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WO2006011637A1 - Tablette recouverte d'une pellicule - Google Patents

Tablette recouverte d'une pellicule Download PDF

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Publication number
WO2006011637A1
WO2006011637A1 PCT/JP2005/014149 JP2005014149W WO2006011637A1 WO 2006011637 A1 WO2006011637 A1 WO 2006011637A1 JP 2005014149 W JP2005014149 W JP 2005014149W WO 2006011637 A1 WO2006011637 A1 WO 2006011637A1
Authority
WO
WIPO (PCT)
Prior art keywords
film
compound
coated tablet
coating
citrate
Prior art date
Application number
PCT/JP2005/014149
Other languages
English (en)
Japanese (ja)
Inventor
Takayuki Murakami
Keiichi Fujiwara
Teruaki Kuriyama
Original Assignee
Dainippon Sumitomo Pharma Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dainippon Sumitomo Pharma Co., Ltd. filed Critical Dainippon Sumitomo Pharma Co., Ltd.
Priority to HK07112896.3A priority Critical patent/HK1107258B/xx
Priority to JP2006527889A priority patent/JP4874797B2/ja
Priority to CN2005800254806A priority patent/CN1993131B/zh
Publication of WO2006011637A1 publication Critical patent/WO2006011637A1/fr

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Classifications

    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the present invention relates to a film-coated tablet containing 4-1-amino-5-chloro-2-ethoxy-1-N-[[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof.
  • a film-coated tablet containing 4-1-amino-5-chloro-2-ethoxy-1-N-[[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof.
  • Mosapride 1-Amino-5-chloro-2-ethoxy 1-N- [[4 1 (4-Fnoreo benzyl) 1 2-morpholyl] methyl] benzamide (hereinafter sometimes referred to as “mosapride”) It is a selective serotonin 4 receptor agonist and has a good gastrointestinal motility promoting action (US Pat. No. 4,870,074). Mosapride or its physiologically acceptable salt is also useful as a treatment for reflux esophagitis, post-gastrectomy syndrome, and other gastrointestinal symptoms.
  • Example 2 45 5 of U.S. Pat. No. 4,870,074 describes a film-uncoated tablet containing quenate mosapride.
  • the tablet is a solid preparation containing mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropylcellulose, light anhydrous caustic acid and magnesium stearate.
  • Censic acid mosapride ⁇ dihydrate has already been put into practical use for the purpose of improving gastrointestinal symptoms associated with chronic gastritis.
  • Tablets containing 2.5 mg or 5 mg as mosapride (anhydride) citrate (1.72 mg or 3.4 4 mg as mosapride) are named under the trademark “Gasmotin” in Japan. It is commercially available.
  • Commercially available tablets are in the form of film-coated tablets because mosapride is a bitter drug, and is further packaged with aluminum to prevent the formation and coloring of by-products under long-term storage. .
  • the subject of the present invention contains mosapride or a physiologically acceptable salt thereof. It is an object of the present invention to provide a fast-dissolving film-coated tablet with excellent storage stability without the need for protective packaging such as aluminum packaging.
  • the present inventors have intensively studied to solve this problem, and promote the degradation of mosapride depending on the type of a specific plasticizer considered necessary for forming a coating layer in a film-coated tablet. Some have found that there is something that inhibits (or does not affect) the degradation of mosapride. Therefore, we first tried to produce a film-coated tablet using a film coating composition from which the plasticizer had been removed. Unexpectedly, it was possible to decompose mosapride for long-term storage or without aluminum packaging. Was found to be suppressed, and coloring to the preparation was suppressed, and the present invention was completed.
  • the present inventors have found that if a formulation is prepared using a film coating composition containing a specific formulation component that can suppress the degradation of mosapride or does not affect the degradation, the production will be hindered.
  • the present invention has been completed by finding that the decomposition of mosapride is suppressed and the coloring of the preparation is suppressed even without long-term storage and without aluminum packaging.
  • the present invention relates to 4-amino-5-chloro-2-ethoxy-1-N — [[4- (4′-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof.
  • a fast-dissolving film-coated tablet comprising a film-coated tablet which is substantially free of a plasticizer or is covered with a coating layer containing a specific formulation component.
  • Compound A 4-monoamino-5-chloro-2-ethoxy-1-N — [[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide (hereinafter referred to as “Compound A”) or its physiologically acceptable A fast-dissolving film-coating tablet containing a salt,
  • the surface of the uncoated tablet is substantially free of a plasticizer or is triaceti , Jetyl phthalate, Diptyl sebacate, Tryptyl catenate, Jetyl cepacate, Glycerin fatty acid ester, Acetylated monodaliselide, Acetyl triethyl thioate, Acetyl liptaylate, Monostearin, Sorbitan monolaurate, Coating layer containing at least one specific formulation component selected from the group consisting of dioctyl phthalate, butyl phthalinole butyl dalicolate and medium chain fatty acid triglycerides
  • a film-coated tablet having:
  • Item 2 The film coating tablet according to Item 1, having a coating layer substantially free of a plasticizer.
  • Item 3 Triacetin, Jetyl phthalate, Diptyl sepacate, Triptyl citrate, Jetyl sebacate, Glycerin fatty acid ester, Acetylated monoglyceride, Acetyl triethyl citrate, Acetyl tributyl citrate, Monostearin, Sorbitan monolaurate Item 2.
  • Item 4 Specific formulation ingredients are triacetin, decyl phthalate, dibutyl sepacate, tryptyl citrate, decyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl cetyl catenate, and acetyl catenate Item 4.
  • Item 5 The film-coated tablet according to Item 3, wherein the specific formulation component is selected from the group consisting of triacetin, decyl phthalate, dibutyl sepacate and triptyl citrate.
  • Item 6 The film-coated tablet according to Item 3, wherein the specific formulation component is triacetin.
  • Item 7 The content of the specific formulation component is about 0.1 to about 30% by weight in the coating layer Item 4.
  • Item 8 The film coating tablet according to any one of Items 1 to 7, wherein the physiologically acceptable salt of Compound A is a dihydrate of the citrate salt of Compound A.
  • Item 9 The content of Compound A or a physiologically acceptable salt thereof is about 0.5 to about 70% by weight in terms of Compound A in the uncoated tablet, according to any one of Items 1 to 8 The film-coated tablet as described.
  • Item 10 When the film-coated tablet is stored in a container at 40 ° C and 75% RH for 6 months, the ratio of the amount of compound A related substance produced is Item 10.
  • Item 11 A commercial package containing the film-coated tablet according to Item 1 and a document relating to the film-coated tablet, wherein the film-coated tablet is used to promote gastrointestinal motility function, improve symptoms after gastrectomy, or gastroesophageal
  • the film-coated tablet of the present invention has the above-mentioned characteristics, compound A or a physiologically acceptable salt thereof is difficult to be decomposed and stored in a stable state without applying protective packaging such as aluminum packaging. can do. Furthermore, when the film-coated tablet of the present invention is taken, no bitterness is felt.
  • FIG. 1 is a graph showing the results of a contact test of a compound A-a (a racemate of Compound A) of the present invention with a citrate and various components.
  • FIG. 2 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.
  • FIG. 3 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.
  • FIG. 4 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2. It is fu.
  • FIG. 5 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2.
  • the first aspect of the present invention is a fast-dissolving film comprising a plain tablet containing compound A or a physiologically acceptable salt thereof, and a coating layer substantially free of a plasticizer on the surface of the plain tablet. It is a coated tablet.
  • the film-coated tablet has the effect of suppressing the decomposition of the compound A, which is an active ingredient, and preventing coloration of the preparation even if it is stored for a long period of time without being subjected to protective packaging such as aluminum packaging.
  • Film-coated Fi / REM coated tablets usually contain a plasticizer in the coating layer (coating layer), and the plasticizer has been considered not to react with the active ingredient.
  • certain plasticizers specifically polyethylene glycol, poloxamer, polysorbate, polyoxyethylene hydrogenated castor oil, glycerin, etc., and compound A or its physiologically acceptable It was found that contact with the salt promotes the decomposition of Compound A. Specifically, as shown in the following Reference Examples, when a compound A or a physiologically acceptable salt in the present invention is brought into contact with the above components, a very large amount of decomposed substances (related substances) are produced. It has been found. On the other hand, it was also found that there is a plasticizer that suppresses the decomposition of Compound A.
  • substantially free of a plasticizer means not only a plasticizer having an action of promoting the decomposition of the compound A when contacted with the compound A but also suppressing the decomposition of the compound A (or It means not containing any plasticizer (which has no effect).
  • plasticizer poloxamer, polysorbate, propylene glycol , Polyethylene glycol, glycerin, polyoxyethylene hydrogenated castor oil, triacetin, cetyl phthalate, dibutyl sepacate, tryptyl decanoate, jetyl sepacate, glyceryl fatty acid ester, acetylated monoglyceride, acetytrimethyl quinate
  • plasticizer poloxamer, polysorbate, propylene glycol , Polyethylene glycol, glycerin, polyoxyethylene hydrogenated castor oil, triacetin, cetyl phthalate, dibutyl sepacate, tryptyl decanoate, jetyl sepacate, glyceryl fatty acid ester, acetylated monoglyceride, acetytrimethyl quinate
  • examples include acetyl butyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, but
  • a rapid dissolution comprising an uncoated tablet containing Compound A or a physiologically acceptable salt thereof, and a coating layer containing at least one specific formulation component on the surface of the uncoated tablet.
  • Film-coated tablets are a compound A which is an active ingredient even if it is not subjected to protective packaging such as aluminum packaging even in long-term storage because the coating process proceeds smoothly by blending specific formulation ingredients in the coating layer. It has the effect of not promoting the degradation of or inhibiting the degradation and inhibiting the coloring of the preparation. Also, there will be no trouble in manufacturing.
  • Examples of the “specific formulation component” in this embodiment include triacetin, dimethyl phthalate, diptyl cepacate, triptinole citrate, cetyl cepacate, glyceryl fatty acid ester, acetylated monodaricelide, acetiltyl citrate, and acetyl butyl triacetate. , Monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl dalicolate, and medium chain fatty acid triglycerides. These compounds are generally blended into the preparation as a plasticizer. In addition, some of these compounds are incorporated into the preparations as dispersants, brighteners, stabilizers, surfactants, and the like.
  • At least one of the specific formulation ingredients specifically triacetin, decyl phthalate, diptyl cepacate, tryptyl citrate, cetyl sepacate, glyceryl fatty acid ester, acetylated monodaliselide, cetyl triethyl catenate, Acetylliptyl taenoate, monostearin, sorbita It is preferable that at least one component selected from the group consisting of dimethyl monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acid triglyceride is blended in the coating layer.
  • Compound A is further suppressed, the coating layer becomes stronger, and tablet sliding (including fluidity) is also possible.
  • Preferred are triacetin, phthalate, dibutyl sebacate, dibutyl sebacate, tributyl taenoate, cetyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetiltyl ethyl citrate and cetyl citrate, more preferably Triacetin, decyl phthalate, dibutyl septate and triptyl citrate.
  • the content of these specific formulation components is preferably about 0.1 to about 30% by weight, preferably about 2 to about 25% by weight, and more preferably about 7 to about 20% by weight in the coating layer.
  • the “fast dissolution” of the film-coated tablet according to the present invention is the dissolution test described in the 14th revised Japanese Pharmacopoeia (37 ° C, paddle method, 50 rpm Z min, solvent 90 O m 1 In water), the elution rate after 30 minutes is about 85% or more.
  • the elution rate is preferably 90% or more, more preferably 95% or more.
  • Compound A according to the present invention namely 4-amino-1-5-chloro-2-ethoxy-N — [[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide, has the following formula:
  • Compound A according to the present invention may be a racemate or one of the optically active forms, but a racemate is preferred.
  • Compound A may be a free form or a physiologically acceptable salt thereof.
  • the salt is preferably an acid addition salt.
  • organic acid addition salts include formate, acetate, lactate, adipate, kenate, tartaric acid, fumarate, methanesulfonate, maleate, etc. Addition of inorganic acids Examples of the salt include hydrochloride, sulfate, nitrate, phosphate and the like. Of these, citrate is particularly preferable.
  • Compound A or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. The hydrate of citrate is preferable, and citrate dihydrate is particularly preferable.
  • the above compound A or a physiologically acceptable salt thereof can be produced, for example, by the method described in US Pat. No. 4,887,074 or a method analogous thereto.
  • “Uncoated tablet” may be Compound A or its physiologically acceptable salt alone. Generally, it is formed by blending other formulation ingredients. Any of these other formulation ingredients can be used as long as they are not inconvenient to be added and need to be added. For example, binders, excipients, fluidizing agents, disintegrating agents and the like can be mentioned as examples.
  • the content of Compound A or a physiologically acceptable salt thereof is about 0.01 to about 90 weight in uncoated tablet in terms of Compound A. /.
  • binder examples include gum arabic, starch paste, hydroxypropenoresenorerose, hydroxypropinoremethinoresenorerose, polyvinylinorenoreconole, Examples include punoleran, gelatin, ethinorescenellose, methinorecellulose, canolemellose sodium, dextrin, and povidone. Preferable examples include hydroxypropinoresenorerose, hydroxypropinoremethinoresenellose, povidone and the like.
  • the amount of the binder should be an amount that maintains the hardness of the tablet and does not hinder disintegration in the gastrointestinal tract, and is usually about 0.5 to about 10% by weight in the uncoated tablet, preferably About 1 to about 7% by weight.
  • excipients include lactose, starch, mannitol, crystalline cellulose, sucrose, erythritol, trehalose, anhydrous calcium hydrogen phosphate, sulfated sulfate, and lactose, starch, mannitol, crystalline cellulose, etc. Is preferred.
  • the amount is usually about 5 to about 97% by weight in the uncoated tablet, preferably about 10 to about 80% by weight.
  • the fluidizing agent include light anhydrous caustic acid, magnesium metasilicate aluminate, etc., and light anhydrous caustic acid is preferred.
  • the amount thereof is usually about in plain tablet 0. 0 1 to about 1 0 wt ° / 0, preferably about 0. 1 about 5 wt%.
  • the disintegrating agent examples include low-substituted hydroxypropylcellulose, carmellose strength, croscarmellose sodium, crospovidone and the like. Of these, low-substituted hydroxypropylcellulose has a hydroxypropoxyl group content of usually about 5 to about 16% by weight, preferably about 7 to about 16% by weight. More preferably, about 10 to about 16% by weight is used.
  • the blending amount of the disintegrating agent is usually about 2 to about 30% by weight, preferably about 5 to about 25% by weight in the uncoated tablet.
  • formulation ingredients such as lubricants such as magnesium stearate, zinc stearate, calcium stearate and the like may be blended as necessary.
  • the uncoated tablet should be compression-molded according to conventional methods by combining the above formulation ingredients as appropriate. Can be manufactured. Among these ingredients, lactose and starch as excipients, hydroxypropylcellulose as binder, light anhydrous caustic acid as fluidizing agent, low substituted hydroxypropyl cellulose as a disintegrating agent, stearic acid as lubricant It is preferred to select magnesium.
  • examples of the ingredients contained in the coating layer include the following.
  • Film bases include: Hydroxypropyl methylcellulose (HPMC), Hydroxypropylcellulose (HPC), Cellulose derivatives such as methylcellulose (MC), Ethylcellulose (EC), Polybulol alcohol (PVA), Polybulolpyrrolidone Examples thereof include vinyl polymers such as (PVP) and acrylic polymers such as methacrylic acid copolymers.
  • HPMC can be exemplified.
  • the concentration of the film base in the coating layer is about 5 to about 100% by weight, preferably about 30 to about 100% by weight, especially about 50 to about 98% by weight in the case of a coating layer not containing a plasticizer. % Is preferred. In the case of a coating layer containing a specific formulation component, about 5 to about 99.9% by weight, preferably about 30 to about 98% by weight, especially about 50 to about 93% by weight is preferable.
  • Ingredients that may be added to the coating layer other than the above film base and the above specific formulation ingredients include, for example, colorants such as titanium oxide and iron sesquioxide (content in the coating layer: about 0 1 to about 50 wt./ 0 ), anti-sticking agent such as talc (content in coating layer: about 0.1 to about 50 wt%), brightening agent such as light anhydrous caustic anhydride (coating layer Content: about 0.1 to about 10 weight ° / 0 ).
  • colorants such as titanium oxide and iron sesquioxide (content in the coating layer: about 0 1 to about 50 wt./ 0 )
  • anti-sticking agent such as talc
  • brightening agent such as light anhydrous caustic anhydride (coating layer Content: about 0.1 to about 10 weight ° / 0 ).
  • Other formulation ingredients may be added as needed.
  • one or more film bases (or film bases and specific formulation ingredients) described above are selected, and this is added to an organic solvent such as water or ethanol, preferably Liquid composition prepared by dissolving or suspending in water Can be carried out by spraying on the uncoated tablet.
  • an organic solvent such as water or ethanol, preferably Liquid composition prepared by dissolving or suspending in water Can be carried out by spraying on the uncoated tablet.
  • the coating liquid may contain the colorant, the anti-sticking agent, or the brightening agent, if necessary.
  • the film-coated tablet of the present invention is stable even during long-term storage. Therefore, when the film-coated tablet of the present invention is stored in a container and stored in the container for 6 months under an opening condition of 40 ° C and 75% RH, the amount of related substances produced (total amount of related substances) ) Is measured by high performance liquid chromatography, the percentage of the total related mass in area percentage is about 1% or less. It is preferably about 0.6% or less.
  • the amount of related substances (total related substances) is the total amount of decomposition products of compound A, intermediates during production, impurities during production, etc., which are measured under the high-performance liquid chromatographic method described later. This means the total amount that can be detected.
  • the area percentage refers to the number expressed in ° / 0 of the ratio of the total peak area of related substances to the total peak area obtained by the high-speed liquid kumatograph method described later.
  • the measurement conditions in the high performance liquid chromatographic method are as described in the examples.
  • the film coating agent of the present invention is suitably used for promoting gastrointestinal motility function, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (G E R D).
  • the racemate of Compound A is defined as Compound A—a
  • the citrate dihydrate of Compound A—a is defined as Compound A—b.
  • a product manufactured by Nippon Pharmaceutical Co., Ltd. was used (average particle diameter of about 7 m).
  • Polyethylene Daricol 1 5 0 0 is “Polyethylene Glycol 1 5 0 0” manufactured by Nacalai Testa Co., Ltd.
  • Polyethylene Glycol 4 0 0 is “Macrogol 4 0 0” of Maruishi Pharmaceutical Co., Ltd.
  • Polyethylene Glycol 6 00 0 is “Macro Goal 6 0 0 0” manufactured by Nippon Oil & Fats Co., Ltd.
  • Polysorbate 8 0 is “Polyoxyethylene sorbitan monooleate” manufactured by Nacalai Tesque Co., Ltd.
  • Poloxamer 1 88 is “Pull-mouth Nick PE 6800” manufactured by BAS F Japan Co., Ltd.
  • Glycerin is manufactured by Wako Pure Chemical Industries, Ltd.
  • sorbitan monolaurate is manufactured by Nacala Tester Co., Ltd. Jetyl phthalate was manufactured by Wako Pure Chemical Industries. Monostearin was manufactured by Nacalai Testa Co
  • lactose “Pharma tose R 200mesh” manufactured by DMV was used.
  • starch “Corn Starch” manufactured by Nippon Food Processing Co., Ltd. was used.
  • Light anhydrous Kei acid was used to "Ae ro S i 1 (registered trademark) 200" manufactured by Nippon Aerojiru CO., LTD.
  • hydroxypropyl cellulose “Nisso HPC L” manufactured by Nippon Soda Co., Ltd. was used.
  • L-HP C (LH-1 l) j manufactured by Shin-Etsu Chemical Co., Ltd. was used as the low-substituted hydroxypropyl cellulose.
  • magnesium stearate plant-derived “magnesium stearate” manufactured by Taihei Chemical Industry Co., Ltd. was used.
  • hydroxypropyl methylcellulose “TC-1 5RW” manufactured by Shin-Etsu Chemical Co., Ltd. was used.
  • Titanium oxide was “Titanium oxide” manufactured by Ishihara Sangyo Co., Ltd.
  • the talc used was made by 3 Talc Co., Ltd.
  • Compound A—b and various ingredients (polyethylene glycol 6000, polyethylene glycolol 1500, polyethylene glycolol 400, polysonolate 80, poloxamer 188, glycerin, sorbitan monolaurate, dimethyl phthalate, monostearin, triacetin)
  • a change test was performed. That is, Compound A-b and various components were mixed in a glass container at a weight ratio of 1: 1, and a storage test was conducted at 60 ° C for 1 month after sealing. If it did not dissolve during compounding, it was in suspension or contact.
  • compound A—b was placed in a glass container, and after sealing, a storage test was also conducted at 60 ° C. for 1 month.
  • the amount of related substances produced was measured.
  • the amount of related substances produced was measured by high performance liquid chromatography (area percentage).
  • the total amount of related substances is It means the total amount of decomposition products, intermediates during production, impurities during production, etc. of compound Aa.
  • the sample was prepared by adding water: methanol at a ratio of 1: 9 to the glass container and shaking for 20 minutes, followed by centrifugation to obtain a supernatant.
  • the column used was D everosil ODS-7 (Nomura Chemical), and the mobile phase was a sodium citrate buffer (pH 3.4) nomethanol noacetonitrile mixture (24: 9: 7).
  • the measurement wavelength was 274 nm.
  • the area percentage was determined by the following formula: (total peak area of related substances / total peak area) ⁇ 100.
  • Uncoated tablet 130 mg According to the formulation shown in Table 1, uncoated tablets containing 3.43 mg of Compound Aa per tablet were produced. (1 3 Omg per tablet, round tablet, diameter 7. Omm).
  • Titanium oxide, talc, and light anhydrous caustic acid are added to and suspended in purified water, and then a 10% by weight hydroxypropylmethylcellulose aqueous solution prepared in advance is added and dispersed, and sieved with a sieve (No. 80). A coating solution was prepared.
  • Example 1 Film-coated tablets in which the uncoated tablets obtained in (1) were coated with the coating described in Table 3 per tablet were produced as follows. Table 3: Coating components of film-coated tablets
  • Example 1 (1) 400 g of uncoated tablets obtained in Example 1 (1) (about 3100 tablets) are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 1 tablet. Coated to 5.0 Omg per unit. After coating, drying was performed in a high coater.
  • HC-LAB0 type, Freund Sangyo HC-LAB0 type, Freund Sangyo
  • the tablets obtained in Example 1 and Comparative Example 1 are (1) stored for 6 months at 40 ° C 75% RH in a glass bottle cap, or (2) stored for 6 months at 40 ° C 75% RH in a glass bottle opener.
  • the amount of related substances produced (total amount of related substances) and hue changes were examined at regular intervals.
  • the amount of related substances produced was determined by adding 1 ml of water and 9 ml of methanol to 2 tablets and preparing a sample according to the method described in the reference example.
  • the high-speed liquid kumatograph method described in the reference example area percentage
  • the hue change was determined visually.
  • the results are shown in Figure 2 (glass bottle cap), Figure 3 (glass bottle cap), Table 4 (glass bottle cap) and Table 5 (glass bottle cap).
  • the film-coated tablet of the present invention was excellent in stability under the conditions of 40 ° C. and 75% RH. Therefore, the film-coated tablet of the present invention can be stored in a certain amount without being individually packaged (for example, PTP packaging), so-called para-packaging is also possible. Therefore, the film-coated tablet of the present invention can be prescribed to patients in a simple packaged form (for example, wrapping with dalassin paper, medicine wrapping paper, etc.) or in a wand package packaged together at the time of taking. .
  • Example 1 The bitterness masking test of the tablet obtained in Example 1 was conducted. That is, it was tested by three panelists whether or not there was an unpleasant taste shielding effect as compared with Compound A-b. As a result, the tablets of the example clearly have a shielding effect and the unpleasant taste I could't feel it at all.
  • Example 2 The uncoated tablets obtained in Example 2 were coated with the composition shown in Table 8 per tablet to produce film-coated tablets.
  • Example 2 400 g (about 5,000 tablets) of the uncoated tablets obtained in Example 2 are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 3.0 Omg per tablet. It was coated to become. After coating, drying was performed in a high coater.
  • HC-LAB0 type, Freund Sangyo high coater
  • Example 2 Store the tablets obtained in Example 2 and Comparative Example 2 at 40 ° C 75% RH for 6 months in a glass bottle cap, or (2) 6 bottles at 40 ° C 75% RH in a glass bottle opener Stored for a month and examined the amount of related substances produced (total amount of related substances) and hue changes at regular intervals. The amount of related substances produced was measured in the same manner as in Test Example 1, and the hue change was judged visually.
  • the film-coated tablets of the present invention have a reference value (1) for the amount of related substances produced (total amount of related substances), even after 6 months of storage, regardless of the conditions of opening and sealing. %) Or less. Moreover, the hue change was not recognized and it was stable. Table 9: Hue change of glass bottle seals
  • Film-coated tablets in which the uncoated tablets obtained in Example 1 (1) were coated with the coating described in Table 11 per tablet, were produced as follows. Table 11 1: Coating components of film-coated tablets
  • Example 1 (1) 400 g of uncoated tablets obtained in Example 1 (1) (approximately 3100 tablets) are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 1 tablet. Coated to 5.0 O mg per unit. After coating, drying was performed in a high coater.
  • HC-LAB0 type, Freund Sangyo HC-LAB0 type, Freund Sangyo
  • Example 3 The tablets obtained in Example 3 were (1) stored for 1 month at 40 ° C and 75% RH by opening the glass bottle. The amount of related substances generated (total related substances) was The measurement was performed in the same manner. As a result, both tablets were stable.
  • Example 1 Using the tablet of Example 1, the dissolution test was performed according to the dissolution test described in the 14th revised Japanese Pharmacopoeia (37 ° C, paddle method, 50 rpm, solvent 90 0 m 1 water). . So As a result, the elution rate after 30 minutes was 98.5%.
  • compound A or a physiologically acceptable salt thereof is hardly decomposed and can be stored in a stable state without carrying out protective packaging such as aluminum packaging. In addition, it will not interfere with production. Furthermore, it does not have a bitter taste when taken. While some of the specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed in the following claims.

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Abstract

Cette tablette recouverte d'une pellicule qui se dissout rapidement contient du 4-amino-5-chloro-2-éthoxy-N-[[4-(4-fluorobenzyle)-2-morpholinyl]méthyle]benzamide (ci-après appelé 'composé (A)') ou un sel physiologiquement acceptable de ceci, qui présente une excellente stabilité au stockage. La tablette recouverte d'une pellicule qui se dissout rapidement comprend (a) une tablette non recouverte contenant le composé (A) ou un sel physiologiquement acceptable de celui-ci et (b) une couche de revêtement formée sur la surface de la tablette non recouverte, la couche de revêtement ne contenant presque pas de plastifiant ou contenant au moins un plastifiant choisi dans le groupe constitué de composés ayant une ou plusieurs liaisons d'ester (par ex. de la triacétine).
PCT/JP2005/014149 2004-07-28 2005-07-27 Tablette recouverte d'une pellicule WO2006011637A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
HK07112896.3A HK1107258B (en) 2004-07-28 2005-07-27 Film-coated tablet
JP2006527889A JP4874797B2 (ja) 2004-07-28 2005-07-27 フィルムコーティング錠
CN2005800254806A CN1993131B (zh) 2004-07-28 2005-07-27 薄膜包衣片

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004220864 2004-07-28
JP2004-220864 2004-07-28

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WO2006011637A1 true WO2006011637A1 (fr) 2006-02-02

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KR (1) KR101045508B1 (fr)
CN (1) CN1993131B (fr)
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WO (1) WO2006011637A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011236188A (ja) * 2010-05-06 2011-11-24 Takada Seiyaku Kk パロキセチン含有フイルムコ−テイング経口製剤
JP2012201597A (ja) * 2011-03-23 2012-10-22 Nihon Generic Co Ltd モサプリドを含有する固形製剤
US11331273B2 (en) 2016-03-31 2022-05-17 Intercept Pharmaceuticals, Inc. Film-coated tablet having high chemical stability of active ingredient

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106943369B (zh) * 2016-01-07 2020-06-26 江苏豪森药业集团有限公司 枸橼酸莫沙必利的药物组合物及其制备方法
CN106214657B (zh) * 2016-09-06 2018-04-06 江苏豪森药业集团有限公司 枸橼酸莫沙必利的薄膜包衣片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63264467A (ja) * 1986-04-30 1988-11-01 Dainippon Pharmaceut Co Ltd ベンズアミド誘導体
US20030007962A1 (en) * 2001-05-23 2003-01-09 Vergez Juan A. Pharmaceutical composition containing mosapride and pancreatin
WO2003011256A1 (fr) * 2001-07-30 2003-02-13 Sun Pharmaceutical Industries Limited Composition pharmaceutique d'agent procinetique a liberation orale controlee

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63264467A (ja) * 1986-04-30 1988-11-01 Dainippon Pharmaceut Co Ltd ベンズアミド誘導体
US20030007962A1 (en) * 2001-05-23 2003-01-09 Vergez Juan A. Pharmaceutical composition containing mosapride and pancreatin
WO2003011256A1 (fr) * 2001-07-30 2003-02-13 Sun Pharmaceutical Industries Limited Composition pharmaceutique d'agent procinetique a liberation orale controlee

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011236188A (ja) * 2010-05-06 2011-11-24 Takada Seiyaku Kk パロキセチン含有フイルムコ−テイング経口製剤
JP2012201597A (ja) * 2011-03-23 2012-10-22 Nihon Generic Co Ltd モサプリドを含有する固形製剤
US11331273B2 (en) 2016-03-31 2022-05-17 Intercept Pharmaceuticals, Inc. Film-coated tablet having high chemical stability of active ingredient

Also Published As

Publication number Publication date
KR101045508B1 (ko) 2011-06-30
HK1107258A1 (en) 2008-04-03
TW200605920A (en) 2006-02-16
CN1993131B (zh) 2010-10-13
JP4874797B2 (ja) 2012-02-15
CN1993131A (zh) 2007-07-04
KR20070046117A (ko) 2007-05-02
JPWO2006011637A1 (ja) 2008-05-01

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