examples of edible inorganic compounds include titanium oxide and talc. The particle size of the powder used as a material for edible films is smaller than the thickness of the edible film. Examples of edible liquids include water, edible alcohol, edible glycol, glycerin, and edible oils and fats. Examples of edible alcohol include ethyl alcohol. Examples of edible glycols include propylene glycol. The edible powder and edible liquid used as the base may be used alone, or both may be used together. When using an edible powder, it is more preferable to use an edible liquid as well, as this makes it easier for the various materials used in the film preparation to be combined.

[0021] Loperamide or a pharmaceutically acceptable salt of loperamide is used as an active ingredient in antidiarrheal agents. By incorporating loperamide or a pharmaceutically acceptable salt of loperamide into the base of a film preparation, when the film preparation is orally administered, the film preparation dissolves or disintegrates in the oral cavity, and the loperamide or the pharmaceutically acceptable salt of loperamide is absorbed into the body. For example, loperamide hydrochloride can be used as a pharmaceutically acceptable salt of loperamide. Furthermore, loperamide or a salt of loperamide has an extremely strong bitter taste.

[0022] The bitterness masking agent is used to suppress the bitterness of loperamide or a pharmaceutically acceptable loperamide salt. The bitterness masking agent is contained in the base of the film formulation together with loperamide or a pharmaceutically acceptable loperamide salt. When the film formulation is orally administered, the film formulation dissolves or disintegrates in the oral cavity, releasing loperamide or a pharmaceutically acceptable loperamide salt and the bitterness masking agent simultaneously. Even as the film formulation dissolves or disintegrates, the simultaneous release of loperamide or a pharmaceutically acceptable loperamide salt and the bitterness masking agent allows the bitterness masking agent to be adsorbed first by taste buds on the tongue, thereby suppressing the adsorption of bitter components and maintaining the bitterness suppression effect. Alternatively, the bitterness masking agent may encapsulate loperamide or a loperamide salt itself, thereby maintaining the bitterness suppression effect. In particular, for β-cyclodextrin, experimental results using a PEAQ-ITC apparatus showed an exothermic reaction due to encapsulation, suggesting that the bitterness is also suppressed by the effect of β-cyclodextrin encapsulating loperamide or loperamide salt.

[0023] Examples of bitterness-masking agents that can be used include β-cyclodextrin, ι-carrageenan, λ-carrageenan, and calcium lactate, which can reduce the bitterness of loperamide or a pharmaceutically acceptable salt of loperamide.

[0024] The amount of β-cyclodextrin contained is preferably 254 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide. When the amount of β-cyclodextrin is 254 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide, the bitterness can be more effectively masked. Furthermore, the amount of β-cyclodextrin contained is preferably 600 mg or less, based on the limit of oral intake.

[0025] The amount of ι-carrageenan contained is preferably 0.0036 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide. If the amount of ι-carrageenan is 0.0036 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide, the bitterness can be more effectively masked. If the amount of ι-carrageenan is less than 0.0036 times the amount of loperamide or a pharmaceutically acceptable salt of loperamide, the concentration of ι-carrageenan becomes too low, making adjustment difficult. Furthermore, the amount of ι-carrageenan contained is preferably 300 mg or less. If the amount of ι-carrageenan contained is 300 mg or less, the amount becomes easily soluble in the raw material liquid used in producing the film formulation.

[0026] The amount of λ-carrageenan contained is preferably 0.073 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide. If the amount of λ-carrageenan contained is 0.073 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide, the bitterness can be more effectively masked. Furthermore, the amount of λ-carrageenan contained is preferably 600 mg or less. If the amount of λ-carrageenan contained is 600 mg or less, the amount is easily soluble in the raw material liquid used in producing the film preparation.

[0027] The amount of calcium lactate contained is preferably 18.9 times or more the amount of loperamide or a pharmaceutically acceptable salt thereof. If the molar concentration of calcium lactate is 18.9 times or more the amount of loperamide or a pharmaceutically acceptable salt thereof, the bitterness can be more effectively masked. Furthermore, the amount of calcium lactate contained is preferably 330 mg or less, based on the limit of oral intake.

[0028] Flavoring agents adjust the taste of the film formulation and can be contained in the film formulation together with a bitterness-masking agent, if necessary. Examples include aspartame, DL-alanine, erythritol, reduced maltose syrup, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, succinic acid, sodium succinate, acetic acid, saccharin, tartaric acid, sodium tartrate, sucralose, thaumatin, sodium bicarbonate, chili pepper, trehalose, sucrose, honey, povidone, D-mannitol, and menthol.

[0029] Binders increase the strength of film formulations. Examples of binder materials include amylopectin, sodium alginate, pregelatinized starch, carmellose, carmellose sodium, agar, glycerin, crystalline cellulose, polymeric polyvinylpyrrolidone, wheat starch, rice starch, sucrose fatty acid esters, purified gelatin, purified shellac, refined white sugar, gelatin, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, concentrated glycerin, crystalline cellulose, hydroxyethyl cellulose, hypromellose, pullulan, pectin, polysorbate, macrogol, D-mannitol, and methylcellulose.

[0030] Excipients are used to bulk up film formulations to make them easier to handle. Examples of excipient materials include alginic acid, sodium alginate, pregelatinized starch, ethyl cellulose, carrageenan, carmellose, carmellose sodium, agar, glycerin, croscarmellose sodium, crospovidone, magnesium silicate, crystalline cellulose, wheat flour, wheat starch, rice flour, rice starch, titanium oxide, sucrose fatty acid esters, refined white sugar, gelatin, skim milk powder, talc, dextran, dextrin, potato starch, hypromellose, pullulan, pectin, polysorbate, macrogol, maltose, and methylcellulose.

[0031] Disintegrants impart disintegrating properties to film formulations. Examples of disintegrant materials include alginic acid, pregelatinized starch, carmellose, carmellose sodium, agar, croscarmellose sodium, crospovidone, crystalline cellulose, wheat starch, rice starch, sucrose fatty acid esters, gelatin, dextrin, corn starch, potato starch, hydroxypropyl cellulose, hypromellose, polysorbate, macrogol, magnesium aluminum metasilicate, methylcellulose, and sodium lauryl sulfate.

[0032] Wetting agents prevent film preparations from drying out and improve their flexibility. Examples of wetting agents include reduced starch syrup, glycerin, sucrose fatty acid esters, D-sorbitol, propylene glycol, polysorbate, macrogol, and methylcellulose.

[0033] The colorant imparts color to the film formulation, and examples of colorant materials include titanium oxide, food dyes, and talc.

[0034] Emulsifiers are used to mix ingredients well, and examples of emulsifier materials include polysorbates, refined soybean lecithin, medium-chain triglycerides, and sodium lauryl sulfate.

[0035] Next, a method for producing a film preparation according to one embodiment of the present invention will be described. An excipient, a binder, and a disintegrant are kneaded in advance to produce a powdery mixture. A solution is prepared by dissolving or dispersing a humectant, a flavoring agent, an emulsifier, a bitterness-masking agent, and loperamide hydrochloride in an edible liquid base. The kneaded powder mixture is added to this solution and further kneaded to produce a solid mixture. The film preparation is produced by forming the prepared mixture into a film. When an edible powder is used as the base, it is similarly kneaded together with the base, excipient, binder and disintegrant to prepare a powdery kneaded product. Furthermore, although loperamide hydrochloride is used in the film preparation according to one embodiment of the present invention, loperamide or a pharmaceutically acceptable salt of loperamide other than loperamide hydrochloride may also be used. Furthermore, the film preparation may contain at least a base, a bitterness-masking agent, and loperamide or a salt of loperamide, and other materials may be used as needed.

[0036] Next, the bitterness-masking effect of loperamide by a bitterness-masking agent will be explained using examples and comparative examples. Since the bitterness-masking effect of the bitterness-masking agent does not decrease even when the content is increased beyond the amount at which the bitterness-masking effect is observed, the following examples and comparative examples mainly evaluated the lower limit of the bitterness-masking agent content. In the examples and comparative examples that explain the bitterness-masking effect of the bitterness-masking agent, the bitterness-masking effect was measured using a sample solution. However, since it is believed that the same effect can be obtained when the bitterness-masking agent is used in a film preparation even in the sample solution state, the bitterness-masking effect was examined in the sample solution state.

[0037] The bitterness-masking effect of β-cyclodextrin on loperamide hydrochloride will be described below. Referring to Table 1, the masking effects of Example 1, Comparative Example 1, and Comparative Example 2 were confirmed. The bitterness masking effect was measured and evaluated using a taste sensor, a taste recognition device (TS-5000Z) manufactured by Intelligent Sensor Technology Co., Ltd. The measurement sensor used a pharmaceutical bitter taste (BT0 membrane), and the CPA (Change of membrane Potential caused by Absorption) value, which indicates the aftertaste that remains in the mouth, was measured and evaluated. The CPA value is calculated by subtracting the potential (mV) obtained by first measuring a reference solution equivalent to saliva (30 mM KCl containing 0.3 mM tartaric acid) from the potential (mV) obtained after measuring the sample solution, cleaning the electrode, and then measuring a new reference solution. The method for preparing the sample solution is described below. Based on the results of the sensory test and other tests, it is believed that the bitterness of loperamide hydrochloride is sufficiently suppressed if the CPA value is -7 mV or less.

[0038] [Table 1]

[0039] Example 1 0.85 mg of loperamide hydrochloride and 119.85 mg of β-cyclodextrin were dissolved in 60 mL of 10 mM aqueous potassium chloride solution to prepare a solution containing 0.0275 mM loperamide hydrochloride and 7 mM β-cyclodextrin. In this manner, the sample solution to be measured using the taste sensor of Example 1 was prepared. Since the sample solution of Example 1 was prepared from a solution containing 0.0275 mM loperamide hydrochloride and 7 mM β-cyclodextrin, the amount of β-cyclodextrin was 254 times the amount of loperamide hydrochloride. In Table 1, the "β-cyclodextrin / loperamide hydrochloride" denotes the ratio of the amount of β-cyclodextrin to the amount of loperamide hydrochloride. The sample solution of Example 1 was found to have a good bitterness-masking effect, as the CPA value of the pharmaceutical bitterness (BT0 film) measured with a taste sensor was −17.46 mV.

[0040] (Comparative Example 1) The sample solution of Comparative Example 1 was prepared in the same manner as in Example 1, except that 29.96 mg of β-cyclodextrin was used to prepare a solution with a β-cyclodextrin concentration of 0.44 mM. The sample solution of Comparative Example 1 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.44 mM β-cyclodextrin, so the amount of β-cyclodextrin was 16 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Comparative Example 1 for pharmaceutical bitterness (BT0 film) measured with a taste sensor was -3.3 mV, indicating that a sufficient bitterness-masking effect was not obtained.

[0041] (Comparative Example 2) The sample solution of Comparative Example 1 was prepared in the same manner as in Example 1, except that 119.85 mg of β-cyclodextrin was used to prepare a solution with a β-cyclodextrin concentration of 1.76 mM. The sample solution of Comparative Example 1 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 1.76 mM β-cyclodextrin, so the amount of β-cyclodextrin was 64 times the amount of loperamide hydrochloride. The sample solution of Comparative Example 2 did not provide a sufficient bitterness-masking effect, as the CPA value of the pharmaceutical bitterness (BT0 film) measured with a taste sensor was -5.94 mV.

[0042] From Example 1, Comparative Example 1, and Comparative Example 2, it was found that a sufficient bitterness-suppressing effect against the bitterness of loperamide hydrochloride can be obtained when the amount of β-cyclodextrin is 254 times or more the amount of loperamide hydrochloride. Furthermore, the amount of β-cyclodextrin administered orally is regulated to 600 mg or less. Therefore, the amount of β-cyclodextrin is preferably 254 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide but not more than 600 mg.

[0043] Next, the bitterness-masking effect of l-carrageenan on loperamide hydrochloride will be described. Sample solutions of Examples 2 to 7 were prepared with reference to Table 2. For each example, the CPA value was measured in the same manner as when β-cyclodextrin was used as the bitterness-masking agent. A CPA value of -7 mV or less indicates a sample solution in which the bitterness of loperamide hydrochloride is sufficiently suppressed.

[0044] [Table 2]

[0045] Example 2 0.85 mg of loperamide hydrochloride and 0.007 mg of ι-carrageenan were dissolved in 60 mL of 10 mM potassium chloride aqueous solution to prepare a solution containing 0.0275 mM loperamide hydrochloride and 0.0001 mM ι-carrageenan. In this manner, a masking solution for measurement with the taste sensor of Example 2 was prepared. Since the sample solution of Example 2 was prepared from a solution containing 0.0275 mM loperamide hydrochloride and 0.0001 mM ι-carrageenan, the amount of ι-carrageenan by mass was 0.0036 times the amount of loperamide hydrochloride by mass. In Table 2, the "ι-carrageenan / loperamide hydrochloride" denotes the ratio of the amount of ι-carrageenan by mass to the amount of loperamide hydrochloride by mass. The sample solution of Example 2 was found to have a good bitterness-masking effect, as the CPA value of the pharmaceutical bitterness (BT0 film) measured with a taste sensor was −17.03 mV.

[0046] Example 3 A masking solution for measurement with the taste sensor of Example 3 was prepared in the same manner as in Example 2, except that 0.027 mg of l-carrageenan was used to prepare a solution with an l-carrageenan concentration of 0.0005 mM. The sample solution of Example 3 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.0005 mM l-carrageenan, so the amount of l-carrageenan by mass was 0.0018 times the amount of loperamide hydrochloride by mass. The CPA value of the sample solution of Example 3 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -18.05 mV, indicating that it had a good bitterness-masking effect.

[0047] Example 4 A masking solution for measurement with the taste sensor of Example 4 was prepared in the same manner as in Example 2, except that 0.11 mg of l-carrageenan was used to prepare a solution with an l-carrageenan concentration of 0.002 mM. The sample solution of Example 4 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.002 mM l-carrageenan, so the amount of l-carrageenan by mass was 0.072 times the amount of loperamide hydrochloride by mass. The CPA value of the sample solution of Example 4 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -18.94 mV, indicating that it had a good bitterness-masking effect.

[0048] Example 5 A masking solution for measurement with the taste sensor of Example 5 was prepared in the same manner as in Example 2, except that 0.57 mg of ι-carrageenan was used to prepare a solution with an ι-carrageenan concentration of 0.01 mM. The sample solution of Example 5 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.01 mM ι-carrageenan, so the amount of ι-carrageenan was 0.36 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 5 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -18.71 mV, indicating that it had a good bitterness-masking effect.

[0049] Example 6 A masking solution for measurement with the taste sensor of Example 6 was prepared in the same manner as in Example 2, except that 2.27 mg of l-carrageenan was used to prepare a solution with an l-carrageenan concentration of 0.04 mM. The sample solution of Example 6 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.04 mM l-carrageenan, so the amount of l-carrageenan was 1.45 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 6 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -20.47 mV, indicating that it had a good bitterness-masking effect.

[0050] Example 7 A masking solution for measurement with the taste sensor of Example 7 was prepared in the same manner as in Example 2, except that 6.8 mg of l-carrageenan was used to prepare a solution with an l-carrageenan concentration of 0.14 mM. The sample solution of Example 7 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.14 mM l-carrageenan, so the amount of l-carrageenan was 5.09 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 7 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -20.29 mV, indicating that it had a good bitterness-masking effect.

[0051] Examples 2 to 7 show that a good bitterness-masking effect is achieved when the amount of ι-carrageenan is 0.0036 to 5.09 times the amount of loperamide hydrochloride. Therefore, a good bitterness-masking effect is achieved when the amount of ι-carrageenan is at least 0.0036 times the amount of loperamide hydrochloride. On the other hand, when the amount of loperamide hydrochloride is less than that of the film formulation of Example 2, i.e., when the amount of ι-carrageenan is less than 0.0036 times the amount of loperamide hydrochloride, the concentration of ι-carrageenan becomes too low, making adjustment difficult. Furthermore, when the amount of ι-carrageenan exceeds 300 mg, it becomes difficult to form a film formulation from the raw material solution used in producing the film formulation. Therefore, the amount of ι-carrageenan is preferably at least 0.0036 times the amount of loperamide or a pharmaceutically acceptable salt of loperamide but not more than 300 mg.

[0052] Next, the bitterness-masking effect of λ-carrageenan on loperamide hydrochloride will be described. Film preparations of Examples 8 to 11 and Comparative Example 3 were prepared with reference to Table 3. For each example, the CPA value was measured in the same manner as when β-cyclodextrin was used as the bitterness-masking agent. If the CPA value was −7 mV or less, a film preparation in which the bitterness of loperamide hydrochloride was sufficiently suppressed could be prepared.

[0053] [Table 3]

[0054] Example 8 0.85 mg of loperamide hydrochloride and 0.85 mg of λ-carrageenan were dissolved in 60 mL of 10 mM aqueous potassium chloride solution to prepare a solution containing 0.0275 mM loperamide hydrochloride and 0.02 mM λ-carrageenan. In this manner, a masking solution for measurement with the taste sensor of Example 8 was prepared. Since the sample solution of Example 8 was prepared from a solution containing 0.0275 mM loperamide hydrochloride and 0.02 mM λ-carrageenan, the amount of λ-carrageenan per molecule was 0.72 times the amount of loperamide hydrochloride per molecule. In Table 3, the "λ-carrageenan / loperamide hydrochloride" denotes the ratio of the amount of λ-carrageenan per molecule to the amount of loperamide hydrochloride per molecule. The sample solution of Example 8 was found to have a good bitterness-masking effect, as the CPA value of the pharmaceutical bitterness (BT0 film) measured with a taste sensor was −7.88 mV.

[0055] Example 9 A masking solution for measurement with the taste sensor of Example 9 was prepared in the same manner as in Example 8, except that 1.7 mg of λ-carrageenan was used to prepare a solution with a λ-carrageenan concentration of 0.05 mM. The sample solution of Example 9 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.05 mM λ-carrageenan, so the amount of λ-carrageenan was 1.81 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 9 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -8.37 mV, indicating that it had a good bitterness-masking effect.

[0056] Example 10 A masking solution for measurement with the taste sensor of Example 10 was prepared in the same manner as in Example 8, except that 3.4 mg of λ-carrageenan was used to prepare a solution with a λ-carrageenan concentration of 0.1 mM. The sample solution of Example 10 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.1 mM λ-carrageenan, so the amount of λ-carrageenan was 3.63 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 10 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -8.99 mV, indicating that it had a good bitterness masking effect.

[0057] Example 11 A masking solution for measurement with the taste sensor of Example 11 was prepared in the same manner as in Example 8, except that 6.8 mg of λ-carrageenan was used to prepare a solution with a λ-carrageenan concentration of 0.2 mM. The sample solution of Example 11 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.2 mM λ-carrageenan, so the amount of λ-carrageenan was 7.27 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 11 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -9.11 mV, indicating that it had a good bitterness masking effect.

[0058] (Comparative Example 3) A masking solution for measurement with the taste sensor of Comparative Example 3 was prepared in the same manner as in Example 8, except that 0.425 mg of λ-carrageenan was used to prepare a solution with a λ-carrageenan concentration of 0.01 mM. The sample solution of Comparative Example 3 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.01 mM λ-carrageenan, so the amount of substance of λ-carrageenan was 0.36 times the amount of substance of loperamide hydrochloride. The CPA value of the sample solution of Comparative Example 3 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -5.84 mV, indicating that a sufficient bitterness masking effect was not obtained.

[0059] Examples 8 to 11 and Comparative Example 3 demonstrated that a sufficient bitterness-suppressing effect against the bitterness of loperamide hydrochloride can be achieved when the amount of λ-carrageenan is 0.72 times or more the amount of loperamide hydrochloride. Furthermore, if the amount of λ-carrageenan exceeds 600 mg, the λ-carrageenan becomes less soluble in the raw material solution used to produce the film formulation. Therefore, the amount of λ-carrageenan is preferably 0.72 times or more the amount of loperamide or a pharmaceutically acceptable salt of loperamide and 600 mg or less.

[0060] Next, the bitterness-masking effect of calcium lactate on loperamide hydrochloride will be described. Film preparations of Examples 12 to 14 and Comparative Examples 4 and 5 were prepared with reference to Table 4. For each example, the CPA value was measured in the same manner as when calcium lactate was used as the bitterness-masking agent. A CPA value of -7 mV or less indicates a film preparation in which the bitterness of loperamide hydrochloride is sufficiently suppressed.

[0061] [Table 4]

[0062] Example 12 0.85 mg of loperamide hydrochloride and 6.8 mg of calcium lactate were dissolved in 60 mL of 10 mM potassium chloride aqueous solution to prepare a solution containing 0.0275 mM loperamide hydrochloride and 0.52 mM calcium lactate. In this manner, a masking solution for measurement with the taste sensor of Example 12 was prepared. Since the sample solution of Example 12 was prepared from a solution containing 0.0275 mM loperamide hydrochloride and 0.52 mM calcium lactate, the amount of calcium lactate in the sample was 18.9 times the amount of loperamide hydrochloride in the sample. In Table 4, the "Calcium lactate / Loperamide hydrochloride" denotes the ratio of the amount of calcium lactate to the amount of loperamide hydrochloride in the sample. The sample solution of Example 12 was found to have a good bitterness-masking effect, as the CPA value of the pharmaceutical bitterness (BT0 film) measured with a taste sensor was −7.23 mV.

[0063] Example 13 A masking solution for measurement with the taste sensor of Example 13 was prepared in the same manner as in Example 12, except that 27.2 mg of calcium lactate was used to prepare a solution with a calcium lactate concentration of 2.1 mM. The sample solution of Example 13 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 2.1 mM calcium lactate, so the amount of calcium lactate was 76.3 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 13 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -11.73 mV, indicating that it had a good bitterness-masking effect.

[0064] Example 14 A masking solution for measurement with the taste sensor of Example 14 was prepared in the same manner as in Example 12, except that 108.8 mg of calcium lactate was used to prepare a solution with a calcium lactate concentration of 8.3 mM. The sample solution of Example 14 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 8.3 mM λ-carrageenan, so the amount of calcium lactate was 301 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Example 14 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -13.93 mV, indicating that it had a good bitterness-masking effect.

[0065] Comparative Example 4 A masking solution for measurement with the taste sensor of Comparative Example 4 was prepared in the same manner as in Example 12, except that 0.1 mg of calcium lactate was used to prepare a solution with a calcium lactate concentration of 0.008 mM. The sample solution of Comparative Example 4 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.008 mM λ-carrageenan, so the amount of calcium lactate was 0.29 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Comparative Example 4 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -6.44 mV, indicating that a sufficient bitterness masking effect was not obtained.

[0066] (Comparative Example 5) A masking solution for measurement with the taste sensor of Comparative Example 5 was prepared in the same manner as in Example 12, except that 1.7 mg of calcium lactate was used to prepare a solution with a calcium lactate concentration of 0.13 mM. The sample solution of Comparative Example 5 was prepared using a solution of 0.0275 mM loperamide hydrochloride and 0.13 mM λ-carrageenan, so the amount of calcium lactate was 4.72 times the amount of loperamide hydrochloride. The CPA value of the sample solution of Comparative Example 5 for pharmaceutical bitterness (BT0 film) measured with the taste sensor was -6.87 mV, indicating that a sufficient bitterness masking effect was not obtained.

[0067] Examples 12 to 14 and Comparative Examples 4 and 5 demonstrate that a sufficient bitterness-suppressing effect against the bitterness of loperamide hydrochloride can be achieved when the amount of calcium lactate is at least 18.9 times the amount of loperamide hydrochloride. Furthermore, the oral dosage of calcium lactate is restricted to 330 mg or less. Therefore, the amount of β-cyclodextrin contained is preferably at least 18.9 times the amount of loperamide or a pharmaceutically acceptable salt of loperamide but not more than 330 mg.

Claims

1. A base and loperamide or a pharmaceutically acceptable salt of loperamide; and a bitterness masking agent, A film preparation, wherein the bitterness-masking agent is any one of β-cyclodextrin, ι-carrageenan, λ-carrageenan, and calcium lactate.

2. The bitterness masking agent is β-cyclodextrin, The film preparation according to claim 1, wherein the content of the β-cyclodextrin is 254 times or more and 600 mg or less of the amount of the loperamide or pharmaceutically acceptable salt of loperamide.

3. the bitterness masking agent is ι-carrageenan; 2. The film preparation according to claim 1, wherein the content of the ι-carrageenan is 0.0036 times or more and 300 mg or less of the amount of the loperamide or pharmaceutically acceptable salt of loperamide.

4. The bitterness masking agent is λ-carrageenan, 2. The film preparation according to claim 1, wherein the amount of the λ-carrageenan is 0.073 times or more and 600 mg or less of the amount of loperamide or the pharmaceutically acceptable salt of loperamide.

5. The bitterness masking agent is calcium lactate, The film preparation according to claim 1, wherein the content of the calcium lactate is 18.9 times or more and 330 mg or less of the amount of the loperamide or pharmaceutically acceptable salt of loperamide.

6. The film formulation according to claim 1, wherein the CPA output value measured with a BT0 sensor is −7 mV or less.

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