JP7119913B2 - Film coating composition, solid formulation and method for producing solid formulation - Google Patents

Description

TECHNICAL FIELD 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 into a certain shape, such as by compressing the ingredients of the medicine, so that a certain amount of medicine can be taken easily. There are various types of tablets, depending on how they are taken, how they are used, and how they are made. They are selected according to their purposes and effects, such as enteric-coated tablets, sustained-release tablets, sugar-coated tablets/film-coated tablets, orally-disintegrating tablets, chewable tablets, and adhesive tablets.

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

Sugar-coated tablets and film-coated tablets are tablets that are easy to swallow by covering the periphery of the tablet with sugar or film to hide the original bitterness and odor of the drug ingredients. In some cases, the coating protects the drug from light and moisture, increasing its stability.

In recent years, compositions containing polyvinyl alcohol-based resins (hereinafter referred to as PVA-based resins) having excellent gas barrier properties have been studied as film coating compositions. When a PVA-based resin is used as a coating composition, the PVA-based resin alone tends to cause sticking between the coated tablets. It has been proposed to include (for example, Patent Document 2).

WO2015/122477 JP 2016-56208 A

However, although sticking can be eliminated by containing glycols as in Patent Document 1, the compatibility between the PVA-based resin and the glycols is poor, and the problem is that the glycols bleed out (separate) over time. It has become. In addition, it has been proposed to contain a lubricant such as talc to prevent sticking as in Patent Document 2. The problem was that I could not see it.

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a film coating composition which has high transparency and does not bleed out the plasticizer from the coating layer containing the film coating composition.

The present inventors have made intensive studies to solve the above problems, and found that the above objects can be achieved by using plasticizers with different molecular weights, that is, a low-molecular-weight plasticizer and a high-molecular-weight plasticizer. and completed the present invention.

That is, the gist of the present invention is a film coating composition containing a polyvinyl alcohol resin (A) and a plasticizer (B) and containing no lubricant,
As a plasticizer (B), polyethylene glycol (b1-1) and/or glycerin (b1-2) having a weight average molecular weight of 100 to 700, and polyethylene glycol (b2) having a weight average molecular weight of 2000 to 4000000, A film coating composition characterized by containing 10 to 300 parts by weight of polyethylene glycol (b2) with respect to 100 parts by weight of the total amount of polyethylene glycol (b1-1) and/or glycerin (b1-2). It is.

The present invention also provides a solid preparation containing the film coating composition and a method for producing the same.

The film coating composition of the present invention is highly transparent and can provide a film coating composition in which the plasticizer does not bleed out from the coating layer containing the film coating composition. Since the film coating composition of the present invention has high transparency, it is suitably used as a film coating for colored tablets.

The effect of the present invention is that plasticizers with different molecular weights are used in combination, so the low-molecular-weight plasticizer acts as a compatibilizer between the PVA-based resin and the high-molecular-weight plasticizer, and both transparency and bleed-out suppression are achieved. presumed to have been made.

The film coating composition of the present invention contains a PVA resin (A) and a plasticizer (B) and does not contain a lubricant,
The plasticizer (B) contains polyethylene glycol (b1-1) and/or glycerin (b1-2) having a weight average molecular weight of 100-700, and polyethylene glycol (b2) having a weight average molecular weight of 2000-4000000.

First, the PVA-based resin (A) will be explained.
The PVA-based 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-based resin obtained by polymerizing a vinyl ester-based monomer. is composed of vinyl alcohol structural units and vinyl ester structural units.

The saponification degree of the PVA-based resin (A) is 70 to 100 mol%, preferably 75 to 95 mol%, more preferably 80 to 94 mol%, particularly preferably 85 to 93 mol%. If the degree of saponification of the PVA-based resin (A) is too low, sticking tends to occur, 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-based resin (A) is determined by a method conforming to JIS K6726.

The average degree of polymerization of the PVA-based resin (A) used in the present invention is 300-3300, preferably 400-3000, and particularly preferably 500-2800.
If the average degree of polymerization of the PVA-based resin is too low, it tends to be difficult to form a continuous coating film.
In addition, in the present invention, the average degree of polymerization of the PVA-based resin is obtained by a method based on JIS K 6726.

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

A method for producing the PVA-based resin used in the present invention will be described.
A PVA-based resin is obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based 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.

Further, a monomer having copolymerizability with the vinyl ester monomer can be copolymerized to the extent that the effect of the present invention is not impaired. Examples of such copolymerizable monomers include ethylene, propylene, isobutylene, and -Olefins such as octene, α-dodecene and α-octadecene, 3-buten-1-ol, 4-penten-1-ol, 5-hexene-1-ol, 3,4-dihydroxy-1-butene Hydroxy group-containing α-olefins and derivatives such as acylated products thereof, unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid, salts thereof, monoesters, or dialkyls nitriles such as esters, acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide and methacrylamide; olefin sulfonic acids such as ethylenesulfonic acid, allylsulfonic acid and methallylsulfonic acid, or salts thereof; Vinyl compounds such as allyl vinyl ketone, N-vinyl pyrrolidone, 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 Hydroxymethylvinylidene diacetate such as propionyloxy-2-methylenepropane, 1,3-dibutyronyloxy-2-methylenepropane, and the like. The content of such copolymerizable monomers 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, unmodified PVA consisting only of vinyl alcohol structural units and unsaponified vinyl ester structural units is preferred from the viewpoint of adhesion.

There are no particular restrictions on the polymerization of the vinyl ester-based monomers and copolymerizable monomers, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. 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.
The polymerization reaction is carried out using known radical polymerization catalysts such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, lauroyl peroxide and various known low temperature active catalysts. Also, the reaction temperature is selected from the range of about 35° C. to the boiling point.

The obtained polyvinyl ester polymer is then saponified in a continuous or batch manner. For such saponification, either alkali saponification or acid saponification can be employed. Industrially, the polymer is dissolved in alcohol and the saponification is carried out in the presence of an alkali catalyst. Examples of alcohols include methanol, ethanol, butanol, and the like. The concentration of polymer in alcohol is selected from the range of 20-60% by weight. In addition, if necessary, about 0.3 to 10% by mass of water may be added, and further, various esters such as methyl acetate, benzene, hexane, and various solvents such as DMSO (dimethyl sulfoxide) are added. You may

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

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

As a washing method, a continuous type (rotating cylinder type, countercurrent contact type, centrifugal sprinkle washing, etc.) may be used, but a batch type is usually adopted. Examples of the stirring method (apparatus) for washing include a screw blade, a ribbon blender, and a kneader. The bath ratio (mass of cleaning solution/mass of polyvinyl ester polymer particles) is usually 1-30, preferably 2-20. If the bath ratio is too large, a large washing apparatus is required, which tends to lead to an increase in cost.

The temperature during washing is usually 10 to 80°C, preferably 20 to 70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, and there is a tendency to require a reflux facility. If the temperature is too low, cleaning efficiency tends to decrease. The washing time is usually 5 minutes to 12 hours, preferably 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 times of washing is usually 1 to 10 times, preferably 1 to 5 times. Too many washes tend to reduce productivity and increase costs.

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

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 the alkali catalyst used for 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, relative to the PVA resin powder. be.
Methods for adjusting the content of the alkali metal salt include, for example, adjusting the amount of alkali catalyst used in saponification and washing the PVA-based resin with an alcohol such as ethanol or methanol.
The alkali metal salt used in the present invention is quantified according to JIS K6726 (1994) 3.6.1 titration method.

Next, the plasticizer (B) will be explained.
The plasticizer (B) used in the present invention includes polyethylene glycol (b1-1) and/or glycerin (b1-2) having a weight average molecular weight of 100 to 700, and polyethylene glycol (b2) having a weight average molecular weight of 2000 to 4000000. It contains
The weight average molecular weight of polyethylene glycol is determined by a method based on the Japanese Pharmacopoeia 16th Edition.

The weight average molecular weight of such polyethylene glycol (b1-1) is 100-700, preferably 150-680, more preferably 170-650. If it is too large, the compatibility with the aqueous solution of PVA-based resin tends to decrease.

The weight average molecular weight of polyethylene glycol (b2) is 2,000 to 4,000,000, preferably 2,300 to 500,000, more preferably 2,500 to 20,000. If the weight-average molecular weight is too small, sticking tends to occur.

The mass ratio of the content of the PVA-based resin (A) and the plasticizer (B) in the film coating composition of the present invention is 90:10 to 60:40, preferably 80:20 to 70:30. be. If the proportion of the PVA-based resin (A) is too high, the improvement in adhesiveness will not be complete, resulting in poor productivity. On the other hand, if the proportion of the plasticizer (B) is too high, moisture resistance will be poor.

The film coating composition of the present invention may contain, if necessary, known additives generally accepted in pharmaceuticals, but does not contain a lubricant. Examples of such known additives include plasticizers other than the plasticizer (B) (eg, sorbitol, propylene glycol, etc.), surfactants, coloring agents, sweeteners, coating agents, antifoaming agents, and the like. be done. The content when these are added is not particularly limited as long as it does not interfere with the effects of the present invention, but is preferably 200% by mass or less, more preferably 100% by mass or less, relative to the PVA-based resin (A). .

The film coating composition of the present invention does not contain lubricants, but examples of lubricants include talc, titanium oxide, yellow iron sesquioxide, iron sesquioxide, legal pigments, light anhydrous silicic acid, and hydrous silicon dioxide. and other powders.

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

Various additives commonly used in this field, such as excipients, binders, disintegrants, lubricants (antiaggregation agents), fluidizers, colorants, and dissolution aids for pharmaceutical compounds, are added to the core. agents may be added.

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

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, and hydroxypropylcellulose. , macrogol (eg, macrogol 4000, macrogol 6000, macrogol 20000, etc.), gum arabic, gelatin, agar, starch (cornstarch, etc.), and the like.

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

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

The fluidizing agent is not particularly limited, but examples thereof include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.

The coloring agent is not particularly limited, but for example, yellow ferric oxide, ferric oxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2 , Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, and the like.

Furthermore, examples of solubilizers 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 drug and the like.

The coating portion may contain at least the film coating composition of the present invention, and the film coating composition of the present invention alone may be used as the coating portion (coating layer). In addition, an undercoating may be performed using a coating base. As the coating base, various coating bases 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-shaped, or the like.

Oral solid preparations to be coated with the film-coating composition of the present invention are not particularly limited, and include tablets, powders, granules, fine granules, pills, lozenges, capsules and the like. Tablets are preferred. 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 (compression-coated tablets), and the like. Coated tablets (including multilayer film-coated tablets) and enteric-coated tablets are preferred.

Next, a method for producing an oral solid preparation will be described.
The oral solid preparation of the present invention can be produced by dissolving or dispersing the film-coating composition in a solvent to prepare a film-coating composition solution, and applying the solution to the core.

The solvent is not particularly limited, and for example, an organic solvent such as water or ethanol can be used. These may be used alone, or two or more may be mixed and used as a mixed solvent. can. The temperature at which the film coating composition is dissolved or dispersed in the 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 in which the film coating composition solution prepared as described above is coated on the drug-containing core portion by spraying or the like using a conventionally known coating apparatus.

In addition, when the oral solid preparation of the present invention is a multi-layer film-coated tablet, under the film layer composed of the film-coating composition, before coating by the above-mentioned coating method, various types of agents such as HPMC that are commonly used in this field are applied. A method of forming a plurality of films by adding a step of undercoating using the coating base of .

The coating apparatus is not particularly limited, and conventionally known means can be used. Spray coating is generally used as a coating method, and in that case, pan coating equipment, drum type coating equipment, fluidized bed coating equipment, and stirring fluidized coating equipment may be used. Any of an air spray, an airless spray, a three-fluid spray, and the like can be used for the spray device attached to the apparatus.

The coating amount of the film-coating composition coated on the surface of the core (uncoated tablet) varies depending on the type, shape, size, and surface condition of the solid preparation, as well as the properties of the drug and excipients contained in the solid preparation. is, for example, preferably 1 to 10% by mass, more preferably 1 to 7% by mass, particularly preferably 2 to 6% by mass, relative to the uncoated tablet. If the coating amount is too small, a complete film cannot be obtained, while if the coating amount is too large, the time required for coating may be required.

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. In addition, simply "parts" and "%" are based on weight.

Example 1
PVA-based resin (A) (unmodified, saponification degree 88 mol%, polymerization degree 500, 4% aqueous solution viscosity 5 mPa s) 100 parts, polyethylene glycol (b1-1) having a weight average molecular weight of 400 as a plasticizer (B) 14 parts of (PEG400), 29 parts of polyethylene glycol (b2) (PEG4000) having a weight average molecular weight of 4000, and 567 parts of water were blended and heated to 85° C. for dissolution to obtain a film coating liquid.
The resulting film coating liquid was applied onto a PET film, dried at 60° C. for 2 hours, and made into a film having a thickness of 30 μm, and was conditioned at 23° C. and 50% RH for 1 week.

[Transparency of film]
The internal haze of the film obtained above was measured with a Haze Meter NDH2000 (manufactured by Nippon Denshoku Co., Ltd.) at n=5. Table 1 shows the average values.

[Presence or absence of bleeding out]
The film obtained above was touched with a bare hand, and if it was sticky, it was rated as "Yes", and if it was not sticky, it was rated as "No".

Example 2
A film coating composition was prepared and evaluated in the same manner as in Example 1, except that 21 parts of PEG400 and 21 parts of PEG4000 were used as plasticizers.

Example 3
A film coating composition was prepared and evaluated in the same manner as in Example 1, except that 29 parts of glycerin and 14 parts of PEG4000 were used as plasticizers.

Comparative example 1
A film coating composition was prepared and evaluated in the same manner as in Example 1, except that only 43 parts of PEG400 was used as the plasticizer.

Comparative example 2
A film coating composition was prepared and evaluated in the same manner as in Example 1, except that only 43 parts of PEG4000 was used as the plasticizer.

Comparative example 3
A film coating composition was prepared and evaluated in the same manner as in Example 1, except that 25 parts of PEG4000 was used as the plasticizer.

Examples 1-3 using the film coating composition of the present invention had high transparency and no bleed-out.
On the other hand, Comparative Example 1 using a film coating composition containing no high-molecular-weight plasticizer had high transparency, but the plasticizer bleed out, making the film cloudy and sticky.
Also, Comparative Examples 2 and 3 using film coating compositions containing no low-molecular-weight plasticizer had low transparency.

INDUSTRIAL APPLICABILITY The film coating composition of the present invention has high transparency and is useful as a film coating for colored tablets.

Claims (5)

A film coating composition containing a polyvinyl alcohol resin (A) and a plasticizer (B) and containing no lubricant,
polyethylene glycol (b1-1) and/or glycerin (b1-2) having a weight average molecular weight of 100 to 700 as the plasticizer (B);
and a polyethylene glycol (b2) having a weight average molecular weight of 2000 to 4000000,
Per 100 parts by weight of the total amount of polyethylene glycol (b1-1) and/or glycerin (b1-2),
A solid preparation coated with a film coating composition containing 10 to 300 parts by weight of polyethylene glycol (b2). 2. The solid preparation coated with the film coating composition according to claim 1, wherein the content of the plasticizer (B) is 25 parts by weight or more per 100 parts by weight of the polyvinyl alcohol resin (A). 3. A solid preparation coated with the film coating composition according to claim 1, wherein the polyvinyl alcohol resin has a degree of saponification of 80 to 95 mol %. A solid preparation comprising a drug-containing core and a coating covering the core, wherein the coating contains the film coating composition according to any one of claims 1 to 3. A method for producing a solid preparation, comprising at least the step of applying the film coating composition according to any one of claims 1 to 4 to a drug-containing core.