JP2013095730A - Film coating composition and oral solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a film coating composition which has excellent texture in the oral cavity and also has improved leachability, and to provide an oral solid preparation imparted with high luster by being coated using the film coating composition.SOLUTION: The film coating composition at least comprises: a base including methylcellulose alone or hydroxypropyl cellulose and/or polyvinyl alcohol in addition to methylcellulose in 100 pts.mass; a plasticizer in 18 to 150 pts.mass; and talc in 40 to 500 pts.mass. Further, the oral solid preparation at least comprises: a core part at least including a medicine; and the film coating composition coating the core part. Further, a method for producing an oral solid preparation at least including: a step of coating a solution in which the film coating composition is dissolved or dispersed into a solvent; and the subsequent drying step is provided.

Description

  The present invention relates to a film coating composition and an oral solid preparation using the same.

  Film coating and sugar coating are used to mask the unpleasant taste of drugs in oral solid preparations, light-shielding to maintain drug stability, colored coatings to improve the discrimination of oral solid preparations, and in the process of transporting oral solid preparations Widely used for the purpose of preventing wear and improving the aesthetics of products.

  In particular, regarding the aesthetics of tablets, it is known that high gloss can be obtained by applying a sugar coating. As an attempt to impart high gloss to a tablet, it has been proposed that high gloss can be imparted to the tablet surface by using a composition in which polyethylene glycol and talc are blended in a specific ratio with hydroxypropylmethylcellulose (Patent Literature). 1). Moreover, as a bitterness masking method, a film coating that does not disintegrate in the oral cavity has been proposed by applying the gelation characteristics of methylcellulose and film coating using methylcellulose (Patent Document 2). Furthermore, a method has been proposed in which saccharides or sugar alcohols are blended with methylcellulose, which is excellent in bitterness masking and improves drug elution (Patent Document 3).

JP 2008-201713 A JP 60-13719 A JP 2001-151672 A

  However, the sugar coating requires a long time for the sugar coating process, increases the manufacturing cost, becomes so large that the preparation is difficult to take, and the protein that is the main component of gelatin used for coating is denatured and stable. There is a problem of lacking. In addition, although the film coating composition of Patent Document 1 can produce tablets with high gloss, oral solid preparations coated with hydroxypropylmethylcellulose dissolve quickly in the mouth, and feel sticky and slimy in the mouth. There was a problem that it was difficult to take depending on patients such as elderly people and infants. This is because hydroxypropylmethylcellulose has a high thermal gelation temperature and does not cause thermal gelation in the oral cavity, so that the film dissolves quickly. On the other hand, when methylcellulose is used as described in Patent Document 2, methylcellulose cannot be dissolved due to thermal gelation at 37 ° C., so it can be taken without feeling sticky or slimy. However, there is a concern that the dissolution of the drug may be delayed due to thermal gelation. Therefore, in Patent Document 3, it is proposed that the elution is improved by adding saccharide or sugar alcohol to methylcellulose, but the improvement of the elution by this method is not sufficient, and saccharide or the like is added. As a result, moisture permeability was improved, and there was a problem that stability during storage of tablets could not be ensured.

  The present invention provides a film coating composition that has an excellent mouthfeel and improved elution properties compared to conventional film coatings, and high gloss is imparted by coating with such film coating compositions. An object of the present invention is to provide an oral solid preparation.

As a result of intensive studies to solve the above problems, the present inventors have found that the above object can be achieved by blending a plasticizer and talc at a specific ratio in methylcellulose, and completed the present invention. .
According to the present invention, methylcellulose alone or in addition to methylcellulose, 100 parts by mass of a base having hydroxypropylcellulose and / or polyvinyl alcohol, 18-150 parts by mass of plasticizer, and 40-500 parts by mass of talc are included at least. A film coating composition is provided. Also provided is an oral solid preparation comprising at least a core containing a drug and at least the film coating composition covering the core. Furthermore, a method for producing an oral solid preparation comprising at least a step of applying a solution obtained by dissolving or dispersing the film coating composition in a solvent to a core containing at least a drug and a subsequent drying step is provided.

  If an oral solid preparation is coated using the film coating composition of the present invention, the stickiness and sliminess in the oral cavity are improved compared to conventional film coating, the mouthfeel is excellent, and smooth swallowing Therefore, it is possible to provide an oral solid preparation with improved dissolution that can quickly dissolve the active ingredient. Moreover, according to this invention, the oral solid formulation to which high glossiness was provided without carrying out sugar coating can be provided.

The result of the elution test of Examples 1-8 and Comparative Example 1 is shown.

The film coating composition of the present invention contains at least a base having a hydroxypropyl cellulose and / or polyvinyl alcohol, a plasticizer and talc in addition to methyl cellulose alone or methyl cellulose.
The viscosity of methylcellulose (hereinafter also referred to as “MC”) is preferably low so that it can be sprayed as a highly concentrated solution to perform coating. Specifically, the viscosity of a 2% by mass aqueous solution at 20 ° C. is preferably 2 to 50 mPa · s, more preferably 2 to 25 mPa · s, and particularly preferably 2 to 15 mPa · s. If it is less than 2 mPa · s, the degree of polymerization of MC is extremely lowered, so that the strength as a film may not be maintained. On the other hand, if it exceeds 50 mPa · s, the concentration of the aqueous coating solution must be kept low, which may be impractical. In addition, the said viscosity can be measured with the viscosity measuring method as described in the 16th revision Japanese Pharmacopoeia.
Although the substitution degree of the methoxy group of MC is not particularly limited, it is preferably 26.0 to 33.0% by mass, more preferably 27.5 to 31.5% by mass. The degree of substitution of MC can be measured by a method based on the method for measuring the degree of substitution of methylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose described in the 16th revised Japanese Pharmacopoeia.

Other MC sole base, MC hydroxypropyl cellulose (hereinafter also referred to as "HPC") and polyvinyl alcohol (hereinafter, also referred to as "PVA") may be used base compounded with.
The viscosity of the HPC is preferably lower in order to carry out the coating. Specifically, the viscosity of a 2 mass% aqueous solution at 20 ° C is preferably 2 to 50 mPa · s, more preferably 3 to 10 mPa · s, and particularly preferably 6 to 10 mPa · s. If it is less than 2 mPa · s, the degree of polymerization of MC is extremely lowered, so that the strength as a film may not be maintained. On the other hand, if it exceeds 50 mPa · s, the concentration of the aqueous coating solution must be kept low, which may be impractical. It can be measured by the same measurement method as MC.
Further, the degree of substitution of the hydroxypropoxy group is not particularly limited, but is preferably 53.4-77.5% by mass, more preferably 60.0-70.0% by mass. In addition, the substitution degree of HPC can be measured by the same measurement method as MC.
The blending amount of HPC is not particularly limited, but from the viewpoint of improving the dissolution property of MC, the mass ratio of MC to HPC is preferably 49:51 to 10:90, more preferably 45:55 to 35:65. is there. When the amount of HPC is small, the dissolution property is inferior. On the other hand, when the amount of HPC is large, there is a risk of feeling slimy and sticky in the oral cavity when taking an oral solid preparation.

PVA is preferably polyvinyl alcohol (completely saponified product) or polyvinyl alcohol (partially saponified product) specified by the pharmaceutical additive standards. The fully saponified polyvinyl alcohol has a saponification degree of 97 mol% or more, and the partially saponified polyvinyl alcohol preferably has a saponification degree of 78 to 96 mol%.
The average degree of polymerization of PVA is preferably 200-3500, more preferably 400-1000. The average degree of polymerization of PVA can be measured by the method for measuring the average degree of polymerization described in JIS K6726.
The amount of PVA is not particularly limited, but from the viewpoint of compatibility with MC, the mass ratio of MC to PVA is preferably 90:10 to 10:90, more preferably 50:50 to 15:85, and particularly preferably Is in the range of 40:60 to 20:80. When the amount of PVA is less than the above preferred range, the dissolution may be inferior, and when the amount of PVA is more than the above preferred range, when the oral solid preparation is taken, the mouth feels sticky and sticky. You may feel

Examples of the plasticizer that can be used in the present invention include polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, and the like. From the viewpoint of excellent compatibility with MC and imparting high gloss, polyethylene glycol is particularly preferable. Is preferred.
The weight average molecular weight of polyethylene glycol is not particularly limited, but is preferably 200 to 35000, and more preferably 1500 to 35000, from the viewpoint of imparting high gloss. The weight average molecular weight of polyethylene glycol is obtained in terms of polystyrene using gel permeation chromatography (GPC).
Although content of the plasticizer in a film coating composition is 18-150 mass parts with respect to 100 mass parts of bases, Preferably it is 22-100 mass parts, More preferably, it is 40-80 mass parts. When the content of the plasticizer is less than 18 parts by mass, the gloss of the tablet is inferior, and even if the plasticizer is added more than necessary, the economy is inferior. The base can be selected from a base consisting of MC alone, a base consisting of MC and HPC, a base consisting of MC and PVA, and a base consisting of MC, HPC and PVA.

The content of talc in the composition for film coating is 40 to 500 parts by mass, preferably 80 to 380 parts by mass, and more preferably 150 to 250 parts by mass with respect to 100 parts by mass of the base. If the content of talc is low, the gloss of the tablet is inferior. On the other hand, even if more talc is added than necessary, the economy is inferior.
Since the film coating composition of the present invention contains the plasticizer and talc in the above ratio, the coating film disintegration is promoted at the edge portion where the coating amount is small, and the MC coating film that does not normally dissolve at 37 ° C. It is thought that drug elution occurs.

  If necessary, the coating composition may be added with drugs that are generally recognized pharmaceutically, surfactants that improve the dispersibility of the composition, colorants, pigments, sweeteners, coating agents, antifoaming agents, and the like. good.

The oral solid preparation includes at least a core containing a drug and at least a film coating composition for covering the core.
The drug is not particularly limited as long as it can be administered orally.

  In the core containing at least the drug, various additives that can be commonly used in this field, such as excipients, binders, disintegrants, lubricants, anti-aggregation agents, and solubilizing agents for pharmaceutical compounds, are blended. May be. Examples of the excipient include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate and the like, and binders include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, Examples include glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, gum arabic, gelatin, agar, starch, and the like. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose or a salt thereof, croscarmellose sodium, sodium carboxymethyl starch, cros polyvinylpyrrolidone, crystalline cellulose, crystalline cellulose / carmellose sodium, and the like. Further, examples of the lubricant and the aggregation inhibitor include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oil, polyethylene glycols, sodium benzoate and the like. Furthermore, examples of solubilizing agents for pharmaceutical compounds include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid. The content of these additives can be appropriately determined according to the type of the drug.

  Examples of the oral solid preparation coated with the film coating composition of the present invention include tablets, granules, fine granules, capsules, etc. Among them, tablets are particularly preferable.

Next, the manufacturing method of an oral solid formulation is demonstrated.
Conventionally known means can be used for the coating apparatus. Although spray coating is generally performed, in that case, it may be performed using a pan coating apparatus, a drum type coating apparatus, a fluidized bed coating apparatus, and a stirring fluidized coating apparatus. As the spray device, any of air spray, airless spray, three-fluid spray, and the like can be used.

As a method for applying the film coating composition solution of the present invention, for example, using the above-described coating apparatus, a film coating composition in which MC, a plasticizer, and talc are further added with additives as necessary to the core containing the drug. A solution prepared by dissolving or dispersing the product in water or an organic solvent such as ethanol or a mixture thereof may be prepared and applied by spraying or the like.
MC, HPC, PVA, and the plasticizer polyethylene glycol are water-soluble and dissolve in a mixed solution of water and an organic solvent such as ethanol. Talc is an inorganic powder and is not dissolved in water or an organic solvent but is dispersed. In consideration of dispersion, the average particle diameter of talc is preferably in the range of 0.1 to 20 μm using a laser diffraction scattering method.

Then, it can take out in the coating apparatus or from the coating apparatus, and can be dried by heating or the like to produce an oral solid preparation.
Drying is not particularly limited, but in terms of imparting high gloss, it is preferable to perform polishing together with drying, and preferably a state in which oral solid preparations are rubbed with each other during drying (polishing). Drying is preferably performed at a temperature of 20 to 100 ° C., more preferably 30 to 80 ° C. in the above-described coating apparatus. By rotating or stirring the inside of the coating apparatus, polishing can be performed together with drying. The drying is preferably performed for 10 minutes or more, more preferably 20 minutes to 60 minutes, and particularly preferably 20 minutes to 40 minutes, regardless of the presence or absence of polishing. Even if polishing is performed while drying or drying for 60 minutes or more, the glossiness does not change and the economy is inferior.

  The coating amount of the film coating composition coated on the surface of the core (uncoated tablet) depends on the type, shape, size, surface state of the solid preparation, and the properties of the drug and additives contained in the solid preparation. Although different, for example, it is preferably 1 to 10% by mass, more preferably 1 to 7% by mass, and particularly preferably 2 to 6% by mass with respect to the uncoated tablet. If the coating amount is too small, a complete film cannot be obtained. On the other hand, if the coating amount is too large, the time required for coating may be required.

  The oral solid preparation of the present invention forms a plurality of films by undercoating with various coating bases that can be commonly used in this field such as hydroxypropylmethylcellulose under the film layer comprising the film coating composition. A multilayer film-coated oral solid preparation may also be used.

  Until the oral solid preparation thus produced releases 85% or more of the drug in the dissolution test described in the 16th revised Japanese Pharmacopoeia (37 ° C., paddle method, 50 rotations / min, solvent 900 mL water) Is preferably within 10 minutes from the start of the test. Further, the glossiness of the surface of the oral solid preparation was determined by measuring a 60-degree specular gloss using a precision gloss meter (GM-26D (20 ° / 60 °) type, manufactured by Murakami Color Research Laboratory) (tablet holder 5 mmφ, (Measurement area: about 3 × 3 mm), it is preferably 6.0 or more. Furthermore, the oral solid preparation can be taken without feeling slimy or sticky in the oral cavity when taken.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these.
Example 1
2 parts by mass of riboflavin (manufactured by Tanabe Seiyaku Co., Ltd.), 90 parts by mass of lactose (manufactured by Freund Sangyo Co., Ltd., Dilactose S), 8 parts by mass of low-substituted hydroxypropylcellulose (hydroxypropyl group substitution degree 11% by mass), magnesium stearate 0.5 parts by mass are mixed with powder, and a rotary tableting machine (Vergo, manufactured by Kikusui Seisakusho) is 8 mm in diameter, tableting pressure 1 t, tableting preload 0.3 t, rotation speed 20 rpm, and weight per tablet is 200 mg. Tableting was carried out so that an uncoated tablet containing riboflavin in the drug was prepared.
Next, MC (28% by mass of methoxy group substitution, viscosity of 2% by mass aqueous solution at 20 ° C. is 4.0 mPa · s) 13.5 g, polyethylene glycol (manufactured by NOF Corporation, Macrogol 6000) 8.1 g (MC 0.60), talc (manufactured by Crown) 27.0 g (2.0 to MC), and titanium oxide (manufactured by Ishihara Sangyo) 5.4 g were dissolved and dispersed in 396.0 g of purified water and coated A solution was prepared.
Using the above coating solution, coating was performed up to 5 parts by mass with a solid content based on 100 parts by mass of the uncoated tablet. After the coating was completed, drying and polishing were performed for 30 minutes in a coating apparatus at an air supply temperature of 60 ° C. and a pan rotation speed of 24 rpm, to obtain a target coated tablet.
The coating conditions used are as follows.
Equipment: Ventilated pan coater (inner diameter 33cm)
Charge amount: 1kg
Intake air temperature: 80 ℃
Exhaust temperature: 47-50 ° C
Intake air volume: 1m ³ / min
Pan rotation speed: 18-24rpm
Spray speed: 6g / min
Spray air pressure: 150kPa

Example 2
In the preparation of the coating solution of Example 1, 24.75 g of MC, 5.45 g of polyethylene glycol (0.22 with respect to MC), 19.80 g of talc (0.8 with respect to MC), and titanium oxide A coating solution was prepared by changing 9.90 g and purified water to 490.11 g, and a coated tablet was obtained in the same manner as in Example 1.

Example 3
In the preparation of the coating solution of Example 1, 10.5 g of MC, 2.31 g of polyethylene glycol (0.22 with respect to MC), 39.9 g of talc (3.8 with respect to MC), and titanium oxide A coating solution was prepared by changing 4.2 g and purified water to 293.09 g, and a coated tablet was obtained in the same manner as in Example 1.

Example 4
In the preparation of the coating solution of Example 1, 18.0 g of MC, 22.5 g of polyethylene glycol (1.25 with respect to MC), 14.4 g of talc (0.8 with respect to MC), and titanium oxide A coating solution was prepared by changing 7.2 g and purified water to 537.9 g, and a coated tablet was obtained in the same manner as in Example 1.

Example 5
In the preparation of the coating solution of Example 1, 10.5 g of MC, 13.13 g of polyethylene glycol (1.25 for MC), 39.9 g of talc (3.8 for MC), and titanium oxide A coating solution was prepared by changing 4.2 g and purified water to 282.28 g, and a coated tablet was obtained in the same manner as in Example 1.

Example 6
In the preparation of the coating solution of Example 1, 16 g of MC, 2.88 g of polyethylene glycol (0.18 with respect to MC), 32 g of talc (2.0 with respect to MC), 6.4 g of titanium oxide, Purified water was changed to 342.72 g to prepare a coating solution, and coated tablets were obtained in the same manner as in Example 1.

Example 7
In the preparation of the coating solution of Example 1, 25 g of MC, 15 g of polyethylene glycol (0.60 with respect to MC), 12.5 g of talc (0.5 with respect to MC), 10 g of titanium oxide, and purified water Was changed to 437.5 g to prepare a coating solution, and coated tablets were obtained in the same manner as in Example 1.

Example 8
In the preparation of the coating solution of Example 1, 6.4 g of MC and HPC (manufactured by Nippon Soda Co., Ltd., hydroxypropoxy group substitution degree 63 mass%, viscosity of 2 mass% aqueous solution at 20 ° C. is 8.0 mPa · s) 9 .6 g (MC: HPC = 4: 6), polyethylene glycol 9.6 g (0.60 for MC / HPC), talc 32.0 g (2.0 for MC / HPC), A coating solution was prepared by changing 6.4 g of titanium oxide and 336.0 g of purified water, and a coated tablet was obtained in the same manner as in Example 1.

Example 9
In the preparation of the coating solution of Example 1, 4.8 g of MC, and further 11.2 g (MC: PVA = 3: 7) of PVA (manufactured by Nippon Acetate / Poval, polymerization degree 500, saponification degree 88 mol%). In addition, 9.6 g of polyethylene glycol (0.60 with respect to MC / PVA), 32.0 g of talc (2.0 with respect to MC / PVA), 6.4 g of titanium oxide, and 336. of purified water. The coating solution was changed to 0 g, and a coated tablet was obtained in the same manner as in Example 1.

Comparative Example 1
In the preparation of the coating solution of Example 1, without adding polyethylene glycol, talc and titanium oxide, MC56.0 g was changed to purified water 744.0 g to prepare a coating solution, and a coated tablet was obtained in the same manner as in Example 1. It was.

Comparative Example 2
In the preparation of the coating solution of Example 1, 14 g of MC, 53.2 g of talc (3.8 to MC), 5.6 g of titanium oxide, and 277.2 g of purified water without adding polyethylene glycol. A coating solution was prepared by changing, and coated tablets were obtained in the same manner as in Example 1.

Comparative Example 3
In the preparation of the coating solution of Example 1, 22.5 g of MC without talc, 28.13 g of polyethylene glycol (1.25 with respect to MC), 9 g of titanium oxide, and 390.32 g of purified water were changed. A coating solution was prepared and coated tablets were obtained in the same manner as in Example 1.

Comparative Example 4
In the preparation of the coating solution of Example 1, 16 g of MC, 2.4 g of polyethylene glycol (0.15 with respect to MC), 32 g of talc (2.0 with respect to MC), 6.4 g of titanium oxide, Purified water was changed to 343.2 g to prepare a coating solution, and coated tablets were obtained in the same manner as in Example 1.

Comparative Example 5
In preparation of the coating solution of Example 1, 25 g of MC, 15 g of polyethylene glycol (0.60 with respect to MC), 7.5 g of talc (0.3 with respect to MC), 10 g of titanium oxide, and purified water Was changed to 442.5 g to prepare a coating solution, and coated tablets were obtained in the same manner as in Example 1.

Comparative Example 6
In the preparation of the coating solution of Example 1, MC was changed to hydroxypropylmethylcellulose (methoxy group substitution degree 28%, hydroxypropoxy group substitution degree 9%), hydroxypropylmethylcellulose 16.0 g, polyethylene glycol 9.6 g, talc Was changed to 32.0 g, titanium oxide 6.4 g, and purified water 334.0 g to prepare a coating solution. In the same manner as in Example 1, a coated tablet was obtained.

<Evaluation of dissolution characteristics of coated tablets>
The dissolution test of the coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 was evaluated by the dissolution test described in the 16th revised Japanese Pharmacopoeia (37 ° C., paddle method, 50 rotations / minute, solvent 900 mL water). Went. The elution behaviors of Examples 1 to 9 and Comparative Example 1 are shown in FIG.
Sampling of the dissolution test was performed 1 minute, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 20 minutes, and 30 minutes after the start of the dissolution test, and the time at which 85% or more of the drug was dissolved was determined as the dissolution time. Shown in
As is apparent from FIG. 1 and Table 1, the coated tablet of the present invention has improved dissolution compared to the coated tablet of Comparative Example 1.

<Evaluation of glossiness of coated tablets>
The glossiness of the coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 was measured using a precision gloss meter (GM-26D (20 ° / 60 °) type, manufactured by Murakami Color Research Laboratory) with a mirror surface of 60 °. Table 1 shows the results of measuring the glossiness (tablet holder 5 mmφ, measurement area: about 3 × 3 mm).
As is apparent from Table 1, the coated tablet of the present invention showed higher glossiness than the coated tablets of Comparative Examples 1 to 5.

<Evaluation of the presence or absence of sliminess in the oral cavity>
The coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 were administered to 6 healthy adults, and the number of people who felt slimy in the oral cavity was summarized in Table 1.
As is clear from Table 1, the coated tablet of the present invention did not show a slimy feeling in the oral cavity, whereas the coated tablet of Comparative Example 6 showed a slimy feeling.

Claims (5)

  A film coating composition comprising at least 100 parts by weight of a base having hydroxypropylcellulose and / or polyvinyl alcohol in addition to methylcellulose alone or methylcellulose, 18 to 150 parts by weight of a plasticizer, and 40 to 500 parts by weight of talc. .   The film coating composition according to claim 1, wherein the plasticizer is polyethylene glycol.   3. An oral solid preparation comprising at least a core containing a drug and at least the film coating composition according to claim 1 which covers the core.   A method for producing an oral solid preparation comprising at least a step of applying a solution obtained by dissolving or dispersing the film coating composition of claim 1 or 2 in a solvent to a core containing at least a drug, and a subsequent drying step.   The method for producing an oral solid preparation according to claim 4, wherein the drying step includes polishing while drying the oral solid preparation after application, and is performed for 10 minutes or more.

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