WO2010087462A1 - 内核を有する口腔内崩壊錠 - Google Patents
内核を有する口腔内崩壊錠 Download PDFInfo
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- WO2010087462A1 WO2010087462A1 PCT/JP2010/051294 JP2010051294W WO2010087462A1 WO 2010087462 A1 WO2010087462 A1 WO 2010087462A1 JP 2010051294 W JP2010051294 W JP 2010051294W WO 2010087462 A1 WO2010087462 A1 WO 2010087462A1
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- Prior art keywords
- light
- outer layer
- food
- yellow
- inner core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
Definitions
- the present invention relates to an orally disintegrating tablet having improved light stability of a light-labile drug.
- Patent Document 1 discloses a soft capsule of nifedipine that prevents degradation and alteration by light, in which nifedipine, which is a drug unstable to light, is sealed in a soft capsule in which a colorant is dispersed in a film.
- nifedipine which is a drug unstable to light
- a colorant is dispersed in a film.
- Patent Document 2 discloses a tablet stabilized with respect to light obtained by coating a film containing iron oxide on a tablet of a dihydropyridine derivative.
- the present technology only discloses the effect when iron oxide is used in combination with titanium oxide, which is a light shielding material. Titanium oxide has a photocatalytic action, and some drugs may promote decomposition by light. Furthermore, with this technique, the number of steps increases due to the coating, which takes a lot of time and effort and increases the cost. Furthermore, when a coating is applied to the whole preparation, the rapid disintegration property and fast dissolution property in the oral cavity are impaired, and the function as an orally disintegrating tablet cannot be expressed.
- Patent Document 3 discloses one or more substances selected from light-labile fat-soluble drugs and yellow and red colorants. A composition having improved light stability is disclosed. However, even if these light stabilization methods are used, the light stabilization effect is not sufficient.
- Patent Document 4 discloses a fast-disintegrating molded product.
- this document does not disclose anything about light stabilization.
- Patent Document 5 has a description that it can be light-stabilized by further coating a dry coated tablet with titanium oxide or the like, but this also means that film coating is performed eventually, and functions as an orally disintegrating tablet. It is thought that it does not have.
- the present situation is that an orally disintegrating tablet in which the photostability of a photolabile drug is sufficiently improved has not yet been achieved.
- the problem to be solved by the present invention is to provide an orally disintegrating tablet with improved light stability of a light-labile drug.
- the present inventors have paid attention to the dry-coated tablet technology in order to solve the above-mentioned problems. That is, it was considered to improve the photostability of a photolabile drug by containing a photolabile drug only in the inner core and coating it with an outer layer.
- the present inventors have surprisingly found that when the inner core contains a light-labile drug and the outer layer contains a light-absorbing substance, the light-labile drug has excellent light stability. And found that the decomposition can be almost completely suppressed. Regardless of the concentration of the light-absorbing substance contained in the outer layer and the thickness of the outer layer, by adding a certain amount or more of the light-absorbing substance into the outer layer, it is possible to produce light without using titanium oxide, which is a light shielding substance, in combination. It was found that the degradation of unstable drugs by light can be almost completely suppressed, and that this preparation has the function of an orally disintegrating tablet, and the present invention has been completed.
- the present invention relates to the following.
- An orally disintegrating tablet having an inner core and an outer layer covering the surface thereof, wherein the inner core contains a light unstable drug and the outer layer contains a light absorbing substance.
- the light-absorbing substances are food red 2, food red 3, food red 102, food red 104, food red 105, food red 106, food yellow 4, food yellow 5, food green No. 3, Edible Blue No. 1, Edible Blue No. 2, Edible Red No. 3 Aluminum Lake, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5 Aluminum Lake, Edible Blue No. 1 Aluminum Lake, Edible Blue No.
- the light-absorbing substances are food red 2, food red 3, food red 102, food red 104, food red 105, food red 106, food yellow 4, food yellow 5, food green No. 3, Edible Red No. 3 Aluminum Lake, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No.
- the light-absorbing substances are food red 2, food red 3, food yellow 4, food yellow 5, food blue 1, food red 3, aluminum lake, food yellow 4, aluminum lake, food yellow 5 No. 1 aluminum lake, Edible blue No. 1 aluminum lake, Edible blue No. 2 aluminum lake, iron sesquioxide, yellow iron sesquioxide, black iron oxide, carmine, and copper chlorophyllin sodium, [1 Orally disintegrating tablets.
- the outer layer contains a light-absorbing substance in an amount of 0.01 to 600 ⁇ g / mm 2 per unit surface area of the inner core.
- the outer layer contains a light absorbing substance in an amount of 0.1 to 150 ⁇ g / mm 2 per unit surface area of the inner core.
- a method for producing an orally disintegrating tablet having an inner core containing a light-unstable drug and an outer layer covering the surface of the inner core, and molding the core granule containing a light-unstable drug to form the core A step of manufacturing, a step of supplying the core into a die of a dry-coated tableting machine filled with a powder for outer layer containing a light-absorbing substance, and a step of further supplying and compressing the powder for outer layer The manufacturing method containing.
- the outer layer supplying step 1 for supplying the outer layer granular material containing the light-absorbing substance to the space above the lower central wall, and the light on the outer layer granular material supplied in the previous step surrounded by the lower outer rod is not exposed to light.
- Inner core supply and filling step for supplying and filling inner core powder containing a stable drug
- outer layer inner particle forming step for compressing and molding outer layer powder and inner core powder supplied and filled up to the previous step, and die
- the outer layer powder is supplied to the outer layer core molded product molded in the previous process and the space around it.
- Outer layer supply step 2 the manufacturing method comprising the whole molding step of compression molding the outer layer in the core molding and the outer layer for granular material that.
- Inner core supply and filling process for supplying and filling inner core powder containing light-unstable drug in the space above the lower central collar, inner core molding process for compressing and molding the inner core powder and powder supplied in the previous process,
- the outer layer powder is supplied to the molded product in the die formed in the previous process and the space around it until the tip of the lower center punch finally protrudes from the tip of the lower outer punch.
- Outer layer supply and filling step of filling, the inner core molded product with the tip of the lower center punch and the tip of the lower outer punch aligned Manufacturing method comprising the whole molding step of compression molding the layers for granular material.
- a method for improving the photostability of an orally disintegrating tablet containing a photolabile drug wherein the orally disintegrating tablet is composed of an inner core and an outer layer covering the surface of the orally disintegrating tablet.
- a method of containing a drug and containing a light-absorbing substance in the outer layer A method for improving the light stability of an orally disintegrating tablet having an inner core containing a photolabile drug and an outer layer covering the surface, the method comprising incorporating a light-absorbing substance in the outer layer Feature method.
- a method for stabilizing a photolabile drug comprising coating a tablet containing a photolabile drug with an outer layer containing a light-absorbing substance.
- an orally disintegrating tablet with improved light stability of a photolabile drug very easily it is possible to maintain the quality of easy-to-use preparations such as orally disintegrating tablets of drugs that cannot be coated by light stabilization, and patients who have difficulty in swallowing such as elderly people and people who have a busy social life
- a light-stable orally disintegrating tablet that can be easily taken in any situation.
- the orally disintegrating tablet of the present invention is an orally disintegrating tablet having an inner core and an outer layer covering the surface thereof, wherein the inner core contains a light-unstable drug, and the outer layer contains a light-absorbing substance. It can be taken by dissolving or disintegrating rapidly in the oral cavity without water and can be taken with water in the same manner as a normal preparation.
- the dissolution or disintegration time in the oral cavity of the orally disintegrating tablet in the present invention is usually within 1 minute, preferably within 45 seconds, more preferably within 30 seconds.
- the hardness of the orally disintegrating tablet is preferably the absolute hardness 0.5 N / mm 2 or more, more preferably 1.0 N / mm 2 or more. “Absolute hardness” is the absolute hardness per unit area of a tablet, and is a value obtained by “hardness / cross-sectional area when tablet is made into half tablet”.
- the values are calculated as follows based on the cracking hardness measured by a tablet hardness meter and the tablet cross-sectional area (diameter ⁇ thickness).
- the “photolabile drug” means, for example, an uncoated tablet having a drug content of 5% by weight without adding a light stabilizing substance such as a light absorbing substance or a light shielding substance to the drug ( (However, it does not include the dry-coated tablets as in the present invention).
- photolabile drugs examples include nifedipine, nisoldipine, nitrendipine, benidipine, manidipine, balnidipine, efonidipine, nilvadipine and other dihydripyridine skeleton drugs, norfloxacin, ofloxacin, lomefloxacin, sparfloxacin and other new quinolone series Vitamins such as drugs, vitamins A, B2, B6, B12, D, K, and the like can be mentioned, but not limited thereto.
- the “light-absorbing substance” means a substance having a coloring action other than white by absorbing a wavelength involved in the photodecomposition of a drug, and specifically, a white pigment that can be used as a pharmaceutical additive. Colorants, pigments, etc. are excluded.
- the “light-shielding substance” is a substance that does not transmit light even when irradiated with light, for example, when the tablet itself is tableted to form a tablet having a thickness of 0.5 mm. It means a substance that looks almost white, and specifically includes titanium oxide, talc, kaolin, and the like.
- the particle size of the light-absorbing substance is not particularly limited as long as it is a size that can be uniformly dispersed and blended in the oral solid composition in terms of quality as a pharmaceutical product.
- the volume average particle diameter is 0.01 to 1.0 ⁇ m, more preferably 0.01 to 0.5 ⁇ m, still more preferably 0.1 to 0.5 ⁇ m, when measured using a laser diffraction / scattering particle size distribution analyzer. Is mentioned.
- the orally disintegrating tablet of the present invention is characterized in that the inner core contains a light-unstable drug and the outer layer contains the light-absorbing substance.
- the appropriate content of the light-absorbing substance in the outer layer varies depending on the light-absorbing substance to be blended, the surface area of the inner core, and the thickness of the outer layer.
- the diameter of the inner core of the tablet is about 6 mm
- the thickness is about 1 mm
- the diameter of the outer layer of the tablet is When the thickness is about 8 mm and the thickness of the outer layer is about 1 mm, a preferable content is 0.001 to 40 mg.
- a more preferable content is 0.005 to 15 mg, a further more preferable content is 0.01 to 10 mg, a further more preferable content is 0.02 to 4 mg, and a further more preferable content is May be 0.02 to 2 mg, more preferably 0.03 to 1 mg, and particularly preferably 0.1 to 0.7 mg.
- a preferable content of the light absorbing substance in the outer layer is 0.01 to 600 ⁇ g / mm 2 when converted per unit surface area of the inner core. More preferable content is 0.06 to 200 ⁇ g / mm 2 , further preferable content is 0.1 to 150 ⁇ g / mm 2 , and further preferable content is 0.2 to 60 ⁇ g / mm 2. More preferable content is 0.2 to 20 ⁇ g / mm 2 , more preferable content is 0.5 to 15 ⁇ g / mm 2 , and particularly preferable content is 1.5 to An example is 10 ⁇ g / mm 2 .
- the content of the light absorbing material in the outer layer per unit surface area of the inner core is a value obtained by dividing the total amount of the light absorbing material contained in the outer layer by the surface area of the inner core.
- the concentration of the light-labile drug contained in the inner core of the orally disintegrating tablet in the inner core is not particularly limited, but may be 0.001 to 100% by weight.
- the inner core of the orally disintegrating tablet in the present invention is 10 mg to 400 mg by weight, more preferably 20 mg to 300 mg, and still more preferably 50 mg to 150 mg.
- the outer layer of the orally disintegrating tablet has a weight of 50 mg to 800 mg, more preferably 70 mg to 600 mg, and still more preferably 100 mg to 300 mg.
- the weight ratio of the inner core to the outer layer is usually 0.05 to 2, preferably 0.2 to 1, and more preferably 0.3 to 0.5.
- the thickness of the outer layer is 0.3 mm to 2 mm, more preferably 0.5 mm to 1.5 mm.
- the components other than the light-labile drug in the inner core and the components other than the light-absorbing substance in the outer layer include components usually known in orally disintegrating tablets, for example, excipients, disintegrants, binders , Sweeteners, fragrances, flavoring agents and / or flavoring agents, lubricants and the like. Both may be the same component or may be different.
- the inner core may be weak in strength.
- examples of the excipient include sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, trehalose, glucose, sucrose, lactose hydrate, calcium sulfate, calcium carbonate, reduced palatinose, erythritol, anhydrous phosphorus
- examples thereof include calcium oxyhydrogen, crystalline cellulose, and the like, and two or more of them may be mixed at an appropriate ratio.
- disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, low-substituted carboxymethyl starch sodium, croscarmellose sodium, and crospovidone. These may be used by mixing two or more of them in an appropriate ratio.
- Starch includes all starches derived from any natural starch that can be used in pharmaceuticals. Examples thereof include potato starch, corn starch, wheat starch, rice starch and soluble starch, partially pregelatinized starch, pregelatinized starch, and hydroxypropylated starch.
- binder examples include starch (including partially pregelatinized starch), agar, dextrin, pullulan, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, methylcellulose, ethylcellulose, carboxymethylethylcellulose. , Carmellose sodium, gum arabic, gum arabic powder, polyvinyl alcohol, alkylhydroxyethyl cellulose, and the like, and two or more of these may be mixed at an appropriate ratio.
- sweetening agent examples include aspartame, acesulfame K, saccharin, saccharin sodium, stevia, sucralose, thaumatin, neotame and the like, and two or more of these may be used in an appropriate ratio.
- fragrances examples include peppermint, spearmint, menthol, lemon, orange, grapefruit, pine, fruit, yogurt and the like, and two or more of these may be used in an appropriate ratio.
- flavoring agent and / or flavoring agent examples include various amino acids such as sodium aspartate, alanine, arginine, glycine, glutamine, glutamic acid or salts thereof, adipic acid, ascorbic acid, citric acid, succinic acid, tartaric acid, malic acid, and the like.
- Organic acids, licorice, triethyl citrate, taurine, tannic acid and the like may be used, and two or more of these may be mixed at an appropriate ratio.
- lubricant examples include stearic acid, metal stearate, sodium stearyl fumarate, sucrose fatty acid ester, talc, hydrogenated oil, macrogol and the like.
- non-toxic and inert additives usually used in the pharmaceutical field can also be added.
- additives include those that do not substantially affect the effects of the present invention and are generally added as pharmaceutical additives, such as colorants, fluidizers, surfactants, adsorbents, preservatives. , Stabilizers, wetting agents, antistatic agents, pH adjusting agents and the like.
- the dry coated tablet of the present invention can be produced using a known method.
- an inner core powder containing a light-unstable drug is molded in advance (for example, 1 to 5 kN) using another tableting machine to produce the core, and the core as the molded product is used as the outer layer powder.
- the dry-coated tablet of the present invention can be produced by the method described in Patent Document 6.
- it has ridges in both the upper and lower directions of the mortar, and both upper and lower ridges have a double structure that surrounds the center ridge and the outer periphery of the center ridge, but both the center ridge and the outer heel slide.
- Inner core supply and filling step for supplying and filling inner core granules containing a drug unstable to light into the space on the outer layer granular material supplied in the previous step, surrounded by the outer layer, and the outer layer supplied and filled by the previous step
- a method for producing an orally disintegrating tablet having an inner core containing a light-unstable drug and an outer layer covering the surface thereof, having a ridge in both the upper and lower directions of the mortar, And the outer shell surrounding the outer periphery of the center rod, and the center rod and the outer rod are both slidable and compressed using compression molding means and surrounded by the lower outer rod
- An inner core supplying and filling step for supplying and filling the inner core powder containing a light-unstable drug in the space above the lower central wall, an inner core forming step for compressing and molding the inner core granular material supplied and filled in the previous step, Furthermore, in the space around the molded product in the die formed in the previous step, the outer layer powder particles are finally placed until the tip of the lower center punch protrudes from the tip of the lower outer punch.
- the inner core and outer layer components may be granulated in advance and mixed.
- the granulation method include extrusion granulation method, crushing granulation method, dry compaction granulation method, fluidized bed granulation method, tumbling granulation method, tumbling fluidized bed granulation method, and high speed stirring granulation method.
- the tableting method for the inner core and outer layer include a wet tableting method and a direct tableting method.
- Preparation of inner core Weighed 1 tablet prescription amount of the inner core powder and compressed it with a pressure of 2kN using a simple molding machine 20kN table press TB-20H (NPa System Co., Ltd.) to obtain a tablet with a diameter of 6mm. .
- the thickness of the inner core was about 1 mm.
- the lower part of the outer layer was produced. 50 mg of the outer layer granular material was weighed and compressed with a pressure of 2 kN using a table press to obtain a tablet having a diameter of 8 mm and a thickness of about 1 mm.
- the previously prepared inner core was placed on the lower part of the outer layer so as to be in the center, and the powder as the outer layer side part and upper part was added.
- the outer layer side and upper part weigh out 85 mg of powder for outer layer, compress it with a pressure of 10 kN using a table press, and make a dry-coated tablet with a diameter of 8 mm and a thickness of about 3 mm on the top and bottom surfaces of which are flat. Obtained.
- Test example 1 The photostability test was performed on the tablets of Examples 1 to 3 and Comparative Examples 1 to 4.
- Tablets were tested for 8 days at 3500 Lux using a photostability test device (Nagano Kagaku Seisakusho, model: LT-120D3CJ), D65 daylight color (20W, FLR20S-D-EDL-D65 / M) for color comparison and inspection. Irradiated with light.
- a photostability test device Nagano Kagaku Seisakusho, model: LT-120D3CJ
- the degradation product (oxidized substance) of nifedipine in the tablet after light irradiation was quantified by liquid chromatography (HPLC).
- Oxidant production ⁇ sample preparation method>
- the pre-light-irradiated product tablette stored at 5 ° C. in the dark after preparation
- each tablet after light irradiation were weighed into a 100 mL brown volumetric flask.
- 10 mg of the active ingredient (API) nifedipine
- 20 mL of water was added to each and sonicated for 10 minutes.
- Oral disintegration time The average value of the time (seconds) from when the healthy three testers hold the tablet in the oral cavity until the disintegration of the prepared orally disintegrating tablet before light irradiation. was calculated.
- Absolute hardness [N / mm 2 ] Hardness [N] ⁇ (Tablet diameter [mm] ⁇ Tablet thickness [mm]) If it is 1N / mm 2 or more, it is considered to be compatible with automatic packaging machines.
- the rate of increase in oxidant is calculated by (area percentage value of oxidant in tablet after light irradiation) ⁇ (area percentage value of oxidant in product before light irradiation).
- This dry-coated tablet has a rapid oral disintegration time of 20 seconds and has an absolute hardness of 1 N / mm 2 or more, so it is considered to be compatible with automatic packaging machines, and is a very high quality orally disintegrating tablet. it is conceivable that.
- the rate of increase in oxidant is calculated by (area percentage value of oxidant in tablet after light irradiation) ⁇ (area percentage value of oxidant in product before light irradiation).
- Table 4 shows that edible red No. 2, edible yellow No. 4, edible blue No. 1, iron sesquioxide, and black iron oxide are added almost 0.1% to the outer layer of the dry-coated tablets, and the rate of increase in oxidant is almost completely achieved. It was possible to suppress. Furthermore, iron sesquioxide could be added almost 0.01% to the outer layer of the dry coated tablet to almost completely suppress the oxidant increase rate (Example 9). Further, regardless of the amount of nifedipine added to the inner core, 0.1% of yellow ferric oxide was added to the outer layer of the dry-coated tablet, and the increase in the oxidized form of nifedipine could be almost completely suppressed (Example 10). . On the other hand, even when 10% of talc and kaolin, which have an effect of shielding light, are added to the outer layer of the dry-coated tablet, increase in oxidant could not be suppressed.
- a dry-coated tablet having the formulation shown in Table 5 was produced in the same manner as in Experimental Example 1, and the rate of increase in oxidant after light irradiation was measured by the same method as in Test Example 1 to change the appearance of the tablet after light irradiation. Was observed. The results are shown in Table 6.
- the thickness of the outer layer of the dry coated tablet was adjusted by adjusting the addition amount.
- the rate of increase in oxidant is calculated by (area percentage value of oxidant in tablet after light irradiation) ⁇ (area percentage value of oxidant in product before light irradiation).
- the thickness of the outer layer and the concentration of yellow ferric oxide added to the outer layer also affect the light stabilization of nifedipine, but the amount of light-absorbing material present in the outer layer per surface area of the inner core is the light stabilization of nifedipine. It was found to affect the
- Orally disintegrating tablets having the formulations shown in Table 7 were produced in the same manner as in Experimental Example 1, except that the final molding pressure of the dry-coated tablets was 6 kN.
- Test example 2 The photostability test was performed on the tablets of Comparative Examples 7 and 8 and Examples 19-22.
- the conditions for light irradiation on the tablets are shown below.
- the tablet was irradiated with light at 20,000 Lux for 60 hours using a light stability tester (model: LTX-01, Nagano Kagaku Seisakusho) and a light source (xenon lamp).
- the amount of related substances produced was measured as follows.
- Menaquinone-4 Sample preparation method> Preparation of standard solution 1. About 5 mg of menaquinone was accurately weighed and dispersed by adding 10 mL of water. 2. Ethanol (99.5) was added to this solution to make exactly 50 mL to obtain a standard solution (0.1 mg / mL).
- Sample solution preparation 1. The tablets were ground in a mortar and weighed into a 10 mL volumetric flask to 1.0 mg menaquinone. 2. 2 mL of water was added and sonicated for 5 minutes. 3. Ethanol (99.5) was added to this solution and sonicated for another 5 minutes. 4. Make exactly 10 mL (0.1 mg / mL) with ethanol (99.5). 5. Centrifuged at 3000 rpm for 10 minutes.
- Mecobalamin preparation method> Preparation of standard solution 1. About 20 mg of mecobalamin was accurately weighed, and the sample solution (water) was added to make exactly 100 mL. 2. Pipet 5 mL of this solution into a 20 mL volumetric flask and add sample solution (water) to make a constant volume to make a standard solution (50 ⁇ g / mL).
- Detector UV spectrophotometer column: Inertsil ODS-3 (150 ⁇ 4.6 mm, 3 ⁇ m) Column temperature: 40 ° C Measurement wavelength: 220 nm Flow rate: 1.0 mL / min Injection volume: 100 ⁇ L Sample cooler: 20 °C Retention time: Approx. 15 minutes Syringe washing solution: Water mobile phase: A: 0.02 mol / L Phosphoric acid / dibasic potassium phosphate buffer (pH 2.6) / acetonitrile (21: 4) containing 1-sodium 1-heptanesulfonate Solution dissolved in mg / mL, B: acetonitrile
- the related substance increase rate is calculated by (area percentage value of the related substance in the tablet after light irradiation) ⁇ (area percentage value of the related substance in the product before light irradiation).
- Table 9 shows that not only nifedipine but also other light-unstable drugs can be obtained by adding a light-absorbing substance such as yellow iron sesquioxide, iron sesquioxide or black iron oxide to the outer layer of the dry coated tablet. It has been found that the increase of can be almost completely suppressed.
- an orally disintegrating tablet having improved light stability of a light-unstable drug. This improves the quality of orally disintegrating preparations of drugs that are unstable to light, and at the same time enables simpler and more portable packaging, enabling elderly people and busy modern adults to go anywhere. It is possible to easily take an orally disintegrating preparation of a drug that is unstable to light in any scene without taking water.
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Abstract
Description
コーティングを施さない錠剤、顆粒剤、細粒剤、散剤等の光安定化方法としては、特許文献3に光に不安定な脂溶性薬物に黄色及び赤色の着色剤から選ばれる1種以上の物質を配合してなる光安定性の向上した組成物が開示されている。しかしながら、これらの光安定化方法を用いても光安定化効果は十分なものではない。
〔1〕内核とその表面を覆う外層を有する口腔内崩壊錠であって、内核が光に不安定な薬物を含有し、外層が光吸収物質を含有する口腔内崩壊錠。
〔2〕光吸収物質が、食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用青色1号、食用青色2号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、食用青色1号アルミニウムレーキ、食用青色2号アルミニウムレーキ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄、カルミン、銅クロロフィリンナトリウム、銅クロロフィル及びベンガラからなる群から選ばれる少なくとも1種である、〔1〕に記載の口腔内崩壊錠。
〔3〕光吸収物質が、食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄、カルミン、銅クロロフィリンナトリウム、銅クロロフィル及びベンガラからなる群から選ばれる少なくとも1種である、〔1〕に記載の口腔内崩壊錠。
〔4〕光吸収物質が、食用赤色2号、食用赤色3号、食用黄色4号、食用黄色5号、食用青色1号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、食用青色1号アルミニウムレーキ、食用青色2号アルミニウムレーキ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、カルミンおよび銅クロロフィリンナトリウムからなる群から選ばれる少なくとも1種である、〔1〕記載の口腔内崩壊錠。
〔5〕光吸収物質が、三二酸化鉄、黄色三二酸化鉄および黒酸化鉄からなる群から選ばれる少なくとも1種である、〔1〕~〔4〕のいずれかに記載の口腔内崩壊錠。
〔6〕外層が、光吸収物質を、内核の単位表面積あたり0.01~600μg/mm2となるような量含有する、〔1〕~〔5〕のいずれかに記載の口腔内崩壊錠。
〔7〕外層が、光吸収物質を、内核の単位表面積あたり0.1~150μg/mm2となるような量含有する、〔1〕~〔5〕のいずれかに記載の口腔内崩壊錠。
〔8〕外層が、光吸収物質を、内核の単位表面積あたり0.2~20μg/mm2となるような量含有する、〔1〕~〔5〕のいずれかに記載の口腔内崩壊錠。
〔9〕外層が、光吸収物質を、内核の単位表面積あたり1.5~10μg/mm2となるような量含有する、〔1〕~〔5〕のいずれかに記載の口腔内崩壊錠。
〔10〕光に不安定な薬物を含む内核とその表面を覆う外層を有する口腔内崩壊錠の製造方法であって、光に不安定な薬物を含む内核用粉粒体を成型して核を製造する工程、光吸収物質を含む外層用粉粒体が供給充填された有核打錠機の臼内に該核を供給する工程、及びさらに該外層用粉粒体を供給し圧縮成型する工程、を含む製造方法。
〔11〕光に不安定な薬物を含む内核とその表面を覆う外層を有する口腔内崩壊錠の製造方法であって、臼の上下両方向に杵を有し、上下いずれの杵も、中心杵とその中心杵の外周を取り巻く外杵との2重構造からなり、該中心杵と外杵がどちらも摺動可能であるとともに圧縮操作が可能である圧縮成型手段を用い、下外杵に囲まれる下中心杵上の空間に光吸収物質を含む外層用粉粒体を供給する外層供給工程1、下外杵に囲まれ前工程で供給された該外層用粉粒体上の空間に光に不安定な薬物を含む内核用粉粒体を供給充填する内核供給充填工程、前工程までに供給充填された外層用粉粒体と内核用粉粒体を圧縮成型する外層内核成形工程、更に、臼内の前工程で成型された外層内核成型品上およびその回りの空間に該外層用粉粒体を供給する外層供給工程2、前記外層内核成型品と該外層用粉粒体を圧縮成型する全体成型工程を含む製造方法。
〔12〕光に不安定な薬物を含む内核とその表面を覆う外層を有する口腔内崩壊錠の製造方法であって、臼の上下両方向に杵を有し、上下いずれの杵も、中心杵とその中心杵の外周を取り巻く外杵との2重構造からなり、該中心杵と外杵がどちらも摺動可能であるとともに圧縮操作が可能である圧縮成型手段を用い、下外杵に囲まれる下中心杵上の空間に光に不安定な薬物を含む内核用粉粒体を供給充填する内核供給充填工程、前工程で供給充填された内核用粉粒体を圧縮成型する内核成型工程、更に、前工程で成型された臼内の成型品上及びその回りの空間に、最終的に下中心杵の杵先が下外杵の杵先より突出した状態になるまで外層用粉粒体を供給充填する外層供給充填工程、下中心杵の杵先と下外杵の杵先とを揃えて前記内核成型品と外層用粉粒体を圧縮成型する全体成型工程を含む製造方法。
〔13〕光に不安定な薬物を含む口腔内崩壊錠における該薬物の光安定性を向上させる方法であって、口腔内崩壊錠を内核とその表面を覆う外層で構成させ、該内核に該薬物を含有させ、該外層に光吸収物質を含有させることを特徴とする方法。
〔14〕光に不安定な薬物を含む内核とその表面を覆う外層を有する口腔内崩壊錠における該薬物の光安定性を向上させる方法であって、該外層に光吸収物質を含有させることを特徴とする方法。
〔15〕光に不安定な薬物を含む錠剤を、光吸収物質を含有する外層で被覆することを特徴とする、該光に不安定な薬物の安定化方法。
[実験例1]
錠剤処方(mg)
コーンスターチ(XX16)W(日本食品化工株式会社)
ニフェジピン(和光純薬工業株式会社)
ステアリン酸マグネシウム(太平化学産業株式会社)
酸化チタン(和光純薬工業株式会社)
黄色三二酸化鉄(癸巳化成化成株式会社)
実施例1~3および比較例3、4に関しては表1の処方に従い、有核錠の内核、外層の各成分をそれぞれ乳鉢にてよく混合した。
内核用粉粒体の1錠処方量を秤取して簡易成形機20kNテーブルプレスTB-20H(NPaシステム株式会社)を用いて2kNの圧力で圧縮し、直径6mmの錠剤を得た。内核の厚みは約1mmであった。
まず、外層下部を作製した。外層用粉粒体50mgを秤取し、テーブルプレスを用いて2kNの圧力で圧縮し、直径8mm、厚み約1mmの錠剤を得た。次に先ほど作製した内核を外層下部の上に中央に来るように設置し、外層側部及び上部としての粉末を添加した。外層側部及び上部としては外層用粉粒体85mgを秤取し、テーブルプレスを用いて10kNの圧力で圧縮し、直径8mm、厚み約3mmの上面及び下面の表面が平面である有核錠を得た。
実施例1~3および比較例1~4の錠剤について光安定性試験を実施した。
(1)酸化体生成量
<サンプル調整方法>
試料液用として光照射前品(作製後、暗所で5℃に保存しておいた錠剤)、光照射後の各錠剤1錠を100mL褐色メスフラスコに秤量した。別途、標準液用として主薬(API)(ニフェジピン)10mgを100mL褐色メスフラスコに秤量した。それぞれに水を20mL加え、10分間超音波処理を行った。
<HPLC分析条件>
カラムSupercosil LC-18-DB (150×4.6mm, 3 μm)
カラム温度 25℃
波長270nm
移動相 20%アセトニトリル/30%メタノール/50% 0.01M TEAA Buffer*1) (pH5.0)
流速 0.75mL/min
注入量 50μm
シリンジ洗浄液 水/アセトニトリル混液(1:1)
*1) TEAA Buffer(Triethylamine-acetate buffer);0.01Mトリエチルアミン水溶液に酢酸を添加し、pH5.0に調整した。
作製した口腔内崩壊錠の光照射前品について、健常な男性3名の試験者が、錠剤を口腔内に保持してから崩壊するまでの時間(秒)の平均値を算出した。
錠剤硬度計TH-203MP(富士産業株式会社)を用いて、作製した口腔内崩壊錠の光照射前品について、硬度を測定した。絶対硬度は、以下の式に従って算出した。
1N/mm2以上あれば自動分包機に適合可とされている。
錠剤処方(mg)
食用黄色4号(株式会社たけとんぼ)
食用青色1号(株式会社たけとんぼ)
三二酸化鉄(株式会社たけとんぼ)
黒酸化鉄(株式会社たけとんぼ)
タルク(林化成株式会社)
カオリン(竹原化学工業株式会社)
実験例1と同様の方法によって表3の処方の有核錠を製造し、試験例1と同様な方法により光照射後の酸化体の増加率を測定し、光照射後の錠剤の外観の変化を観察した。その結果を表4に示す。
錠剤処方(mg)
錠剤処方(mg)
比較例7、8および実施例19~22の錠剤について光安定性試験を実施した。
<サンプル調製方法>
標準溶液の調製
1. メナキノン約5 mgを精密に量り、水10 mLを加えて分散させた。
2. この液にエタノール(99.5) を加えて正確に50 mLとし、標準溶液とした(0.1 mg/mL)。
1. 錠剤を乳鉢ですりつぶし、メナキノンとして1.0 mgとなるように10 mL容メスフラスコに秤量した。
2. 水2 mLを加えて5分間超音波処理した。
3. この液にエタノール(99.5) を加えてさらに5分間超音波処理した。
4. エタノール(99.5) で正確に10 mLとした(0.1 mg/mL)。
5. 3000 rpmにて10分遠心分離した。
<HPLC分析条件>
検出器: 紫外吸光光度計
カラム: L-column ODS (150×4.6 mm, 5 μm)
カラム温度: 40℃
測定波長: 270 nm
流量: 1.0 mL/min
注入量: 50 μL
サンプルクーラー: 25℃
保持時間: 約7分
シリンジ洗浄液: エタノール(99.5)
移動相: メタノール
<サンプル調製方法>
標準溶液の調製
1. メコバラミン約20 mgを精密に量り、試料溶解液(水)を加えて正確に100 mLとした。
2. この液5 mLを20 mL容メスフラスコに正確に取り、試料溶解液(水)を加えて定容とし、標準溶液とした(50 μg/mL)。
1. 錠剤を乳鉢ですりつぶし、メコバラミンとして0.25 mgとなるように秤量した。
2. 試料溶解液5 mLを加え撹拌・超音波処理した。
3. フィルター(ADVANTEC DISMIC=25HP, PTFE 0.45 μm)でろ過し、はじめのろ液4 mLを捨て残りのろ液を試料溶液とした(50 μg/mL)。
<HPLC分析条件>
検出器: 紫外吸光光度計
カラム: Inertsil ODS-3 (150×4.6 mm, 3 μm)
カラム温度: 40℃
測定波長: 220 nm
流量: 1.0 mL/min
注入量: 100 μL
サンプルクーラー: 20℃
保持時間: 約15分
シリンジ洗浄液: 水
移動相: A:0.02 mol/L リン酸・リン酸二水素カリウム緩衝液(pH 2.6)/アセトニトリル混液(21:4)に1-ヘプタンスルホン酸ナトリウムを2 mg/mLで溶解させた液、B:アセトニトリル
Claims (11)
- 内核とその表面を覆う外層を有する口腔内崩壊錠であって、内核が光に不安定な薬物を含有し、外層が光吸収物質を含有する口腔内崩壊錠。
- 光吸収物質が、食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用青色1号、食用青色2号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、食用青色1号アルミニウムレーキ、食用青色2号アルミニウムレーキ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄、カルミン、銅クロロフィリンナトリウム、銅クロロフィル及びベンガラからなる群から選ばれる少なくとも1種である、請求項1に記載の口腔内崩壊錠。
- 光吸収物質が、食用赤色2号、食用赤色3号、食用赤色102号、食用赤色104号、食用赤色105号、食用赤色106号、食用黄色4号、食用黄色5号、食用緑色3号、食用赤色3号アルミニウムレーキ、食用黄色4号アルミニウムレーキ、食用黄色5号アルミニウムレーキ、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、黄酸化鉄、カルミン、銅クロロフィリンナトリウム、銅クロロフィル及びベンガラからなる群から選ばれる少なくとも1種である、請求項1に記載の口腔内崩壊錠。
- 光吸収物質が、三二酸化鉄、黄色三二酸化鉄および黒酸化鉄からなる群から選ばれる少なくとも1種である、請求項1~3のいずれかに記載の口腔内崩壊錠。
- 外層が、光吸収物質を、内核の単位表面積あたり0.01~600μg/mm2となるような量含有する、請求項1~4のいずれかに記載の口腔内崩壊錠。
- 外層が、光吸収物質を、内核の単位表面積あたり0.1~150μg/mm2となるような量含有する、請求項1~4のいずれかに記載の口腔内崩壊錠。
- 外層が、光吸収物質を、内核の単位表面積あたり0.2~20μg/mm2となるような量含有する、請求項1~4のいずれかに記載の口腔内崩壊錠。
- 外層が、光吸収物質を、内核の単位表面積あたり1.5~10μg/mm2となるような量含有する、請求項1~4のいずれかに記載の口腔内崩壊錠。
- 光に不安定な薬物を含む口腔内崩壊錠における該薬物の光安定性を向上させる方法であって、口腔内崩壊錠を内核とその表面を覆う外層で構成させ、該内核に該薬物を含有させ、該外層に光吸収物質を含有させることを特徴とする方法。
- 光に不安定な薬物を含む内核とその表面を覆う外層を有する口腔内崩壊錠における該薬物の光安定性を向上させる方法であって、該外層に光吸収物質を含有させることを特徴とする方法。
- 光に不安定な薬物を含む錠剤を、光吸収物質を含有する外層で被覆することを特徴とする、該光に不安定な薬物の安定化方法。
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WO2016076280A1 (ja) * | 2014-11-11 | 2016-05-19 | 塩野義製薬株式会社 | 光に対して不安定な薬物を含有する多層錠剤 |
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EP3868366A4 (en) * | 2018-10-19 | 2022-07-20 | Towa Pharmaceutical Co., Ltd. | COATED SOLID PREPARATION |
US12083226B2 (en) | 2018-07-30 | 2024-09-10 | Daiichi Sankyo Company, Limited | Stabilizer-containing solid drug formulation |
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JP2012041290A (ja) * | 2010-08-18 | 2012-03-01 | Sawai Pharmaceutical Co Ltd | ラフチジン含有固形製剤 |
WO2015008825A1 (ja) | 2013-07-19 | 2015-01-22 | 株式会社三和化学研究所 | 口腔内崩壊錠 |
WO2016076280A1 (ja) * | 2014-11-11 | 2016-05-19 | 塩野義製薬株式会社 | 光に対して不安定な薬物を含有する多層錠剤 |
JP6075818B2 (ja) * | 2014-11-11 | 2017-02-08 | 塩野義製薬株式会社 | 光に対して不安定な薬物を含有する多層錠剤 |
US10398694B2 (en) | 2014-11-11 | 2019-09-03 | Shionogi & Co., Ltd. | Multi-layered tablet containing drug unstable to light |
JPWO2016148264A1 (ja) * | 2015-03-19 | 2017-12-28 | 第一三共株式会社 | 着色剤を含有する固形製剤 |
WO2016148264A1 (ja) * | 2015-03-19 | 2016-09-22 | 第一三共株式会社 | 着色剤を含有する固形製剤 |
US10603285B2 (en) | 2015-03-19 | 2020-03-31 | Daiichi Sankyo Company, Limited | Solid preparation including colorant |
US10561628B2 (en) | 2015-03-19 | 2020-02-18 | Daiichi Sankyo Company, Limited | Solid preparation including antioxidant |
JP2016210760A (ja) * | 2015-04-28 | 2016-12-15 | 大原薬品工業株式会社 | 光安定性を向上したシロドシン含有着色錠剤 |
JP2018123146A (ja) * | 2015-04-28 | 2018-08-09 | 大原薬品工業株式会社 | 光安定性を向上したシロドシン含有着色錠剤 |
JP2020200348A (ja) * | 2015-04-28 | 2020-12-17 | 大原薬品工業株式会社 | 光安定性を向上したシロドシン含有着色錠剤 |
JP2017014151A (ja) * | 2015-07-01 | 2017-01-19 | 大原薬品工業株式会社 | 光安定性を向上した、シロドシンを含有する有核錠 |
US10350194B2 (en) | 2015-10-07 | 2019-07-16 | Kyowa Hakko Kirin Co., Ltd. | Pharmaceutical composition containing an arylalkylamine compound |
WO2017061621A1 (ja) * | 2015-10-07 | 2017-04-13 | 協和発酵キリン株式会社 | アリールアルキルアミン化合物含有医薬組成物 |
JP2017071599A (ja) * | 2015-10-07 | 2017-04-13 | 協和発酵キリン株式会社 | アリールアルキルアミン化合物含有医薬組成物 |
US12083226B2 (en) | 2018-07-30 | 2024-09-10 | Daiichi Sankyo Company, Limited | Stabilizer-containing solid drug formulation |
EP3868366A4 (en) * | 2018-10-19 | 2022-07-20 | Towa Pharmaceutical Co., Ltd. | COATED SOLID PREPARATION |
Also Published As
Publication number | Publication date |
---|---|
CN102300563A (zh) | 2011-12-28 |
EP2382971A1 (en) | 2011-11-02 |
US20190290579A1 (en) | 2019-09-26 |
KR20110117133A (ko) | 2011-10-26 |
JP5591128B2 (ja) | 2014-09-17 |
CN106344533A (zh) | 2017-01-25 |
EP2382971A4 (en) | 2014-01-08 |
JPWO2010087462A1 (ja) | 2012-08-02 |
US20110305758A1 (en) | 2011-12-15 |
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