Lotion formulation, and method for manufacturing a lotion formulation

Abstract

To allow the effect of a cationic disinfectant to be expressed in the oral cavity for a longer period of time.SOLUTION: A drop agent contains a cationic disinfectant and a crystalline cellulose. The angle of repose of the crystalline cellulose is 30° or more.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a drop agent and a method for producing the drop agent.

Background Art

[0002] Patent Document 1 describes an oral or pharyngeal composition containing one or more cationic bactericides selected from cetylpyridinium chloride, also known as cetylpyridinium chloride hydrate, benzethonium chloride, and benzalkonium chloride, and hesperidin. By containing the above components, the bitterness peculiar to the cationic bactericide is reduced.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] By the way, a drop agent containing a cationic bactericide is required to exhibit the effect of the cationic bactericide in the oral cavity for a longer time.

Means for Solving the Problems

[0005] The drop agent for solving the above problems is a drop agent containing a cationic bactericide and crystalline cellulose, and the gist is that the angle of repose of the crystalline cellulose is 30° or more.

[0006] Regarding the above drop agent, the angle of repose of the crystalline cellulose is preferably 50° or more and 60° or less. Regarding the above drop agent, the cationic bactericide preferably contains cetylpyridinium chloride hydrate.

[0007] The above-mentioned drop formulation is preferably used in the oral cavity for the long-term expression of bactericidal effects and virus inactivation. The method for producing a drop agent to solve the above problems comprises a mixing step of mixing a cationic bactericide with crystalline cellulose having an angle of repose of 30° or more to produce a mixed composition, and a molding step of molding the mixed composition. [Effects of the Invention]

[0008] According to the present invention, the lozenge and the method for producing the lozenge can allow the cationic bactericide to exert its effect for a longer period of time in the oral cavity. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 is a graph showing the relationship between the angle of repose and duration of crystalline cellulose. [Figure 2] Figure 2 is a graph showing the change in the concentration of cetylpyridinium chloride hydrate in saliva. [Modes for carrying out the invention]

[0010] The following describes one embodiment of the lozenge formulation of the present invention. The drop agent of this embodiment contains a cationic disinfectant and crystalline cellulose, wherein the angle of repose of the crystalline cellulose is 30° or higher.

[0011] By including crystalline cellulose with an angle of repose within the above-mentioned range, the effect of cationic disinfectants can be sustained for a longer period in the oral cavity. The following describes the ingredients of each lozenge.

[0012] <Cationic bactericides> The cationic disinfectant is not particularly limited, and any known cationic disinfectant can be used. Specific examples of cationic disinfectants include, for example, cetylpyridinium chloride hydrate (hereinafter also referred to as CPC), benzethonium chloride, and benzalkonium chloride.

[0013] The cationic disinfectants described above may be used individually or in combination of two or more. Among these, CPC is preferred because it is widely used as an oral disinfectant and readily provides a suitable bactericidal effect.

[0014] The content of cationic disinfectant in the drops is not particularly limited, but is preferably 0.005% by mass or more, and more preferably 0.01% by mass or more. It is also preferably 0.15% by mass or less, and more preferably 0.1% by mass or less.

[0015] <Crystalline cellulose> Crystalline cellulose is obtained by acid hydrolysis or alkali hydrolysis of plant pulp fibers to extract and purify the crystalline region of cellulose. It is a material that is relatively insoluble in water and oil. The inclusion of crystalline cellulose in the lozenge can extend its duration of action in the oral cavity.

[0016] Crystalline cellulose is in powder form. The shape of the individual particles is not particularly limited, but it is preferable that they be in the form of small pieces such as plates, rods, or fibers, and not spherical. Here, "not spherical" means a shape in which the particle flattening ratio is 1.5 or greater. That is, the flattening ratio of crystalline cellulose is preferably 1.5 or greater, more preferably 3 or greater, and even more preferably 5 or greater.

[0017] Note that the aspect ratio means the ratio (maximum diameter / minimum diameter) of the dimension of the largest diameter part (also referred to as the maximum diameter) to the dimension of the smallest diameter part (also referred to as the minimum diameter) in the particles of crystalline cellulose. The aspect ratio is measured for a plurality of particles and represented by the average value thereof.

[0018] The angle of repose of the crystalline cellulose is preferably 50° or more. Also, the angle of repose of the crystalline cellulose is preferably 60° or less. When the angle of repose of the crystalline cellulose is 30° or more, the shape of the crystalline cellulose becomes closer to a fibrous state than a spherical state. Also, when the angle of repose of the crystalline cellulose is 50° or more, the shape of the crystalline cellulose becomes closer to a fibrous state and the surface area becomes large. Since the cationic bactericide has the property of being easily adsorbed on the surface of the crystalline cellulose, although the cationic bactericide is eluted along with the duration of the drop agent, the elution rate tends to be slower as the surface area is larger.

[0019] The method for measuring the angle of repose is not particularly limited, and a known method can be adopted. For example, the method introduced in the item of fluidity of powders in the reference information of the 18th revised Japanese Pharmacopoeia can be adopted.

[0020] The angle of repose of the crystalline cellulose means the angle of repose of the crystalline cellulose used in the drop agent. The angle of repose of the crystalline cellulose may be measured after taking out the crystalline cellulose from the drop agent. As a method for taking out the crystalline cellulose from the drop agent, for example, the drop agent is heated and melted. Then, the crystalline cellulose is separated and recovered from the cationic bactericide and other components described later. The angle of repose can be measured by performing the above-described method for measuring the angle of repose on the recovered crystalline cellulose.

[0021] The average particle diameter of the crystalline cellulose is not particularly limited, but is preferably 5 μm or more, more preferably 10 μm or more. Also, it is preferably 200 μm or less, more preferably 100 μm or less.

[0022] The method for measuring the average particle size of crystalline cellulose is not particularly limited, and known methods can be employed. For example, it can be measured on a volume basis using a known laser diffraction particle size distribution analyzer.

[0023] The crystalline cellulose content in the lozenges is not particularly limited, but is preferably 0.5% by mass or more, and more preferably 1% by mass or more. Furthermore, from a safety standpoint, it is preferably 3.5% by mass or less, and more preferably 2.5% by mass or less.

[0024] <Other ingredients> Depending on the intended use, form, and application, the lozenges may also contain other ingredients besides those mentioned above, such as sweeteners, excipients, flavoring agents, fragrances, pH adjusters (acidifiers), colorants, stabilizers, binders, solvents, and surfactants. These ingredients may be those known to be used in lozenges. Each of these ingredients may be used individually or in combination of two or more.

[0025] Specific examples of sweeteners include saccharin, sodium saccharin hydrate, sucralose, stevioside, acesulfame potassium, aspartame, xylitol, maltitol, erythritol, cycloheptamylose, sorbitol (also called sorbitol solution), and palatinose (also called reduced palatinose). Among these, it is preferable to include reduced palatinose. Sweeteners are also referred to as sugar alcohols.

[0026] Specific examples of excipients include refined white sugar, white sugar, honey, brown sugar, glucose syrup, D-sorbitol, reduced palatinose, reduced starch syrup, reduced maltose syrup, starch syrup, caramel, and the like.

[0027] Specific examples of flavoring agents include, for example, aspartame, acesulfame potassium, stevia extract, sodium chloride, saccharin, sodium saccharin hydrate, ascorbic acid, xylitol, L-glutamate hydrochloride, and tartaric acid.

[0028] In addition to being used as a sweetener and excipient, reduced palatinose is sometimes used as a flavoring agent. The above-mentioned sweeteners, excipients, and flavoring agents may also be used as bases.

[0029] Specific examples of fragrances include l-menthol, d-carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, vanillin, and others.

[0030] Specific examples of pH adjusters include citric acid, sodium citrate, DL-malic acid, succinic acid, sodium succinate, L-glutamic acid, sodium L-glutamate, lactic acid, and sodium lactate.

[0031] Specific examples of colorants include legally approved pigments such as Green No. 1, Green No. 3, Blue No. 1, Yellow No. 4, Yellow No. 5, Red No. 102, and Red No. 3, as well as sodium copper chlorophyllin and titanium dioxide.

[0032] Specific examples of stabilizers include sodium edetate, sodium thiosulfate, sodium sulfite, calcium lactate, lanolin, triacetin, castor oil, and magnesium sulfate.

[0033] Specific examples of binders include sodium polyacrylate, carrageenan, sodium carboxymethylcellulose, sodium alginate, xanthan gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, and propylene glycol alginate.

[0034] Specific examples of solvents include water, alcohol, and so on. The surfactant is not particularly limited, and known surfactants used in oral compositions can be used.

[0035] Specific examples of surfactants include nonionic surfactants, anionic surfactants, and amphoteric surfactants. (Nonionic surfactant) Specific examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters and maltose fatty acid esters, sugar alcohol fatty acid esters such as maltitol fatty acid esters, sorbitan fatty acid esters such as sorbitan monolaurate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monostearate, fatty acid alkanolamides such as lauric acid diethanolamide, polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether and polyoxyethylene oleyl ether, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and polyethylene glycol monolaurate, alkyl glycosides such as lauryl glycoside and decyl glycoside, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters, alkyl glucosides, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, and polyoxyethylene propylene block copolymers.

[0036] (Anionic surfactant) Specific examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate, sulfosuccinates such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate, acyl amino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methylalanine, and sodium cocoyl methyl taurate.

[0037] (Amphoteric surfactant) Specific examples of amphoteric surfactants include amino acid-type amphoteric surfactants such as N-lauryldiaminoethylglycine and N-myristyldiethylglycine, and betaine-based amphoteric surfactants such as alkyldimethylaminoacetic acid betaine, N-alkyl-N'-carboxymethyl-N'-hydroxyethylethylenediamine salt, and 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine.

[0038] The above-mentioned surfactants may be used individually or in combination of two or more types. <Manufacturing method for lozenges> The method for producing the drops includes a mixing step of mixing a cationic disinfectant with crystalline cellulose having an angle of repose of 30° or more to produce a mixed composition. The method also includes a molding step of molding the mixed composition obtained in the mixing step. Preferably, the angle of repose of the crystalline cellulose is 50° or more and 60° or less.

[0039] In the mixing process, other components may be mixed together as needed. Furthermore, it is preferable to heat each raw material while mixing, as this allows for efficient mixing. For example, a temperature of 90°C to 180°C is preferable. If necessary, moisture may be removed under low pressure using a vacuum vessel or the like.

[0040] In the molding process, it is preferable to place the raw material composition obtained in the mixing process into a mold and mold it. By placing the raw material composition into a mold and molding it, it becomes possible to efficiently mold drop agents having a predetermined shape.

[0041] <Application forms, uses, and dosage forms of lozenges> The application form of the lozenges is not particularly limited and can be used, for example, as a pharmaceutical product or a designated quasi-drug. Specifically, it can be used as an oral and pharyngeal drug.

[0042] The use of the drops is not particularly limited, but they can be used for the long-term expression of bactericidal effect and virus inactivation. The above-mentioned long-term expression of bactericidal effect and virus inactivation means the long-term expression of at least one of bactericidal effect and virus inactivation.

[0043] The dosage form of the lozenges is not particularly limited and may be a lozenge, hard candy, or other form with a predetermined hardness. It may also be a gummy, gum, or other form with a predetermined flexibility. Furthermore, the shape of the lozenges may be spherical, plate-shaped, film-shaped, or the like.

[0044] The diameter of the drop is not particularly limited. Preferably, the diameter of the drop is 20 mm or less, more preferably 15 mm or less. Also, it is preferably 5 mm or more, more preferably 10 mm or more. If the drop is not spherical, the diameter refers to the diameter of the circumscribed circle, assuming the entire drop is enclosed within that circle.

[0045] <Mechanism and Effects> The action of the lozenge of this embodiment will now be explained. When the angle of repose of crystalline cellulose is 30° or higher, the shape of the crystalline cellulose becomes closer to a fibrous state than a spherical one. Consequently, the surface area of ​​the crystalline cellulose becomes relatively larger. In addition, the hydroxyl groups of crystalline cellulose readily interact with cationic disinfectants. Due to the relatively large surface area of ​​crystalline cellulose and the ease with which it interacts with cationic disinfectants, more cationic disinfectants are adsorbed onto the surface of the crystalline cellulose. Although cationic disinfectants are leached out as the duration of the drop agent increases, the leaching rate tends to be slower as the surface area of ​​crystalline cellulose increases. Furthermore, the synergistic effect of crystalline cellulose's poor solubility in water and oil further slows down the leaching rate of cationic disinfectants.

[0046] The effects of the lozenges of this embodiment will now be explained. (1) Contains a cationic disinfectant and crystalline cellulose, wherein the angle of repose of the crystalline cellulose is 30° or higher.

[0047] By adsorbing more cationic disinfectants onto the surface of crystalline cellulose, which is poorly soluble in water and oil, the elution rate of the cationic disinfectant can be slowed. Therefore, the effect of the cationic disinfectant can be sustained for a longer period in the oral cavity.

[0048] (2) The angle of repose of crystalline cellulose is between 50° and 60°. Therefore, the duration of action of the drops in the oral cavity can be extended, and the effect of the cationic disinfectant can be exerted for an even longer period of time in the oral cavity.

[0049] (3) The cationic bactericide is cetylpyridinium chloride hydrate. Therefore, a suitable bactericidal effect is more easily obtained. (4) The drops are used to provide long-term bactericidal and viral inactivation effects in the oral cavity. The drops of the present invention can extend the duration of action in the oral cavity, thereby allowing the cationic bactericidal effect to be exerted for a longer period of time. Therefore, they can be suitably used to prevent viral infections in situations where many people stay in one space for a long time, such as on a train during rush hour.

[0050] (5) The method for producing the lozenges comprises a mixing step of mixing a cationic disinfectant with crystalline cellulose having an angle of repose of 30° or more to produce a mixed composition, and a molding step of molding the mixed composition. Therefore, it is possible to produce lozenges that can exert the effect of the cationic disinfectant for a longer period of time in the oral cavity.

[0051] <Example of changes> This embodiment can be implemented with the following modifications. This embodiment and the following modifications can be combined with each other to the extent that they do not contradict each other technically.

[0052] In this embodiment, the lozenges may contain active ingredients used in cough suppressants and expectorants. Examples of active ingredients used in cough suppressants and expectorants include chlorhexidine hydrochloride and decalinium chloride. [Examples]

[0053] The following are examples to illustrate the structure and effects of the present invention in more detail, but the present invention is not limited to these examples. (Evaluation test of the relationship between the angle of repose and duration of crystalline cellulose) The relationship between the angle of repose and duration of crystalline cellulose was evaluated.

[0054] First, crystalline cellulose with the angles of repose shown in Table 1 was prepared. Each crystalline cellulose was mixed with reduced palatinose according to a conventional method so that the crystalline cellulose content was 2% by mass, and the lozenges for Test Examples 1 to 7 were prepared. The lozenges were spherical with a particle size of 15 mm and a mass of approximately 2 g. In Test Example 1, the lozenges were prepared using only reduced palatinose, without using crystalline cellulose.

[0055] Next, 500g of 37°C distilled water was placed in each of several beakers and stirred with a rotor. While stirring with the rotor, the drop formulations for each test example were added to each beaker. The time it took for the drop formulations to disappear was measured by visual observation. The time it took for the drop formulations to disappear was defined as the duration. Each test was performed three times, and the average duration was calculated. The results are shown in Table 1 and Figure 1.

[0056] The average particle size, angle of repose, and duration of crystalline cellulose in Test Examples 1-7 are shown in the "Average Particle Size (μm)", "Angle of Repose (°)", and "Duration (minutes)" columns of Table 1, respectively.

[0057] [Table 1] Table 1 and Figure 1 show that in Test Examples 2-7, where the angle of repose of crystalline cellulose was 30° or higher, the duration of action was longer compared to Test Example 1. In particular, in Test Examples 6 and 7, where the angle of repose of crystalline cellulose was 50° or higher, the duration of action was even longer.

[0058] The drop formulations of Example 1, Comparative Example 1, and Comparative Example 2 shown in Table 2 were manufactured by mixing each component according to a conventional method.

[0059] [Table 2] As shown in Table 2, CPC was used as the cationic disinfectant. The CPC content was 1.0 mg per drop in Example 1 and Comparative Example 1, and 0.5 mg per drop in Comparative Example 2. In Example 1, the same crystalline cellulose as in Test Example 7 was used, with a content of 2% by mass. Comparative Examples 1 and 2 did not contain crystalline cellulose. In addition, reduced palatinose was added as a residue in Examples 1, Comparative Example 1, and Comparative Example 2. The mass per drop was 2.0 g in Example 1 and Comparative Example 1, and 1.48 g in Comparative Example 2. The diameter of the drops was 15 mm in Example 1 and Comparative Example 1, and 12 mm in Comparative Example 2.

[0060] (Evaluation test of CPC concentration in saliva) The concentration of CPC in saliva was evaluated using the following method. First, the monitor ingested the lozenge from Example 1. 1 mL of the monitor's saliva was collected at predetermined intervals starting from the start of administration. The CPC concentration in the saliva was quantified using a known high-performance liquid chromatography method. The duration from the start of administration until the lozenge was depleted (hereinafter referred to as the oral duration) was also measured. The same test was performed twice, and the average values ​​of the CPC concentration and the oral duration at each measurement time were determined.

[0061] For Comparative Examples 1 and 2, the average CPC concentration and the average duration in the oral cavity were determined using the same method. Note that for Comparative Example 2, the lozenge had a small mass of 1.48g per lozenge and a small CPC content of 0.5mg; therefore, after the lozenge was consumed, another lozenge was taken immediately afterward to conduct the test. The results of the evaluation of duration in the oral cavity are shown in Table 2. The results of the evaluation of CPC concentration are shown in Figure 2.

[0062] As shown in Table 2, in Comparative Example 1, the duration of oral cavity activity was 11 minutes and 1 second. In Comparative Example 2, the duration of oral cavity activity was 7 minutes and 5 seconds and 6 minutes and 40 seconds. In contrast, in Example 1, the duration of oral cavity activity was confirmed to be longer at 24 minutes and 25 seconds.

[0063] Furthermore, as shown in Figure 2, in Comparative Example 1, the CPC concentration was highest 2 minutes after the start of administration, and then rapidly decreased. After 20 minutes from the start of administration, the CPC concentration remained stable at 4 μg / mL.

[0064] In Comparative Example 2, the CPC concentration was highest 2 minutes after the start of administration. It remained nearly constant at 40 μg / mL and then decreased. After 20 minutes from the start of administration, the CPC concentration remained stable at 5 μg / mL.

[0065] In contrast, in Example 1, although the CPC concentration was highest 2 minutes after the start of administration, it remained high at 50 μg / mL or higher, specifically 62 μg / mL, even after 10 minutes. Furthermore, the CPC concentration remained high at 20 μg / mL or higher, specifically 27 μg / mL, even after 20 minutes. Even after 30 minutes, the CPC concentration remained high at 6 μg / mL or higher, specifically 8 μg / mL.

[0066] Based on these results, it was confirmed that the drop formulation of the present invention can prolong the duration of its effects in the oral cavity. Furthermore, a relatively high concentration of CPC was maintained in the oral cavity. It was confirmed that the effects of CPC can be exerted for a longer period of time in the oral cavity.

Claims

1. A drop containing a cationic disinfectant and crystalline cellulose, The angle of repose of the crystalline cellulose is 50° or more and 60° or less. A lozenge characterized by not containing sorbitol and erythritol.

2. The drop agent according to claim 1, wherein the cationic disinfectant contains cetylpyridinium chloride hydrate.

3. A drop agent according to claim 1 or 2, used for long-term expression of bactericidal effect and virus inactivation in the oral cavity.

4. A mixing step of preparing a mixed composition by mixing a cationic disinfectant with crystalline cellulose having an angle of repose of 50° or more and 60° or less, The process includes a molding step for molding the mixed composition, A method for producing a drop formulation characterized by not containing sorbitol and erythritol.

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