Solid dosage forms with printing on the film coating

Abstract

To provide a solid preparation with printing applied on a film coating that can suppress the bleeding of dye ink even under a high-humidity condition.SOLUTION: A solid preparation has a core, and a film coating that coats the core. The film coating has printing with dye ink applied thereon. In the solid preparation or the film coating, the content of polyethylene glycol is in a specific range.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a solid dosage form having a film coating onto which printing is applied. [Background technology]

[0002] A solid preparation may have a film coating on its surface for the purposes of stabilizing the drug, masking the taste, odor, etc. The film coating is usually formed from a coating agent containing hydroxypropylmethylcellulose as a base and polyethylene glycol as a plasticizer. In addition, solid preparations tend to be similar in size, color, shape, etc., and in order to distinguish them from one another, the company name, company emblem, product name, ingredient content, etc. are printed on the surface. Pigment inks and dye inks are used for printing. Summary of the Invention [Problem to be solved by the invention]

[0003] The present inventors have found that when a solid preparation in which a dye ink is printed on a film coating containing a predetermined amount or more of polyethylene glycol is exposed to high humidity, the dye ink bleeds or disappears.

[0004] An object of the present invention is to provide a solid preparation having a printing film coating, which can suppress bleeding or disappearance of dye ink even when exposed to humid conditions. [Means for solving the problem]

[0005] As a result of intensive research aimed at solving the above problems, the present inventors have found that a solid preparation in which a dye ink is printed on a film coating containing a polyethylene glycol content of a predetermined amount or less can suppress bleeding or disappearance of the dye ink even when exposed to high humidity. Based on this finding, the present inventors have further researched and completed the present invention.

[0006] The present invention includes the following aspects. [1] A solid dosage form having a core and a film coating covering the core, the film coating being printed with a dye ink; The film coating contains a base and may further contain additives, The content of polyethylene glycol as an additive in the film coating is less than 22.3% by mass when the total amount of the film coating is 100% by mass. Solid dosage forms. [2] The solid formulation according to [1], wherein the content of polyethylene glycol as an additive in the film coating is 10% by mass or less. [3] The solid formulation according to [1] or [2], wherein the content of polyethylene glycol as an additive in the film coating is 5% by mass or less. [4] The solid formulation according to any one of [1] to [3], wherein the base comprises at least one selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. [5] The solid preparation according to any one of [1] to [4], wherein the content of polyethylene glycol in the solid preparation is less than 0.86% by mass when the total amount of the solid preparation is taken as 100% by mass. [6] The solid preparation according to any one of [1] to [5], wherein the content of polyethylene glycol in the solid preparation is 0.38% by mass or less, when the total amount of the solid preparation is taken as 100% by mass. [7] The solid preparation according to any one of [1] to [6], wherein the content of polyethylene glycol in the solid preparation is 0.19% by mass or less, when the total amount of the solid preparation is taken as 100% by mass. [8] The solid formulation according to any one of [1] to [7], which is a tablet. [9] The solid formulation according to any one of [1] to [8], wherein the rate of change in the area of ​​the printed portion after storage for 6 months under conditions of 40°C and 75% RH is 30% or less. Effect of the Invention

[0007] The solid preparation having the film coating of the present invention printed thereon can be prevented from bleeding or disappearance of the dye ink even when exposed to humid conditions. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a set of photographs showing the initial print state and the print state after humidification when the PEG addition rate is changed. [Diagram 2] FIG. 2 is a graph showing the initial printed area, the printed area after humidification, and the rate of change in the printed area when the PEG addition rate is changed. [Diagram 3] FIG. 3 is a photograph showing the print state after six months of humidification when the PEG addition rate was 0.86%. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The solid preparation of the present invention (hereinafter simply referred to as "solid preparation") is a solid preparation having a core and a film coating covering the core, wherein the film coating is printed with a dye ink, the film coating contains a base and may further contain additives, and the polyethylene glycol content in the film coating is within a specific range.

[0010] The base is not particularly limited as long as it is a component capable of forming a film, and is usually a water-soluble base. Specific examples include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, polyvinylpyrrolidone, dextrin, pullulan, aminoalkyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl alcohol, polyvinylpyrrolidone, dextrin, pullulan, aminoalkyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate ... TakuExamples of the base include acrylate copolymer, (meth)acrylic acid copolymer, carboxyvinyl polymer, sucrose, mannitol, gelatin, etc. The base may be used alone or in combination of two or more. The base preferably contains at least one selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.

[0011] The content of the base in the solid preparation may be, for example, 0.5% by mass or more, preferably 1% by mass or more, and for example, 10% by mass or less, preferably 5% by mass or less, when the total amount of the solid preparation is taken as 100% by mass. The content of the base in the film coating may be, for example, 50% by mass or more, preferably 55% by mass or more, and for example, 80% by mass or less, preferably 75% by mass or less, when the total amount of the film coating is taken as 100% by mass.

[0012] In this specification, the lower and upper limits of the numerical ranges can be combined in any combination. In addition, each numerical value can include a value that is obtained by rounding off.

[0013] The film coating may contain additives (hereinafter referred to as "film coating additives") in addition to the base. The film coating additives refer to all components that can be added to the film coating other than the base, and are not particularly limited as long as they are pharma- ceutically acceptable additives, and examples of such additives include lubricants, plasticizers, and colorants. The film coating additives may be used alone or in combination of two or more.

[0014] Lubricants include, for example, talc.

[0015] Examples of the plasticizer include polyethylene glycol, triacetin, medium-chain fatty acid triglyceride, acetylglycerin fatty acid ester, triethyl citrate, and combinations of two or more of these. Among these, plasticizers other than polyethylene glycol are preferred.

[0016] Examples of colorants include iron oxides (eg, iron sesquioxide, yellow iron sesquioxide, black iron oxide), titanium oxide, and combinations of two or more of these.

[0017] The film coating preferably contains a base and a film coating additive, more preferably a base, a lubricant, and a colorant. The content of each component of the lubricant and colorant in the solid formulation may be, for example, 0.01% by mass or more (preferably 0.1% by mass or more) or 1% by mass or less (preferably 0.9% by mass or less) when the total amount of the solid formulation is taken as 100% by mass. When the total amount of the film coating is taken as 100% by mass, the content of the lubricant may be, for example, 5% by mass or more (preferably 10% by mass or more) or 30% by mass or less (preferably 25% by mass or less), and the content of the colorant may be, for example, 1% by mass or more (preferably 5% by mass or more) or 25% by mass or less (preferably 20% by mass or less).

[0018] The content of polyethylene glycol in the solid preparation is preferably less than 0.86% by mass, more preferably 0.38% by mass or less, and even more preferably 0.19% by mass or less (e.g., 0.15% by mass or less, 0.08% by mass or less, or 0% by mass) when the total amount of the solid preparation is taken as 100% by mass. The content of polyethylene glycol as an additive (or plasticizer) in the film coating is preferably 20% by mass or less, more preferably 15% by mass or less, even more preferably 10% by mass or less, and particularly preferably 5% by mass or less (e.g., 4% by mass or less, 2% by mass or less, or 0% by mass). When the content is expressed as less than % or %, the range includes 0% by mass. It is also preferable that the solid preparation and / or film coating does not substantially contain polyethylene glycol. Here, "substantially" means excluding the case where it is inevitably contained. The term "polyethylene glycol" is used to include polyethylene glycols having a number average molecular weight of 200 to 20,000 (e.g., macrogol 200, 400, 1500, 4000, 6000, 20,000). The lower the content of polyethylene glycol, the more the dye ink can be prevented from bleeding or disappearing. The content of the plasticizer in the solid preparation or film coating can be selected from the same range as the content of polyethylene glycol, and it is also preferable that the solid preparation or film coating does not substantially contain a plasticizer.

[0019] The film coating may be one layer or two or more layers. When the film coating is multi-layered, the content of polyethylene glycol as an additive (or plasticizer) in the outermost layer is preferably 22.3% by mass or less, more preferably 20% by mass or less, even more preferably 15% by mass or less, even more preferably 10% by mass or less, and particularly preferably 5% by mass or less, when the total amount of the outermost layer is taken as 100% by mass. The content of the plasticizer in the outermost layer can be selected from the same range as the content of polyethylene glycol, and it is also preferable that the outermost layer does not substantially contain a plasticizer.

[0020] In a solid preparation, the mass proportion of the film coating is, for example, 1 to 15 parts by mass, preferably 2 to 10 parts by mass, per 100 parts by mass of the core.

[0021] The core means the object to be film-coated, and when the solid preparation is a tablet (film-coated tablet), it means a plain tablet. The core usually contains an active ingredient. The active ingredient is not limited in type, and various disease treatments (or preventive agents) can be used, such as lifestyle-related disease treatments (hypertension treatments, diabetes treatments, diabetic neuropathy treatments, hyperlipidemia treatments, platelet aggregation inhibitors, osteoporosis treatments, angina pectoris treatments, heart failure treatments, antiarrhythmic agents, etc.), catecholamine oversecretion treatments, malignant tumor treatments, antipyretics and analgesics, anti-inflammatory agents, asthma treatments, nausea and vomiting treatments, allergy treatments, gastrointestinal antispasmodics, gastrointestinal drugs, intestinal regulators, esophagitis treatments, pancreatitis treatments, antirheumatism drugs, dementia treatments, Parkinson's disease treatments, urinary disorder treatments (overactive bladder treatments, etc.), insulin preparations, peripheral circulatory disorder treatments, sleep-inducing agents, etc.

[0022] Typical active ingredients include diabetes treatments (such as sitagliptin phosphate and dapagliflozin), diabetic neuropathy treatments (such as epalrestat), osteoporosis treatments (such as minodronic acid), catecholamine hypersecretion treatments for pheochromocytoma (such as metyrosine), malignant tumor treatments (such as tirabrutinib, encorafenib, binimetinib), bronchial asthma or allergic rhinitis treatments (such as pranlukast), nausea or vomiting treatments (such as aprepitant), chronic pancreatitis or postoperative reflux esophagitis treatments (such as camostat), chronic stable angina or chronic heart failure treatments (such as ivabradine), overactive bladder treatments (such as imidafenacin), peripheral circulatory disorder treatments (limaprost) These include drugs for treating Parkinson's disease (such as opicapone), drugs for treating cancer cachexia (such as anamorelin), vitamins, amino acids, peptides, minerals, and herbal medicines.

[0023] The form of the active ingredient is not particularly limited, and it may be in the form of a salt, a hydrate, or a solvate.

[0024] The active ingredients can be used alone or in combination of two or more.

[0025] The content of the active ingredient in the solid preparation, when the total amount of the solid preparation is taken as 100% by mass, may be, for example, 0.1% by mass or more, preferably 0.5% by mass or more, and more preferably 1% by mass or more, and may be, for example, 30% by mass or less, preferably 20% by mass or less, and more preferably 10% by mass or less.

[0026] The core may contain an additive (hereinafter referred to as "core additive"). The core additive is not particularly limited as long as it is a pharma- ceutically acceptable additive, and examples thereof include excipients, disintegrants, disintegration aids, binders, flow agents, lubricants, flavorings, odorants, surfactants, flavorings, colorants, antioxidants, and wetting agents. These may be used alone or in combination of two or more.

[0027] Examples of excipients include lactose hydrate, anhydrous lactose, sucrose, refined sucrose, D-mannitol, D-sorbitol, glucose, trehalose, fructose, starch (e.g., wheat starch, rice starch, corn starch, potato starch), dextrin, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, macrogol 20000, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, precipitated calcium carbonate, and kaolin.

[0028] Examples of disintegrants include starch (e.g., wheat starch, rice starch, corn starch, potato starch), sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, agar powder, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, D-mannitol, and the like.

[0029] Examples of disintegration aids include crystalline cellulose, lactose, macrogol 1500, macrogol 4000, and anhydrous calcium hydrogen phosphate.

[0030] Examples of binders include starch, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carmellose sodium, pullulan, methyl cellulose, gum arabic, gelatin, tragacanth, sodium alginate, and polyvinylpyrrolidone.

[0031] Examples of the fluidizing agent include light anhydrous silicic acid, talc, and hydrous silicon dioxide.

[0032] Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, talc, carnauba wax, white beeswax, beeswax, sucrose fatty acid esters, sodium lauryl sulfate, and sodium oleate.

[0033] Examples of flavoring agents include sucrose, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizinate, sodium glutamate, 5-sodium inosinate, and 5-sodium guanylate.

[0034] Examples of flavoring agents include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, and cardamom essential oil.

[0035] Examples of surfactants include polysorbates (such as polysorbate 80), polyoxyethylene-polyoxypropylene copolymers, and sodium lauryl sulfate.

[0036] Examples of the flavoring include lemon oil, orange oil, menthol, peppermint oil, and the like.

[0037] Examples of colorants include iron oxide (iron sesquioxide, yellow iron sesquioxide, black iron oxide, etc.), titanium oxide, and the like.

[0038] Antioxidants include, for example, sodium ascorbate, L-cysteine, sodium sulfite, vitamin E, and the like.

[0039] Examples of wetting agents include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid esters, macrogol, and hydroxypropyl cellulose.

[0040] Representative cores include a core containing an active ingredient, an excipient, a binder, a disintegrant, and a lubricant, and a core further containing a fluidizing agent. In these cores, when the total amount of the solid preparation is taken as 100% by mass, The content of the active ingredient may be, for example, 0.5% by weight or more, or 1% by weight or more, and may be 15% by weight or less, or 10% by weight or less. The content of the excipient may be, for example, 50% by mass or more, 55% by mass or more, or 60% by mass or more, and may be 75% by mass or less, 70% by mass or less, or 65% by mass or less. The binder content may be, for example, 1% by weight or more or 5% by weight or more, and may be 20% by weight or less or 15% by weight or less; The content of the disintegrant may be, for example, 10% by mass or more, 15% by mass or more, or 20% by mass or more, and may be 30% by mass or less, or 25% by mass or less. The content of the fluidizing agent may be, for example, 0.1% by mass or more, 1% by mass or less, or 0.5% by mass or less; The content of the lubricant may be, for example, 0.1% by mass or more, 1% by mass or less, or 0.5% by mass or less.

[0041] Dye inks used for printing on film coatings include, for example: (1) Synthetic colors approved for human consumption under the Food, Drug, and Cosmetic Act as administered by the U.S. Food and Drug Administration (FDA), referred to as "FD&C dyes"; (2) Natural dyes derived from natural (usually plant) sources; Examples include:

[0042] Examples of FD&C dyes include Red No. 3 (Erythrosine), Red No. 40 (Allura Red), Yellow No. 6 (Sunset Yellow FCF), Yellow No. 5 (Tartrazine), Green No. 3 (First Green FCF), Blue No. 1 (Brilliant Blue FCF), Blue No. 2 (Indigotine), and combinations of two or more of these.

[0043] Examples of natural pigments include porphyrin pigments (such as chlorophyll), carotenoid pigments (such as carotene and xanthophyll), flavonoid pigments (such as chalcone, anthocyanin, 3-deoxyanthocyanin, and flavonoid polymers), quinoid pigments (such as anthraquinone), betalain, monascus, iridoid, and combinations of two or more of these.

[0044] The solid preparation can suppress bleeding or disappearance of the dye ink even under humid conditions. For example, the change rate of the printed area after storage for 6 months under conditions of 40°C and 75% RH is preferably 30% or less, more preferably 25% or less, and even more preferably 20% or less. The change rate of the printed area may be 0% or more, but is usually 0.01% or more. The change rate of the printed area means the change rate from the initial printed area. Here, "initial" means immediately after production; immediately after removal from the final packaging (packaging for the sale or presentation of pharmaceuticals, in the form of a product to be shipped or distributed on the market with labeling or the like specified by laws and regulations); etc. The change rate of the printed area can be calculated by automatic area measurement based on brightness using a digital microscope (manufactured by Keyence Corporation, model: VHX-5000).

[0045] The solid preparation is not particularly limited in dosage form as long as it can be printed on the film coating, but is preferably a tablet or capsule, and more preferably a tablet. The solid preparation may be a supplement (or a nutritional functional food). The solid preparation may be an oral preparation or a parenteral preparation.

[0046] The shape of the solid preparation is not particularly limited as long as it is possible to apply printing to the film coating. For example, in the case of tablets, they may be round or irregularly shaped (e.g., oval, diamond, triangular, etc.).

[0047] The solid preparation can be produced by a known method. For example, the active ingredient (or the active ingredient obtained by granulating the active ingredient by a known granulation method and, if necessary, drying, sieving, classifying, etc.) is mixed with a pharma- ceutically acceptable additive if necessary, and the mixture is compressed into tablets using a tablet press (e.g., a rotary tablet press, a single punch tablet press, etc.) or filled into a capsule to prepare a core, which is then coated with a coating agent, and the coating is printed on with a dye ink using a printer to obtain a solid preparation. EXAMPLES

[0048] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. In the examples, "%" means "% by mass" unless otherwise specified.

[0049] <Preparation of test formulation> 216.0 g of lactose hydrate, 17.5 g of crystalline cellulose, 70 g of corn starch, 35 g of dextrin, 1.4 g of light anhydrous silicic acid, and 0.7 g of magnesium stearate were mixed and compressed using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain plain tablets. Next, 20.3 g of hypromellose, 7.2 g of talc, 4.9 g of titanium oxide, 0.07 g of black iron oxide, and polyethylene glycol in the proportions shown in Table 1 were mixed and suspended in 333.6 g of purified water to prepare a coating agent, and the plain tablets were placed in a ventilated coating machine (manufactured by Freund Corporation), and the required amount of the prepared coating agent was sprayed to obtain coated tablets. Then, the tablets were printed with dye ink using a tablet printing machine.

[0050] The formulation is shown in Table 1 below. <Prescription Table> [Table 1]

[0051] <Measurement method> The printed tablets of each formulation were placed on a petri dish and placed in a stability tester at a temperature of 40°C and a relative humidity of 75%, and samples were taken periodically to observe bleeding of the print. In addition, photographs were taken or image analysis was performed using a digital microscope (Keyence Corporation, model: VHX-5000) for the initial samples and samples placed in the stability tester 7 days and 6 months after placement. Specifically, the total area to the right of the printed area was calculated by automatic area measurement based on brightness (extraction: brightness 0-128, shaping: filling in holes ON, small particles other than the printed area were manually removed). The 6-month samples were also measured under the same conditions as the initial samples.

[0052] <Results / Discussion> Figure 1 shows a photograph of the print before the stability test was set up, and a photograph of the print after one week under humid conditions. When the PEG addition rate was 0.86%, bleeding of the dye ink was observed when stored under humid conditions. Next, the results of the image analysis are shown in Figure 2. When the PEG addition rate was 0.86%, the area of ​​the printed part of the 6-month product changed significantly compared to the initial product, and the area became extremely small because the letters had disappeared due to bleeding (Figure 3).

Claims

1. A solid dosage form having a core and a film coating covering the core, A dye ink is printed on the film coating, The film coating contains a base and may further contain additives, the base is at least one selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl cellulose, polyvinyl acetal diethyl amino acetate, polyvinyl pyrrolidone, dextrin, pullulan, aminoalkyl methacrylate copolymer, (meth)acrylic acid copolymer, carboxyvinyl polymer, sucrose, mannitol, and gelatin; The content of polyethylene glycol as an additive in the film coating is less than 22.3% by mass when the total amount of the film coating is 100% by mass; The content of polyethylene glycol in the solid preparation is 0.08% by mass or more and 0.15% by mass or less, when the total amount of the solid preparation is taken as 100% by mass. A solid preparation (excluding the solid preparation having the film coating consisting of hydroxypropyl methylcellulose, polyethylene glycol, and titanium oxide (IV) in a mass ratio of 87.5:3.8:8.8, the solid preparation having the film coating consisting of aminoalkyl methacrylate copolymer, polyethylene glycol, and titanium oxide (IV) in a mass ratio of 87.5:3.8:8.8, the solid preparation having the film coating consisting of methacrylic acid copolymer, polyethylene glycol, and titanium oxide (IV) in a mass ratio of 87.5:3.8:8.8, and the solid preparation having the film coating consisting of ammonioalkyl methacrylate copolymer, polyethylene glycol, and titanium oxide (IV) in a mass ratio of 87.5:3.8:8.8).

2. 2. The solid formulation according to claim 1, wherein the content of polyethylene glycol as an additive in the film coating is 10% by mass or less.

3. 3. The solid formulation according to claim 1, wherein the content of polyethylene glycol as an additive in the film coating is 5% by mass or less.

4. The solid formulation according to any one of claims 1 to 3, wherein the base comprises at least one selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methylcellulose.

5. The solid preparation according to any one of claims 1 to 4, which is a tablet.

6. 6. The solid preparation according to claim 1, wherein the rate of change in the area of ​​the printed portion after storage for 6 months under conditions of 40° C. and 75% RH is 30% or less.

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