JP2018111668A - Oral formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral formulation that is useful for maintaining oral health that can be discharged smoothly into the oral cavity at an appropriate dose of active ingredients and that does not impose an excessive burden or cause feelings of discomfort to a user.SOLUTION: The oral formulation is configured with an oral component and a coating material that encapsulates same. The coating material comprises a water-soluble cellulose and a saliva secretion promoter. It is preferable for the water soluble cellulose to be one or more selected from the group consisting of hydroxypropylmethylcellulose and hydroxymethylcellulose. The coating material may also contain a plasticizer.SELECTED DRAWING: None

Description

  The present invention relates to an oral preparation capable of efficiently applying an oral component useful for maintaining oral health to the oral cavity.

  In the human body, the oral cavity is a part that breathes and consumes food, and also a part that appropriately transports air and food to the lungs and esophagus. Also, when talking, the tongue in the oral cavity, larynx and mucous membranes can make proper pronunciations by performing appropriate movements. Oral care, which is an important organ in this way, is usually recognized as brushing or gargle, but dirt in the oral cavity is not only in the teeth but also in the gums, tongue, cheek inside, and tongue. It is difficult to keep the oral environment hygienic by adhering to it and removing only the dirt from each part of the oral cavity by daily oral care such as toothpaste and gargle to suppress the growth of harmful bacteria. It is a fact. Saliva, in particular, plays an important role in maintaining the oral environment hygienically. Since saliva secretion decreases with age, the oral environment of the elderly can be sanitized simply by brushing teeth and gargle. In recent years, the importance of oral care has been pointed out at nursing care sites where there are many elderly people.

  For oral care, oral preparations containing oral ingredients useful for maintaining the oral environment hygienically have been used, and oral preparations such as lozenges are typical oral preparations. There is known a type of preparation that is composed of a uniform mixture of ingredients and excipients, binders, etc., and is used by licking and dissolving in the oral cavity. However, in order to release an effective amount of oral ingredients into the oral cavity, conventional troche type oral preparations need to be licked and melted by the user over several minutes to several tens of hours, In particular, it imposes an excessive burden on elderly people whose oral cavity function is reduced.

  In Patent Document 1, as a preparation for oral cavity that can be used as a substitute for tobacco or as a smoking cessation support product, a core containing nicotine is enclosed by a film coating, and nicotine is released into the oral cavity by being taken. Solid pharmaceutical dosage forms are described. In this solid pharmaceutical dosage form, it is preferable that nicotine is released as soon as possible after taking, and from this point of view, film coating is preferably dissolved or disintegrated in less than 30 seconds after taking. As a film coating composition having such solubility and disintegration, a composition containing a film-forming polymer such as hydroxypropylmethylcellulose and a plasticizer is described.

  Patent Document 2 describes an oral dispersible film agent in which various oral components, a film-forming polymer, a disintegrant, and polyvinyl alcohol or hydroxypropylmethylcellulose are uniformly mixed as a film-form oral preparation. ing. Patent Document 2 describes that a salivary secretion promoter may be contained in the mouth-dispersible film agent from the viewpoint of promoting more rapid disintegration of the mouth-dispersible film agent in the oral cavity. Examples of the salivary secretion promoter include acidic compounds such as citric acid and malic acid, and sweeteners such as glucose and fructose.

JP-T-2015-503581 JP-T-2006-525572

  Regarding oral care using oral preparations containing oral components having predetermined functions such as anti-inflammatory and sterilization, in order to keep such oral care more effective, the oral environment can be maintained hygienically. It is preferable that the release of the oral component is started after a lapse of a certain time from the administration of the preparation for use, and the release continues for a fixed time. In this regard, the solid pharmaceutical dosage form described in Patent Document 1 has been devised so that the oral component (nicotine) is released immediately after taking and the release time is as short as possible. It is difficult to use as an oral preparation for the purpose of sterilization. The mouth-dispersible film preparation described in Patent Document 2 also has room for improvement in terms of controlling the release of oral components, as with the solid pharmaceutical dosage form described in Patent Document 1, and further the mouth-dispersible film preparation. Since it is in the form of a film, it tends to stick to the mucous membrane in the oral cavity, and the oral cavity tends to be in an overdried state with little saliva, which may cause discomfort to the user.

  Therefore, an object of the present invention is to release an appropriate amount of an active ingredient smoothly into the oral cavity without causing an excessive burden or discomfort to the user, which is useful for maintaining oral health. Providing a pharmaceutical preparation.

  The present invention is an oral preparation comprising an oral component and a coating material encapsulating the oral component, wherein the coating material contains water-soluble cellulose and a saliva secretion promoting component.

  According to the present invention, an appropriate amount of an active ingredient can be smoothly released into the oral cavity without causing an excessive burden or discomfort to the user, which is useful for maintaining oral health. A formulation is provided. Since the oral preparation of the present invention has a configuration in which the oral ingredient as an active ingredient is coated with a coating material containing a saliva secretion promoting ingredient, the oral preparation of the saliva is retained while the oral preparation is held in the oral cavity. Secretion is promoted, and the large amount of saliva secreted as a result promotes dissolution or disintegration of the coating material and prevents the oral cavity from being overdried. Without giving a strong or uncomfortable feeling, an appropriate amount of oral components can be released into the oral cavity after a certain period of time, which can greatly contribute to keeping the oral environment hygienic.

  The oral preparation of the present invention comprises an oral component that is an active ingredient and a coating material that encapsulates the oral component. That is, in the oral preparation of the present invention, since the oral component is arranged on the inner side and the coating material is arranged on the outer side, the oral component is not released into the oral cavity immediately after taking the oral preparation. As it dissolves or disintegrates, it is gradually released into the oral cavity. As described above, the oral preparation of the present invention is appropriately controlled for release of the oral component into the oral cavity by devising the arrangement of the oral component and the coating material. It is easy to be held, and a predetermined function such as extinguishing or sterilization of the oral component is easily exhibited.

  As one of typical configurations of the oral preparation of the present invention, a configuration in which a core agent containing an oral component is coated with a coating material can be exemplified. Such a central agent dosage form has a state in which at least a surface layer portion of the central agent coated with a coating material can be applied with a paint (coating liquid) containing the coating material and can form a film (typically solid). ), And dosage forms conventionally used for oral use can be appropriately applied. Examples thereof include tablets, capsules, orally disintegrating agents, chewable agents, granules, etc. Can be done by law. In particular, when the central agent is an orally disintegrating agent (an agent that can be taken without water) or a chewable agent (an agent that can be chewed in the oral cavity or dissolved in saliva), the release of the oral component becomes even smoother Because it is made, it is preferable.

  The coating material according to the present invention contains water-soluble cellulose. Water-soluble cellulose serves as a base (coat base material) for the coating film of the coating material. For example, use of a water-insoluble component such as sodium alginate or pullulan may be considered as the coating substrate, but if a water-insoluble component is used as the coating substrate, sufficient film-forming properties and film strength can be obtained. Therefore, there is a possibility that release of oral components cannot be controlled sufficiently. By containing water-soluble cellulose as a coating substrate in the coating material, good film-forming properties and film strength can be obtained, and release of oral components can be appropriately controlled.

  Examples of the water-soluble cellulose include alkyl cellulose (eg, methyl cellulose (MC), ethyl cellulose, etc.), hydroxyalkyl cellulose (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), hydroxyalkyl alkyl cellulose (eg, hydroxypropyl methyl cellulose, hydroxyethyl). Methyl cellulose, hydroxyethyl ethyl cellulose, etc.), and the like can be used alone or in combination of two or more. Among these water-soluble celluloses, hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC) is particularly preferable, and HPMC and HPC are more preferably used in combination. When HPMC and HPC are used in combination, the content ratio of both is preferably 1 or more, more preferably 5 or more, as HPMC / HPC.

  The content of the water-soluble cellulose in the oral preparation of the present invention is preferably 50 to 99% by mass, more preferably 60 to 95% by mass as the solid content with respect to the total mass of the coating material solid content. If the water-soluble cellulose content is too small, the coating film of the coating material may become soft and the workability during the production of the oral preparation may be deteriorated. It becomes easy to dissolve or disintegrate, and there is a possibility that release control of oral components into the oral cavity may not be properly performed. On the other hand, if the content of water-soluble cellulose is too large, it may take time to dissolve or disintegrate the coating material and increase the burden on the user, and the content of the salivary secretion-promoting component described later is relatively low. There is a possibility that the salivary secretion promoting action may not be sufficiently obtained.

  The coating material according to the present invention further contains a saliva secretion promoting component in addition to the water-soluble cellulose. Since the saliva secretion promoting component is contained in the coating material forming the surface layer of the oral preparation, saliva secretion is promoted when the oral preparation is taken, so that the coating material can be dissolved or disintegrated. Sufficient amount of saliva is secreted quickly, resulting in an excessive burden on the user to lick and dissolve the coating material, or to make the oral cavity over-dried due to lack of saliva, causing discomfort to the user Therefore, even if the user is an elderly person whose saliva secretion amount has decreased, an appropriate amount of oral components can be smoothly released into the oral cavity.

  Salivary secretion-promoting ingredients include plant extracts (eg, olive leaf extract, grapefruit seed extract, black moji extract, beech shimeji extract, kankanikujuyou extract, germinated broccoli extract, Sasahihi Toyotake extract, Daio extract, aloe Extract, senna extract, legume extract, Dutch sennici extract, karin juice, salamander extract, luteolin, kombu extract, salmon tea extract, salmon tannin extract), herbal medicine (eg, koboku, quintuplet, carrot, crust ), Inorganic salts (eg, zinc phosphate, zinc ascorbyl phosphate), organic acids or salts thereof (eg, citric acid, trisodium citrate), mucopolysaccharides or salts thereof (eg, hyaluronic acid, hyaluronic acid) Sodium), protein or enzymatic degradation product thereof (eg, thaumatin, salmine fermentation) Degradation products), peptides, amino acids or derivatives thereof or salts thereof (for example, theanine, sodium polyglutamate), bacterial cells or cultures thereof or extracts thereof (for example, lactic acid bacteria, lactic acid bacteria cultures, nameko mycelium extracts) antibacterial An agent, a nucleic acid, a fragrance | flavor, etc. are mentioned, These 1 type can be used individually or in combination of 2 or more types. Among these salivary secretion-promoting components, among others, Dutch sennici extract, karin juice, salamander extract, thaumatin, theanine, sodium polyglutamate, luteolin, salmine enzyme degradation product, kombu extract, carrot, cinnamon, rahan fruit, citric acid Or its salt is preferable.

The content of the salivary secretion-promoting component in the oral preparation of the present invention is preferably 1 to 25% by mass, more preferably 5 to 15% by mass as the solid content with respect to the total mass of the coating material solid content. If the content of the salivary secretion-promoting component is too small, it is not meaningful to use the salivary secretion-promoting component. Conversely, if the content is too large, the content of water-soluble cellulose will be relatively small, resulting in a softer coating film. It may be too hard or too hard and may adversely affect the release control of oral components into the oral cavity.
Moreover, the content ratio by solid content conversion of the water-soluble cellulose and the saliva secretion promoting component in the coating material according to the present invention is preferably 2 to 15 and more preferably 5 to 10 as the water-soluble cellulose / saliva secretion promoting component. It is.

  The coating material according to the present invention may further contain a plasticizer in addition to the water-soluble cellulose and the saliva secretion promoting component. By including a plasticizer in the coating material, the strength of the coating material coating, that is, the surface layer of the oral preparation, is further improved, and the release control of oral components into the oral cavity is more appropriately performed. . As the plasticizer, those usually used in the food field or pharmaceutical field can be used without particular limitation. For example, in addition to polyhydric alcohols such as glycerin, sorbitol, maltitol, glycerin fatty acid ester, polyglycerin fatty acid ester. , Organic acid monoglyceride, diglycerin, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, lecithin, sorbitan fatty acid ester, medium chain fatty acid triglyceride, sucrose ester, etc., one kind of these alone or two or more kinds Can be used in combination. Of these plasticizers, polyhydric alcohols are particularly preferred.

The content of the plasticizer in the oral preparation of the present invention is preferably 1.5 to 35% by mass, more preferably 7.5 to 25% by mass as the solid content with respect to the total mass of the coating material solid content. is there.
Further, the content ratio by mass of the water-soluble cellulose and the plasticizer in the coating material according to the present invention is preferably 50 or less, more preferably 10 or less, as the water-soluble cellulose / plasticizer.

  The coating material according to the present invention may contain components other than the above components (water-soluble cellulose, salivary secretion promoting component, plasticizer). A sweetener can be illustrated as this other component. Since the seasoning is achieved by the sweetener contained in the coating material, an effect of reducing the burden of taking the oral preparation can be expected. As the sweetener, those usually used in the food field or pharmaceutical field can be used without particular limitation, and examples thereof include erythritol, xylitol, sucralose, and the like. One of these may be used alone or two or more may be used. They can be used in combination.

The content of the sweetener in the oral preparation of the present invention is preferably 25% by mass or less, more preferably 15% by mass or less as a solid content with respect to the total mass of the coating material solid content.
Further, the content ratio by mass of the water-soluble cellulose and the sweetener in the coating material according to the present invention is preferably 50 or less, more preferably 10 or less, as the water-soluble cellulose / sweetener.

  The oral preparation of the present invention is typically produced by applying a paint (coating liquid) containing a coating material to a central agent containing an oral ingredient by a method such as application or spraying. More specifically, for example, fluidized bed granulation coating device (flow coater, manufactured by Freund Sangyo Co., Ltd.), centrifugal rolling granulation coating device (CF granulator, Granurex, manufactured by Freund Sangyo Co., Ltd.), composite granulation Various coatings such as coating equipment (Spiraflow, manufactured by Freund Sangyo Co., Ltd.), sugar coating film coating equipment (High Coater, Aqua Coater: manufactured by Freund Sangyo Co., Ltd.), ventilated coating equipment (Paurek Coater: manufactured by Powrek Co., Ltd.) The surface of the central agent is sprayed onto the surface of the central agent by using a coating liquid application means such as a spray while allowing the central agent to flow in the apparatus and supplying dry air using the apparatus. A coating of coating material is formed on the center agent (oral component) Oral formulations of the invention encapsulated in a coating material is obtained. The oral preparation of the present invention can also be obtained by a method of coating the central agent with a coating material previously formed into a film instead of the method of applying such a coating liquid to the central agent.

  The coating liquid is prepared by dissolving the coating material (a constituent component of the coating material) according to the present invention in a solvent. The content of the coating material solid content in the coating liquid is preferably 1 to 50% by mass, more preferably 5 to 20% by mass with respect to the total mass of the coating liquid from the viewpoint of improving the production efficiency of the oral preparation. %.

  The solvent contained in the coating solution is preferably a solvent capable of dissolving the water-soluble cellulose contained in the coating material according to the present invention, and examples thereof include water and alcohols such as ethanol. When the coating liquid contains an alcohol such as ethanol, the volatility of the coating liquid is increased, and solvent drying after applying the coating liquid to the central agent and formation of a coating material on the coating are promoted. In that case, the content of alcohol (ethanol) in the coating solution is preferably 5 to 50% by mass with respect to the total mass of the coating solution.

  The ratio of the mass of the solid content of the coating material to the total mass of the oral preparation of the present invention is not particularly limited, and may be appropriately adjusted so that the release timing of the oral component into the oral cavity is appropriate, preferably Is 0.2 to 10% by mass, more preferably 0.3 to 5% by mass, and more preferably 1 to 4% by mass.

  Most of the oral components contained in the oral preparation of the present invention are preferably retained in the oral cavity for a certain period of time from the viewpoint of sufficiently exerting their functions in the oral cavity. In consideration of such points, the time from immediately after taking the oral preparation of the present invention to the time when the oral component is completely released into the oral cavity (oral component release time) is not zero, but a certain amount of time. Specifically, it is preferably 1 minute or more, more preferably 3 to 10 minutes, and more preferably 4 to 7 minutes. The oral component release time is measured by a disintegration test. As the disintegration test, a disintegration test method described in the Japanese Pharmacopoeia, an oral disintegration test method using a tricoop tester, or the like can be used. The oral component release time can be adjusted by appropriately adjusting the type and amount of the coating material.

  Hereinafter, the present invention will be described in more detail with reference to production examples, but the present invention is not limited to the following production examples.

[Production Examples 1-30 and Comparative Production Examples 1-2]
A coating solution containing the components shown in Tables 1 to 3 below was prepared as a component of the coating material. In addition, “PGA” in the following Tables 1 to 3 means sodium polyglutamate. Then, using a film coater high coater mini type (manufactured by Freund Sangyo Co., Ltd.), the prepared coating solution was applied to the surface of the simulated central agent to form a coating film, and an oral preparation was produced. The application amount of the coating liquid was adjusted so that the ratio of the mass of the coating material solid to the total mass of the oral preparation was 4% by mass. As a simulation centering agent, a tablet of 300 mg per tablet produced by a conventional method using a tableting machine RTM-S36-DC (manufactured by Kikusui Seisakusho Co., Ltd.) was used.
Further, as Comparative Production Examples 1 and 2, an oral preparation having only a simulated central agent, ie, no coating material, was produced. The oral preparation of Comparative Production Example 1 has the same composition as the simulated central agent in each of the production examples, whereas the oral preparation of Comparative Production Example 2 has HPMC and the simulated central agent raw material used in each of the production examples. PGA is contained in the same ratio as in Production Example 1.

[Test Example 1 (Production Examples 1 to 30 only)]
Each coating solution used for the production of oral preparations of Production Examples 1 to 30 was poured into a tray and dried at room temperature for 18 hours to produce a casting film (film-shaped coating material). The film forming properties at the time of film production and the film strength of the produced film were evaluated according to the following evaluation criteria.
Moreover, in manufacture of the oral preparation of the manufacture examples 1-30, the coating property at the time of providing the coating liquid to the surface of the simulation center agent was evaluated by the following evaluation criteria.
Moreover, about the oral preparation of the manufacture examples 1-30, the disintegration property was tested using the disintegration test apparatus of a Japanese pharmacopoeia, and the following evaluation criteria evaluated.
Among the above evaluations, the film-forming property and film strength of the film, and the disintegration property of the oral preparation are prepared for each sample by preparing 10 samples, and the evaluation points of these 10 samples. Was used as the evaluation of the production example. Moreover, the coating property of the oral preparation was evaluated by performing coating treatment 10 times for each preparation, and the average value of 10 times was regarded as the evaluation of the production example. The results are shown in Tables 1 to 3 below.

<Evaluation criteria for film-forming properties>
5 points: A very uniform and smooth film is formed.
4 points: A uniform and smooth film is formed.
3 points: A film having unevenness on the surface is formed.
2 points: A film having a rough surface is formed.
1 point: Almost no film is formed.
<Evaluation criteria for film strength>
5 points: Even if it is bent or pulled, it does not break easily, and it is flexible and very elastic.
Four points: Even if it is bent or pulled, it does not break easily and is elastic.
3 points: Even if bent or pulled, it does not break easily, but its elasticity is not high.
2 points: Although it does not break even when pulled, it has low elasticity and easily breaks when bent.
1 point: It breaks easily when bent or pulled.

<Evaluation criteria for coating properties>
5 points: The drying state of the coating liquid is very good, and there is no sticking between the simulated central agents through the coating liquid (undried coating material).
4 points: The drying state of the coating liquid is good, and there is almost no sticking between the simulated central agents made through the coating liquid (undried coating material).
3 points: The drying state of the coating liquid is normal, and there is little sticking between the simulated central agents made through the coating liquid (undried coating material).
Two points: The drying state of the coating liquid is poor, and there is a little amount of sticking between the simulated central agents made through the coating liquid (undried coating material).
1 point: The drying state of the coating liquid is very poor, and the simulated central agents are very often stuck together via the coating liquid (undried coating material).
<Evaluation criteria for disintegration>
5 points: Completely disintegrates within 7 minutes.
4 points: almost collapses within 7 minutes.
3 points: Partially collapses within 7 minutes.
2 points: Disintegrate slightly within 7 minutes.
1 point: No collapse within 7 minutes.

[Test Example 2]
The ingestion feeling of the preparations for oral cavity of Production Examples 1 to 30 and Comparative Production Examples 1 to 2 was evaluated. Specifically, 10 panelists take the oral preparation to be evaluated. At that time, the oral preparation is rolled on the tongue for about 10 seconds, and then the saliva secretion degree is evaluated according to the following evaluation criteria. We had you evaluate by. Tables 1 to 3 below show the average of the evaluation scores (up to 5 points) of 10 panelists.

<Evaluation criteria for feeling of taking>
5 points: A salivary secretion promoting action is recognized very quickly after taking.
4 points: Salivary secretion promoting action is recognized immediately after taking.
3 points: After taking, gradually promotes salivary secretion.
2 points: A salivary secretion promoting action is observed after a certain time after taking.
1 point: Almost no saliva secretion promoting action is observed after taking.

In Table 1, from comparison between each production example and comparative production example 2, as in comparative production example 2, even if the salivary secretion promoting component is used in the form of an uncoated tablet without a coating material, the effect of improving the feeling of taking is poor, In order to promote salivation and improve the feeling of dosing, as in each production example, a layer structure having an oral component and a coating material encapsulating the oral component is used, and the salivation promoting component is added to the coating material. It turns out that it is effective to contain.
Further, in Table 1, from the comparison between Production Examples 1 to 4 and Production Examples 5 and 6, as the coating base material of the coating material, HPMC, HPC, MC rather than thickening polysaccharides such as sodium alginate and pullulan. Such water-soluble cellulose is more preferable, and it can be seen from the comparison between Production Examples 1, 3, and 4 that HPMC is particularly preferable among the water-soluble celluloses.
In Table 1, the highest evaluations were Production Examples 7 to 9 using HPMC and HPC in combination as water-soluble cellulose. On the other hand, although the manufacture example 10 used HPMC and HPC together, it became a little low evaluation compared with the manufacture examples 7-9. From this, it can be seen that the content ratio by mass of HPMC and HPC is preferably 1 or more as in Production Examples 7 to 9 as HPMC / HPC.

From Table 2, it can be seen that the content of water-soluble cellulose (HPMC) in the coating material is preferably 50 to 99% by mass as the solid content as in Production Examples 12 to 18.
Moreover, it turns out from Table 2 that the content of the salivary secretion promoting component (PGA) in the coating material is preferably 1 to 25% by mass as the solid content as in Production Examples 14 to 18.
Also, from Table 2, the mass ratio of the water-soluble cellulose (HPMC) and the saliva secretion-promoting component (PGA) in the coating material in terms of solid content is as water-soluble cellulose / saliva secretion-promoting component as in Production Examples 14-16. 3 to 9 (range of more than 1.7 and less than 19) is preferable.

In Table 3, from the comparison between Production Examples 20 to 26 and Production Example 1 in Table 1 or the comparison between Production Example 29 and Production Example 30, the film strength can be further improved by adding a plasticizer to the coating material. I understand that.
Further, in Table 3, from the comparison between Production Examples 22 to 25, the content ratio by mass of water-soluble cellulose (HPMC) and plasticizer (glycerin) in the coating material is Production Examples 23 to 25 as water-soluble cellulose / plasticizer. As can be seen, 10 or less is particularly preferable.
In Table 3, from the comparison between Production Examples 27 to 29 and Production Example 1 in Table 1, when the coating solution contains ethanol, that is, the coating material is produced with an ethanol-containing solvent, the film-forming property is further improved. I know you get.

Claims (5)

  An oral preparation comprising an oral component and a coating material encapsulating the oral component, wherein the coating material contains water-soluble cellulose and a saliva secretion promoting component.   The oral preparation according to claim 1, wherein the water-soluble cellulose is at least one selected from the group consisting of hydroxypropylmethylcellulose and hydroxymethylcellulose.   The oral preparation according to claim 1 or 2, wherein the content of the water-soluble cellulose in the coating material is 50 to 99 mass%.   The oral preparation according to any one of claims 1 to 3, wherein the coating material further contains a plasticizer.   The saliva secretion-promoting component is Dutch sennici extract, karin juice, salamander extract, thaumatin, theanine, sodium polyglutamate, luteolin, salmine enzyme degradation product, kombu extract, carrot, cinnamon, rahan fruit, citric acid and citric acid The oral preparation according to any one of claims 1 to 4, wherein the preparation is one or more selected from the group consisting of salts of the above.