JP2007332063A - Povidone-iodine-containing intraoral disintegration type solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a solid preparation having enhanced uniformity of povidone-iodine content and stability of effective iodine. <P>SOLUTION: The intraoral disintegration type solid preparation comprises povidone iodine as an active ingredient and is composed of an inner core tablet obtained by directly tableting a mixture of a powdery sugar alcohol and povidone iodine (the mixture is a mixture containing no basic component and not made by wet granulation) and an outer layer containing a powdery sugar alcohol and covering the inner core tablet (the outer layer is made to have an oral disintegration time of 0.5-2 minutes and contains no povidone iodine). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an orally disintegrating solid preparation containing povidone iodine. More specifically, the present invention relates to an orally disintegrating solid preparation containing povidone iodine, and by adopting a two-layer structure, it relates to a solid preparation having improved uniformity of povidone iodine content and stability of effective iodine. Is.

  Povidone-iodine (The Merck Index 13th edition, 2001) is a complex of polyvinylpyrrolidone, which is a polymer of 1-vinyl-2-pyrrolidone, and iodine. Widely used all over the world for applications such as disinfection of fingers and sterilization of the oral cavity and pharynx. As povidone iodine for sterilization in the oral cavity and pharynx, a mouthwash diluted with water at the time of use is generally used. There is a disadvantage that it is complicated.

  As a preparation that overcomes this drawback, there is provided a spray agent in which povidone iodine is dissolved in water and glycerin, and an appropriate sweetness and flavor are added. However, this preparation has a problem that the container is bulky and thus is not portable and liquid leakage from the container occurs. In addition, since this spray is directly sprayed on the pharynx, it can be sterilized only in the throat, and in order to sterilize the oral cavity, it is necessary to use a mouthwash, which is not convenient.

  If we can provide an orally disintegrating solid preparation containing povidone iodine, there is a possibility that the above problem can be solved. However, since the content of povidone iodine per unit solid preparation is very small (unit weight 300 to 1,000 mg It is desirable to provide a solid preparation containing about 5 mg of povidone iodine in a tablet), and it is difficult to make the content of povidone iodine uniform.

Orally administrable solid preparation containing povidone iodine is tableted with povidone iodine and citric acid as a core tablet and coated with diclofenac sodium and hydroxypropylmethylcellulose on the core tablet. Is known (China Patent Application Publication CN1203792A). The core tablet used for this tablet can be obtained by wet granulating a mixture containing povidone iodine and citric acid, sugar powder, gum arabic, etc., and then tableting and molding the resulting granulated product. Japanese Patent Application Laid-Open No. 63-77805 discloses a water-soluble composition in the form of granules or powder comprising povidone iodine and at least one of urea and sugar alcohol. This composition dissolves at the time of use and is used as a mouthwash or the like, but is not administered into the oral cavity in the form of a tablet or the like.
Published Chinese patent application CN1203792A JP 63-77805 JP

  An object of the present invention is to provide an orally disintegrating solid preparation containing povidone iodine. More specifically, it is an object of the present invention to provide a solid preparation with improved uniformity of povidone iodine content and stability of effective iodine, and in particular, solids with significantly improved stability of effective iodine. It is an object of the present invention to provide a formulation.

  Generally, in order to make the content of the active ingredient contained in the solid preparation uniform, a method of dissolving the active ingredient in a solvent and performing wet granulation to tablet the granulated product is employed. The present inventors initially conducted research on the assumption that the above-mentioned problems can be solved by wet granulation, but since the iodine sublimates from the preparation in the drying process to remove the solvent, the content per solid preparation is low. We faced the new problem that the production equipment was corroded by iodine sublimated from the formulation, and the safety of workers was also raised. Furthermore, it was found that in order to distribute povidone iodine throughout the oral cavity using a solid preparation that disintegrates and dissolves in the oral cavity, it is necessary to produce a solid preparation having an oral disintegration time of about several minutes, It has also been found that the solid preparation containing glucose normally used as an excipient has a problem that the disintegration time in the oral cavity is too short to sufficiently distribute povidone iodine in the oral cavity.

  As a result of researches to solve the above problems, the present inventors have used granular sugar alcohol as an excipient, do not contain a basic component, and are directly powdered without going through a wet granulation process. It has been found that by preparing a solid preparation with a tablet, it is possible to provide a preparation having a uniform content of povidone iodine per unit solid preparation and containing effective iodine stably (PCT / JP2005 / 023701).

  As a result of further studies and various studies to provide a solid preparation excellent in the stability of effective iodine in the preparation, the present inventors have found a mixture containing granular sugar alcohol and povidone iodine (however, the mixture is a basic component) Does not contain povidone iodine so that the oral disintegration time is in the range of 0.5 to 2 minutes on the outside of the core tablet obtained by direct powder tableting. By providing the outer layer part, it was found that a solid preparation in which the stability of effective iodine in the preparation was dramatically improved, and the present invention was completed.

 That is, according to the present invention, an orally disintegrating solid preparation containing povidone iodine as an active ingredient, which is a mixture containing granular sugar alcohol and povidone iodine (however, the mixture does not contain a basic component and is wet granulated). An inner core tablet obtained by direct powder tableting of the mixture, and an outer layer containing granular sugar alcohol and covering the inner core tablet (however, the outer layer has an oral disintegration time in the range of 0.5 to 2 minutes) And a solid formulation comprising no povidone iodine).

  According to a preferred embodiment of the present invention, the above-mentioned solid preparation in which the above-mentioned mixture does not contain a binder usually used in the art; Said solid preparation containing a sweetener such as aspartame or acesulfame potassium; the above described solid preparation wherein the oral disintegration time of the core tablet is about 1 to 10 minutes, preferably about 2 to 4 minutes; the hardness of the core tablet A solid preparation as described above, wherein is 40 to 200 N, preferably 80 to 120 N; the ingredients contained in the outer layer are the same as those contained in the inner core tablet (excluding povidone iodine).

  Another aspect of the present invention is a method for producing an orally disintegrating solid preparation containing povidone iodine as an active ingredient, wherein a mixture containing granular sugar alcohol and povidone iodine (however, the mixture does not contain a basic component) is wet. A process of producing an inner core tablet by directly tableting without granulation, and a process of coating the inner core tablet with an outer layer containing a sugar alcohol (however, the outer layer has an oral disintegration time in the range of 0.5 to 2 minutes) And is free of povidone iodine) is provided by the present invention.

  The solid preparation of the present invention is a solid preparation having a uniform povidone iodine content per unit solid preparation and excellent stability of effective iodine, and produced by sublimation of iodine from the preparation generated during wet granulation It has the feature that it can be manufactured without causing problems such as corrosion of equipment and deterioration of working environment. In addition, when the solid preparation of the present invention is taken into the oral cavity, the outer layer part collapses in a short time and a sufficient amount of saliva is secreted into the oral cavity, and then povidone iodine, which is the active ingredient, is eluted from the core tablet. Therefore, for example, povidone iodine can be distributed throughout the oral cavity even when the oral cavity is dry, such as in winter, and the oral cavity and the pharynx can be reliably sterilized.

  The solid preparation of the present invention is an orally disintegrating solid preparation containing povidone iodine as an active ingredient, and a mixture containing granular sugar alcohol and povidone iodine (however, the mixture does not contain a basic component and is wet granulated) An outer core part comprising an inner core tablet obtained by direct powder compression of a non-mixed mixture and a granular sugar alcohol provided so that the oral disintegration time is in the range of 0.5 to 2 minutes (the outer layer part) Does not contain povidone iodine, and is hereinafter simply referred to as “outer layer”).

  Povidone iodine is a drug listed in the 14th revision of the Japanese Pharmacopoeia, and is a complex of 1-vinyl-2-pyrrolidone polymer (polyvinylpyrrolidone) and iodine. Usually, the content of iodine in povidone iodine is about 9-12%. Commercial products are available as povidone iodine (for example, “Povidone iodine” manufactured by BASF Japan, “Povidone iodine” manufactured by ISP Japan, etc.). The particle size of the povidone iodine crystals is not particularly limited, and for example, crystals having a particle size of about 20 to 300 μm can be used.

  The type of sugar alcohol used for the production of the inner core tablet and the outer layer of the solid preparation of the present invention is not particularly limited, and for example, D-sorbitol, D-mannitol and the like are preferable. As the sugar alcohol, sugar alcohol shaped into granules can be used, and the particle size of the sugar alcohol granules is, for example, about 50 to 1,500 μm, preferably about 50 to 1,000 μm. Commercial products are available as such sugar alcohols (for example, “Neosolv P20 / 60” (average particle size 650 μm), “Neosolv P30 / 60” (average particle size 480 μm), “Neosolv P60W” manufactured by Rocket Co., Ltd. (Average particle size 180 μm), “Neosolv P100T” (average particle size 110 μm), “Pearitol 100SD” (average particle size 100 μm), “Pairitol 200SD” (average particle size 200 μm, etc.)). In the production of the inner core tablet, the ratio of sugar alcohol to povidone iodine is not particularly limited, but is usually an amount sufficient to make the weight of one dosage unit of the inner core tablet about 50 to 500 mg, preferably about 60 to 400 mg. The amount of povidone iodine may be adjusted to contain about 1 to 10 mg, preferably about 5 mg of povidone iodine per dosage unit of inner core tablet. More specifically, the weight ratio of sugar alcohol to povidone iodine is desirably about 100: 1 to 10: 1, preferably about 60: 1 to 15: 1.

  In manufacturing the inner core tablet of the solid preparation of the present invention, a disintegrant may be added to the above mixture. As the disintegrant, a basic disintegrant is usually used. However, since povidone iodine is unstable under basicity, it is desirable to use an acidic disintegrant. As such a disintegrant, for example, carmellose or alginic acid can be used. The ratio of the disintegrant in the mixture is not particularly limited, but when the weight of one dosage unit of the inner core tablet is about 50 to 500 mg, preferably about 60 to 400 mg, the disintegrant is about 0.5 to 50 mg, preferably 0.6 to About 30mg can be blended. Usually, by using the sugar alcohol in the above amount, the disintegration time in the oral cavity can be reduced to about several minutes, but the disintegration time can be further adjusted using a disintegrant. The disintegration time of the inner core tablet is preferably several minutes in the oral cavity, more preferably 1 minute to 10 minutes, still more preferably about 2 minutes to 4 minutes. It is desirable to include a combination of a sugar alcohol and a disintegrant so that such a disintegration time can be achieved. The hardness of the inner core tablet is preferably 40 to 200N, more preferably 50 to 120N.

  In addition to the above-described components, formulation additives such as a corrigent, sweetener, stabilizer, or lubricant may be added to the mixture. As a corrigent, for example, L-menthol, caramel, various fruit flavors and the like can be used, and as a sweetener, for example, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, saccharin, sodium saccharin and the like can be used. . As the stabilizer, for example, croscarmellose sodium, corn starch, rice starch, starch such as potato starch, and the like can be used. As the lubricant, for example, sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like can be used. These pharmaceutical additives can be used in an amount of about 0.1 to 10% by weight, preferably about 0.5 to 5% by weight, based on the total weight of the mixture.

  The inner core tablet of the solid preparation of the present invention can be produced by directly tableting a mixture obtained by mixing povidone iodine and the above-mentioned granular sugar alcohol. In the present specification, “direct powder tableting” means that the powder is directly compressed without wet granulation in compression molding (tablet) of the powder. That is, in addition to povidone iodine and granular sugar alcohol, a mixture containing the above-mentioned optional components (disintegrant, corrigent, sweetener, etc.) is prepared, and in the form of powder without going through a wet granulation step. A direct tableting process is performed using the above mixture.

  It is not necessary to add a binder that is usually used when preparing a solid preparation by compression molding such as a tablet to the above mixture. Without being bound by any particular theory, in a mixture containing povidone iodine in the above proportions, povidone iodine exerts a modest binding action on sugar alcohols, and directly by compression molding without the use of conventional binders. Powder tableting becomes possible. In general, the production of lozenges employs a step of tableting after blending 3 to 5% by weight of a binder and performing wet granulation using a solvent such as ethanol or water. In the method of the present invention, an inner core tablet having a desirable oral disintegration time can be obtained very easily by directly tableting the mixture without wet granulation.

  The solid preparation of the present invention can be produced by coating the inner core tablet with an outer layer. In addition to the granular sugar alcohol, the components contained in the outer layer can include components used in the production of ordinary solid preparations. More specifically, for example, excipients, binders, disintegrants, sweeteners , Lubricants, fragrances and the like can be used, but are not limited thereto. As the granular sugar alcohol, those described above can be used. However, the outer layer does not contain povidone iodine. Further, the outer layer is preferably composed of the same components as those contained in the above-mentioned mixture constituting the inner core tablet (excluding povidone iodine) from the viewpoint of taste such as taste and touch.

  Examples of excipients constituting the outer layer include starches such as lactose, corn starch, rice starch, and potato starch, crystalline cellulose, sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, maltitol, hydrogenated oil And calcium hydrogen phosphate, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium aluminate silicate, and magnesium aluminate metasilicate. As the binder, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, gum arabic, macrogol and the like can be used. As the disintegrant, for example, carmellose, carmellose calcium, carmellose sodium, alginic acid, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium and the like can be used. As the sweetening agent, for example, honey, aspartame, dipotassium glycyrrhizinate, saccharin, saccharin sodium, acesulfame potassium and the like can be used. As the lubricant, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid ester and the like can be used. As a fragrance | flavor, L-menthol, caramel, various fruit type | system | groups, etc. can be used, for example.

  The solid preparation of the present invention can be produced, for example, by compressing and coating the mixture constituting the outer layer with respect to the inner core tablet using a dry tableting machine or the like, but the production method is limited to the specific method described above. It will never be done. The hardness of the solid preparation of the present invention obtained after coating the outer layer is not particularly limited, but is preferably 40 to 200N, more preferably 80 to 150N. The weight of the outer layer per unit dosage form of the solid preparation is not particularly limited, but is preferably about 250 to 1,000 mg, preferably about 300 to 800 mg. The weight ratio of the inner core tablet to the outer layer is, for example, 1: 2 to 1:20. Is preferable, and 1: 4 to 1:15 is particularly preferable. The outer layer is provided so as to disintegrate in 0.5 to 2 minutes after being taken into the oral cavity, but it is more preferable that the outer layer disintegrate in about 0.5 to 1 minute. The outer layer having such properties can be appropriately prepared by appropriately selecting the components and blending amount contained in the outer layer, or adjusting the tableting pressure at the time of coating the outer layer, etc. It is possible to adjust.

  The solid preparation of the present invention may contain one or more pharmaceutically active ingredients other than povidone iodine in the inner core tablet and / or the outer layer part depending on the purpose of use. The type of the pharmaceutically active ingredient is not particularly limited, but, for example, Acacia yak, fennel, cetylpyridinium chloride, lysozyme chloride, perch, licorice, kyoukyo, kyounin, potassium guaiacol sulfonate, dipotassium glycyrrhizinate, potassium cresolsulfonate, cinnamon, shazenshi , Genus japonicus, ginger, senega, sakuhakuhi, soyo, chikutsujinjin, chimpi, carrot, noscapine, bacmond, mint, hanger, chlorpheniramine maleate, menthol, eucalyptus, and the like.

Although the form of the solid preparation of the present invention is not particularly limited, it is usually preferably in the form of a tablet, such as a troche.
When about 1 to 2 unit dosage forms of the solid preparation of the present invention are placed in the oral cavity and brought into contact with saliva, the outer layer collapses in the oral cavity in 0.5 to 2 minutes and a sufficient amount of saliva is secreted in the oral cavity. Thereafter, the entire solid preparation is disintegrated and povidone iodine as an active ingredient is eluted from the inner core tablet, and povidone iodine is distributed throughout the oral cavity and the pharynx (the upper pharynx, the oropharynx, and the lower pharynx). The solid preparation of the present invention rapidly disintegrates in the oral cavity even when it is dried, for example, in the winter season, and particularly relieves pain caused by inflammation of the throat associated with the common cold, sterilization and disinfection of the oral cavity and throat during tonsillitis This is effective. The dose of the solid preparation of the present invention is not particularly limited. For example, the dose of povidone iodine is about 5 to 50 mg per day.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited by the following Example.
Example 1
Povidone iodine (Japanese Pharmacopoeia Povidone iodine, BASF Japan) 50 g, Carmellose (NS-300, Nichirin Chemical Industries) 35 g, Aspartame (Aspartame, Ajinomoto Co.) 7 g, D-sorbitol (Neosolv P60W, Rocket) 594g, 20% L-menthol powder 7g, sodium stearyl fumarate (Pruv, Kimura Sangyo Co., Ltd.) 7g was mixed in the following examples and 1 tablet 70 mg using a tableting machine. An inner core tablet was produced. The hardness of the inner core tablet was 89N.

  Carmellose 165 g, aspartame 33 g, D-sorbitol 3036 g, 20% L-menthol powder 33 g, and sodium stearyl fumarate 33 g were mixed. The obtained mixture was compressed and coated with 330 mg per tablet as an outer layer of the inner core tablet using a tableting machine to obtain 400 mg lozenge tablets. The tablet hardness was 105N. The above 20% L-menthol powder is a mixture of L-menthol (1-menthol, manufactured by Takasago International Corporation) and hydrous silicon dioxide (Adsolider 102, manufactured by Freund Corporation) in a ratio of 1: 4. The same applies to Examples 2 to 5 below.

Example 2
Povidone iodine 50g, carmellose 53g, acesulfame potassium (Sanet, manufactured by Nutriva) 14g, D-sorbitol 569g, 20% L-menthol powder 7g, magnesium stearate (magnesium stearate, manufactured by Taihei Chemical Industrial Co., Ltd.) 7g, One tablet 70 mg inner core tablet was produced using a tableting machine. The hardness of the inner core tablet was 82N. Carmellose 247 g, acesulfame potassium 56 g, D-sorbitol 2931 g, 20% L-menthol powder 33 g, and magnesium stearate 33 g were mixed. The obtained mixture was compression coated with 330 mg per tablet as an outer layer of the inner core tablet by a tableting machine to obtain 400 mg lozenge tablets. The tablet hardness was 96N.

Example 3
50 g of povidone iodine, 100 g of carmellose, 20 g of aspartame, 1790 g of D-sorbitol, 20 g of 20% L-menthol powder, and 20 g of sodium stearyl fumarate were mixed to produce an inner core tablet of 200 mg per tablet using a tableting machine. The hardness of the inner core tablet was 137N. Carmellose 400 g, aspartame 80 g, D-sorbitol 7360 g, 20% L-menthol powder 80 g, and sodium stearyl fumarate 80 g were mixed. The obtained mixture was compression coated with 800 mg per tablet as an outer layer of the inner core tablet by a tableting machine to obtain 1000 mg of troche tablets. The hardness of the tablet was 147N.

Example 4
10 g of povidone iodine, 40 g of carmellose, 8 g of aspartame, 726 g of D-sorbitol, 8 g of 20% L-menthol powder, 8 g of sodium stearyl fumarate were mixed, and 400 mg of a lozenge was prepared using a tableting machine. Tablet hardness was 104N.
Example 5
10 g of povidone iodine, 60 g of carmellose, 16 g of acesulfame potassium, 698 g of D-sorbitol, 8 g of 20% L-menthol powder and 8 g of magnesium stearate were mixed, and 400 mg of a troche was prepared using a tableting machine. The tablet hardness was 118N.

Test Example 1: Measurement of effective iodine content For each troche tablet of Examples 1 to 5 above, the effective iodine content immediately after production and after storage at 60 ° C for 1 week (packing form is bottle-sealed) is neutralized with sodium thiosulfate solution. Measurement was performed using a titration method, and the residual ratio was calculated. The results are shown in Table 1. In the lozenge tablets of Examples 4 and 5, the effective iodine amount was maintained at 70% after storage at 60 ° C. for 1 week, and good stability was observed. In each of the troche tablets of Examples 1 to 3, an effective iodine amount of 80% or more was maintained, and higher stability was observed.

Test Example 2: Uniformity of povidone iodine content The effective iodine content was measured for the solid preparations of Examples 1, 2, and 3 (each 10 tablets), and the relative standard deviation was calculated. As a result, 1.3%, 1.3%, 1.5%, respectively. The variation in effective iodine content was small, and the uniformity of effective iodine content was good.

Test Example 3: Measurement of oral disintegration time
The time for disappearance in the oral cavity of the solid preparations of Examples 1, 2, and 3 was measured by a panel of 10 people. As a result, the oral disintegration times (average values of 10 persons) of the solid preparations of Examples 1, 2, and 3 were 3.8 minutes, 4.6 minutes, and 5.5 minutes, respectively. In any of the solid preparations, sterilization with high povidone iodine was performed. The time required for the force to provide a sufficient bactericidal effect in the entire oral cavity and pharynx (usually over 1 minute) was guaranteed. In addition, they were satisfied with the feeling of taking such as taste and touch.

Claims (6)

An orally disintegrating solid preparation containing povidone iodine as an active ingredient, and a mixture containing granular sugar alcohol and povidone iodine (however, the mixture does not contain a basic ingredient and is not wet granulated) An inner core tablet obtained by direct powder tableting, and an outer layer containing granular sugar alcohol and covering the inner core tablet (provided that the oral disintegration time is in the range of 0.5 to 2 minutes, And does not contain povidone iodine). The solid preparation according to claim 1, wherein the mixture contains a disintegrant selected from the group consisting of alginic acid and carmellose. The solid preparation according to claim 1 or 2, wherein the mixture further comprises a sweetener selected from the group consisting of aspartame and acesulfame potassium. The solid preparation according to any one of claims 1 to 3, wherein the oral disintegration time of the inner core tablet is in the range of 1 minute to 10 minutes. The solid preparation according to any one of claims 1 to 4, wherein the outer layer is composed of components (excluding povidone iodine) contained in the mixture constituting the inner core tablet. The solid preparation according to any one of claims 1 to 5, wherein the weight ratio of the inner core tablet to the outer layer is 1: 2 to 1:20.