JP7623627B2 - Solid dosage forms with printing on the film coating - Google Patents

Description

The present invention relates to a solid formulation having a film coating on which printing is applied.

A solid preparation may have a film coating on its surface for the purposes of stabilizing the drug, masking the taste and 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.

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

The present invention aims to provide a solid formulation having a printing film coating that can suppress bleeding or disappearance of the dye ink even when exposed to high humidity.

The inventors conducted extensive research to solve the above problems and found that a solid preparation in which dye ink is printed on a film coating containing a polyethylene glycol content of a specified amount or less can prevent bleeding or disappearance of the dye ink even when exposed to high humidity. Based on this knowledge, the inventors conducted further research and completed the present invention.

The present invention includes the following aspects.
[1] 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,
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.

Solid formulations printed on the film coating of the present invention can prevent bleeding or disappearance of the dye ink even when exposed to humid conditions.

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. 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. FIG. 3 is a photograph showing the state of printing after six months of humidification when the PEG addition rate is 0.86%.

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, the film coating is printed with a dye ink, the film coating contains a base and may further contain an additive, and the content of polyethylene glycol in the film coating is within a specific range.

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, for example, 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, polyvinyl pyrrolidone, dextrin, pullulan, amino alkyl methacrylate copolymer, (meth)acrylic acid copolymer, carboxyvinyl polymer, sucrose, mannitol, gelatin, etc.The base can be used alone or in combination of two or more.The base preferably includes at least one selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.

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.

In this specification, the lower and upper limits of the numerical ranges can be combined in any way. In addition, each numerical value can include a value that is rounded off to the nearest integer.

In addition to the base, the film coating may contain an additive (hereinafter referred to as "film coating additive"). The film coating additive means all components that can be added to the film coating other than the base, and is not particularly limited as long as it is a pharma- ceutically acceptable additive, 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.

An example of a lubricant is talc.

Examples of plasticizers include polyethylene glycol, triacetin, medium-chain triglycerides, acetylglycerin fatty acid esters, triethyl citrate, and combinations of two or more of these. Of these, plasticizers other than polyethylene glycol are preferred.

Colorants include, for example, iron oxide (e.g., iron sesquioxide, yellow iron sesquioxide, black iron oxide), titanium oxide, and combinations of two or more of these.

The film coating preferably contains a base and a film coating additive, and more preferably contains 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).

The content of polyethylene glycol in the solid formulation 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 formulation 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 formulation 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 with number average molecular weights of 200 to 20,000 (e.g., macrogol 200, 400, 1500, 4000, 6000, and 20,000). The lower the polyethylene glycol content, 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 is substantially free of plasticizer.

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.

In solid formulations, the mass ratio 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.

The core refers to the object to be film-coated, and in the case where the solid preparation is a tablet (film-coated tablet), it refers to the plain tablet. The core usually contains an active ingredient. There is no limit to the type of active ingredient, 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.

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.

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

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

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

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 of the core additive include excipients, disintegrants, disintegration aids, binders, flow agents, lubricants, flavorings, odorants, surfactants, fragrances, colorants, antioxidants, and wetting agents. These may be used alone or in combination of two or more.

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.

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, etc.

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

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

Examples of fluidizing agents include light anhydrous silicic acid, talc, and hydrous silicon dioxide.

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.

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.

Flavoring agents include, for example, trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, and cardamom essential oil.

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

Fragrances include, for example, lemon oil, orange oil, menthol, peppermint oil, etc.

Colorants include, for example, iron oxide (iron sesquioxide, yellow iron sesquioxide, black iron oxide, etc.), titanium oxide, etc.

Examples of antioxidants include sodium ascorbate, L-cysteine, sodium sulfite, and vitamin E.

Examples of wetting agents include polysorbate 80, sodium laurate sulfate, sucrose fatty acid esters, macrogol, and hydroxypropyl cellulose.

Representative cores include a core containing an active ingredient, an excipient, a binder, a disintegrant, and a lubricant, and a core further containing a fluidizer. 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 mass or more or 1% by mass or more, and may be 15% by mass or less or 10% by mass 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 flow 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.

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), known as "FD&C dyes";
(2) Natural colours derived from natural (usually plant) sources;
Examples include:

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 (Fast Green FCF), Blue No. 1 (Brilliant Blue FCF), Blue No. 2 (Indigotine), and combinations of two or more of these.

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.

The solid preparation can suppress bleeding or disappearance of the dye ink even under humid conditions. For example, the rate of change in 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 rate of change in the printed area may be 0% or more, but is usually 0.01% or more. The rate of change in the printed area means the rate of change from the initial printed area. Here, "initial" means immediately after production; immediately after removal from the final packaging (packaging for the sale or administration of pharmaceuticals, in the form of a product to be shipped or distributed to the market with labeling, etc., as specified by laws and regulations). The rate of change in the printed area can be calculated by automatic area measurement based on brightness using a digital microscope (Keyence Corporation, model: VHX-5000).

The solid preparation is not particularly limited in its dosage form as long as it can be printed on the film coating, but tablets or capsules are preferred, and tablets are particularly preferred. The solid preparation may be a supplement (or a nutritional functional food). The solid preparation may be an oral preparation or a parenteral preparation.

There are no particular limitations on the shape of the solid preparation, so long as it is possible to apply printing to the film coating. For example, tablets may be round or irregularly shaped (e.g., oval, diamond, triangular, etc.).

A solid formulation can be produced by a known method. For example, the active ingredient (or the active ingredient granulated by a known granulation method and dried, sized, classified, etc., as required) is mixed with pharma- ceutically acceptable additives as required, 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 with a dye ink using a printing machine to obtain a solid formulation.

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

Preparation of test formulations
216.0g of lactose hydrate, 17.5g of crystalline cellulose, 70g of corn starch, 35g of dextrin, 1.4g of light anhydrous silicic acid, and 0.7g of magnesium stearate were mixed and compressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain plain tablets. Next, 20.3g of hypromellose, 7.2g of talc, 4.9g of titanium oxide, 0.07g of black iron oxide, and polyethylene glycol in the proportions shown in Table 1 were mixed and suspended in 333.6g of purified water to prepare a coating agent, and the plain tablets were placed in a ventilated coating machine (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.

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

<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 or image analysis using a digital microscope (Keyence Corporation, model: VHX-5000) were performed on 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: hole filling 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.

<Results and Discussion>
Figure 1 shows a photograph of the printed state before the stability test was set up, and a photograph of the printed state 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 (6)

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 .
Solid preparations (excluding, however, the solid preparations 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 preparations 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 preparations 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 preparations 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) . 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. The solid formulation according to claim 1 or 2, wherein the content of polyethylene glycol as an additive in the film coating is 5% by mass or less. 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. The solid preparation according to any one of claims 1 to 4 , which is a tablet. 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.

Images