Hard capsule formulation sealed with a band seal including a tag

Abstract

Provided is a method capable of attaching a micro tag to a product even in a product processing place other than those in a manufacturer, such as a dispensing pharmacy. The present invention also addresses the problem of more easily attaching a micro tag with a hard capsule.　Provided is a band seal preparation for sealing a hard capsule, the band seal preparation including a micro tag capable of identifying a product.

Description

[Technical field]

[0001] This specification discloses a hard capsule sealed with a band seal including a tag, a band seal preparation solution including a tag, a method for preparing a hard capsule sealed with a band seal including a tag, a method for preventing counterfeiting of hard capsules using tags, and a method for tracking hard capsules using tags. [Background technology]

[0002] In the pharmaceutical and food sectors, a manufacturer may produce a genuine drug or supplement, and then a third party may modify the product.

[0003] As a method for monitoring such post-manufacturing alterations of products, Patent Documents 1 and 2 disclose tracer particles for tracking products and tagging products with the tracer particles to track the products after manufacture. In Patent Document 1, the tracer particles are used for tagging medicines, animal feed, etc. This product is sold by Micro-Tracers, Inc. (San Francisco, California, USA) under the name SECURtracers (Non-Patent Documents 1 and 2). Patent Document 2 also discloses the use of porous silicon microtags as product labels. The label described in Patent Document 2 is sold by TruTag Technologies, Inc. (Kapolei, Hawaii, USA) under the name TruTag™ microtag (Non-Patent Document 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Pat. No. 10,175,199 [Patent Document 2] U.S. Patent Application Publication No. 10,175,199 [Patent Document 3] U.S. Pat. No. 10,078,766 [Non-patent literature]

[0005] [Non-Patent Document 1] Webpage: https: / / www.securtracers.com / aboutsecurtracers [Non-Patent Document 2] Webpage: https: / / www.securtracers.com / applications [Non-Patent Document 3] Webpage https: / / trutags.com / pharmaceutical-nutraceutical / Summary of the Invention [Problem to be solved by the invention]

[0006] Patent Documents 1 and 2 describe a method of tagging a product by mixing tracer particles into a solid excipient used in the manufacture of tablets or into a liquid excipient used in the manufacture of liquids, thereby containing tracer particles throughout a single drug. Patent Documents 1 and 2 also describe a method of mixing tracer particles into a coating liquid for tablets and attaching tracer particles to the entire tablet surface. In the method of mixing or coating tracer particles into the entire drug, the process of attaching tracer particles to the product must be performed by the manufacturer of the drug, supplement, etc. Furthermore, the method described in Non-Patent Document 3 also requires attaching microtags directly to products such as medicines and supplements.

[0007] However, in recent years, dispensing pharmacies and the like have been purchasing bulk materials of active ingredients such as medicines, packaging the active ingredients within the dispensing pharmacy, and prescribing the medicines. In the methods described in Patent Document 1, Patent Document 2, and Non-Patent Document 3, it is difficult for the dispensing pharmacy to tag the product with tracer particles or microtags, and it is difficult to track which dispensing pharmacy the product was packaged at.

[0008] In view of such problems, an object of the present invention is to provide a method that allows a tag to be attached to a product even at a product processing facility other than the manufacturer, such as a dispensing pharmacy.

[0009] In addition, Non-Patent Document 2 describes adding tracer particles onto the capsule band. However, when adding tracer particles onto the capsule band, it is necessary to apply the tracer particles onto the original capsule band seal using a different solution. Therefore, it is complicated to prepare a solution containing tracer particles that is different from the band seal preparation solution. In view of these problems, an object of the present invention is to attach tags to hard capsules more easily. [Means for solving the problem]

[0010] After extensive research, the inventors discovered that if a tag is dispersed in a band seal preparation liquid used to seal a hard capsule and the hard capsule is sealed using this band seal preparation liquid, the tag can be detected without dissolving the hard capsule. The present invention has been completed based on this finding, and includes the following aspects. Item 1. A hard capsule formulation sealed with a band seal preparation containing a tag that can identify the product. Item 2. The hard capsule formulation according to Item 1, wherein the tag has a length of 400 μm or less. Item 3. The hard capsule formulation according to Item 1 or 2, wherein the tag has an identifier for identifying the product. Item 4. The hard capsule formulation according to Item 3, wherein the identifier is readable when irradiated with light in a predetermined wavelength range. Item 5. The hard capsule formulation according to Item 3 or 4, wherein the identifier is at least one selected from the group consisting of a character, a color, a graphic, a trademark, a mark, a one-dimensional barcode, a two-dimensional barcode, and a rugate structure. Item 6. The hard capsule formulation according to any one of Items 1 to 5, wherein the shell of the hard capsule contains a base and a component other than the base, the base being at least one selected from the group consisting of gelatin, a cellulose compound, polyvinyl alcohol, a polyvinyl alcohol copolymer, and pullulan, and the component other than the base being at least one selected from the group consisting of a gelling agent, a gelling aid, a plasticizer, a lubricant, a metal sequestering agent, a colorant, a light-blocking agent, and residual moisture. Item 7. A band seal preparation for sealing hard capsules containing tags that can identify products. Item 8. The band seal preparation solution according to Item 7, which has a specific gravity capable of dispersing a tag for a predetermined period of time. Item 9. A method for preparing a hard capsule formulation, comprising filling a hard capsule with contents, fitting a cap part and a body part together, applying the band seal preparation liquid according to Item 7 or 8 to the formed fitting part, and drying the liquid to seal the hard capsule. Item 10. A method for preventing counterfeiting of a hard capsule formulation, comprising filling a hard capsule with contents, fitting a cap part and a body part together, applying the band seal preparation liquid according to item 7 or 8 to the formed fitting part, and drying the same to seal the hard capsule. Item 11. A method for tracking a hard capsule formulation, comprising the steps of irradiating the hard capsule formulation according to any one of items 1 to 6 with light in a predetermined wavelength range and detecting a tag or identifier. Effect of the Invention

[0011] According to the present invention, tags can be attached to hard capsule formulations at product processing facilities other than the manufacturer. In addition, by adding tags to the band seal, the amount of tags attached to the capsule product can be reduced. Furthermore, since there is no need to separate the tag from other components when detecting the tag, detection is simple. [Brief description of the drawings]

[0012] [Figure 1] This shows a method for sealing a hard capsule. [Diagram 2] FIG. 1 shows a schematic diagram of a tagged hard capsule. [Diagram 3] Shown is an image of a capsule sealed with the band seal described in Example 1 under a fluorescent lamp (left) and an image under B excitation light. [Figure 4] 1 shows a fluorescence microscope image (B excitation) of the sealed portion of a capsule sealed with a band seal as described in Example 1. [Diagram 5] Shown is an image of a capsule sealed with the band seal described in Example 2 under a fluorescent lamp (left) and an image under B excitation light. [Figure 6] 1 shows a fluorescence microscope image (B excitation) of the sealed portion of a capsule sealed with a band seal as described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] 1. Explanation of terms In this specification, the term "band seal" refers to a band-shaped sealing film (symbol 5) formed by applying a band seal preparation liquid once or multiple times in the circumferential direction to the outer peripheral surface of the body part (symbol 2) and the outer peripheral surface of the cap part (symbol 1) of a hard capsule formulation prepared by combining the body part (symbol 2) and the cap part (symbol 1) with a width spanning the cut part (edge ​​part) (symbol a) as shown in Figure 1, and then drying the band seal preparation liquid. Also, Figure 2 shows a schematic diagram of a tagged hard capsule. The hard capsule shown in Figure 2 is sealed with a band seal (symbol 5) including a tag (symbol 8).

[0014] In this specification, the term "band seal preparation solution" refers to a solution for forming the band seal, i.e., a solution in which the components for forming the band seal (hereinafter also referred to as "seal components") are dissolved in a solvent such as water or ethanol. The seal components can be selected according to the components of the base material (hereinafter also referred to as "base components") of the hard capsule shell (hereinafter also simply referred to as "shell") described below. The seal components may be the same as or different from the base components of the shell. In general, the seal components include the base components of the shell to which the band seal is applied. For example, when gelatin is used as the base component of the shell, gelatin can be used as the seal component. Also, when hydroxypropyl methylcellulose (also referred to as HPMC or hypromellose) is used as a cellulose compound as the base component of the shell, hydroxypropyl methylcellulose can be used as the seal component. For example, examples of cellulose compounds other than hydroxypropylmethylcellulose include ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and cellulose acetate phthalate. Other base components include pullulan, polyvinyl alcohol (PVA), polyvinyl alcohol (PVA) copolymers, mixtures of PVA and PVA copolymers, and methacrylic acid copolymers. Examples of band seal preparation solutions containing cellulose compounds include the band seal preparation solutions described in JP-A-2005-187412. Examples of band seal preparation solutions containing PVA, PVA copolymers, and mixtures of PVA and PVA copolymers include the band seal preparation solutions described in WO 2008 / 099835.

[0015] The solvent for the band seal preparation liquid may be water, a mixture of water and ethanol, or a mixture of water and isopropanol, etc. The solvent may be selected according to the material of the base material as well as the material of the tag substrate (base).

[0016] The band seal preparation solution may contain additives that are commonly used in the preparation of hard capsule shells, such as plasticizers, colorants, opacifiers, or flavorings, in addition to the sealing components, as long as they do not inhibit the formation of the band seal. The additives can be selected according to the sealing components and the base components of the hard capsule shell to which the band seal is applied. For example, when gelatin is used as the sealing component, polysorbate 80 can be used as the plasticizer.

[0017] In addition, a solution containing a sealing component other than the base component of the shell to which the band seal is applied can be used as the band seal preparation solution. For example, a band seal preparation solution containing gelatin as a sealing component may be applied to a hard capsule using hydroxypropyl methylcellulose as the base component of the shell. In addition, as the band seal preparation liquid, for example, a band seal preparation liquid containing monoacetyl monoacylglycerin as a sealing component as described in JP 2015-218131 A, a band seal preparation liquid containing a plant polysaccharide thickening agent having low or no gel-forming ability and film-forming ability, such as pullulan, starch or cellulose as a sealing component as described in JP 2006-22028 A, and a band seal preparation liquid containing one or more of the following as a sealing component: (a) polyvinylpyrrolidone having a molecular weight of 100,000 to 4,000,000; (b) polyvinylpyrrolidone having a molecular weight of 10,000 to 80,000, whose weight is 90% or less by weight based on the total weight of the band seal; and (c) a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate as described in WO 2006 / 070578 A.

[0018] The content of the sealing component in the band seal preparation liquid is not limited as long as the band seal can be formed. For example, when the volume of the band seal preparation liquid is 100 g, the content of the base can be selected from the range of 10% (mass / mass) to 40% (mass / mass). In addition, when the volume of the band seal preparation liquid is 100 g, the content of the components other than the sealing component can be selected from the range of 0% (mass / mass) or more up to about 5% (mass / mass). In order to prevent dripping when applying the band seal preparation liquid, the viscosity of the band seal preparation liquid can be adjusted so that the final viscosity of the preparation liquid is usually in the range of 100 to 5,000 mPa·s. The viscosity specified in the present invention refers to the viscosity measured using a B-type rotational viscometer with rotor number 2 for a viscosity of less than 500 mPa s, rotor number 3 for a viscosity of 500 mPa s or more but less than 2,000 mPa s, and rotor number 4 for a viscosity of 2,000 mPa s or more, at 23°C, a rotation speed of 12 rpm, and a measurement time of 1 minute. As used herein, the band seal preparation includes a tag.

[0019] There are no limitations to the tag as long as it can identify the product to which it is attached. A product can be identified by the presence or absence of the tag, or by an identifier that the tag has.

[0020] The tags are also referred to as tracer particles in U.S. Patent No. 5,399,433 and U.S. Patent No. 5,499,442, and as porous silicon microtags in U.S. Patent No. 5,499,442. They may also be referred to as microtags, taggants, markers and / or microparticles as described in U.S. Patent No. 5,399,433 and U.S. Patent No. 5,499,442, and may also be referred to as identification (ID) tags.

[0021] The size of the tag is not limited as long as it can be attached to a tablet, capsule, etc. and does not affect the swallowing of the person who takes it. In addition, it can be set according to the size of the identifier to be attached to the tag. The size of the tag is preferably on the micrometer scale.

[0022] The tag may be in the form of a plate or film. Preferably, the tag is produced by applying a detection reagent to a plate or film base. The shape of the tag can be selected from a substantially rectangular shape, a substantially triangular shape, a substantially circular shape, a substantially oval shape, a substantially polygonal shape having five or more sides, and the like.

[0023] The length of the tag is, for example, 400 μm or less, more preferably 300 μm or less. The width of the tag is, for example, 100 μm or less, preferably 50 μm or less, more preferably 10 μm or less. Even if the width is 5 μm or less, an identifier can be attached. In the present invention, one of the objectives is to easily detect the tag, so if the width is less than 1 μm, it is not preferable because the identifier cannot be read without using a high-resolution microscope. Here, when the shape of the tag is approximately rectangular, if the approximately rectangular shape is assumed to be a rectangular shape, the length is the length of the long side, and the width is the length of the short side. When the shape of the tag is approximately triangular, if the approximately triangular shape is assumed to be a triangular shape, the length is the length of the base, and the width is the length of the line segment representing the height of the triangle perpendicular to the base. When the shape of the tag is approximately circular, if the approximately circular shape is assumed to be a circular shape, the length and width are the diameters. When the shape of the tag is approximately elliptical, if the approximately elliptical shape is assumed to be an elliptical shape, the length is the major axis, and the width is the minor axis. If the tag shape is an approximate polygon, the length is the length of the line segment that passes through the center of gravity of the approximate polygon and is sandwiched between the intersections with the sides of the approximate polygon. If the tag shape is an approximate polygon, the width is the length of the longest line segment among the line segments that intersect at right angles with the line segment indicating the length and are sandwiched between the intersections with the sides of the approximate polygon.

[0024] The substrate (base) of the tag is not limited as long as it can form a tag of the above shape. The tag base is preferably made of a material that is approved for use in orally ingested medicines and supplements.

[0025] More specifically, examples of the base material for the tag include cellulose compounds such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate phthalate; gelatin; pullulan; PVA; PVA copolymers, silicone, and mixtures thereof.

[0026] The tag preferably has an identifier. The identifier attached to the base is not limited as long as it is information that directly or indirectly gives a person an identification effect, such as characters, figures, colors (including fluorescence), trademarks, marks, one-dimensional barcodes, two-dimensional barcodes, rugate-type structures, etc. The direct identification effect means that a person can grasp the meaning of the identifier when observing it with a magnifying glass, or can confirm that a substance that emits fluorescence is contained by irradiating it with a specific wavelength, and can confirm the identifier visualized by fluorescence. For example, such identifiers can be exemplified as characters, trademarks, marks, etc. In addition, the indirect identification effect means that a person can grasp the information recorded as the identifier by reading the identifier with a reading device or the like and converting the identifier information on a computer. For example, such identifiers can be exemplified as one-dimensional barcodes, two-dimensional barcodes, rugate-type structures, etc. The identifier can include not only meaningful information, but also information that is meaningless in its arrangement itself, such as a mere list of characters, symbols, and figures.

[0027] The character used as the identifier may be one character or multiple characters. For example, examples of the character include the company name and business name of the manufacturer of pharmaceutical products, supplements, etc., or the pharmaceutical processing business, or their abbreviations; trademark; the name of the drug to which the tag is attached, the name of the active ingredient, or their abbreviations; the capacity of the drug or active ingredient, etc.

[0028] Examples of graphics include the symbol marks, trademarks, and product symbol marks of companies and establishments that manufacture pharmaceuticals, supplements, and other products, or pharmaceutical processing facilities.

[0029] A trademark may consist of only words or devices as described above, or may be a combination of words and devices. A trademark is intended to identify the origin of a product or to distinguish a product.

[0030] A mark may consist of only letters or only figures as described above, or may include a combination of letters and figures. A mark is not intended to indicate the origin of a product, but is intended to be, for example, a mark indicating a specification or technical standard.

[0031] Examples of one-dimensional barcodes include JAN (Japanese Article Number), NW-7 (CODABAR), Code 2 of 5 (Industrial 2 of 5), ITF (INTERLEAVED 2 of 5), Code39, Code93, Code128, and GS1 DataBar (RSS).

[0032] Examples of two-dimensional barcodes include QR Code (registered trademark), Micro QR Code, DataMatrix, MaxiCode, PDF417, and MicroPDF417. An example of an identifier having a rugate structure is given in US Pat. No. 5,399,633.

[0033] The method for attaching an identifier to a tag is not limited, and examples thereof include a positive or negative photoresist method, a microcontact printing method, and the method described in Patent Document 3.

[0034] For example, in the microcontact printing method, a stamp is first made of silicone rubber (PDMS) that is molded with a master of the identifier. A solution of a detection reagent containing a detection substance containing at least one selected from a magnetic substance such as iron powder, a reflective substance such as titanium dioxide, and a fluorescent substance, and a component of the base or a component similar thereto, is applied to both sides or one side of the base, and then dried. Then, a component capable of dissolving the base or a component similar thereto contained in the detection reagent is applied to the stamp, and the stamp is pressed against the base to which the detection reagent has been applied, thereby dissolving a portion of the detection reagent. For example, in the methods described in Patent Documents 1 and 2, ethyl cellulose is used as the base, and a stamp coated with ethanol is pressed against a base to which a detection reagent containing ethyl cellulose has been applied, thereby dissolving a portion of the dried detection reagent, and attaching the identifier. The detection reagent is preferably dissolved on both sides of the tag.

[0035] The specific gravity of the tag is preferably about the same as or slightly higher than that of the band seal preparation liquid. Preferably, the specific gravity of the tag is about 0.1 to 300% higher than that of the band seal preparation liquid. By adopting such a configuration, after dispersing the tag in the band seal preparation liquid, the dispersed state can be maintained for a predetermined time. Such a characteristic is advantageous because the band seal preparation liquid containing the tag can be left set in the sealing machine for a certain period of time. The predetermined period of time is about 1 to 8 hours, preferably about 3 to 6 hours. The specific gravity of the band seal preparation liquid can be measured, for example, by "6. Method for measuring density and specific gravity using a pycnometer" described in JIS Z 8804:2012. The specific gravity of the tag can be measured, for example, by referring to the specific gravity of the base.

[0036] The amount of tag added to the band seal preparation solution can be 0.01% (mass / mass) to 2.0% (mass / mass). By adding the tag to the band seal preparation solution, the amount of tag used can be reduced.

[0037] It is preferable that the detection substance emits reflected light or emits fluorescence when irradiated with light in a predetermined wavelength region. With such a configuration, the tag body can be detected, and the identifier attached to the tag can be read. Examples of light in the predetermined wavelength region include light in the visible light region and light in the ultraviolet light region. Examples of light in the visible light region include light in the range of about 380 nm to 750 nm. Light in the visible light region is preferably light in the blue region of 460 nm to 495 nm. The light in the predetermined wavelength region can be selected according to the detection substance and / or the color of the hard capsule or the color of the band seal.

[0038] Tags may use SECURtracers (Micro-Tracers, Inc., San Francisco, Calif., USA), TruTag™ microtags (TruTag Technologies, Inc., Kapolei, Hawaii, USA).

[0039] The "hard capsule" to which the band seal preparation solution containing the tag disclosed in this specification can be applied is a type of capsule in which the capsule shell is first produced and then the contents are filled into the produced capsule shell. Usually, it is composed of a cap part and a body part, and is also called a hard capsule or a two-piece capsule. The "hard capsule" of the present invention does not include a soft capsule produced by filling the contents between two films and gluing the films together, a seamless capsule produced by dropping the contents together with a film solution into a coagulating liquid, and a microcapsule prepared by incorporating an active ingredient inside the capsule by precipitating or emulsifying a base.

[0040] The shell that forms the hard capsule (also called the "hard capsule shell") may contain a base component and components other than the base.

[0041] The hard capsule shell may be gastric or enteric. The base component of the hard capsule shell is not limited. Examples of the base component of the hard capsule shell include gelatin, pullulan, cellulose compounds, PVA, PVA copolymers, and methacrylic acid copolymers. Examples of the cellulose compounds include ethyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate phthalate, methacrylic acid copolymers, and the like.

[0042] The hard capsule shell may contain, as components other than the base component, at least one selected from a gelling agent, a gelling aid, a plasticizer, a lubricant, a metal sequestering agent, a colorant, a light-blocking agent, and residual moisture, which are pharma- ceutical and food additive acceptable.

[0043] Examples of gelling agents include carrageenan, tamarind seed polysaccharide, pectin, xanthan gum, locust bean gum, curdlan, gelatin, furcellaran, agar, gellan gum, etc. These may be used alone or in any combination of two or more.

[0044] Among the above gelling agents, carrageenan is the most suitable gelling agent because it has high gel strength and shows excellent gelling properties even when used in small amounts in the presence of specific ions. Three types of carrageenan are generally known: kappa-carrageenan, iota-carrageenan, and lambda-carrageenan. In the present invention, kappa-carrageenan and iota-carrageenan, which have relatively high hardness and gelling ability, can be preferably used. Pectin can be classified into LM pectin and HM pectin depending on the degree of esterification, and gellan gum can be classified into acylated gellan gum (native gellan gum) and deacylated gellan gum depending on the presence or absence of acylation, but either can be used without distinction.

[0045] The gelling aid can be selected according to the type of gelling agent used. When carrageenan is used as a gelling agent, gelling aids that can be used in combination include compounds capable of providing one or more of potassium ions, ammonium ions, and calcium ions in water for kappa-carrageenan, such as potassium chloride, potassium phosphate, ammonium chloride, ammonium acetate, and calcium chloride. When iota-carrageenan is used, compounds capable of providing calcium ions in water, such as calcium chloride. When gellan gum is used as a gelling agent, gelling aids that can be used in combination include compounds capable of providing one or more of sodium ions, potassium ions, calcium ions, and magnesium ions in water, such as sodium chloride, potassium chloride, calcium chloride, and magnesium sulfate. In addition, citric acid or sodium citrate can be used as an organic acid or a water-soluble salt thereof.

[0046] When the base material for the hard capsule shell is hydroxypropylmethylcellulose, it is preferable to use a gelling agent and a gelling assistant.

[0047] The composition may contain a plasticizer, a surfactant (emulsifier), a base (excluding nonionic water-soluble cellulose compounds), a binder (excluding PVA), a coating agent, etc., which are acceptable as pharmaceutical and food additives. In addition, the composition may contain a sustained-release agent, a dissolution aid, a solubilizer, etc., for controlling solubility, particularly dissolution characteristics in the neutral pH range. As the additives acceptable as pharmaceutical additives, for example, those listed by the above-mentioned uses in the Pharmaceutical Additives Dictionary, 2016 Edition (edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha) can be used, but are not limited to these. Note that these additives may be classified into multiple uses.

[0048] The plasticizer is not necessarily limited to the specific substances shown in the above-mentioned Dictionary of Pharmaceutical Additives, and is not particularly limited as long as it can be used in pharmaceutical or food compositions and can be added to the capsule shell to impart flexibility. Suitable substances generally have a molecular weight (Mw) of 100 to 20,000 and have one or more hydrophilic groups, such as a hydroxyl group, an ester group, or an amino group, in one molecule. For example, dioctyl adipate, adipate polyester, epoxidized soybean oil, epoxy hexahydrophthalic acid diester, kaolin, triethyl citrate, glycerin, glycerin fatty acid ester, sesame oil, dimethylpolysiloxane-silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, corn starch derived sugar alcohol liquid, triacetin, concentrated glycerin, castor oil, phytosterol, diethyl phthalate, dioctyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol isopropyl myristate, cottonseed oil-soybean oil mixture, glycerin monostearate, isopropyl linoleate, polyethylene glycol of various molecular weights (macrogol 400, 600, 1500, 4000, 6000), etc. From the viewpoints of excellent compatibility and imparting high gloss, polyethylene glycol is particularly suitable. The weight average molecular weight of polyethylene glycol is not particularly limited, but is preferably 200 to 35,000 from the viewpoint of imparting high gloss.

[0049] Surfactants (also called emulsifiers) are used as solubilizers, suspending agents, emulsifiers, dispersants, solubilizers, stabilizers, etc. Specific examples include benzalkonium chloride, benzethonium chloride polyoxyethylene (40) monostearate (polyoxyl 40 stearate*), sorbitan sesquioleate (sorbitan sesquioleate*), polyoxyethylene (20) sorbitan monooleate (polysorbate 80*), glyceryl monostearate (glyceryl monostearate*), sodium lauryl sulfate, polyoxyethylene lauryl ether (lauromacrogol*), etc. (*: Notation in the Japanese Pharmacopoeia). Other examples include sodium alkylbenzene sulfonate, sucrose fatty acid ester, polyethylene glycol monooleate, polyethylene glycol dioleate, propylene glycol fatty acid ester (proolein glycol monostearate), polyoxyethylene hydrogenated castor oil, polyoxyethylene glycerin monostearate, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene noniphenyl ether.

[0050] The hard capsule shell may further contain up to about 5% by mass of a lubricant, a sequestering agent, a coloring agent, a light-shielding agent, a binder, etc. Examples of the sequestering agent include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, β-cyclodextrin, or combinations thereof.

[0051] The lubricant is not particularly limited as long as it can be used in pharmaceutical or food compositions, and examples thereof include calcium stearate, magnesium stearate, sodium stearyl fumarate, carnauba wax, starch, sucrose fatty acid ester, light anhydrous silicic acid, macrogol, talc, hydrogenated vegetable oil, etc.

[0052] Sequestering agents can include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, beta-cyclodextrin, or combinations thereof.

[0053] Colorants and light-shielding agents are not particularly limited as long as they can be used in pharmaceutical or food compositions. Examples of colorants include acacia tannin powder, turmeric extract, methylrosaniline chloride, yellow iron oxide, yellow ferric oxide, opaspray K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene liquid, β-carotene, photosensitizer No. 201, licorice extract, gold leaf, kumazasa extract, black iron oxide, light anhydrous silicic acid, ketket, zinc oxide, titanium oxide, ferric oxide, disazo yellow, food blue No. 1 and its aluminum lake, food blue No. 2 and its aluminum lake, food yellow No. 4 and its aluminum lake, Aluminum lake, Food Yellow No. 5 and its aluminum lake, Food Green No. 3 and its aluminum lake, Food Red No. 2 and its aluminum lake, Food Red No. 3 and its aluminum lake, Food Red No. 102 and its aluminum lake, Food Red No. 104 and its aluminum lake, Food Red No. 105 and its aluminum lake, Food Red No. 106 and its aluminum lake, Sodium hydroxide, Talc, Copper chlorophyll sodium, Copper chlorophyll, Naked barley green tea extract powder, Naked barley green tea extract, Fe Nol red, sodium fluorescein, d-borneol, malachite green, octyldodecyl myristate, methylene blue, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, manganese ammonium phosphate, sodium riboflavin phosphate, rose oil, turmeric color, chlorophyll, carminic acid color, food red no. 40 and its aluminum lake, water-soluble annatto, sodium iron chlorophyllin, dunaliella carotene, chili pepper color, carrot carotene, potassium norbixin, sodium norbixin, palm oil Carotene, beet red, grape skin pigment, black currant pigment, monascus pigment, safflower red pigment, safflower yellow pigment, marigold pigment, sodium riboflavin phosphate, madder pigment, alkanet pigment, aluminum, potato carotene, shrimp pigment, krill pigment, orange pigment, cacao pigment, cacao charcoal powder pigment, oyster pigment, crab pigment, carob pigment, fish scale foil, silver, clover pigment, gardenia blue pigment, gardenia red pigment, gardenia yellow pigment, kuro pigment, chlorophin, sorghum pigment, bone charcoal pigment, bamboo pigment, shea nut pigment,Lithospermum Root Dye, Rosewood Dye, Plant Charcoal Powder Dye, Suo Dye, Spirulina Dye, Onion Dye, Tamarind Dye, Corn Dye, Tomato Dye, Peanut Dye, Phaffia Dye, Pecan Nut Dye, Monascus Yellow Dye, Annatto Powder Dye, Haematococcus Algae Dye, Purple Sweet Potato Dye, Purple Corn Dye, Purple Yam Dye, Lampeolus Dye, Lac Dye, Rutin, Sophora Japonicus Extract, Buckwheat Whole Plant Extract, Logwood Dye, Red Cabbage Dye, Akagome Dye, Red Radish Dye, Azuki Bean Dye, Amacha Extract, Squid Ink Dye, Japanese Bush Warbler Dye, Elderberry Dye, Olive Tea, Cowberry Dye, Gooseberry Dye, Cranberry Dye, Salmonberry color, strawberry color, dark sweet cherry color, cherry color, tumbleberry color, dewberry color, pineapple juice, huckleberry color, grape juice color, blackcurrant color, blackberry color, plum color, blueberry color, berry juice, boysenberry color, whiterberry color, mulberry color, morello cherry color, raspberry color, redcurrant color, lemon juice, loganberry color, chlorella powder, cocoa, saffron color, perilla color, chicory color, seaweed color, hibiscus color, malt extract, paprika powder, red beet juice, carrot juice, etc. can be mentioned.

[0054] Examples of light-blocking agents include titanium oxide, calcium compounds, ferric oxide, yellow ferric oxide, black ferric oxide, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Green No. 3 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 102 Aluminum Lake, Food Red No. 104 Aluminum Lake, Food Red No. 105 Aluminum Lake, Food Red No. 106 Aluminum Lake, and Food Red No. 40 Aluminum Lake.

[0055] In order to prevent deterioration of the contents due to ultraviolet rays, etc., titanium oxide and / or calcium compounds may be added as light-shielding agents to the hard capsule shell. Examples of calcium-containing compounds include inorganic calcium salts such as calcium carbonate and calcium bicarbonate, calcium hydroxide, calcium complexes such as dolomite and hydroxyapatite, and other compounds containing calcium element.

[0056] Specific examples of hard capsules include gelatin capsules; gelatin capsules containing added polyethylene glycol (see, for example, Japanese Patent Application Laid-Open Nos. 11-049667, 2004-035569, and 11-060473); hydroxypropylmethylcellulose capsules (see, for example, Japanese Patent Application Laid-Open Nos. 2000-136126, 2000-202003, 2000-237284, and 2000-297102, International Publication No. 2005 / 113010, JP-T-2009-524573, and International Publication No. JP 2008 / 084823 A, JP 2010-202550 A, WO 2018 / 008660 A, WO 2018 / 105339 A, WO 2019 / 013260 A, etc.); capsules based on enteric cellulose compounds such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate (JP 2006-16372 A, etc.), pullulan capsules (JP 11-11665 A, etc.); alginate capsules (JP 2009-2200616372 A, etc.); enteric capsules comprising a film containing a water-soluble salt of ginic acid and at least one selected from the group consisting of gelatin, agar and curdlan (JP 2009-19696 A, etc.); capsules containing PVA and / or a PVA copolymer (JP 2001-170137 A, WO 2009 / 125483 A, WO 2009 / 125485 A, WO 2018 / 008660 A, etc.); (a) a component comprising a first component and a second component, or (b) a component comprising a first component and a second component, and further comprising a third component and a fourth component an enteric hard capsule comprising a coating containing at least one of the above, wherein the first component is methylcellulose and / or hydroxypropylmethylcellulose having a viscosity value of 6 mPa s or more, the second component is an enteric methacrylic acid copolymer, the third component is a water-insoluble (meth)acrylic acid alkyl ester copolymer and / or ethyl cellulose, and the fourth component is at least one selected from the group consisting of plasticizers and surfactants that are acceptable as medicaments and food additives.

[0057] 2. How to fill and seal hard capsules The filling of the contents into the hard capsule can be carried out using a capsule filling machine known per se, such as a fully automatic capsule filling machine (model name: F-Labo / 5 / 40 / 80 / 100 / 150 / JCF / FUNFIL, manufactured by Qualicaps Co., Ltd.), a capsule sealing machine (model name: S-15 / 125, manufactured by Qualicaps Co., Ltd.), etc. The body part and the cap part of the hard capsule thus obtained are joined by filling the contents into the body part, covering the body part with the cap part, and fitting the two together. If necessary, the filled capsule can then be made tamper-proof by using a suitable technique for sealing the seam. Typically, a sealing or banding technique can be used, where these techniques are well known to those skilled in the art of capsules. As a specific example, the fitting portion can be sealed by applying a polymer solution sealant to the surfaces of the body portion and the cap portion in a constant width centered on the edge portion of the cap portion in the circumferential direction of the body portion and the cap portion one to multiple times, preferably one to two times.

[0058] During capsule sealing, the band seal preparation liquid can generally be used at room temperature or under heating. From the viewpoint of preventing liquid leakage from hard capsules, it is preferable to carry out the sealing at a temperature in the range of about 23 to 60°C. The band seal preparation liquid containing gelatin is preferably heated to about 45 to 60°C. It is desirable to use a band seal preparation liquid containing a cellulose compound at a temperature range of 15 to 45°C, preferably about 23 to 35°C, more preferably about 25 to 35°C. The temperature of the seal preparation liquid can be adjusted by a method known per se, such as a panel heater or a hot water heater, but it is preferable to adjust the temperature with, for example, a circulating hot water heater or a seal pan unit of the integrated capsule filling and sealing machine modified to a circulating hot water heater type, because the temperature range can be finely adjusted. In this specification, a product in which a content is filled into a hard capsule and sealed with a band seal is called a hard capsule formulation. In addition, a method in which a content is filled into a hard capsule and sealed with a band seal is also a method for preparing a hard capsule formulation, which includes sealing a hard capsule with a band seal.

[0059] The contents filled into the hard capsules are not limited, and may include, for example, tonics, health supplements, antipyretics, analgesics, anti-inflammatory drugs, psychotropic drugs, antianxiety drugs, antidepressants, hypnotics, sedatives, antispasmodics, central nervous system drugs, brain metabolism improvers, brain circulation improvers, antiepileptic drugs, sympathetic stimulants, gastrointestinal drugs, antacids, antiulcer drugs, antitussives and expectorants, antiemetics, respiratory stimulants, bronchodilators, allergy drugs, dental and oral drugs, and antihistamines. One or more components selected from drugs, cardiac stimulants, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, antihyperlipidemic drugs, choleretic drugs, antibiotics, chemotherapy drugs, diabetes drugs, osteoporosis drugs, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormone drugs, alkaloid narcotics, sulfa drugs, gout drugs, blood coagulation inhibitors, and anticancer drugs are filled. These medicinal components are not particularly limited and can be widely known. These components can be used alone or in combination with other components. These components are filled in a known appropriate amount appropriately determined according to the patient's disease, age, etc.

[0060] Examples of tonic health supplements include vitamins such as vitamin A, vitamin D, vitamin E (d-α-tocopherol acetate, etc.), vitamin B1 (dibenzoylthiamine, fursultiamine hydrochloride, etc.), vitamin B2 (riboflavin butyrate, etc.), vitamin B6 (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), and vitamin B12 (hydroxocobalamin acetate, cyanocobalamin, etc.), minerals such as calcium, magnesium, and iron, proteins, amino acids, oligosaccharides, and herbal medicines.

[0061] Examples of antipyretic, analgesic, and anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine, serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome, and pentazocine.

[0062] Examples of health foods (including foods for specified health uses or nutritional supplements, such as fucoidan, heme iron, and polyphenols) include peptides and amino acids (for example, royal jelly, ornithine, citrulline, aminolevulinic acid, black vinegar, or hydrophobic amino acids such as methionine, valine, leucine, and isoleucine), proteins (milk proteins such as lactoferrin, collagen, placenta, and the like), glycoproteins, enzyme fermentation foods (such as nattokinase), coenzymes (such as coenzyme Q10), vitamins (such as β-carotene), minerals, live bacteria (yeast, lactic acid bacteria, bifidobacteria, and the like), plant extracts (herbal medicines, herbs, such as turmeric extract, ginseng extract, plum extract, ginkgo leaf extract, blueberry extract, sweet tea extract, and the like), natural organic substances such as propolis, or any combination thereof can be filled. However, the contents are not limited to these.

[0063] By applying the band seal, it is possible to prevent or detect opening before taking the capsule or replacement of the contents. Furthermore, by sealing the hard capsule with a band seal preparation solution containing a tag, the presence or absence of the tag or the identifier of the tag can be detected, which makes it possible to prevent counterfeiting of hard capsule formulations and to confirm the origin of the hard capsule formulation.

[0064] Therefore, the above-mentioned method for sealing a hard capsule can also be said to be a method for preventing counterfeiting of hard capsule formulations, which includes filling the hard capsule with the contents, fitting the cap portion and the body portion together, applying the band seal preparation liquid exemplified in 1. above to the formed fitting portion, and drying to seal the hard capsule.

[0065] 3. Tag detection The tag or the identifier attached to the tag can be detected by irradiating the hard capsule formulation with light in a predetermined wavelength range and using reflected light or fluorescence emitted from the tag as an indicator. The light source for irradiating the light is not limited as long as it can irradiate light in the predetermined wavelength range. For example, blue light or black light can be used as the light source.

[0066] Examples of light in a predetermined wavelength region include light in the visible light region and light in the ultraviolet light region. The explanation of the light in the predetermined wavelength region described in 1 above is incorporated herein by reference.

[0067] The reflected light or fluorescence from the tag can be confirmed by the naked eye, macro (close-up) observation, a magnifying glass, a stereo microscope, a fluorescent microscope, etc. When light in the visible light range is irradiated, the light is reflected by the detection substance applied to the tag, and reflected light is obtained. Furthermore, when the detection substance contains a fluorescent component, fluorescence is obtained when light in the ultraviolet range is irradiated. When detecting fluorescence, the fluorescence to be detected can be selectively observed by using a bandpass filter, etc.

[0068] When detecting only the presence or absence of a tag, it can be detected with the naked eye or macro (close-up) observation at a low magnification of about 2 to 10. When detecting an identifier, the identifier can be read by magnifying it at about 40 to 100 times. Furthermore, if the identifier is a one-dimensional barcode, a two-dimensional barcode, or a rugate-type structure, it can be enlarged and then read by a dedicated reader.

[0069] The methods described in Patent Document 1, Patent Document 2, and Non-Patent Document 2 require dissolving the drug once to separate the tracer particles from other components, which makes checking the tracer particles cumbersome. In addition, the drug to be taken must be wasted in order to check the tracer. However, in this embodiment, the tag can be detected without being separated from the hard capsule formulation, making detection easy. Therefore, the tag can be detected without reducing the amount of medicine that the patient should take.

[0070] Therefore, the tag detection method can also be said to be a method for tracking a hard capsule formulation, which includes a step of irradiating light in a predetermined wavelength range to a hard capsule formulation sealed with a band seal preparation solution containing a tag capable of identifying the product, and detecting the tag or identifier. EXAMPLES

[0071] The present invention will be described in more detail below by showing examples, but the present invention is not limited to these examples.

[0072] I. Example 1 1. Fluorescent pigments The fluorescent pigment used was Fluorescent Pigment Blue manufactured by Kurachi.

[0073] 2. Preparation of Bandseal Preparation Solution An aqueous solution containing 22 wt% gelatin and 2 wt% polysorbate 80 was prepared as a clear band seal preparation solution. Specifically, 228 g of water was added to 66 g of gelatin to swell the gelatin, and then the mixture was heated to 53°C to dissolve the gelatin. After the gelatin was completely dissolved, 6 g of polysorbate 80 was added and stirred with a spatula to prepare a clear band seal preparation solution. A 10 wt% aqueous solution of Blue No. 1 was added to this clear band seal preparation solution to make the concentration 1 wt%, to prepare a blue band seal solution. Each band seal preparation solution was maintained at 53 to 55°C during use.

[0074] 3. Capsule sealing A No. 2 gelatin capsule (product number: A7122L) manufactured by Qualicaps was prepared as a transparent capsule. The cap and body of the capsule were fitted together, and the band seal preparation liquid was applied across the fitting part. A small amount of fluorescent pigment was sprinkled on the band seal part, and then it was dried. A tabletop band sealer (LAB-TOP, manufactured by Schaefer Technologies) was used as the sealing machine, and the band seal preparation liquid placed in the sealing pan was heated to 53°C before sealing.

[0075] 4. Detection of Fluorescent Pigments 4.1.Fluorescence observation conditions Using a system microscope (Olympus BX53F), visible light in the blue region of 460 nm to 495 nm (B excitation) was irradiated and the fluorescence was observed. For B excitation, a 510IF was used as an absorption filter. Observation was performed at a magnification of 40 times.

[0076] 4.2. Low-magnification observation of fluorescent pigments in band seals A transparent capsule was band-sealed with a blue band-seal preparation solution containing a fluorescent pigment, and observed under a magnifying glass under B excitation. The results are shown in Figure 3. The left side of Figure 3 shows the appearance of the capsule under normal fluorescent lighting. The right side of Figure 3 shows the appearance of the capsule when B excitation was performed. The fluorescent pigment in the band seal was visible as pale blue fluorescence. This indicates that it is possible to detect fluorescent pigments in the band seal by irradiating it with light in the ultraviolet range.

[0077] 4.3. High-magnification observation of fluorescent pigments in band seals A transparent capsule was band-sealed with a blue band-seal preparation solution containing a fluorescent pigment, and the fluorescent pigment was observed using a fluorescence microscope under B excitation. The results are shown in Figure 4.

[0078] II. Example 2 The present invention will be described in more detail below by showing examples, but the present invention is not limited to these examples. 1. Fluorescent pigments The fluorescent pigment used was Fluorescent Pigment Blue manufactured by Kurachi.

[0079] 2. Preparation of Bandseal Preparation Solution An aqueous solution containing 16 wt% HPMC and 50.4 wt% absolute ethanol was prepared as a clear band seal preparation solution. Specifically, 151.2 g of absolute ethanol was added to 48.0 g of HPMC to disperse the HPMC, and then 100.8 g of ion-exchanged water was added to completely dissolve the HPMC to prepare a clear band seal preparation solution. A 10 wt% aqueous solution of Blue No. 1 was added to this clear band seal preparation solution to make the concentration 1 wt%, to prepare a blue band seal solution.

[0080] The fluorescent pigment from 1. above was added to the band seal preparation liquid so that the concentration was about 0.2 wt%, and the mixture was stirred with a spatula to prepare a band seal preparation liquid in which the fluorescent pigment was dispersed. Each band seal preparation liquid was kept at 20 to 30°C when used.

[0081] 3. Capsule sealing As the white capsules, No. 2 HPMC capsules (product number: C6149E) manufactured by Qualicaps were prepared. The white capsules contain titanium dioxide. The cap and body of the capsule were fitted together, and the band seal preparation liquid was applied across the fitting portion and then dried. A tabletop band sealer (LAB-TOP, manufactured by Schaefer Technologies) was used as the sealing machine, and the band seal preparation liquid placed in the sealing pan was heated to 25°C before sealing.

[0082] 4. Detection of Fluorescent Pigments 4.1.Fluorescence observation conditions Using a system microscope (Olympus BX53F), visible light in the blue region of 460 nm to 495 nm (B excitation) was irradiated and the fluorescence was observed. For B excitation, a 510IF was used as an absorption filter. Observation was performed at a magnification of 40 times.

[0083] 4.2. Low-magnification observation of fluorescent pigments in band seals The white capsule was band-sealed with a blue band-seal preparation solution containing a fluorescent pigment, and observed under a magnifying glass under B excitation. The results are shown in Figure 5. The left side of Figure 5 shows the appearance of the capsule under normal fluorescent lighting. The right side of Figure 5 shows the appearance of the capsule when B excitation was performed. In observation of all band seals and capsules, the fluorescent pigment in the band seal was visible as pale blue fluorescence.

[0084] 4.3. High-magnification observation of fluorescent pigments in band seals The white capsule was band-sealed with a blue band-seal preparation solution containing a fluorescent pigment, and the fluorescent pigment was observed using a fluorescence microscope under B excitation. The results are shown in Figure 6.

Claims

1. A hard capsule formulation sealed with a band seal preparation solution containing a tag capable of identifying the product, said tag having an identifier for identifying the product, said identifier being readable when the hard capsule formulation is irradiated with light in a specified wavelength range (however, said tag does not contain a magnetic substance).

2. 2. The hard capsule formulation of claim 1, wherein the tag is 400 μm or less in length.

3. The hard capsule formulation according to claim 1 , wherein the identifier is at least one selected from the group consisting of a character, a color, a graphic, a trademark, a mark, a one-dimensional barcode, a two-dimensional barcode, and a rugate structure.

4. The hard capsule shell contains a base and ingredients other than the base, the base is at least one selected from the group consisting of gelatin, a cellulose compound, polyvinyl alcohol, a polyvinyl alcohol copolymer, and pullulan; The component other than the base is at least one selected from a gelling agent, a gelling assistant, a plasticizer, a lubricant, a metal sequestering agent, a colorant, a light-shielding agent, and residual moisture.

4. The hard capsule formulation of claim 1.

5. A band seal preparation solution for sealing a hard capsule, the band seal preparation solution including a tag capable of identifying a product, the tag having an identifier for identifying the product, the identifier being readable when the hard capsule formulation is irradiated with light in a specified wavelength range (however, the tag does not contain a magnetic substance).

6. A method for preparing a hard capsule formulation, comprising filling a hard capsule with contents, fitting a cap portion and a body portion together, applying the band seal preparation liquid according to claim 5 to the formed fitting portion, and drying the applied liquid to seal the hard capsule, wherein the sealing is performed at a product processing facility other than the manufacturer, such as a dispensing pharmacy.

7. A method for preventing counterfeiting of hard capsule formulations, comprising filling a hard capsule with contents, fitting a cap portion and a body portion together, applying the band seal preparation liquid according to claim 5 to the formed fitting portion, and drying the same to seal the hard capsule, wherein the sealing is performed at a product processing facility other than the manufacturer, such as a dispensing pharmacy.

8. A method for tracking a hard capsule formulation, comprising the steps of irradiating the hard capsule formulation according to any one of claims 1 to 3 with light in a predetermined wavelength range and detecting the tag or identifier.

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