Coated active pharmaceutical ingredient particles

Abstract

To provide novel active pharmaceutical ingredient particles in which metal or the like is coated on an active pharmaceutical ingredient itself of a pharmaceutical solid preparation.SOLUTION: Provided are coated active pharmaceutical ingredient particles whose surface is coated by metal or metal oxide (e.g. iron oxide) for example by sputtering, and a method for preparing a drug by using the coated active pharmaceutical ingredient particles to produce a pharmaceutical solid preparation (e.g. tablet). According to the present invention, light stability of the active pharmaceutical ingredient itself or the pharmaceutical solid preparation produced by using the active pharmaceutical ingredient, for example, can be improved.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of Japanese Application No. 2020-30016, filed with the Japan Patent Office on February 26, 2020. The entire application documents (specification, claims, drawings, abstract) are incorporated herein by reference for all purposes as if set forth herein. The present invention relates to the technical field of drug substances. The present invention relates to drug substance particles, and in particular to coated drug substance particles. [Background technology]

[0002] Pharmaceutical solid preparations are usually prepared by blending raw materials such as active ingredients and excipients, and in the case of tablets, these are generally compressed into plain tablets. The manufactured tablets may then be coated to protect the drug from atmospheric moisture, oxygen, carbon dioxide, light, etc., to control drug release or regulate the onset of action, to mask the taste or odor to make it easier to take, to increase commercial value, or to improve distinctiveness. In the case of pharmaceuticals, the above-mentioned coating has traditionally been mainly carried out by film coating or sugar coating. Film coating involves spraying an aqueous solution or organic solvent solution containing a coating base polymer (coating agent) onto the surface of a solid dosage form, either continuously or discontinuously. The water in the droplets that adhere to and spread on the tablet surface evaporates, causing the coating agent particles to aggregate and form a film. Tablet coating in this way is carried out on manufactured uncoated tablets.

[0003] In addition to the above, a method known as atomic layer deposition (ALD) is known as a technique for coating pharmaceutical solid dosage forms (Patent Document 1). Atomic layer deposition is a method in which functional groups present on the surface of a pharmaceutical dosage form react with a coating material, resulting in the deposition of a monolayer film. Patent Document 1 uses atomic layer deposition to form a metal oxide layer on a pharmaceutical solid dosage form containing an active ingredient, with a thickness of about 0.1 to about 100 nm, which is on the order of nanometers, to coat the pharmaceutical solid dosage form.

[0004] Sputtering, also known as dry plating or vacuum plating, is a metal deposition technique. It involves introducing an inert gas (e.g., argon) into a vacuum and applying a negative voltage to a target (a plate-shaped deposition material) to generate a glow discharge, ionizing the inert gas atoms. The gas ions collide with the target's surface at high speed, striking it violently. This violently ejects particles (atoms and molecules) of the deposition material that make up the target, which then forcefully adhere and deposit them on the surface of the substrate, forming a thin film. Sputtering is used for anti-reflective and surface protection applications in television and smartphone displays, transparent electrodes for solar cells and liquid crystal devices, abrasion resistance, and the prevention of water vapor and oxygen permeation. Compared to atomic layer deposition (ALD), sputtering has the advantage of stronger film adhesion and greater film stress. Furthermore, sputtering technology has the advantage of being less susceptible to deterioration of the film material and less susceptible to heat being applied to the target object.

[0005] Sputtering technology has also been applied in the fields of medicine and food. For example, Patent Document 2 discloses that a metal film made of an edible metal such as gold, silver, or platinum is formed on the surface of granular or tablet-shaped objects to provide medicines and the like with excellent decorative properties. However, the invention of Patent Document 2 is not implemented from the perspective of shielding pharmaceutical solid preparations from light or imparting functionality. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2014-510066 [Patent Document 2] Japanese Patent Application Laid-Open No. 2004-43316 Summary of the Invention [Problem to be solved by the invention]

[0007] For example, coating of tablets to ensure light stability is generally applied to uncoated tablets manufactured by tableting. There are no cases where the active pharmaceutical ingredient is coated. A main object of the present invention is to provide novel drug substance particles in which the drug substance of a pharmaceutical solid preparation itself is coated with a metal or the like. [Means for solving the problem]

[0008] As a result of extensive research, the present inventors discovered that a light-blocking agent can be coated on a drug substance by using a sputtering technique, and thus completed the present invention.

[0009] The present invention can include, for example, the following.

[0010] [1] Coated drug substance particles, characterized in that the surface is coated with a metal or metal oxide. [2] The coated drug substance particles according to the above [1], wherein the coating content of the metal or metal oxide is within the range of 0.05 to 10% by mass. [3] Average particle diameter D 50 The coated drug substance particles according to the above [1] or [2], wherein the particle size is in the range of 1 to 1000 μm. [4] The coated drug substance particles according to any one of the above [1] to [3], wherein the metal oxide is iron oxide. [5] The coated drug substance particles according to any one of the above [1] to [4], wherein the coating is performed by sputtering.

[0011] [6] A method for producing coated drug substance particles, comprising a step of coating the surfaces of drug substance particles with a metal or metal oxide. [7] Average particle size of coated drug substance particles D50 The method for producing coated drug substance particles according to [6] above, wherein the particle size is in the range of 1 to 1000 μm. [8] The method for producing coated drug substance particles according to [6] or [7] above, wherein the metal oxide is iron oxide. [9] The method for producing coated drug substance particles according to any one of [6] to [8] above, wherein the coating is carried out by sputtering.

[10] A method for producing a pharmaceutical solid formulation, comprising the steps of: coating the surfaces of drug substance particles with a metal or metal oxide; and formulating the coated drug substance particles obtained in the previous step.

[11] Average particle size of coated drug substance particles D 50

[11] The method for producing a pharmaceutical solid preparation according to the above

[10] , wherein the particle size is in the range of 1 to 1000 μm.

[12] The method for producing a pharmaceutical solid formulation according to the above

[10] or

[11] , wherein the metal oxide is iron oxide.

[13] The method for producing a pharmaceutical solid preparation according to any one of the above

[10] to

[12] , wherein the solid preparation is a tablet.

[14] The method for producing a pharmaceutical solid preparation according to any one of the above

[10] to

[13] , wherein the coating is carried out by sputtering.

[0012]

[15] A pharmaceutical solid preparation comprising the coated drug substance particles according to any one of [1] to [5] above.

[16] The pharmaceutical solid formulation according to

[15] above, wherein the solid formulation is a tablet.

[17] A method for photostabilizing a drug substance or a pharmaceutical solid formulation, comprising the step of coating drug substance particles with a metal or metal oxide.

[18] Average particle size of coated drug substance particles D 50 The photostabilization method according to

[17] above, wherein the particle size is in the range of 1 to 1000 μm.

[19] The photostabilization method according to

[17] or

[18] above, wherein the metal oxide is iron oxide.

[20] The photostabilization method according to any one of

[17] to

[19] above, wherein the solid formulation is a tablet.

[21] The method for photostabilization according to any one of the above

[17] to

[20] , wherein the coating is performed by sputtering. [Effects of the Invention]

[0013] According to the present invention, for example, it is possible to improve the photostability of a drug substance itself or of a pharmaceutical solid preparation produced using the drug substance. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows photographs of the appearance of drug substance granules, from left to right: Comparative Example 1, Comparative Example 2, Example 1, Example 2, and Example 3. [Figure 2] The graph shows the results of photostability. The vertical axis indicates the increase in the amount of decomposition product I (%), and the horizontal axis indicates the amount of light irradiation (10,000 lux·hours). Crosses (×) indicate the results of Comparative Example 1, black triangles the results of Comparative Example 2, black squares the results of Example 1, black diamonds the results of Example 2, and black circles the results of Example 3. [Figure 3] The graph shows the results of photostability. The vertical axis indicates the increase (%) in degradant I. For each drug content, the left column shows the results without iron oxide added, the middle column shows the results with the physical mixture, and the right column shows the results with sputtering. DETAILED DESCRIPTION OF THE INVENTION

[0015] 1. Drug substance particles according to the present invention The drug substance particles according to the present invention (hereinafter referred to as "drug substance of the present invention") are characterized by being coated with a metal or metal oxide.

[0016] The drug substance (drug substance particles) according to the present invention is not particularly limited as long as it is a pharmaceutical active ingredient having pharmacological activity, but a photolabile pharmaceutical active ingredient is preferred. Examples of such active ingredients include calcium antagonists such as nifedipine, amlodipine, nicardipine, and azelnidipine, vitamins, and HMG-CoA reductase inhibitors such as atorvastatin, pitavastatin, and rosuvastatin. When these active ingredients can take the form of a salt, hydrate, solvate, or the like, these are also included.

[0017] The drug substance particles before coating may be in the form of fine granules or granulated granules. Such granules may be granulated products consisting of 100% active ingredients, or granulated products consisting of active ingredients and other raw materials. The drug substance of the present invention is also usually in the form of fine granules or granules (granulated products). Average particle size D of the drug substance of the present invention 50 Although there are no particular limitations on the thickness, it is suitable to be in the range of 1 to 1000 μm, preferably in the range of 2 to 600 μm, and more preferably in the range of 5 to 500 μm. Here, the average particle diameter D 50 " is the volume average particle diameter, and is the particle diameter (D) at which the cumulative distribution from the smallest particle is 50% when measured by laser diffraction. 50 , median diameter).

[0018] The metal or metal oxide used in the present invention is not particularly limited as long as it is pharmaceutically acceptable and can be coated, for example, by sputtering. Metal oxides are suitable. Specific examples of metals include gold, silver, and platinum, and examples of metal oxides include iron oxides such as ferric oxide, yellow ferric oxide, yellow ferric oxide, and black ferric oxide, silicon dioxide, and titanium oxide. Of these, yellow ferric oxide, ferric oxide, and titanium oxide are preferred. The metal or metal oxide can be referred to as a coating agent.

[0019] The coating content of the metal or metal oxide is not particularly limited, but can be, for example, within the range of 0.05 to 10% by mass on the surface of the drug substance particle. A content within the range of 0.08 to 6% by mass is preferred, and a content within the range of 0.1 to 4% by mass is more preferred. If it is less than 0.05% by mass, the intended effect (photostability, etc.) may not be fully achieved, while if it is more than 10% by mass, coating may take a long time or the particles may become larger than necessary.

[0020] The drug substance of the present invention can be used as a raw material for, for example, tablets, granules, powders, pellets, capsules, chewable tablets, troches, and films. Among these, it is preferable to use it as a raw material for tablets. The tablets may be not only regular tablets, but also multi-layer tablets such as two-layer tablets and three-layer tablets, enteric-coated tablets, sustained-release tablets, or orally disintegrating tablets, so-called OD tablets or OD films. The present invention includes the above-mentioned pharmaceutical solid preparations (particularly tablets) containing the drug substance of the present invention.

[0021] Coating of drug substance particles for producing the drug substance of the present invention is usually carried out by sputtering. Sputtering itself is a well-known technology, classified as a dry plating method, and is a film formation technique similar to vacuum evaporation. It involves applying a high voltage between the substrate on which the film is to be formed and the target of the film material while introducing an inert gas (mainly argon gas) into a vacuum, causing the ionized inert gas to collide with the target, and the target material that is ejected collides with and adheres to the substrate, forming a film.

[0022] Various sputtering methods are known, including DC sputtering, in which a direct current voltage is applied between two electrodes, RF sputtering, in which a radio frequency voltage is applied, magnetron sputtering, ion beam sputtering, mirrortron sputtering, ECR sputtering, and PEMS sputtering. These methods are not particularly limited in the present invention, and can be used according to the purpose, etc., while taking into consideration their respective characteristics and drawbacks. Among these, it is preferable in the present invention to coat the drug substance particles using the magnetron sputtering method.

[0023] A specific example of magnetron sputtering involves applying a strong magnetic field in a vacuum containing a light-blocking agent, introducing argon into the vacuum, ionizing the argon atoms (Ar+) using the magnetic field, and causing the ionized argon to collide with the light-blocking agent, causing atoms and molecules on the surface of the light-blocking agent to fly out, which then reach the surface of the active pharmaceutical ingredient particles to be coated, forming a film. Sputtering devices are commercially available, and sputtering can be performed using such devices.

[0024] 2. Manufacturing method of coated drug substance particles The method for producing coated drug substance particles according to the present invention (hereinafter referred to as the "production method of the present invention (drug substance)") is characterized by including a step of coating the surface of drug substance particles with a metal or metal oxide. The coating is usually performed by sputtering. Average particle diameter D of drug substance (drug substance particles), metal, metal oxide, coated drug substance particles (drug substance of the present invention) 50 The metal or metal oxide coating content and the like are the same as those described above.

[0025] In the production method (drug substance) of the present invention, in addition to the coating step, for example, a step of granulating the drug substance, a sizing step, and a drying step can be included. The step of granulating the drug substance can be carried out by a conventional method, for example, by adding water to the drug substance and carrying out extrusion granulation. The granulation step allows the drug substance particles to be formed into granules, and the particle size can be adjusted.

[0026] 3. Other 3.1 Manufacturing method of pharmaceutical solid dosage forms The method for producing a pharmaceutical solid preparation according to the present invention (hereinafter referred to as the "production method (preparation) of the present invention") is characterized by comprising a step of coating the surfaces of drug substance particles with a metal or metal oxide, and a step of formulating the coated drug substance particles obtained in the previous step. The step of coating the surface of drug substance particles with a metal or metal oxide has the same meaning as above, and the coating is usually carried out by the sputtering method. In addition, the average particle diameter D of the drug substance (drug substance particles), metal, metal oxide, or coated drug substance particles (drug substance of the present invention) 50 The metal or metal oxide coating content, pharmaceutical solid preparation, etc. are the same as those defined above.

[0027] The step of formulating the coated drug substance particles obtained in the previous step into a formulation can be carried out by a method known per se, depending on the desired formulation (e.g., tablets, granules, powders, pellets, capsules, chewable tablets, troches, films). For example, in the case of formulating tablets, coated drug substance particles, excipients, disintegrants, etc. are added to prepare a powder mixture, to which a dispersion in which a colorant, etc. is dispersed is added, followed by granulation (e.g., wet granulation) to form granules or slugs, which are then dried and sized, and subsequently excipients, disintegrants, lubricants, etc. are added, followed by tableting (compression). Granulation may also be dry granulation.

[0028] In the production method (formulation) of the present invention, raw materials (additives) that can be used other than the coated drug substance particles (drug substance of the present invention) vary depending on the target formulation, etc., but examples include the following excipients, binders, stabilizers, disintegrants, lubricants, colorants, etc.

[0029] Examples of excipients that can be used in the present invention include lactose, starch (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, D-mannitol, dextrin, sorbitol, anhydrous calcium phosphate, sucrose, talc (hydrated magnesium silicate), kaolin, precipitated calcium carbonate, sodium chloride, titanium oxide, and light anhydrous silicic acid.

[0030] Examples of binders that can be used in the present invention include hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), microcrystalline cellulose, dextrin, tragacanth, gelatin, pregelatinized starch, gum arabic, acacia, alginic acid, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylates, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose.

[0031] Examples of stabilizers that can be used in the present invention include butylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), lecithin, α-tocopherol, hydroquinone, octyl gallate, dodecyl gallate, isoamyl gallate, nordihydroguaiaretic acid, guaiac butter, α-naphthylamine, ascorbyl palmitate, cysteine ​​hydrochloride, sodium ascorbyl stearate, thioglycerol, and thiosorbitol.

[0032] Examples of disintegrants that can be used in the present invention include croscarmellose sodium, crospovidone, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, partially hydrolyzed starch, and powdered agar.

[0033] Examples of lubricants that can be used in the present invention include magnesium stearate, calcium stearate, talc, mineral oil, stearic acid, fumaric acid, polyethylene glycol, calcium, boric acid, paraffin, and cocoa butter.

[0034] Examples of colorants that can be used in the present invention include tar dyes, iron sesquioxide, iron oxide red, iron oxide yellow, titanium dioxide, inorganic pigments, Red No. 3, Red No. 20, Yellow No. 6, Blue No. 2, Green No. 5, Orange No. 5, Red No. 8, and caramel that can be used in pharmaceuticals and the like as specified by the Ministry of Health, Labor and Welfare Ordinance.

[0035] The above-mentioned additives may be used alone or in combination of two or more kinds, and each may be used in an appropriate amount as needed.

[0036] 3.2 Photostabilization method The method for photostabilizing a drug substance or a pharmaceutical solid preparation according to the present invention (hereinafter referred to as the "photostabilization method of the present invention") is characterized by comprising an operation of coating drug substance particles with a metal or metal oxide. The coating operation is usually carried out by sputtering. Average particle diameter D of drug substance (drug substance particles), metal, metal oxide, coated drug substance particles (drug substance of the present invention) 50 The metal or metal oxide coating content, pharmaceutical solid preparation, etc. are the same as those defined above. The photostability of drug substance particles and pharmaceutical solid preparations can be improved by the photostability method of the present invention. [Example]

[0037] The present invention will be explained below with reference to examples, comparative examples, test examples, etc., but the present invention is not limited to these examples, etc.

[0038] [Examples 1 to 3] Production of the drug substance of the present invention Water was added to amlodipine besylate (drug substance), and the mixture was extruded and granulated. The granules were then sized using a malmerizer and dried using a fluidized bed granulator. The resulting powder was sized using 500 μm and 250 μm meshes to form amlodipine besylate drug substance granules (mean particle size D 50 A magnetron sputtering device (power: 400 W, vacuum level: 9.0 × 10 -1Using a coating of about 100 Pa (approximately 100 Pa), raw drug granules of amlodipine besylate were coated with ferric oxide to obtain the raw drug substance of the present invention (Examples 1 to 3). Separately, raw drug granules without ferric oxide (Comparative Example 1) and a physical mixture of raw drug granules and ferric oxide (Comparative Example 2) were prepared. The formulation of each granule is shown in Table 1. The appearance of each granule is shown in Figure 1.

[0039] [Table 1]

[0040] [Examples 4 to 7] Preparation of tablets using the drug substance of the present invention In the same manner as above, drug substance granules without ferric oxide, a physical mixture of drug substance granules and ferric oxide, and the drug substance of the present invention were prepared, and excipients were added to each drug substance granule, which was then compressed at 5 kN using a single-punch tableting machine to produce tablets. The formulation of each tablet is shown in Tables 2 and 3.

[0041] [Table 2]

[0042] [Table 3]

[0043] [Test Example 1] Photostability of the drug substance of the present invention The drug substance granules of Examples 1 to 3 and Comparative Examples 1 and 2 were placed in a photostability tester and subjected to photostability testing under conditions of 25°C and 70% RH, with irradiation from a xenon lamp for 0.3 to 1.2 million lx (lux)·hr. The results are shown in Table 5 and Figure 2 (n=3). The amount of decomposition product I having the following structural formula was measured by high performance liquid chromatography (HPLC) under the following measurement conditions: The increase in the amount of decomposition product I refers to the value obtained by subtracting the initial amount of decomposition product I before the start of light irradiation from the amount of decomposition product I after light irradiation.

[0044] [ka]

[0045] [HPLC measurement conditions] Detector: Waters 2487, ultraviolet absorption spectrophotometer (measurement wavelength: 237 nm) Column: Cadenza CD C18, a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm packed with 3 μm octylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 35°C Sample temperature: constant temperature around 4°C Mobile phase: Potassium dihydrogen phosphate aqueous solution / acetonitrile mixture

[0046] [Table 4]

[0047] Flow rate: 1.0 mL per minute Analysis time: 30 minutes

[0048] [Table 5]

[0049] As is clear from Table 5 and Figure 2, the photostability of amlodipine in the drug substance of the present invention was significantly improved in proportion to the length of the sputtering time.

[0050] [Test Example 2] Photostability of tablets containing the drug substance of the present invention The tablets of Examples 4 to 7 and Comparative Examples 3 to 10 were evaluated for light stability in the same manner as in Test Example 1 (however, the light irradiation dose was only 1.2 million lx·hr). As a result, as shown in Figure 3, the photostability of the tablets produced using the drug substance of the present invention was equal to or greater than that of the physical mixture.

[0051] [Example 8] Production of the drug substance of the present invention Using a magnetron sputtering device, amlodipine besylate drug substance with a particle size of approximately 5 μm was coated with 3.64% by mass of ferric oxide to obtain the drug substance of the present invention (Example 8). Separately, a physical mixture of the drug substance and ferric oxide (Comparative Example 11) was prepared. A photostability test was performed on the drug substance of the present invention in Example 8 and the physical mixture of Comparative Example 11, irradiating them with a xenon lamp at 600,000 lx (lux) hr under conditions of 25°C and 70% RH. As a result, the increase in the amount of decomposition product I was 2.09% for the drug substance of the present invention in Example 8 and 2.68% for the physical mixture of Comparative Example 11. Thus, the increase in the amount of decomposition product was suppressed more for the drug substance of the present invention. [Industrial Applicability]

[0052] INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a drug substance having excellent photostability, which can be used as a raw material for pharmaceuticals, and therefore the present invention is useful in pharmaceutical solid preparations and in the production thereof.

Claims

[Claim 1] Coated drug substance particles, characterized in that they have a sputtered film made of a metal oxide as a pharmaceutically acceptable coating agent on their surfaces, and the coating content of the metal oxide is within the range of 0.08 to 6 mass%.

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