WO2012161240A1 - テガフール、ギメラシル、オテラシルカリウム含有有核錠 - Google Patents
テガフール、ギメラシル、オテラシルカリウム含有有核錠 Download PDFInfo
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- WO2012161240A1 WO2012161240A1 PCT/JP2012/063260 JP2012063260W WO2012161240A1 WO 2012161240 A1 WO2012161240 A1 WO 2012161240A1 JP 2012063260 W JP2012063260 W JP 2012063260W WO 2012161240 A1 WO2012161240 A1 WO 2012161240A1
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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
- A61K9/20—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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- 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
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- A61K9/20—Pills, tablets, discs, rods
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- A61K9/2893—Tablet coating processes
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Definitions
- the present invention relates to a dry-coated tablet for oral administration containing tegafur, gimeracil and oteracil potassium.
- the combination of tegafur, gimeracil and oteracil potassium is a combination of terafur, which is a prodrug of fluorouracil (5-FU), gimeracil, which is a 5-FU degradation inhibitor, and oteracil potassium, which is a phosphorylation inhibitor. It is an antitumor agent characterized by reducing gastrointestinal toxicity while enhancing its antitumor effect, and is widely used in clinical settings as a cancer chemotherapeutic agent that can be administered orally (Patent Document 1).
- tegafur, gimeracil and oteracil potassium combination agents are capsules under the name of “TS-1 combination capsules” with a molar ratio of tegafur: guimeracil: oteracil potassium of 1: 0.4: 1, and “tea” Granules are commercially available under the name of “S-one blended granules” (Patent Document 2).
- capsules and granules may be difficult to swallow for elderly people with reduced swallowing function, and there is a need for orally disintegrating tablets that are easy to take even for those with difficulty swallowing and that disintegrate quickly in the oral cavity. Yes.
- Patent Document 3 discloses a preparation containing tegafur, gimeracil and oteracil potassium which is stable even under humidified conditions and can be administered orally.
- the combination preparation is intended to improve the stability as a preparation, and does not take into consideration the ingestibility of patients who have difficulty in swallowing.
- adding a disintegrant or the like in addition to the stabilized saccharide to improve the function such as disintegration of the tablet leads to destabilization of the active ingredient.
- Patent Document 4 discloses an orally disintegrating tablet containing tegafur, gimeracil and oteracil potassium.
- this patent does not take measures against drug exposure of medical workers, caregivers, etc., despite the fact that this drug is a highly active anticancer agent.
- tegafur, gimeracil, and oteracil potassium combination preparations known to date have sufficiently reduced the risk of drug exposure, have sufficient tablet strength, and do not reduce medication adherence even when taken.
- the formulation is sought after.
- An object of the present invention is to provide a dry-coated tablet containing tegafur, gimeracil and oteracil potassium, which realizes reduction of drug exposure risk, rapid disintegration and sufficient tablet strength.
- the object of the present invention is a combination of an outer core with good moldability and good disintegration and an inner core containing an active ingredient, having sufficient mechanical strength and reducing the risk of drug exposure,
- the object is to provide a dry-coated tablet that rapidly disintegrates in the oral cavity.
- the present invention has been completed by finding a preparation that has sufficient strength and rapidly disintegrates in the oral cavity while reducing the risk of drug exposure.
- the present invention provides the following dry-coated tablets.
- a dry-coated tablet comprising an inner core and an outer shell containing (a) tegafur, (b) gimeracil and (c) oteracil potassium as active ingredients.
- the dry-coated tablet according to (1) containing (a) tegafur, (b) gimeracil and (c) oteracil potassium in a molar ratio of 1: 0.4: 1.
- a pharmacy having a friability of a dry-coated tablet (cumulative rotational speed of 100 revolutions) of 0.3% or less and having substantially no cracking in a drop test from a height of 1 m.
- the active ingredient is not present on the surface of the tablet by containing the drug in the inner core as a dry tablet, the risk of exposure to the drug by medical personnel can be greatly reduced, and moderate tablet strength And quick disintegration can be realized. Furthermore, by separating the inner core and the outer shell, the contact with the additive that promotes the decomposition of the active ingredient can be reduced, so that the decomposition can be suppressed.
- the molar ratio of tegafur, gimeracil and oteracil potassium can be appropriately selected, but a compounding agent of 1: 0.4: 1 is preferred.
- the amount of tegafur, gimeracil and oteracil potassium, which are the active ingredients in the dry-coated tablet of the present invention varies depending on the dosage form, administration plan, etc., and is not particularly limited and may be appropriately selected.
- the content is preferably about 10 to 60% by mass, more preferably 20 to 50% by mass, and particularly preferably 25 to 35% by mass.
- a preferred dry-coated tablet of the present invention has an outer shell having a friability (cumulative rotational speed of 100 revolutions) of 0.3% or less, more preferably an outer shell having a friability of 0.1% or less. It is a dry-coated tablet.
- friability means the meaning normally used in the technical field of pharmaceutical preparations, that is, whether a molded tablet can withstand vibrations and shocks in the next process of coating, printing, packaging, or market / distribution. Therefore, it is a parameter evaluated by the amount of decrease in tablet weight by a friability tester using a rotating drum, and is an index of tablet strength.
- the rotation speed of the drum with an electric motor is, for example, 24 to 26 rotations per minute.
- the tablet weight after the constant rotation was adjusted, and the percentage of decrease relative to the starting tablet weight was calculated as the friability.
- the friability is shown when the cumulative number of revolutions is set to 100, which is calculated from the tablet weight of 25 rpm and 4 minutes.
- a case where the friability of the cumulative number of revolutions of 100 is 0.3% or less is defined as high tablet strength.
- those having a tablet strength of less than 0.3% are defined as low.
- the active ingredient contained in the present invention is an anticancer agent, and it is necessary to increase the tablet strength in order to further reduce the exposure risk as compared with general drugs. It is better to set it.
- the preferred dry-coated tablet of the present invention has an outer shell that is substantially free from cracks in a drop test from a height of 1 m, and more preferably substantially free from cracks in a drop test from a height of 2 m. It is a dry-coated tablet with an outer shell.
- the “drop test” is a test that is usually used in the technical field of pharmaceutical preparations in order to know whether it can withstand vibrations and shocks in manufacturing / distribution or dispensing by an automatic packaging machine. Specifically, the tablet is naturally dropped from a height of 1 m to 2 m onto a stainless steel plate, and the chip cracking of the tablet and the mass reduction rate before and after the test are confirmed. Further, in the present invention, “substantially no cracking and chipping” means that when a drop test is performed on five tablets, cracking and chipping does not occur at all, and the mass reduction rate in the five tablets is Less than 0.1% means to some extent.
- the preferable dry-coated tablet of the present invention has a disintegration time of the entire dry-coated tablet within 120 seconds. Specifically, it is a dry-coated tablet whose disintegration time is 120 seconds or less when a disintegration test is carried out in accordance with the Japanese Pharmacopoeia Fifteenth Revised General Test Method Disintegration Test Method. This disintegration time is preferably within 95 seconds, and more preferably within 80 seconds. When using a rapidly disintegrating dry-coated tablet in the oral cavity, the actual dissolution / disintegration time in the oral cavity is equal to or more than the disintegration time in the disintegration test method by adding friction in the oral cavity and movement by the tongue. May be faster.
- the disintegration test method can be summarized as follows.
- the tester is attached to the receiving shaft, placed in a beaker, and adjusted so that it can move up and down smoothly with 29 to 32 reciprocations for 1 minute and an amplitude of 53 to 57 mm.
- the lower mesh surface is 25 mm from the bottom of the beaker, and the amount of water in the beaker matches the surface of the liquid when the tester is at the lowest position.
- the liquid temperature is maintained at 37 ⁇ 2 ° C. Put one sample into the glass tube of the tester, use water as the test solution, put the auxiliary board, and move up and down. The time until the residue of the sample is not recognized in the glass tube is measured and set as the disintegration time.
- the disintegration time as measured by the orally disintegrating tablet tester ODT-101 of the dry coated tablet of the present invention is preferably within 20 seconds, more preferably within 16 seconds, and particularly preferably within 14 seconds.
- a preferred dry-coated tablet of the present invention has a dissolution rate (CDHP, 15 minute value) measured by the Japanese Pharmacopoeia General Test Method Dissolution Test Method Method 2 (50 min ⁇ 1 , 900 mL of test solution water) of 90% or more, 95% or more is more preferable, and 97% or more is particularly preferable.
- CDHP dissolution rate measured by the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (50 min ⁇ 1 , 900 mL of test solution water) of 90% or more, 95% or more is more preferable, and 97% or more is particularly preferable.
- a particularly preferred dry-coated tablet of the present invention has an outer shell in which the friability of the dry-coated tablet (cumulative rotation speed: 100 rotations) is 0.3% or less, and the disintegration time by the Japanese Pharmacopoeia General Test Method Disintegration Test Method It is a dry-coated tablet that is 120 seconds or less, and more preferably, it has an outer shell in which the friability of the dry-coated tablet (cumulative rotational speed 100 rotations) is 0.2% or less, and the Japanese Pharmacopoeia General Test Method Disintegration Test It is a dry-coated tablet with a disintegration time of 95 seconds or less by the law, More preferably, the dry-coated tablet has a friability (cumulative rotational speed of 100 revolutions) of 0.2% or less, and has an outer shell that is substantially free from cracks in a drop test from a height of 1 m.
- the friability of the dry-coated tablet (cumulative rotational speed 100 rotations) is 0.2% or less
- Disintegration time by pharmacopoeia general test method disintegration test method is 95 seconds or less, disintegration time measured by orally disintegrating tablet tester ODT-101 is within 20 seconds, and Japanese Pharmacopoeia General Test Dissolution Test Method 2 Nucleated tablets with a dissolution rate (CDHP, 15 minutes value) measured by the method (50 min ⁇ 1 , test solution water 900 mL) of 90% or more, particularly preferably the friability (cumulative rotational speed 100 Rotation) is 0.2% or less, and has an outer shell that does not substantially cause cracking in a drop test from a height of 2 m, and the disintegration time by the Japanese Pharmacopoeia General Test Method disintegration test method is 95 seconds or less Orally disintegrating tablet tester ODT Disintegration time measured by 101 is within 16 seconds, the Japanese Pharmacopoeia General Test Methods Dissolution Test Method 2 (50min -1, test liquid water 900 mL) dissolution rate as measured by (CDHP, 15 minutes value) 95% This is the
- Hardness is one index for evaluating tablet strength, and can be measured according to the method described in USP “TABLET” BREAKING “FORCE”. That is, at a constant speed (20 N / sec or less or 3.5 mm / sec or less) between two parallel pressure plates, in the case of a circular tablet, pressure is applied in the diameter direction, and the load when the tablet breaks is measured.
- the hardness of the dry coated tablet of the present invention is preferably 30N to 60N, more preferably 35N to 55N in view of balance with disintegration.
- Examples of the additive to be contained in the outer shell of the dry coated tablet of the present invention include crystalline cellulose, lactose, hydroxypropylcellulose, etc. in order to improve tablet strength, preferably crystalline cellulose, lactose or a mixture thereof. More preferably, it is a mixture of crystalline cellulose and lactose. Furthermore, in order to enhance disintegration and dissolution properties, it is preferable to contain a disintegrating agent such as crospovidone, partially pregelatinized starch, carmellose, corn starch, low-substituted hydroxypropylcellulose, and more preferably crospovidone and / or Or partially pregelatinized starch.
- a disintegrating agent such as crospovidone, partially pregelatinized starch, carmellose, corn starch, low-substituted hydroxypropylcellulose, and more preferably crospovidone and / or Or partially pregelatinized starch.
- the amount of lactose used for the outer shell component is preferably 30 to 65% by mass, more preferably 40 to 60% by mass, and particularly preferably 45 to 55% by mass.
- the amount of crystalline cellulose is preferably 30 to 50% by mass, more preferably 35 to 45% by mass.
- the friability is increased, and when it is greater than 50% by mass, the disintegration property is deteriorated and the mouthfeel tends to be deteriorated.
- the amount ratio of lactose and crystalline cellulose is 1: 0.5 to 1.5 in terms of mass ratio of lactose and crystalline cellulose in consideration of the balance of tablet hardness, disintegration, and feeling of administration. Is more preferable, and 1: 0.8 to 1.3 is particularly preferable.
- the amount of crospovidone is preferably 2.5 to 15% by mass, more preferably 2.5 to 7.5% by mass.
- the amount of partially pregelatinized starch is preferably 2 to 7.5% by mass, more preferably 2.5 to 5% by mass.
- the inner core of the dry coated tablet of the present invention can be composed only of active ingredients composed of tegafur, gimeracil and oteracil potassium.
- the compounding amount of the active ingredient can occupy 50% by mass to 100% by mass of the inner core component, and preferably 70% by mass to 99% by mass.
- an appropriate amount of a pharmaceutically acceptable binder and / or disintegrant can be added.
- Such a binder is not particularly limited as long as it is a binder used in pharmaceutical preparations.
- starch paste methylcellulose, hydroxypropylcellulose (HPC-SSL, HPC-SL, HPC-L, etc.), hydroxy examples thereof include propylmethylcellulose, sodium carboxymethylcellulose (carmellose sodium), gum arabic, gelatin, agar, tragacanth, sodium alginate, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc., and these may be used alone or in combination of two or more.
- it is hydroxypropyl cellulose.
- the binder content can be added in an amount of 0.1 to 2.0% by mass, more preferably 0.4 to 1.0% by mass, based on the total amount of tegafur, gimeracil and oteracil potassium.
- disintegrant examples include carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, etc., and these may be used alone or in combination of two or more. Preferably, crospovidone is used.
- the content of the disintegrant is preferably 3 to 15% by mass with respect to the total amount of tegafur, gimeracil and oteracil potassium.
- a small amount of a disintegration aid can be added to the inner core.
- the disintegration aid include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, Corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, crospovidone, sodium lauryl sulfate, polysorbate, polyoxyethylene polyoxypropylene glycol, sorbitan monooleate, propylene glycol monostearate, polyethylene monolaurate A glycol etc. are mentioned, You may use these in combination of 1 type, or 2 or more types.
- the dry coated tablet of the present invention may contain various commonly used formulation additives in addition to the additives described above as long as the effects of the present invention are not hindered.
- the formulation additive is not particularly limited as long as it is generally used, and examples thereof include a lubricant, a coloring agent, a flavoring agent, and a corrigent.
- the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc and sucrose fatty acid ester.
- the colorant include edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow ferric oxide and titanium oxide.
- flavoring agents include oranges and lemons.
- Examples of the corrigent include L-menthol, camphor, and mint.
- the dry coated tablet of the present invention may be, for example, a dry tablet press such as a tablet press LIBRA2 DC (manufactured by Kikusui Seisakusho), an AP-MS-C type dry tablet press (manufactured by Hata Steel), or an autograph AG.
- -E50k manufactured by Shimadzu Corporation
- the general production method is roughly divided into four stages: (i) supplying a part of the outer shell component into the die, (ii) supplying the previously compressed inner core to the die, (iii) It can be produced by supplying the remaining outer shell components to the mortar, and (iv) pressure molding in the mortar and between the upper and lower ribs. Also, the method described in International Publication No.
- the dry-coated tablet of the present invention has ridges in both the upper and lower directions of the mortar, and at least the upper ridge has a double structure of a central ridge and an outer ridge surrounding the outer periphery of the central ridge. Both can be easily manufactured by a compression molding means which can slide and operate both.
- the dry-coated tablet of the present invention can be produced at a time with a single tableting machine, it can be produced efficiently without carrying out complicated techniques and processes as in the past. Can do.
- the outer shell can be made extremely thin.
- the thickness of the outer shell can be 1 mm or less. This thinning of the outer shell also contributes to improving the disintegration of the dry coated tablets.
- the shape of the dry coated tablet of the present invention is not particularly limited as long as it is easy to grasp or does not feel uncomfortable at the time of taking. preferable.
- size should just be a grade which can be inserted in an oral cavity and does not have difficulty in chewing.
- a circular tablet it may be about 25 mm ⁇ or less, and it may be designed to be 4 to 25 mm ⁇ , preferably 6 to 16 mm ⁇ , more preferably 7 to 12 mm ⁇ .
- the height of the preparation may be about 10 mm or less, and may be designed to be 1 to 10 mm, preferably 1.5 to 7 mm, and more preferably 2 to 5 mm.
- the shape of the inner core depends on the shape of the tip of the heel to be used, but conforms to the shape of the dry-coated tablet.
- the size of the inner core often depends on the size of the entire dry-coated tablet, and it is not preferable that the inner core is too small in order to smoothly perform the molding process of the inner core.
- the inner core may be about 24 mm ⁇ or less in the case of a circular tablet, and may be designed to be 3 to 24 mm ⁇ , preferably 5 to 15 mm ⁇ , more preferably 6 to 11 mm ⁇ .
- the inner core can be divided into a plurality of parts as required.
- the thickness of the outer shell may be set to a thickness that has low friability according to the size of the inner core and can hold the shape of the dry-coated tablet by the outer shell, and is set within a range of 0.2 to 2 mm. Is appropriate. In order to increase the rapid disintegration property in the oral cavity, it is better not to increase the tablet strength of the outer shell part more than necessary. Therefore, the thickness of the outer shell is preferably as thin as possible within the range where the problem of friability does not occur, that is, the shape of the dry-coated tablet can be maintained, and it is actually set to 0.5 to 1.5 mm. And preferred.
- the dry-coated tablet of the present invention is preferably a dry-coated tablet having an inner core of 3 to 24 mm ⁇ , an outer shell thickness of 0.2 to 2 mm, and a preparation height of 1 to 10 mm, and an inner core of 5 to 15 mm ⁇ and an outer shell. More preferable is a dry-coated tablet having a thickness of 0.5 to 1.5 mm and a height of the preparation of 1.5 to 7 mm, an inner core of 6 to 11 mm ⁇ , and an outer shell thickness of 0.5 to 1.5 mm. Particularly preferred is a dry-coated tablet having a preparation height of 2 to 5 mm.
- Tegafur and gimeracil used in the examples are manufactured by Taiho Pharmaceutical Co., Ltd., and oteracil potassium is manufactured by Sumitomo Chemical Co., Ltd.
- Hydroxypropylcellulose (HPC) is manufactured by Nippon Soda Co., Ltd., partially pregelatinized starch and crystalline cellulose are manufactured by Asahi Kasei Chemicals, magnesium stearate is manufactured by Taihei Chemicals, and crospovidone is manufactured by BASF. .
- Reference Example 1 (Preparation 1 of inner core component) Using a fluidized bed granulator multiplex MP-01 (manufactured by Paulek), water was added to a mixture of 66.1 g of tegafur, 19.15 g of gimeracil, 64.75 g of potassium oteracil and 150 g of lactose (manufactured by Borculo Domo Ingredients). 200.0 g was sprayed and granulated to prepare an inner core component.
- Reference Example 2 (Preparation 2 of inner core component)
- 1.0 g of HPC was dissolved in 199.0 g of water in a mixture of 66.1 g of tegafur, 19.15 g of gimeracil, 64.75 g of potassium oteracil and 150 g of lactose (manufactured by Borculo Domo Ingredients).
- the resulting liquid was sprayed and granulated to prepare an inner core component.
- Reference Example 3 (Preparation 3 of inner core component) In the same manner as in Reference Example 1, 200 g of water was sprayed and granulated on a mixture of tegafur 132.2 g, gimeracil 38.3 g and oteracil potassium 129.5 g to prepare an inner core component.
- Reference Example 4 (Preparation 4 of inner core component) In the same manner as in Reference Example 1, a mixture of 132.2 g of tegafur, 38.3 g of gimeracil and 129.5 g of potassium oteracil was sprayed and granulated with a solution of 0.3 g of HPC in 199.7 g of water. Ingredients were prepared.
- Reference Example 5 preparation 5 of inner core component
- a mixture of 132.2 g of tegafur, 38.3 g of gimeracil and 129.5 g of potassium oteracil was sprayed and granulated with a solution of 1.5 g of HPC in 198.5 g of water. Ingredients were prepared.
- Reference Example 6 preparation of inner core component 6)
- a mixture of 132.2 g of tegafur, 38.3 g of gimeracil and 129.5 g of potassium oteracil was sprayed and granulated with a solution of 3.0 g of HPC in 197.0 g of water. Ingredients were prepared.
- Reference Example 7 (Preparation 7 of inner core component) In the same manner as in Reference Example 1, a mixture of 132.2 g of tegafur, 38.3 g of gimeracil and 129.5 g of potassium oteracil was sprayed and granulated with a solution of 4.5 g of HPC in 195.5 g of water. Ingredients were prepared.
- Reference Example 8 (Preparation of inner core component 8) In the same manner as in Reference Example 1, a mixture of 132.2 g tegafur, 38.3 g gimeracil and 129.5 g oteracil potassium was sprayed and granulated with a solution obtained by dissolving 6.0 g HPC in 194.0 g water. Ingredients were prepared.
- Reference Example 9 (Preparation 9 of inner core component)
- a solution prepared by dissolving 4 g of HPC in 396 g of water was sprayed and granulated in a mixture of 200 g of tegafur, 58 g of gimeracil, 196 g of potassium oteracil and 14 g of partially pregelatinized starch (Asahi Kasei Chemicals).
- the inner core component was prepared.
- Reference Example 10 preparation of inner core component 10.
- a mixture of 200 g of tegafur, 58 g of gimeracil and 196 g of potassium oteracil was sprayed and granulated with a solution of 4 g of HPC in 396 g of water to prepare an inner core component.
- Example 1 Using Autograph AG-E50k (manufactured by Shimadzu Corporation), a mixture of 59.88 mg of lactose (manufactured by MEGGLE Excipients & Technology), 60 mg of crystalline cellulose and 0.12 mg of magnesium stearate was used as the outer shell, and A mixture of granulated product 57 mg (25 mg as tegafur) with partially pregelatinized starch 2.84 mg and magnesium stearate 0.28 mg as inner core, outer shell first layer 30 mg, inner core 60.12 mg, and outer shell second layer Packed in the order of 60 mg, a dry-coated tablet with a tablet outer diameter of 8 mm was prepared at a tableting pressure of 5 kN. The schematic diagram regarding the cross section of the obtained dry coated tablet is shown in FIG. The obtained dry coated tablet had an inner core diameter of 6 mm and an outer shell thickness (a) of 1 mm.
- Example 2 A ratio of lactose 53.76 mg (MEGGLE Excipients & Technology), crystalline cellulose 60 mg, crospovidone 6 mg and magnesium stearate 0.24 mg using Autograph AG-E50k (manufactured by Shimadzu Corporation)
- the outer shell is a mixture obtained by adding 2.84 mg of partially pregelatinized starch and 0.28 mg of magnesium stearate to 57 mg (25 mg of tegafur) of the granulated product of Reference Example 5 as the inner core, and 120 mg of the outer shell and the inner core.
- a dry-coated tablet containing 25 mg of tegafur was prepared at 60.12 mg and a tableting pressure of 5 kN.
- the obtained dry coated tablet had an outer diameter of 8 mm, an inner core diameter of 6 mm, and an outer shell thickness of 1 mm.
- Example 3 A desired dry coated tablet was prepared by the same preparation method as in Example 1 except that the inner core components of Reference Examples 1 to 4 and 6 to 10 were used using Autograph AG-E50k (manufactured by Shimadzu Corporation).
- Test example 1 The dry coated tablets 1 to 4 obtained in Example 4 were subjected to hardness, friability, oral disintegration test and dissolution test. The results are shown in Table 1. As a result, the outer shell component was excellent in terms of hardness, friability, disintegration property in the oral cavity and dissolution property at 34 to 64% by mass of lactose for direct hitting, 30 to 50% by mass of crystalline cellulose and 5 to 15% by mass of crospovidone. It was confirmed that it was a dry-coated tablet.
- Example 5 Using the same rotary compression molding machine as in Example 4 (manufactured by Sanwa Chemical Laboratories), the inner shell component was prepared by the same preparation method as in Example 4 using the mixture shown in Table 2 as the outer shell.
- Nucleated tablets 5 to 8 having an outer diameter of 8 mm were prepared.
- Test example 2 The dry coated tablets 5 to 8 obtained in Example 5 were subjected to hardness, friability, oral disintegration test and dissolution test. The results are shown in Table 2. As a result, the hardness and erosion of lactose for direct compression 39-59 mass%, crystalline cellulose 30-50 mass%, crospovidone 2.5-7.5 mass% and partially pregelatinized starch 2.5-7.5 mass% It was confirmed that it was a dry-coated tablet in terms of the degree of disintegration in the oral cavity and dissolution.
- Test example 3 The dry coated tablets 9 to 12 obtained in Example 6 were subjected to hardness, friability, oral disintegration test and dissolution test. The results are shown in Table 3. As a result, the hardness and erosion of lactose for direct compression 39-59 mass%, crystalline cellulose 30-50 mass%, crospovidone 2.5-7.5 mass% and partially pregelatinized starch 2.5-7.5 mass% It was confirmed that it was a dry-coated tablet in terms of the degree of disintegration in the oral cavity and dissolution.
- Test example 4 Each of the dry coated tablets 6 to 8 obtained in Example 5 and the commercially available orally disintegrating tablets (Company A, Company B, Company C, Company D, Company E) are naturally dropped onto a stainless steel plate from a height of 1 m. A tablet drop test was performed. The results are shown in Tables 4 and 5. As a result, it was confirmed that the dry-coated tablets 5 to 8 were excellent in both cracking chipping and mass reduction rate as compared with commercially available orally disintegrating tablets.
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Abstract
Description
(1)(a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムを有効成分として含有する内核と外殻から構成される有核錠。
(2)(a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムをモル比1:0.4:1で含有する(1)に記載の有核錠。
(3)(a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムからなる有効成分が内核成分の50質量%~100質量%を占める、(1)又は(2)に記載の有核錠。
(4)(a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムからなる有効成分が内核成分の70質量%~99質量%を占める、(1)~(3)のいずれかに記載の有核錠。
(5)有核錠における有効成分(a)~(c)の総含有量が10~60質量%である(1)~(4)のいずれかに記載の有核錠。
(6)外殻が乳糖、結晶セルロース、ヒドロキシプロピルセルロースのうちの1種、2種又は3種を含む(1)~(5)のいずれかに記載の有核錠。
(7)外殻が乳糖、結晶セルロースのうちの1種又は2種を含む(6)に記載の有核錠。
(8)外殻が乳糖及び結晶セルロースを含む(7)に記載の有核錠。
(9)外殻に、崩壊剤をさらに含む(6)、(7)又は(8)に記載の有核錠。
(10)崩壊剤が、クロスポビドン、カルメロース、コーンスターチ、低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプンからなる群から選ばれる、(9)に記載の有核錠。
(11)崩壊剤がクロスポビドン及び/又は部分アルファー化デンプンである、(10)に記載の有核錠。
(12)外殻が30~65質量%の乳糖を含む、(1)~(11)のいずれかに記載の有核錠。
(13)外殻が30~50質量%の結晶セルロースを含む、(1)~(12)のいずれかに記載の有核錠。
(14)外殻が2.5~15質量%のクロスポビドンを含む、(1)~(13)のいずれかに記載の有核錠。
(15)外殻が2~7.5質量%の部分アルファー化デンプンを含む、(1)~(14)のいずれかに記載の有核錠。
(16)有核錠の摩損度(累積回転数100回転)が0.3%以下であり、且つ高さ1mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が120秒以下であることを特徴とする、(1)~(15)のいずれかに記載の有核錠。
さらに好ましくは、有核錠の摩損度(累積回転数100回転)が0.2%以下であり、且つ高さ1mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が95秒以下である有核錠であり、さらに好ましくは、有核錠の摩損度(累積回転数100回転)が0.2%以下であり、且つ高さ2mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が95秒以下である有核錠であり、
さらに好ましくは、有核錠の摩損度(累積回転数100回転)が0.2%以下であり、且つ高さ2mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が95秒以下であり、口腔内崩壊錠試験器ODT-101により測定した崩壊時間が20秒以内であり、日本薬局方一般試験法溶出試験法第2法(50min-1、試験液 水900mL)により測定した溶出率(CDHP、15分値)が90%以上である有核錠であり、特に好ましくは、有核錠の摩損度(累積回転数100回転)が0.2%以下であり、且つ高さ2mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が95秒以下であり、口腔内崩壊錠試験器ODT-101により測定した崩壊時間が16秒以内であり、日本薬局方一般試験法溶出試験法第2法(50min-1、試験液 水900mL)により測定した溶出率(CDHP、15分値)が95%以上である有核錠である。
参考例1(内核成分の調製1)
流動層造粒機マルチプレックスMP-01(パウレック社製)を用いて、テガフール66.1g、ギメラシル19.15g、オテラシルカリウム64.75g及び乳糖(Borculo Domo Ingredients社製)150gの混合物に、水200.0gを噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール66.1g、ギメラシル19.15g、オテラシルカリウム64.75g及び乳糖(Borculo Domo Ingredients社製)150gの混合物に、HPC 1.0gを水199.0gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、水200gを噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、HPC 0.3gを水199.7gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、HPC 1.5gを水198.5gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、HPC 3.0gを水197.0gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、HPC 4.5gを水195.5gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール132.2g、ギメラシル38.3g及びオテラシルカリウム129.5gの混合物に、HPC 6.0gを水194.0gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール200g、ギメラシル58g、オテラシルカリウム196g及び部分アルファー化デンプン(旭化成ケミカルズ社製)14gの混合物に、HPC 4gを水396gに溶解した液を噴霧、造粒し、内核成分を調製した。
参考例1と同様の方法で、テガフール200g、ギメラシル58g及びオテラシルカリウム196gの混合物に、HPC 4gを水396gに溶解した液を噴霧、造粒し、内核成分を調製した。
オートグラフAG-E50k(島津製作所製)を用いて、乳糖(MEGGLE Excipients & Technology社製)59.88mg、結晶セルロース60mgおよびステアリン酸マグネシウム0.12mgを混合したものを外殻とし、参考例5の造粒物57mg(テガフールとして25mg)に部分アルファー化デンプン2.84mgおよびステアリン酸マグネシウム0.28mgを添加した混合物を内核として、外殻第1層30mg、内核60.12mg、更に外殻第2層60mgの順に充填し、打錠圧5kNにて錠剤外径8mmの有核錠を調製した。得られた有核錠の断面に関する模式図を図1に示す。得られた有核錠の内核径は6mmであり、外殻の厚さ(a)は1mmであった。
オートグラフAG-E50k(島津製作所製)を用いて、実施例1と同様に、乳糖53.76mg(MEGGLE Excipients & Technology社製)、結晶セルロース60mg、クロスポビドン6mgおよびステアリン酸マグネシウム0.24mgの割合で混合したものを外殻とし、参考例5の造粒物57mg(テガフールとして25mg)に部分アルファー化デンプン2.84mgおよびステアリン酸マグネシウム0.28mgを添加した混合物を内核として、外殻120mg、内核60.12mg、打錠圧5kNにて、テガフール25mgを含有する有核錠を調製した。得られた有核錠の外径は8mmであり、内核径は6mmであり、外殻の厚さは1mmであった。
オートグラフAG-E50k(島津製作所製)を用いて、参考例1~4及び6~10の内核成分を用いた以外は実施例1と同様の調製法で、所望の有核錠を調製した。
国際公開2003-28706号パンフレット記載の回転式圧縮成型機(三和化学研究所製)を用いて、表1に示す割合で混合したものを外殻とし、参考例10の造粒物57.25mg(テガフール量として25mg)にクロスポビドン1.5mg、部分アルファー化デンプン1.5mg、矯味剤1.5mg、ステアリン酸マグネシウム0.25mgを添加した混合物を内核成分として、外殻第1層、内核62mg、更に外殻第2層の順に充填(外殻第1層の量:外殻第2層の量=35:85)し、打錠圧4kNにて錠剤外径8mmの有核錠1~4を調製した。
実施例4で得られた有核錠1~4につき、硬度、摩損度、口腔内崩壊試験および溶出試験を実施した。結果を表1に示す。結果、外殻成分について、直打用乳糖34~64質量%、結晶セルロース30~50質量%及びクロスポビドン5~15質量%において、硬度、摩損度、口腔内崩壊性および溶出性の観点で優れた有核錠であることが確認できた。
硬度 錠剤硬度計 TABLET TESTER 8M、Shleuniger製
摩損度 錠剤摩損度試験器 100回転(25rpm、4分間)
崩壊試験 日本薬局方一般試験法崩壊試験法 試験液 水
口腔内崩壊試験 口腔内崩壊試験器 ODT-101、富山化学製 錘φ20mm20g、回転数75rpm、試験液 水
溶出試験 日本薬局方一般試験法溶出試験法第2法(50min-1)、試験液 水900mL
実施例4と同様の回転式圧縮成型機(三和化学研究所製)を用いて、表2に示す割合で混合したものを外殻とし、実施例4と同様の調製法で内核成分を調製し、外殻第1層、内核60mg、更に外殻第2層の順に充填(外殻第1層の量:外殻第2層の量=35:85)し、打錠圧4kNにて錠剤外径8mmの有核錠5~8を調製した。
実施例5で得られた有核錠5~8につき、硬度、摩損度、口腔内崩壊試験および溶出試験を実施した。結果を表2に示す。結果、直打用乳糖39~59質量%、結晶セルロース30~50質量%、クロスポビドン2.5~7.5質量%及び部分アルファー化デンプン2.5~7.5質量%において、硬度、摩損度、口腔内崩壊性および溶出性の観点で優れた有核錠であることが確認できた。
硬度 錠剤硬度計 TABLET TESTER 8M、Schleuniger製
摩損度 錠剤摩損度試験器 PTF30ERA、PharmaTest Apparatebau製 100回転(25rpm、4分間)
崩壊試験 日本薬局方一般試験法崩壊試験法 試験液 水
口腔内崩壊試験 口腔内崩壊試験器 ODT-101、富山化学製 錘φ20mm20g、回転数75rpm、試験液 水
溶出試験 日本薬局方一般試験法溶出試験法第2法(50min-1)、試験液 水900mL
実施例4と同様の回転式圧縮成型機(三和化学研究所製)を用いて、表3に示す割合で混合したものを外殻とし、参考例10の造粒物45.8mg(テガフール量として20mg)にクロスポビドン2mg、部分アルファー化デンプン0.4mg、矯味剤1.2mg、ステアリン酸マグネシウム0.2mgを添加した混合物を内核成分として、外殻第1層、内核49.6mg、更に外殻第2層の順に充填(外殻第1層の量:外殻第2層の量=30:66)し、打錠圧4kNにて錠剤外径8mmの有核錠9~12を調製した。
実施例6で得られた有核錠9~12につき、硬度、摩損度、口腔内崩壊試験および溶出試験を実施した。結果を表3に示す。結果、直打用乳糖39~59質量%、結晶セルロース30~50質量%、クロスポビドン2.5~7.5質量%及び部分アルファー化デンプン2.5~7.5質量%において、硬度、摩損度、口腔内崩壊性および溶出性の観点で優れた有核錠であることが確認できた。
実施例5で得られた有核錠6~8及び市販されている口腔内崩壊錠(A社、B社、C社D社、E社)につき、1mの高さからステンレス板に自然落下させる錠剤落下試験を実施した。結果を表4及び表5に示す。結果、有核錠5~8は市販されている口腔内崩壊錠と比べ、割れ欠け及び質量減少率ともに優れた有核錠であることが確認できた。
錠剤落下試験 ステンレス板、高さ1m(5個)
Claims (17)
- (a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムを有効成分として含有する内核と外殻から構成される有核錠。
- (a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムをモル比1:0.4:1で含有する請求項1に記載の有核錠。
- (a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムからなる有効成分が内核成分の50質量%~100質量%を占める、請求項1又は2に記載の有核錠。
- (a)テガフール、(b)ギメラシル及び(c)オテラシルカリウムからなる有効成分が内核成分の70質量%~99質量%を占める、請求項1~3のいずれかに記載の有核錠。
- 有核錠における有効成分(a)~(c)の総含有量が10~60質量%である請求項1~4のいずれかに記載の有核錠。
- 外殻が乳糖、結晶セルロース、ヒドロキシプロピルセルロースのうちの1種、2種又は3種を含む請求項1~5のいずれかに記載の有核錠。
- 外殻が乳糖、結晶セルロースのうちの1種又は2種を含む請求項6に記載の有核錠。
- 外殻が乳糖及び結晶セルロースを含む請求項7に記載の有核錠。
- 外殻に、崩壊剤をさらに含む請求項6、7又は8に記載の有核錠。
- 崩壊剤が、クロスポビドン、カルメロース、コーンスターチ、低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプンからなる群から選ばれる、請求項9に記載の有核錠。
- 崩壊剤がクロスポビドン及び/又は部分アルファー化デンプンである、請求項10に記載の有核錠。
- 外殻が30~65質量%の乳糖を含む、請求項1~11のいずれかに記載の有核錠。
- 外殻が30~50質量%の結晶セルロースを含む、請求項1~12のいずれかに記載の有核錠。
- 外殻が2.5~15質量%のクロスポビドンを含む、請求項1~13のいずれかに記載の有核錠。
- 外殻が2~7.5質量%の部分アルファー化デンプンを含む、請求項1~14のいずれかに記載の有核錠。
- 有核錠の摩損度(累積回転数100回転)が0.3%以下である外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が120秒以下であることを特徴とする、請求項1~15のいずれかに記載の有核錠。
- 有核錠の摩損度(累積回転数100回転)が0.2%以下であり、且つ高さ1mからの落下試験において実質的に割れ欠けが生じない外殻を有し、日本薬局方一般試験法崩壊試験法による崩壊時間が95秒以下であることを特徴とする、請求項1~16のいずれかに記載の有核錠。
Priority Applications (14)
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ES12789023.4T ES2671926T3 (es) | 2011-05-25 | 2012-05-24 | Comprimido recubierto en seco que contiene tegafur, gimeracilo y oteracilo potásico |
JP2013516428A JP5689173B2 (ja) | 2011-05-25 | 2012-05-24 | テガフール、ギメラシル、オテラシルカリウム含有有核錠 |
KR1020177016653A KR20170072959A (ko) | 2011-05-25 | 2012-05-24 | 테가푸르, 기메라실 및 오테라실칼륨 함유 구강내 붕괴정 |
RU2013157528/15A RU2601620C2 (ru) | 2011-05-25 | 2012-05-24 | Покрытая сухим способом таблетка, содержащая тегафур, гимерацил и отерацил калия |
AU2012259803A AU2012259803B2 (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
CA2836865A CA2836865C (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
MX2013013563A MX353289B (es) | 2011-05-25 | 2012-05-24 | Tableta revestida en seco que contiene tegafur, gimeracil y oteracil potasico. |
BR112013030093A BR112013030093B1 (pt) | 2011-05-25 | 2012-05-24 | comprimido revestido seco de desintegração oral contendo tegafur, gimeracilo e oteracilo potássico |
KR1020137033946A KR101869127B1 (ko) | 2011-05-25 | 2012-05-24 | 테가푸르, 기메라실 및 오테라실칼륨 함유 구강내 붕괴정 |
NZ617625A NZ617625B2 (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
EP12789023.4A EP2716290B1 (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
US14/118,952 US20140335174A1 (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
SG2013083829A SG194922A1 (en) | 2011-05-25 | 2012-05-24 | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
IL229372A IL229372B (en) | 2011-05-25 | 2013-11-11 | A dry-coated tablet containing tagfor, gimaracil and utracil potassium |
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EP (1) | EP2716290B1 (ja) |
JP (2) | JP5689173B2 (ja) |
KR (2) | KR20170072959A (ja) |
AU (1) | AU2012259803B2 (ja) |
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CA (1) | CA2836865C (ja) |
ES (1) | ES2671926T3 (ja) |
IL (1) | IL229372B (ja) |
MX (1) | MX353289B (ja) |
MY (1) | MY167883A (ja) |
RU (1) | RU2601620C2 (ja) |
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WO2023238929A1 (ja) * | 2022-06-10 | 2023-12-14 | 大鵬薬品工業株式会社 | ピミテスピブを含有する医薬組成物 |
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CA2836865C (en) * | 2011-05-25 | 2018-02-27 | Taiho Pharmaceutical Co., Ltd. | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
CN107865871B (zh) * | 2016-09-23 | 2021-09-03 | 江苏恒瑞医药股份有限公司 | 一种替吉奥组合物及其制备方法 |
CN106619689B (zh) * | 2016-12-30 | 2018-05-01 | 陈晓华 | 一种用于治疗癌症的药物组合物、试剂盒及其应用 |
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CN107837273A (zh) * | 2016-09-18 | 2018-03-27 | 江苏金甙生物技术有限公司 | 一种肠溶替吉奥缓释制剂及其制备方法 |
WO2023238929A1 (ja) * | 2022-06-10 | 2023-12-14 | 大鵬薬品工業株式会社 | ピミテスピブを含有する医薬組成物 |
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Publication number | Publication date |
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TWI566787B (zh) | 2017-01-21 |
US20140335174A1 (en) | 2014-11-13 |
SG10201505503WA (en) | 2015-09-29 |
EP2716290B1 (en) | 2018-03-14 |
EP2716290A4 (en) | 2014-11-26 |
MY167883A (en) | 2018-09-26 |
JPWO2012161240A1 (ja) | 2014-07-31 |
BR112013030093B1 (pt) | 2019-12-10 |
KR20140037879A (ko) | 2014-03-27 |
NZ617625A (en) | 2015-10-30 |
KR20170072959A (ko) | 2017-06-27 |
TWI488659B (zh) | 2015-06-21 |
JP5689173B2 (ja) | 2015-03-25 |
JP2014218523A (ja) | 2014-11-20 |
ES2671926T3 (es) | 2018-06-11 |
SG194922A1 (en) | 2013-12-30 |
AU2012259803B2 (en) | 2016-03-17 |
IL229372B (en) | 2018-12-31 |
TW201529100A (zh) | 2015-08-01 |
TW201300141A (zh) | 2013-01-01 |
MX353289B (es) | 2018-01-05 |
EP2716290A1 (en) | 2014-04-09 |
IL229372A0 (en) | 2014-01-30 |
CA2836865C (en) | 2018-02-27 |
RU2601620C2 (ru) | 2016-11-10 |
BR112013030093A2 (pt) | 2016-09-20 |
KR101869127B1 (ko) | 2018-06-19 |
RU2013157528A (ru) | 2015-06-27 |
CA2836865A1 (en) | 2012-11-29 |
MX2013013563A (es) | 2013-12-16 |
JP5769853B2 (ja) | 2015-08-26 |
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