JP2020055794A - Film coating composition, solid preparation and method for producing solid preparation - Google Patents

Abstract

To provide a tablet coating composition that solves a problem of sticking ad has low hygroscopicity.SOLUTION: The present invention provides a film coating composition described in claim 1, the film coating composition containing a polyvinyl alcohol resin (A) and triacetin (B), a content of the triacetin (B) being 18-40 pts.mass with respect to 100 pts.mass of the polyvinyl alcohol resin (A).SELECTED DRAWING: None

Description

  The present invention relates to a film coating composition, a solid preparation using the same, and a method for producing the same.

  A tablet is made in a form such that a given amount of the drug can be easily taken, such as by compressing the components of the drug. There are various types of pills, depending on how they are taken, how they are used, and how they are made. It is selected according to the purpose and effect, such as enteric-coated tablets, sustained-release tablets, sugar-coated tablets, film-coated tablets, orally disintegrating tablets, chewable tablets and adhesive tablets.

  BACKGROUND ART Film-coated tablets and sugar-coated tablets are widely used in oral solid preparations for the purpose of masking unpleasant taste of drugs, blocking oxygen, preventing moisture, or improving the appearance of products.

  Dragees and film-coated tablets are tablets that cover the periphery of the tablet with sugar or a film to hide the inherent bitterness and odor of the drug component and make it easier to drink. In addition, the coating may protect the medicine from light and moisture, and may have an effect such as an increase in stability.

  In recent years, a composition containing a polyvinyl alcohol-based resin (hereinafter, referred to as a PVA-based resin) having excellent gas barrier properties has been studied as a tablet coating composition. When a PVA-based resin is used as a coating composition, the PVA-based resin alone sticks together the coated tablets, easily causes sticking, and contains polyethylene glycol (anti-adhesive) (for example, Patent Document 1) or hydroxypropyl. It has been proposed to include methylcellulose (HPMC) (for example, Patent Document 2) and to contain an inorganic compound such as talc (for example, Patent Document 3).

International Publication No. 2015/122577 JP 2016-172708 A JP 2006-188490 A

  However, when polyethylene glycol is contained as in Patent Literature 1, the sticking phenomenon in which tablets adhere to each other (sticks together) is eliminated, but there is a problem that the hygroscopicity of the tablets is increased. Further, it has been proposed to use a cellulosic resin such as HPMC in combination to prevent sticking as in Patent Document 2. However, since the solution viscosity is high, the solid concentration of the coating solution cannot be increased, and the It is a problem that the time and drying time are long and the water vapor barrier property is not sufficient. Further, it has been proposed to contain an inorganic compound such as talc for preventing sticking as in Patent Document 3, but the content of the inorganic compound must be increased, and the flexibility of the coating film is reduced. Was a problem.

  An object of the present invention is to provide a film coating composition that eliminates sticking and has low hygroscopicity.

  The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the above objects can be achieved by using a PVA-based resin and a specific anti-adhesive agent in combination, and have completed the present invention.

  It is presumed that such an effect was obtained by preventing sticking by using a polyvinyl alcohol-based resin and a specific anti-adhesive agent in combination and forming a continuous layer.

  The film coating composition of the present invention can provide a film coating composition in which sticking is eliminated and the tablet has low hygroscopicity.

Hereinafter, the configuration of the present invention will be described in detail, but these are shown as an example of a preferred embodiment.
The film coating composition of the present invention contains a polyvinyl alcohol resin (A) and triacetin (B).

First, the PVA-based resin (A) will be described.
The PVA-based resin (A) used in the present invention is a resin mainly composed of vinyl alcohol structural units obtained by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer. It is composed of considerable vinyl alcohol structural units and vinyl ester structural units remaining without saponification.

The degree of saponification of the PVA-based resin (A) is 70 to 100 mol%, preferably 75 to 98 mol%, more preferably 80 to 95 mol%, and particularly preferably 85 to 93 mol%. If the degree of saponification of the PVA-based resin (A) is too low, sticking tends to occur easily, and if it is too high, the stability of the solution tends to decrease.
In the present invention, the saponification degree of the PVA-based resin (A) is a value determined by a method according to JIS K 6726.

The average degree of polymerization of the PVA-based resin (A) used in the present invention is 100 to 3300, preferably 150 to 1000, and particularly preferably 200 to 600.
If the average degree of polymerization of the PVA-based resin is too low, a dense coating layer tends to be hardly formed, and if the average degree of polymerization is too high, the coating speed tends to decrease.
In the present invention, the average degree of polymerization of the PVA-based resin is an average degree of polymerization determined by a method based on JIS K 6726.

  It is also effective to use two or more PVA resins in combination. When used together, PVA-based resins having different degrees of saponification and average polymerization degree can be used in combination. When the PVA-based resin is used in combination, the saponification degree and the average polymerization degree of the PVA-based resin as a whole are preferably within the above range.

The method for producing the PVA-based resin used in the present invention will be described.
The PVA-based resin is obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer.
Such vinyl ester monomers include, for example, vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, vinyl benzoate And vinyl versatate, and vinyl acetate is practically preferable.

  Further, to the extent that the effects of the present invention are not impaired, the vinyl ester-based monomer and a monomer having copolymerizability can be copolymerized. Examples of such a copolymerized monomer include ethylene, propylene, isobutylene and α. Olefins such as octene, α-dodecene and α-octadecene, 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol and 3,4-dihydroxy-1-butene; Derivatives such as hydroxy group-containing α-olefins and acylated products thereof, unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, undecylenic acid, salts, monoesters, and dialkyls Nitriles such as esters, acrylonitrile, methacrylonitrile, diacetone acrylamide Amides such as acrylamide and methacrylamide, olefin sulfonic acids such as ethylene sulfonic acid, allyl sulfonic acid and methallyl sulfonic acid or salts thereof, alkyl vinyl ethers, dimethyl allyl vinyl ketone, N-vinyl pyrrolidone, vinyl chloride, vinyl ethylene Vinyl compounds such as carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, and glycerin monoallyl ether; substituted vinyl acetates such as isopropenyl acetate and 1-methoxyvinyl acetate; vinylidene chloride; -Diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate, 1,3-diacetoxy-2-methylenepropane, 1,3-dipropionyloxy-2-methylenepropane, 1,3-dibutyro Nyloxy- And hydroxymethylvinylidene diacetate such as 2-methylenepropane. The content of such a copolymerized monomer is usually at most 10 mol%, preferably at most 5 mol%, particularly preferably at most 1 mol%, based on the total amount of the polymer. In the present invention, an unmodified PVA-based resin comprising only a vinyl alcohol structural unit and a vinyl ester structural unit in an unsaponified portion is preferable from the viewpoint of adhesiveness.

  There is no particular limitation on the polymerization of the vinyl ester-based monomer and the copolymerized monomer, and a known method such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. Solution polymerization is performed.

Examples of the solvent used in the polymerization include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol, and ketones such as acetone and methyl ethyl ketone. Preferably, methanol is used.
The polymerization reaction is carried out using a known radical polymerization catalyst such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, lauroyl peroxide and various known low-temperature active catalysts. The reaction temperature is selected from the range of 35 ° C. to about the boiling point.

  The obtained polyvinyl ester-based polymer is then saponified in a continuous or batch manner to obtain a PVA-based resin. In this saponification, either an alkali saponification or an acid saponification can be adopted, but industrially, the polymer is dissolved in an alcohol and is carried out in the presence of an alkali catalyst. Examples of the alcohol include methanol, ethanol, butanol and the like. The concentration of the polymer in the alcohol is selected from the range of 20 to 60% by mass. If necessary, about 0.3 to 10% by weight of water may be added. Further, various esters such as methyl acetate and various solvents such as benzene, hexane, and DMSO (dimethyl sulfoxide) may be added. May be.

  Examples of the saponification catalyst include, for example, alkali catalysts such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, alkali metal hydroxides and alcoholates such as potassium methylate, and the like. The use amount of such a catalyst is preferably from 1 to 100 mmole equivalent to the monomer.

  After saponification, the PVA-based resin may be washed with a washing solution. Examples of the washing liquid include alcohols such as methanol, ethanol, isopropyl alcohol, and butanol, and methanol is preferable from the viewpoint of washing efficiency and drying efficiency.

  As a washing method, a continuous method (rotating cylindrical type, countercurrent contact type, centrifugal sprinkling washing, etc.) may be used, but a batch type is usually adopted. As a stirring method (apparatus) at the time of washing, there are a screw blade, a ribbon blender, a kneader, and the like. The bath ratio (mass of washing liquid / mass of polyvinyl ester-based polymer particles) is usually 1 to 30, and particularly preferably 2 to 20. If the bath ratio is too large, a large cleaning device is required, which tends to increase the cost. If the bath ratio is too low, the cleaning effect tends to decrease and the number of times of cleaning tends to increase.

  The temperature at the time of washing is usually 10 to 80C, and particularly preferably 20 to 70C. If the temperature is too high, the amount of volatilization of the cleaning liquid tends to increase, and a reflux facility tends to be required. If the temperature is too low, the cleaning efficiency tends to decrease. The washing time is usually from 5 minutes to 12 hours, particularly preferably from 30 minutes to 4 hours. If the cleaning time is too long, the production efficiency tends to decrease, and if the cleaning time is too short, the cleaning tends to be insufficient. The number of washings is usually 1 to 10 times, and particularly preferably 1 to 5 times. If the number of times of washing is too large, productivity tends to decrease and cost tends to increase.

  The washed PVA-based resin (A) is dried by hot air or the like in a continuous or batch system or dried under reduced pressure to obtain a PVA-based resin used in the present invention. The drying temperature is usually 50 to 150C, preferably 60 to 130C, particularly preferably 70 to 110C. If the drying temperature is too high, the PVA-based resin tends to thermally degrade, and if the drying temperature is too low, drying tends to take a long time. The drying time is usually 1 to 48 hours, and particularly preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally degraded, and if the drying time is too short, the drying tends to be insufficient or high-temperature drying is required.

  The content of the solvent contained in the PVA-based resin (A) after drying is usually 0 to 10% by mass, particularly 0.01 to 5% by mass, particularly 0.1 to 1% by mass. Is preferred.

The PVA-based resin (A) contains an alkali metal salt of acetic acid derived from an alkali catalyst used in saponification. The content of the alkali metal salt is usually 0.001 to 2% by mass, preferably 0.005 to 1% by mass, more preferably 0.01 to 0.1% by mass, based on the PVA-based resin powder. is there.
Examples of the method of adjusting the content of the alkali metal salt include a method of adjusting the amount of an alkali catalyst used in saponification, and a method of washing a PVA-based resin with an alcohol such as ethanol or methanol.
As a method for quantifying an alkali metal salt used in the present invention, a PVA-based resin powder is dissolved in water, methyl orange is used as an indicator, and neutralization titration is performed with hydrochloric acid.

Next, triacetin (B) will be described.
The triacetin (B) used in the present invention includes triacetin used as an additive for pharmaceuticals or foods.

Next, the film coating composition of the present invention will be described.
The content (A + B) of the PVA-based resin (A) and the triacetin (B) in the film coating composition of the present invention is 30 to 98% by mass, preferably 40 to 70% by mass, and more preferably 40 to 65% by mass. %.
When the content is too large, the solid content concentration of the coating liquid cannot be increased, and the coating time tends to be long. When the content is too small, drying takes time and the efficiency tends to be reduced.

The content of the PVA-based resin (A) and triacetin (B) in the film coating composition is preferably 18 to 40 parts by weight of triacetin (B) per 100 parts by weight of the PVA-based resin (A). Is 19 to 38 parts by weight, more preferably 20 to 35 parts by weight. If the ratio of the PVA-based resin (A) is large, the adhesiveness is not completely improved, and the coating speed cannot be increased. On the other hand, if the ratio of triacetin (B) is large, the hygroscopicity tends to increase.

The film coating composition of the present invention dissolves in a solvent and coats tablets, granules, particles and the like as a coating solution.
Examples of such a solvent include water, methanol, ethanol, i-propanol, n-propanol and butanol, and from the viewpoint of safety, water is preferred.

In such a coating liquid, the viscosity at 23 ° C. of a solution in which the PVA resin (A) and the triacetin (B) are dissolved in water as a solvent is usually 3 to 1000 mPa · s, preferably 25 to 700 mPa · s, and particularly preferably. Is 30 to 300 mPa · s, more preferably 35 to 250 mPa · s.
If the viscosity of the coating liquid is too high, the fluidity of the coating liquid tends to decrease and coating tends to be difficult. If the viscosity is too low, drying takes time and efficiency tends to decrease.

The concentration of the PVA-based resin (A) in the coating liquid is usually 3 to 50% by mass, preferably 5 to 30% by mass, and more preferably 7 to 15% by mass.
If the concentration is too high, the fluidity of the coating liquid tends to decrease, and coating tends to be difficult. If the concentration is too low, drying takes time and efficiency tends to decrease.
The concentration of triacetin (B) in the coating liquid is usually 1 to 20% by mass, preferably 1.5 to 10% by mass, more preferably 2 to 7% by mass.
If the concentration is too high, bleed-out tends to occur on the tablet surface, while if it is too low, the tackiness is not completely improved and the coating speed tends not to be increased.

  The film coating composition of the present invention may contain, if necessary, known additives which are generally recognized as pharmaceutically. Such known additives include, for example, tackifiers other than triacetin (B) (eg, glycerin, triethyl citrate, polyethylene glycol), lubricating agents such as magnesium stearate, calcium stearate, and tearic acid; Examples include concealing agents such as titanium, calcium carbonate, and silicon dioxide; inorganic compounds such as talc and colloidal silica; surfactants, coloring agents, pigments, sweeteners, coating agents, and defoamers. The content when these are added is not particularly limited as long as the effects of the present invention are not hindered, but is preferably 200% by mass or less, more preferably 100% by mass or less, based on the PVA-based resin (A). .

Next, the solid preparation of the present invention will be described.
The solid preparation of the present invention has a core containing at least an active ingredient, and a coating covering the core, and the coating contains at least the film coating composition. The active ingredient is not particularly limited as long as it can be orally administered.

  Various additives usually used in this field, such as an excipient, a binder, a disintegrant, a lubricant (anti-agglomeration agent), a fluidizing agent, a coloring agent, and a solubilizing agent for a pharmaceutical compound, are added to the core. You may mix | blend an agent.

  Examples of the excipient include, but are not particularly limited to, sugars such as sucrose, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and calcium sulfate.

  The binder is not particularly limited, for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose Macrogol (eg, Macrogol 4000, Macrogol 6000, Macrogol 20000, etc.), gum arabic, gelatin, agar, starch (such as corn starch).

  The disintegrant is not particularly limited, and examples thereof include low-substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium, carboxymethyl starch sodium, crospolyvinylpyrrolidone, crystalline cellulose, crystalline cellulose and carmellose sodium. Can be

  Examples of the lubricant include, but are not particularly limited to, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oil, polyethylene glycols, and sodium benzoate.

  Although it does not specifically limit as a fluidizing agent, For example, hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, etc. are mentioned.

  Further, examples of the solubilizer for the pharmaceutical compound 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 and the like.

  The coating portion may be any one that contains at least the film coating composition of the present invention, and the film coating composition of the present invention alone may be used as a coating portion (coating layer), or a coating made of the film coating composition of the present invention. Underlayers may be undercoated with a coating base. As the coating base, various coating bases that can be commonly used in this field, such as HPMC, can be used. The form of the covering portion is not limited, and may be a layer, a film, or the like.

  Examples of the solid preparation obtained by coating with the film coating composition of the present invention include tablets, powders, granules, fine granules, pills, troches, capsules, etc. Among them, tablets are particularly preferable. Tablets may be in the form of sugar-coated tablets, gelatin-coated tablets, film-coated tablets (including multilayer film-coated tablets), enteric-coated tablets, dry coated tablets (compressed tablets), and the like. Coated tablets (including multilayer film-coated tablets) and enteric-coated tablets are preferred.

Next, a method for producing a solid preparation will be described.
The solid preparation of the present invention can be produced by preparing a film coating liquid in which the film coating composition of the present invention is dissolved or dispersed in a solvent, and applying the film coating liquid to a core.

  The solvent is not particularly limited, and for example, the above-mentioned organic solvent such as water or ethanol can be used. These may be used alone or as a mixture of two or more. You can also. The temperature at which the film coating composition of the present invention is dissolved or dispersed in a solvent is not particularly limited, but may be heated, or may be about 5 to 70 ° C.

  Examples of the application method include a method of applying the film coating composition solution of the present invention prepared as described above to a core containing an active ingredient by spraying or the like using a conventionally known coating apparatus. .

  When the solid preparation of the present invention is a multilayer film-coated tablet, it is commonly used in the art, such as HPMC, under the film layer composed of the film coating composition of the present invention before the application by the application method. There is also a method of forming a plurality of films by adding a step of undercoating using various obtained coating bases.

  The coating apparatus is not particularly limited, and conventionally known means can be used. As a coating method, spray coating is generally performed. In this case, a pan coating device, a drum type coating device, a fluidized bed coating device, and a stirring fluidized coating device may be used. As a spray device attached to the device, any of an air spray, an airless spray, a three-fluid spray and the like can be used.

  The amount of the film coating composition coated on the surface of the core (uncoated tablet) depends on the type, shape, size, surface condition of the solid preparation, and the properties of the active ingredients 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, based on the core (uncoated tablet). If the coating amount is too small, a complete film cannot be obtained, while if it is too large, the time required for coating may be required.

  In addition, by producing a solid preparation using the tablet coating composition of the present invention, a solid preparation having a smooth surface can be provided. The value of the surface roughness (Ra) is preferably 2.0 μm or less. The surface roughness (Ra) is a roughness parameter defined in JIS B0601-1994, and can be measured using a laser microscope (VK-9510, manufactured by Keyence Corporation) using an objective lens with a magnification of 50. .

  Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Further, “parts” and “%” are based on mass.

Example 1
Coating containing 100 parts of PVA resin (A) (unmodified, saponification degree: 88 mol%, 4% aqueous solution viscosity: 3 mPa · s), 38 parts of talc, 38 parts of titanium dioxide, and 33 parts of triacetin (B) The composition was obtained, mixed with 625 parts of water, heated to 85 ° C. and dissolved to obtain an aqueous solution of the coating composition.

  The core to be coated was 900 parts of plain tablets (φ = 9 mm) and 100 parts of silica tablets (φ = 11 mm) in a continuous ventilation coating apparatus (High Coater Lab, manufactured by Freund Corporation). The mixture was prepared so as to be 1000 parts, and 30 parts of an aqueous solution of the coating composition was sprayed to coat uncoated tablets and silica tablets.

The coating conditions were as follows.
Supply air temperature: 70 ° C
Exhaust temperature: 40-55 ° C
Supply air volume: 1.2m3 / min
Spray gun: 1 atomized air volume: 80 NL / min
Atomized air pressure: 0.3MPa
Spray speed: 6-8g / min

[Presence of sticking]
The uncoated tablets in the coating were visually observed, and the presence or absence of sticking was evaluated according to the following criteria. Table 1 shows the results.
Existence: Some uncoated tablets were bonded to each other No: No uncoated tablets were bonded to each other

(Hygroscopicity)
A set of 10 coated silica tablets obtained above was dried at 60 ° C. for 12 hours or more, and the mass thereof was set as the initial mass, which was left standing in a thermo-hygrostat at 25 ° C. and 75% RH for 8 hours. The subsequent moisture absorption was determined from the increase in mass. Table 1 shows the results.

Example 2
In Example 1, 100 parts of PVA resin (A) (unmodified, saponification degree: 88 mol%, viscosity of 4% aqueous solution: 5 mPa · s), 25 parts of talc, 17 parts of titanium dioxide, and 25 parts of triacetin (B) An aqueous solution of the coating composition was prepared and evaluated in the same manner as in Example 1 except that the composition was changed to 944 parts by weight and 944 parts by weight of water.

Comparative Example 1
A coating aqueous solution was prepared and evaluated in the same manner as in Example 1 except that triacetin (B) was changed to polyethylene glycol (PEG4000) having a weight average degree of polymerization of 4000 in Example 1.

Comparative Example 2
In Example 2, a coating aqueous solution was prepared and evaluated in the same manner as in Example 2, except that propylene glycol was used instead of triacetin (B).

Comparative Example 3
In Example 2, a coating aqueous solution was prepared and evaluated in the same manner as in Example 2, except that glycerin was used as triacetin (B).

Comparative Example 4
A coating composition containing 100 parts of PVA-based resin (A) (unmodified, 88 mol% of saponification degree, viscosity of 4% aqueous solution of 5 mPa · s), 50 parts of talc, and 17 parts of triacetin (B) was obtained. 501 parts of water was blended, heated to 85 ° C. and dissolved to obtain an aqueous solution of the coating composition, which was evaluated in the same manner as in Example 1.

Comparative Example 5
In the same manner as in Example 1, except that the PVA-based resin (A) was unmodified, the saponification degree was changed to 88 mol%, the viscosity of the 4% aqueous solution was changed to 5 mPa · s, and the triacetin (B) was changed to diacetin. An aqueous coating solution was prepared and evaluated similarly.

Examples 1 and 2 using the film coating composition of the present invention had no sticking and low hygroscopicity.
On the other hand, Comparative Examples 1 to 5 in which the coating of the present invention was not used caused sticking or moisture absorption.

  The film coating composition of the present invention is useful as a coating of tablets for pharmaceuticals, health foods, foods, etc., and is particularly useful in coating of tablets containing components having high water activity, and in a coating step in which sticking is concerned. .

Claims (5)

In a film coating composition containing a polyvinyl alcohol-based resin (A) and triacetin (B),
The film coating composition according to claim 1, wherein the content of triacetin (B) is 18 to 40 parts by mass based on 100 parts by mass of the polyvinyl alcohol-based resin (A).   The film coating composition according to claim 1, wherein the polyvinyl alcohol resin (A) has a saponification degree of 80 to 95 mol%.   3. The film coating composition according to claim 1, which is a film coating composition for a solid preparation.   A solid preparation comprising a core containing at least an active ingredient, and a coating covering the core, wherein the coating is the film coating composition according to any one of claims 1 to 4.   A method for producing a solid preparation, comprising at least a step of applying the film coating composition according to any one of claims 1 to 4 to a core containing at least an active ingredient.