JP7363189B2 - Film coating composition, solid preparation, and method for producing solid preparation - Google Patents

Description

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

Tablets are made by compressing drug ingredients into a specific shape so that a fixed amount of the drug can be easily taken. Even though they are called ``tablets,'' there are various types depending on how they are taken, how they are used, and how they are made. Enteric-coated tablets, sustained-release tablets, sugar-coated tablets, film-coated tablets, orally disintegrating tablets, chewable tablets, adhesive tablets, etc. are selected depending on the purpose and effect.

Film-coated tablets and sugar-coated tablets are widely used in oral solid preparations for purposes such as masking unpleasant taste of drugs, blocking oxygen, moisture proofing, and improving the aesthetic appearance of the product.

Sugar-coated tablets and film-coated tablets are tablets that are made easier to swallow by covering the tablet with sugar or film to hide the bitterness and odor of the medicine's ingredients. Coatings can also have effects such as protecting drugs from light and moisture and increasing their stability.

In recent years, compositions containing polyvinyl alcohol resins (hereinafter referred to as PVA resins) with excellent gas barrier properties have been studied as tablet coating compositions. When using PVA-based resin as a coating composition, PVA-based resin alone tends to cause sticking, in which coated tablets stick to each other. It has been proposed to include methyl cellulose (HPMC) (for example, Patent Document 2) and to contain an inorganic compound such as talc (for example, Patent Document 3).

International Publication 2015/122477 Japanese Patent Application Publication No. 2016-172708 Japanese Patent Application Publication No. 2006-188490

However, when polyethylene glycol is included as in Patent Document 1, the sticking phenomenon in which tablets adhere to each other (sticking together) is eliminated, but the problem is that the hygroscopicity of the tablets increases. Furthermore, as in Patent Document 2, it has been proposed to use a cellulose resin such as HPMC in combination to prevent sticking, but due to the high solution viscosity, it is not possible to increase the solid content concentration of the coating liquid, and the coating Problems include long drying times and insufficient water vapor barrier properties. Furthermore, as in Patent Document 3, it has been proposed to contain an inorganic compound such as talc to prevent sticking, but the content of the inorganic compound must be increased, which reduces the flexibility of the film. was the problem.

The present invention aims to provide a film coating composition that eliminates sticking and has low hygroscopicity.

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

It is presumed that this effect was achieved by the combined use of a polyvinyl alcohol resin and a specific anti-blocking agent to prevent sticking and form a continuous layer.

The film coating composition of the present invention can provide a film coating composition that eliminates sticking and provides tablets with low hygroscopicity.

Hereinafter, the structure of the present invention will be explained in detail, but these are shown as examples of desirable embodiments.
The film coating composition of the present invention contains a polyvinyl alcohol resin (A) and triacetin (B).

First, the PVA resin (A) will be explained.
The PVA resin (A) used in the present invention is a resin mainly composed of vinyl alcohol structural units, which is obtained by saponifying a polyvinyl ester polymer obtained by polymerizing vinyl ester monomers, and has a degree of saponification. It is composed of a corresponding vinyl alcohol structural unit and a vinyl ester structural unit that remains unsaponified.

The degree of saponification of the PVA resin (A) is 70 to 100 mol%, preferably 75 to 98 mol%, more preferably 80 to 95 mol%, particularly preferably 85 to 93 mol%. If the saponification degree 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 degree of saponification of the PVA resin (A) is a value determined by a method based on JIS K 6726.

Furthermore, the average degree of polymerization of the PVA resin (A) used in the present invention is from 100 to 3,300, preferably from 150 to 1,000, and particularly preferably from 200 to 600.
If the average degree of polymerization of the PVA-based resin is too low, a dense coating layer tends to be difficult to form, 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 determined by a method based on JIS K 6726.

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

A method for producing the PVA resin used in the present invention will be explained.
The PVA resin can be obtained, for example, by saponifying a polyvinyl ester polymer obtained by polymerizing a vinyl ester monomer.
Examples of such vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, and vinyl benzoate. , vinyl versatate, etc., and vinyl acetate is practically preferred.

In addition, monomers having copolymerizability with the above-mentioned vinyl ester monomers can be copolymerized to the extent that the effects of the present invention are not impaired. Examples of such copolymerizable monomers include ethylene, propylene, isobutylene, α -Olefins such as octene, α-dodecene, α-octadecene, 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, 3,4-dihydroxy-1-butene, etc. Derivatives such as hydroxy group-containing α-olefins and their acylated products, unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid, their salts, monoesters, or dialkyl Esters, nitriles such as acrylonitrile and methacrylonitrile, amides such as diacetone acrylamide, acrylamide and methacrylamide, olefin sulfonic acids or their salts such as ethylene sulfonic acid, allyl sulfonic acid and methalylsulfonic acid, alkyl vinyl ethers, dimethyl Vinyl compounds such as allyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinyl ethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, glycerin monoallyl ether, isopropenyl acetate, 1-methoxyvinyl Substituted vinyl acetates such as acetate, vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate, 1,3-diacetoxy-2-methylenepropane, 1,3-diacetoxy-2-butene, Examples include hydroxymethylvinylidene diacetate such as propionyloxy-2-methylenepropane and 1,3-dibutyronyloxy-2-methylenepropane. The content of such a copolymerizable monomer is usually 10 mol% or less, preferably 5 mol% or less, particularly preferably 1 mol% or less, based on the total amount of the polymer. In the present invention, from the viewpoint of adhesion, unmodified PVA-based resins consisting only of vinyl alcohol structural units and unsaponified vinyl ester structural units are preferred.

There are no particular restrictions on polymerizing the above vinyl ester monomers and copolymerizable monomers, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed, but usually Solution polymerization is carried out.

Solvents used in such polymerization usually 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. Methanol is preferably used.
Further, the polymerization reaction is carried out using a known radical polymerization catalyst such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, lauroyl peroxide, or various known low-temperature active catalysts. Further, the reaction temperature is selected from a range of about 35° C. to the boiling point.

The obtained polyvinyl ester polymer is then saponified in a continuous or batch manner to obtain a PVA resin. In such saponification, either alkali saponification or acid saponification can be employed, but industrially it is carried out by dissolving the polymer in alcohol and 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 20-60% by weight. Furthermore, if necessary, about 0.3 to 10% by mass of water may be added, and various esters such as methyl acetate and various solvents such as benzene, hexane, and DMSO (dimethyl sulfoxide) may be added. You may.

Specific examples of the saponification catalyst include alkali catalysts such as alkali metal hydroxides and alcoholates such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, and potassium methylate. The amount of such catalyst used is preferably 1 to 100 millimole equivalents based on the monomer.

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

The cleaning method may be a continuous type (rotating cylinder type, countercurrent contact type, centrifugal separation sprinkle cleaning, etc.), but a batch type is usually adopted. Examples of stirring methods (devices) during cleaning include screw blades, ribbon blenders, kneaders, and the like. The bath ratio (mass of cleaning liquid/mass of polyvinyl ester polymer particles) is usually 1 to 30, particularly preferably 2 to 20. If the bath ratio is too large, a large cleaning device will be required, which tends to increase costs, and if the bath ratio is too small, the cleaning effect will decrease and the number of cleanings will tend to increase.

The temperature during washing is usually 10 to 80°C, particularly preferably 20 to 70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, which tends to require reflux equipment. If the temperature is too low, cleaning efficiency tends to decrease. The washing time is usually 5 minutes to 12 hours, particularly preferably 30 minutes to 4 hours. If the cleaning time is too long, production efficiency tends to decrease, and if the cleaning time is too short, cleaning tends to be insufficient. Further, the number of times of washing is usually 1 to 10 times, particularly preferably 1 to 5 times. Too many washings tend to reduce productivity and increase costs.

The washed PVA resin (A) is dried continuously or batchwise with hot air or under reduced pressure to obtain the PVA resin used in the present invention. The drying temperature is usually 50 to 150°C, particularly preferably 60 to 130°C, particularly preferably 70 to 110°C. If the drying temperature is too high, the PVA resin tends to be thermally degraded, and if the drying temperature is too low, the drying tends to take a long time. The drying time is usually 1 to 48 hours, particularly preferably 2 to 36 hours. If the drying time is too long, the PVA 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 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.

Note that the PVA-based resin (A) contains an alkali metal salt of acetic acid derived from the alkali catalyst used during saponification. The content of the alkali metal salt is usually 0.001 to 2% by mass, preferably 0.005 to 1% by mass, and more preferably 0.01 to 0.1% by mass based on the PVA resin powder. be.
Examples of methods for adjusting the alkali metal salt content include adjusting the amount of an alkali catalyst used in saponification and washing the PVA resin with alcohol such as ethanol and methanol.
The alkali metal salt used in the present invention can be determined by dissolving PVA resin powder in water, using methyl orange as an indicator, and performing neutralization titration with hydrochloric acid.

Next, triacetin (B) will be explained.
Examples of the triacetin (B) used in the present invention include triacetin used as an additive for pharmaceuticals or foods.

Next, the film coating composition of the present invention will be explained.
The content (A+B) of PVA resin (A) and triacetin (B) in the film coating composition of the present invention is 30 to 98% by mass, preferably 40 to 70% by mass, more preferably 40 to 65% by mass. %.
If the content is too high, the solid content concentration of the coating liquid cannot be increased and the coating time tends to be longer; if the content is too low, drying takes a long time and efficiency tends to decrease.

In addition, the content of PVA resin (A) and triacetin (B) in the film coating composition is preferably 18 to 40 parts by weight for 100 parts by weight of PVA resin (A). is 19 to 38 parts by weight, more preferably 20 to 35 parts by weight. If the ratio of PVA-based resin (A) is high, the adhesion will not be completely improved and the coating speed cannot be increased, while if the ratio of triacetin (B) is high, hygroscopicity tends to increase.

The film coating composition of the present invention is dissolved in a solvent and used as a coating liquid to coat tablets, granules, particles, etc.
Examples of such a solvent include water, methanol, ethanol, i-propanol, n-propanol, butanol, and water is preferred from the viewpoint of safety.

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

The concentration of the PVA resin (A) in the coating liquid is usually 3 to 50% by weight, preferably 5 to 30% by weight, and more preferably 7 to 15% by weight.
If the concentration is too high, the fluidity of the coating liquid tends to decrease, making it difficult to coat, while if it is too low, drying tends to take a long time and efficiency decreases.
The concentration of triacetin (B) in the coating liquid is usually 1 to 20% by weight, preferably 1.5 to 10% by weight, and more preferably 2 to 7% by weight.
If the concentration is too high, there is a tendency for bleed-out on the tablet surface, whereas if it is too low, the improvement in adhesion is not complete and there is a tendency that the coating speed cannot be increased.

The film coating composition of the present invention may contain known additives that are generally accepted pharmaceutically, if necessary. Such known additives include, for example, anti-blocking agents other than triacetin (B) (e.g., glycerin, triethyl citrate, polyethylene glycol), lubricants such as magnesium stearate, calcium stearate, and stearic acid, and oxidized Examples include masking agents such as titanium, calcium carbonate, and silicon dioxide, inorganic compounds such as talc and colloidal silica, surfactants, colorants, pigments, sweeteners, coating agents, and antifoaming agents. The content when adding these is not particularly limited as long as it does not impede the effects of the present invention, but it is preferably 200% by mass or less, more preferably 100% by mass or less based on the PVA resin (A). .

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

The core contains various additives that are commonly used in this field, such as excipients, binders, disintegrants, lubricants (anti-agglomeration agents), fluidizing agents, coloring agents, and solubilizing agents for pharmaceutical compounds. Agents may also be added.

Excipients include, but are not particularly limited to, saccharides such as white sugar, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and calcium sulfate.

Examples of binders include, but are not limited to, 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 (cornstarch, etc.), and the like.

Disintegrants include, but are not particularly limited to, low-substituted hydroxypropyl cellulose, carmellose or its salts, croscarmellose sodium, carboxymethyl starch sodium, crospolyvinylpyrrolidone, crystalline cellulose, and crystalline cellulose/carmellose sodium. It will be done.

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

Examples of the fluidizing agent include, but are not limited to, hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, 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 determined as appropriate depending on the type of drug and the like.

The coating portion may include at least the film coating composition of the present invention, the coating portion (coating layer) may contain only the film coating composition of the present invention, and the coating portion may be a coating made of the film coating composition of the present invention. An undercoating may be performed below the layer using 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 layered, film-like, or the like.

Solid preparations obtained by coating with the film coating composition of the present invention include tablets, powders, granules, fine granules, pills, troches, capsules, etc. Among these, tablets are particularly preferred. The tablets may be in the form of sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets (including multilayer film-coated tablets), enteric-coated tablets, dry-coated tablets (compressed encapsulated tablets), etc. Coated tablets (including multilayer film coated tablets) and enteric coated tablets are preferred.

Next, a method for producing a solid preparation will be explained.
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 the core.

The solvent is not particularly limited, and for example, the above-mentioned organic solvents such as water or ethanol may be used, and these may be used alone or two or more may be used as a mixed solvent. You can also do that. Further, 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, and may be about 5 to 70°C.

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

In addition, when the solid preparation of the present invention is a multilayer film-coated tablet, before applying the above-mentioned coating method under the film layer consisting of the film-coating composition of the present invention, a film coated with HPMC or the like commonly used in this field may be used. There is also a method in which a plurality of films are formed by adding a step of undercoating using various coating bases obtained.

The coating device is not particularly limited, and conventionally known means can be used. Spray coating is commonly used as a coating method, but in that case, it can be carried out using pan coating equipment, drum type coating equipment, fluidized bed coating equipment, and stirring fluidized coating equipment. As the spray device attached to the device, any of air spray, airless spray, three-fluid spray, etc. can be used.

The amount of 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, particularly preferably 2 to 6% by mass, based on the core (uncoated tablet). If the coating amount is too small, a complete film may not be obtained, and if the coating amount is too large, the coating may require more time.

Further, by manufacturing a solid preparation using the tablet coating composition of the present invention, a solid preparation with a smooth surface can be provided. It is preferable that the value of surface roughness (Ra) is 2.0 μm or less. Note that 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) with a 50x objective lens. .

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples in any way. Furthermore, "parts" and "%" are based on mass.

Example 1
Coating containing 100 parts of PVA resin (A) (unmodified, degree of saponification 88 mol%, viscosity of 4% aqueous solution 3 mPa・s), 38 parts of talc, 38 parts of titanium dioxide, and 33 parts of triacetin (B) A composition was obtained, 625 parts of water was blended, and the mixture was heated to 85° C. to dissolve, thereby obtaining an aqueous solution of a coating composition.

The cores to be coated were 900 parts of plain tablets (φ = 9 mm) and 100 parts of silica tablets (φ = 11 mm) in a continuous ventilation coating device (manufactured by Freund Sangyo Co., Ltd., Hi-Coater Lab). A total of 1000 parts was prepared, and 30 parts of an aqueous solution of the coating composition was sprayed to coat plain tablets and silica tablets.

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

[Presence or absence of sticking]
The coated uncoated tablets were visually observed and the presence or absence of sticking was evaluated based on the following criteria. The results are shown in Table 1.
Yes: There were cases where plain tablets were glued together.No: There were no cases where plain tablets were glued together.

[Hygroscopicity]
A set of 10 coated silica tablets obtained above was dried at 60°C for 12 hours or more, its mass was taken as the initial mass, and it was left standing in a constant temperature and humidity chamber at 25°C and 75% RH for 8 hours. The subsequent moisture absorption rate was determined from the mass increase. The results are shown in Table 1.

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

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

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

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

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

Comparative example 5
In Example 1, the same as in Example 1 except that the PVA resin (A) was changed to an unmodified one with a degree of saponification of 88 mol% and a 4% aqueous solution viscosity of 5 mPa・s, and triacetin (B) was replaced with diacetin. A coating aqueous solution was prepared and evaluated in the same manner.

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 for tablets of pharmaceuticals, health foods, foods, etc., and is particularly useful as a coating for tablets containing components with high water activity, and in coating processes where sticking is a concern. .

Claims (5)

In a coating liquid containing a film coating composition containing an unmodified polyvinyl alcohol resin (A) consisting only of vinyl alcohol structural units and unsaponified vinyl ester structural units and triacetin (B),
The degree of saponification of the polyvinyl alcohol resin (A) is 70 to 98 mol%,
The content of triacetin (B) is 20 to 40 parts by mass based on 100 parts by mass of polyvinyl alcohol resin (A),
The triacetin (B) content based on the solid content in the coating liquid is 15% by mass or more.
, a coating liquid containing a film coating composition characterized in that it does not contain sugars. A coating liquid containing the film coating composition according to claim 1, wherein the degree of saponification of the polyvinyl alcohol resin (A) is 80 to 95 mol%. A coating liquid comprising the film coating composition according to claim 1 or 2, which is a film coating composition for solid preparations. A coating liquid comprising a core portion containing at least an active ingredient and a coating portion covering the core portion, the coating portion containing the film coating composition according to any one of claims 1 to 3.
A solid preparation formed from . A method for producing a solid preparation, which comprises at least the step of applying a coating liquid containing the film coating composition according to any one of claims 1 to 3 to a core portion containing at least an active ingredient.