JPWO2018190294A1 - Escitalopram pharmaceutical composition - Google Patents
Escitalopram pharmaceutical composition Download PDFInfo
- Publication number
- JPWO2018190294A1 JPWO2018190294A1 JP2018540506A JP2018540506A JPWO2018190294A1 JP WO2018190294 A1 JPWO2018190294 A1 JP WO2018190294A1 JP 2018540506 A JP2018540506 A JP 2018540506A JP 2018540506 A JP2018540506 A JP 2018540506A JP WO2018190294 A1 JPWO2018190294 A1 JP WO2018190294A1
- Authority
- JP
- Japan
- Prior art keywords
- escitalopram
- pharmaceutical composition
- salt
- mannitol
- particles
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 229960004341 escitalopram Drugs 0.000 title claims abstract description 41
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 title claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 43
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K47/02—Inorganic compounds
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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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- 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
- A61K47/30—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
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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Abstract
エスシタロプラムを有効成分として含有する、医薬として保存安定性（光安定性、熱安定性）が担保された新規な医薬組成物を提供することを主な課題とする。
本発明として、例えば、エスシタロプラムまたはその塩と酸化鉄とを含むことを特徴とする医薬組成物、平均粒子径Ｄ５０が４０μｍ以下のエスシタロプラムまたはその塩の粒子とマンニトールとを含む混合物を造粒する工程を含むことを特徴とする医薬組成物の製法、エスシタロプラムまたはその塩と賦形剤とを含む核粒子、およびエチルセルロースを含む被覆層を有することを特徴とする顆粒を挙げることができる。The main object of the present invention is to provide a novel pharmaceutical composition containing escitalopram as an active ingredient and assuring storage stability (light stability, heat stability) as a medicine.
As the present invention, for example, a pharmaceutical composition comprising escitalopram or a salt thereof and iron oxide, and granulating a mixture containing particles of escitalopram or a salt thereof having an average particle diameter D 50 of 40 μm or less and mannitol. The preparation method of the pharmaceutical composition characterized by including a process, The core particle containing an escitalopram or its salt, and an excipient, and the granule characterized by having a coating layer containing an ethyl cellulose can be mentioned.
Description
本発明は、医薬組成物の技術分野に属する。本発明は、エスシタロプラムまたはその塩を有効成分として含有する医薬組成物に関するものであって、医薬品として保存安定性が担保された医薬組成物に関するものである。 The present invention belongs to the technical field of pharmaceutical compositions. The present invention relates to a pharmaceutical composition containing escitalopram or a salt thereof as an active ingredient, and relates to a pharmaceutical composition in which the storage stability is ensured as a pharmaceutical.
エスシタロプラムは、シタロプラムのＳ体の一般名であり、化学名：（Ｓ）−１−［３−（ジメチルアミノ）プロピル］−１−（４−フルオロフェニル）−１，３−ジヒドロイソベンゾフラン−５−カルボニトリル）という化合物である。このものは、選択的セロトニン再取り込み阻害作用 （ＳＳＲＩ） を有し、そのシュウ酸塩（下記構造式参照）は、抗うつ薬としてレクサプロ（登録商標、Ｌｅｘａｐｒｏ）などの商品名で市販されている。 Escitalopram is a general name of S-form of citalopram, chemical name: (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5. A carbonitrile) compound. It has selective serotonin reuptake inhibitory activity (SSRI), and its oxalate (see structural formula below) is marketed under the trade name of Lexapro (registered trademark, Lexapro) as an antidepressant. .
エスシタロプラムの医薬組成物に関する発明としては、例えば、特許文献１および２を挙げることができる。
特許文献１には、高い生物学的利用性を有し、製造時に生じる不純物が最小にされたシュウ酸エスシタロプラムのための医薬剤形を開発することを課題とし、その課題を、１００μｍ未満の平均粒径を有するシュウ酸エスシタロプラムと、少なくとも１種の充填剤を含む粒状物とすることにより解決した発明が記載されている。特許文献１には、色素として酸化チタンの使用が好ましいことが記載されているが（段落［００３７］参照）、それ以外の具体的な色素は実施例を含め、特に挙げられていない。また、膜形成剤も医薬分野で通常使用しうる種々のものが挙げられ、セルロース誘導体も挙げられているが、かかる膜形成剤は、素錠をコーティングするためのものである。As an invention regarding a pharmaceutical composition of escitalopram, for example, Patent Documents 1 and 2 can be mentioned.
Patent Document 1 aims to develop a pharmaceutical dosage form for escitalopram oxalate which has high bioavailability and minimized impurities generated during production, and the problem is an average of less than 100 μm. The invention has been described which was solved by means of particles comprising escitalopram oxalate having a particle size and at least one filler. Patent Document 1 describes that the use of titanium oxide as a dye is preferable (see paragraph [0037]), but other specific dyes including those in Examples are not particularly mentioned. Also, various film-forming agents which can be generally used in the pharmaceutical field are mentioned, and cellulose derivatives are also mentioned, but such film-forming agents are for coating uncoated tablets.
特許文献２には、直接圧縮するのに適したエスシタロプラムシュウ酸塩の大きな結晶性粒子とその製造方法が記載されている。そして、かかる結晶性粒子は、平均粒子径（Ｄ５０）で少なくとも４０μｍの粒度を有する。Patent Document 2 describes large crystalline particles of escitalopram oxalate suitable for direct compression and a method for producing the same. And, such crystalline particles have a particle size of at least 40 μm in average particle size (D 50 ).
一方、特許文献３は、賦形剤と混合した薬物をエチルセルロースで被覆してなる薬物含有顆粒を含む、苦味などの不快な味を低減した口腔内崩壊錠剤を開示する。しかし、エスシタロプラムの医薬組成物に関する記載はない。 On the other hand, Patent Document 3 discloses an orally disintegrating tablet having reduced bitter taste and other unpleasant tastes including drug-containing granules obtained by coating a drug mixed with an excipient with ethyl cellulose. However, there is no description about the pharmaceutical composition of escitalopram.
本発明は、エスシタロプラムまたはその塩を有効成分として含有する、医薬品として保存安定性（光安定性、熱安定性）が担保された新規な医薬組成物を提供することを主な課題とする。 The main object of the present invention is to provide a novel pharmaceutical composition containing escitalopram or a salt thereof as an active ingredient and assuring storage stability (light stability, heat stability) as a pharmaceutical.
本発明者らは、鋭意検討を重ねた結果、酸化鉄をエスシタロプラムの医薬組成物に含めること、また、エスシタロプラムの平均粒子径（Ｄ５０）を４０μｍ以下とし、そのエスシタロプラム粒子とマンニトールとを含む混合物を造粒することにより、上記課題を解決しうることを見出し、本発明を完成した。さらには、エスシタロプラムと賦形剤とを含む核粒子をエチルセルロースで被覆することによっても上記課題を解決しうることを見出し、本発明を完成した。As a result of intensive studies, the present inventors include iron oxide in a pharmaceutical composition of escitalopram, and a mixture containing escitalopram particles and mannitol, with the average particle size (D 50 ) of escitalopram being 40 μm or less. It has been found that the above problems can be solved by granulating, and the present invention has been completed. Furthermore, it discovered that the said subject could be solved also by coat | covering the core particle which contains an escitalopram and an excipient | filler with an ethyl cellulose, and completed this invention.
本発明としては、例えば、下記を挙げることができる。 Examples of the present invention include the following.
［１］エスシタロプラムまたはその塩と酸化鉄とを含むことを特徴とする、医薬組成物。
［２］酸化鉄が、黄色三二酸化鉄、三二酸化鉄である、上記［１］に記載の医薬組成物。
［３］塩がシュウ酸塩である、上記［１］または［２］に記載の医薬組成物。
［４］前記エスシタロプラムまたはその塩が、４０μｍ以下の平均粒子径Ｄ５０を有し、かつ、Ｄ−マンニトールを含む顆粒内に含有されていることを特徴とする、上記［１］〜［３］のいずれか一項に記載の医薬組成物。
［５］前記エスシタロプラムまたはその塩と賦形剤とを含む核粒子の外側に、エチルセルロースを含む被覆層を有する顆粒を含むことを特徴とする、上記［１］〜［４］のいずれか一項に記載の医薬組成物。
［６］前記賦形剤が、Ｄ−マンニトールまたは結晶セルロースである、上記［５］に記載の医薬組成物。
［７］医薬組成物が錠剤である、上記［１］〜［６］のいずれか一項に記載の医薬組成物。[1] A pharmaceutical composition comprising escitalopram or a salt thereof and iron oxide.
[2] The pharmaceutical composition according to the above [1], wherein the iron oxide is yellow ferric oxide or ferric oxide.
[3] The pharmaceutical composition according to the above [1] or [2], wherein the salt is oxalate.
[4] The above-mentioned [1] to [3], wherein the escitalopram or a salt thereof has an average particle diameter D 50 of 40 μm or less and is contained in granules containing D-mannitol. The pharmaceutical composition according to any one of the preceding claims.
[5] Any one of the above-mentioned [1] to [4], which comprises a granule having a coating layer containing ethylcellulose on the outside of the core particle containing escitalopram or a salt thereof and an excipient Pharmaceutical composition as described in-.
[6] The pharmaceutical composition according to [5] above, wherein the excipient is D-mannitol or crystalline cellulose.
[7] The pharmaceutical composition according to any one of the above [1] to [6], wherein the pharmaceutical composition is a tablet.
［８］平均粒子径Ｄ５０が４０μｍ以下のエスシタロプラムまたはその塩の粒子とＤ−マンニトールとを含む混合物を造粒する工程を含むことを特徴とする、医薬組成物の製法。[8] The average particle diameter D 50, characterized in that it comprises a step of granulating a mixture comprising the particles and D- mannitol following escitalopram or a salt thereof 40 [mu] m, preparation of pharmaceutical compositions.
［９］エスシタロプラムまたはその塩と賦形剤とを含む核粒子の外側に、エチルセルロースを含む被覆層を有することを特徴とする、顆粒。
［１０］賦形剤が、Ｄ−マンニトールまたは結晶セルロースである、上記［９］に記載の顆粒。[9] A granule characterized by having a coating layer containing ethylcellulose on the outside of core particles containing escitalopram or a salt thereof and an excipient.
[10] The granule according to the above [9], wherein the excipient is D-mannitol or crystalline cellulose.
本発明によれば、エスシタロプラムまたはその塩を有効成分として含有する医薬組成物において、医薬品としての保存安定性（光安定性、熱安定性）を担保することができる。 According to the present invention, in the pharmaceutical composition containing escitalopram or a salt thereof as an active ingredient, storage stability (light stability, heat stability) as a pharmaceutical product can be ensured.
１ 本発明の医薬組成物
１．１ エスシタロプラム
本発明の医薬組成物（以下、「本発明組成物」という。）は、エスシタロプラムまたはその塩を有効成分として含有する。
本発明に係るエスシタロプラムまたはその塩（以下、これらを併せて単に「エスシタロプラム」ともいう。）は、公知の化合物であって、容易に製造することができ、また入手することができる。当該エスシタロプラムは、粒子であっても、また結晶多形のいずれの結晶形であってもよい。 1 Pharmaceutical Composition of the Present Invention 1.1 Escitalopram The pharmaceutical composition of the present invention (hereinafter referred to as “the composition of the present invention”) contains escitalopram or a salt thereof as an active ingredient.
Escitalopram or a salt thereof (hereinafter collectively referred to simply as “escitalopram”) according to the present invention is a known compound, which can be easily produced and can be obtained. The escitalopram may be in the form of particles or any crystalline form of the crystalline polymorph.
エスシタロプラムの塩としては、医薬上許容される酸付加塩であれば特に制限されず、有機酸との塩、無機酸との塩が挙げられる。有機酸との塩としては、例えば、シュウ酸、酢酸、クエン酸、酒石酸、マレイン酸、コハク酸、フマル酸、ｐ−トルエンスルホン酸、ベンゼンスルホン酸、メタンスルホン酸との塩を挙げることができる。無機酸との塩としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸との塩を挙げることができる。この中、シュウ酸との塩が好ましい。当該塩には、水和物や溶媒和物も含まれる。 The salt of escitalopram is not particularly limited as long as it is a pharmaceutically acceptable acid addition salt, and includes salts with organic acids and salts with inorganic acids. Examples of salts with organic acids include salts with oxalic acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid . Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid. Among these, salts with oxalic acid are preferred. The salts also include hydrates and solvates.
本発明に係るエスシタロプラムは、４０μｍ以下または５〜４０μｍの範囲内の平均粒子径を有することが好ましく、１０〜４０μｍの範囲内の平均粒子径を有することがより好ましい。ここで「平均粒子径」とは、体積平均粒子径であって、レーザー回折法で測定したときに、小さい方からの累積分布が５０％となる粒子径（Ｄ５０、メディアン径）をいう。The escitalopram according to the present invention preferably has an average particle size within the range of 40 μm or less, or 5 to 40 μm, and more preferably 10 to 40 μm. Here, the "average particle diameter" is a volume average particle diameter, and refers to a particle diameter (D 50 , median diameter) of which the cumulative distribution from the smaller one is 50% when measured by a laser diffraction method.
本発明組成物中における単位形態（製剤）あたりのエスシタロプラムの含有量としては、剤型などによって異なるが、エスシタロプラムの量として、１〜５０ｍｇの範囲内が適当であり、５〜２０ｍｇの範囲内が好ましい。 The content of escitalopram per unit form (formulation) in the composition of the present invention varies depending on the dosage form and the like, but the amount of escitalopram is suitably in the range of 1 to 50 mg and in the range of 5 to 20 mg preferable.
１．２ 酸化鉄を含む本発明組成物
本発明組成物は、酸化鉄を含むことが好ましい。酸化鉄を含めることにより、特に光安定性の向上を図ることができる。
上記酸化鉄としては、医薬上許容されるものであれば特に制限されないが、例えば、黄色三二酸化鉄、三二酸化鉄、褐色酸化鉄、黒酸化鉄を挙げることができる。この中、黄色三二酸化鉄、三二酸化鉄が好ましい。1.2 Composition of the Invention Comprising Iron Oxide The composition of the invention preferably comprises iron oxide. By including iron oxide, the light stability can be particularly improved.
The iron oxide is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include yellow ferric oxide, ferric oxide, brown iron oxide, and black iron oxide. Among these, yellow ferric oxide and ferric oxide are preferred.
本発明組成物中における酸化鉄の含有量としては、エスシタロプラムの含有量、酸化鉄の種類、剤型などによって異なるが、０．０１〜１５質量％の範囲内が適当であり、０．０５〜１０質量％の範囲内が好ましく、０．１〜５質量％の範囲内がより好ましい。０．０１質量％未満であると、保存安定性が十分に得られないおそれがある。１５質量％を超えると、粉体物性の悪化や色むらのおそれがある。 The content of iron oxide in the composition of the present invention varies depending on the content of escitalopram, the type of iron oxide, the dosage form, etc., but the range of 0.01 to 15% by mass is suitable, The range of 10 mass% is preferable, and the range of 0.1 to 5 mass% is more preferable. If the amount is less than 0.01% by mass, sufficient storage stability may not be obtained. If it exceeds 15% by mass, there is a possibility that the physical properties of the powder may be deteriorated or the color may be uneven.
１．３ 単位形態と添加剤
本発明組成物の単位形態（製剤）としては、例えば、錠剤、カプセル剤、顆粒剤、細粒剤、散剤を挙げることができる。この中、錠剤が好ましく、かかる錠剤としては、例えば、普通錠、フィルムコーティング錠、糖衣錠、多層錠、腸溶錠、マトリックス錠、口腔内崩壊錠、徐放性錠剤、分散錠、咀嚼錠、舌下錠、トローチ、チュアブル錠を挙げることができる。なお、錠剤の硬度は、特に制限されないが、例えば、３５〜１３０Ｎとすることが好ましい。1.3 Unit Forms and Additives As unit forms (preparation) of the composition of the present invention, for example, tablets, capsules, granules, fine granules and powders can be mentioned. Among them, tablets are preferred, and such tablets are, for example, plain tablets, film coated tablets, sugar coated tablets, multi-layered tablets, enteric tablets, matrix tablets, orally disintegrating tablets, sustained release tablets, dispersible tablets, chewing tablets, tongue There may be mentioned under tablets, troches and chewable tablets. The hardness of the tablet is not particularly limited, but preferably 35 to 130 N, for example.
本発明組成物には、その剤型および必要に応じて、前述の酸化鉄以外に、医薬上許容される添加剤が含まれる。かかる添加剤としては、特に制限されないが、例えば、賦形剤、崩壊剤ないし崩壊促進剤、結合剤、滑沢剤ないし流動化剤（付着防止剤）、コーティング剤、可塑剤、着色剤、矯味剤、保存剤、分散剤、香料を挙げることができる。本発明組成物は、剤型等に応じて、これらを適宜適量有することができる。 The composition of the present invention contains, in addition to the above-mentioned iron oxide, a pharmaceutically acceptable additive, as well as its dosage form and optionally. Such additives are not particularly limited, and, for example, excipients, disintegrants or disintegrators, binders, lubricants or fluidizers (antiadhesion agents), coatings, plasticizers, colorants, taste masking Agents, preservatives, dispersants, perfumes can be mentioned. The composition of the present invention can have an appropriate amount of these according to the dosage form and the like.
上記添加剤の具体例としては、Ｄ−マンニトール、乳糖、結晶セルロース、トウモロコシデンプン、カンテン、ゼラチン、沈降炭酸カルシウム、リン酸水素カルシウム、白糖などの賦形剤；カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、炭酸カルシウム、炭酸ナトリウム、トウモロコシデンプン、カルメロースカルシウム、クロスポビドンなどの崩壊剤ないし崩壊促進剤；カルボキシメチルセルロースナトリウム、メチルセルロース、ヒプロメロース、ゼラチン、ポリビニルピロリドン、ポリビニルアルコール、ポビドンなどの結合剤；コロイド状のシリカ、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、含水二酸化ケイ素、軽質無水ケイ酸、マクロゴールなどの滑沢剤ないし流動化剤；メチルセルロース、エチルセルロース、ヒプロメロース、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム、酢酸フタル酸セルロース、フタル酸ヒドロキシプロピルメチルセルロース、ポリアクリレートおよびポリメタクリレート（オイドラギッド（登録商標））、ポリビニルピロリドン、酢酸フタル酸ポリビニル、セラックなどのコーティング剤；ポリエチレングリコール、トリアチン、グリセリン脂肪酸エステル、流動パラフィンなどの可塑剤；酸化チタンなどの着色剤；アスパルテーム、サッカリンなどの矯味剤を挙げることができる。 Specific examples of the above additives include: D-mannitol, lactose, crystalline cellulose, corn starch, agarten, gelatin, precipitated calcium carbonate, calcium hydrogen phosphate, excipients such as sucrose, carboxymethylcellulose, carboxymethylcellulose calcium, low substitution Hydroxyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate, corn starch, carmellose calcium, disintegrant or disintegrator such as crospovidone; sodium carboxymethyl cellulose, methyl cellulose, hypromellose, gelatin, polyvinyl alcohol Binders such as pyrrolidone, polyvinyl alcohol, povidone, colloidal silica, talc, magnesium stearate, Lubricant or fluidizing agent such as calcium aluminate, stearic acid, hydrous silicon dioxide, light anhydrous silicic acid, macrogol, methylcellulose, ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, phthalate Acid agents such as hydroxypropyl methylcellulose, polyacrylate and polymethacrylate (Eudragit (registered trademark)), polyvinyl pyrrolidone, polyvinyl acetate phthalate, shellac, etc .; polyethylene glycol, triatin, glycerin fatty acid ester, plasticizer such as liquid paraffin; titanium oxide And colorants; and flavoring agents such as aspartame and saccharin.
１．４ その他
本発明組成物が錠剤の場合、４０℃相対湿度７５％の開放条件下において、１カ月保存した後のエスシタロプラム総類縁物質が０．２重量％以下であるものが好ましい。０．１５重量％以下であるものがより好ましい。０．１重量％以下であるものが更に好ましい。
1.4 Others When the composition of the present invention is a tablet, one having an escitalopram total related substance of 0.2% by weight or less after storage for 1 month under an open condition of 40 ° C and a relative humidity of 75% is preferable. It is more preferable that it is 0.15 weight% or less. More preferably, it is 0.1% by weight or less.
２ 本発明組成物の製法
本発明組成物は、採用する剤型に応じて、常法により製造することができる。
例えば、錠剤は、賦形剤、崩壊剤等を加えて粉末混合物を作り、これに着色剤等を分散させた分散液を加えて造粒（例えば、湿式造粒）して顆粒化もしくはスラグ化し、乾燥・整粒し、次いで賦形剤や崩壊剤、滑沢剤等を加えた後、打錠（圧縮）することにより製造することができる。造粒は、乾式造粒でもよい。 2. Process for Producing the Composition of the Present Invention The composition of the present invention can be produced by a conventional method, depending on the type of preparation employed.
For example, tablets are prepared by adding excipients, disintegrants and the like to make a powder mixture, adding a dispersion in which a coloring agent and the like are dispersed thereto, granulating (for example, wet granulation), granulating or slugging After drying and sizing, and then adding excipients, disintegrants, lubricants and the like, it can be produced by tableting (compression). Granulation may be dry granulation.
本発明組成物（錠剤）の製法においては、平均粒子径が４０μｍ以下または５〜４０μｍの範囲内のエスシタロプラム粒子とマンニトールとを含む混合物を造粒する工程を含むことが好ましい。かかる製法におけるエスシタロプラム粒子の平均粒子径は、１０〜４０μｍの範囲内がより好ましい。造粒は、湿式造粒、乾式造粒のいずれでもあってもよいが、湿式造粒が好ましい。
当該製法により製造された本発明組成物は、特に光安定性の向上に優れる。The method for producing the composition (tablet) of the present invention preferably includes the step of granulating a mixture containing escitalopram particles having an average particle diameter of 40 μm or less or in the range of 5 to 40 μm and mannitol. The average particle size of escitalopram particles in such a production method is more preferably in the range of 10 to 40 μm. Granulation may be either wet granulation or dry granulation, but wet granulation is preferred.
The composition of the present invention produced by the production method is particularly excellent in the improvement of the light stability.
また、本発明組成物（錠剤）は、エスシタロプラムと賦形剤とを含む核粒子の外側にエチルセルロースを含む被覆層を有する顆粒を用いて製造することが好ましい。当該賦形剤としては、前記と同様のものを挙げることができるが、Ｄ−マンニトールや結晶セルロースが好ましい。かかる製法により製造された本発明組成物は、特に熱安定性の向上に優れる。 Moreover, it is preferable to manufacture this invention composition (tablet) using the granule which has a coating layer containing an ethylcellulose on the outer side of the core particle containing an escitalopram and an excipient | filler. Although the said thing can be mentioned as the said excipient | filler, D-mannitol and crystalline cellulose are preferable. The composition of the present invention produced by such a production method is particularly excellent in the improvement of the heat stability.
上記顆粒は、常法により製造することができる。具体的には、例えば、各配合成分を混合し、造粒（例えば、湿式造粒）し、整粒・乾燥して当該核粒子を作製し、その核粒子を、エチルセルロースを含む被覆剤で常法により被覆することにより製造することができる。当該核粒子とエチルセルロースを含む被覆層との間に中間被覆層を有していてもよい。
当該核粒子には、酸化鉄などを含めることができる。また、エチルセルロースを含む被覆層には、タルク、酸化鉄などを含めることができる。The above granules can be produced by a conventional method. Specifically, for example, each compounding component is mixed, granulated (for example, wet granulation), sized and dried to prepare the core particle, and the core particle is usually coated with a coating agent containing ethyl cellulose. It can be manufactured by coating by a method. An intermediate coating layer may be provided between the core particles and the coating layer containing ethylcellulose.
The core particles can include iron oxide and the like. Further, talc, iron oxide and the like can be contained in the coating layer containing ethyl cellulose.
当該核粒子およびエチルセルロースを含む被覆層を有する上記顆粒と、賦形剤、滑沢剤等とを加え混合した後、常法により打錠（圧縮）することにより、本発明組成物（錠剤）を製造することができる。 The composition of the present invention (tablet) is prepared by adding and mixing the above-mentioned granules having a coating layer containing the core particles and ethylcellulose, an excipient, a lubricant and the like, and compressing (compressing) according to a conventional method. It can be manufactured.
さらに、本発明組成物（錠剤）は、必要に応じて、錠剤表面を被覆剤でフィルムコーティングすることができ、また糖類で糖衣することもできる。かかるフィルムコーティングで使用しうる被覆剤としては、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、エチルセルロース、ポリアクリレートおよびポリメタクリレート（オイドラギッド（登録商標））を挙げることができる。 Furthermore, the composition of the present invention (tablet) can be film-coated with a coating on the tablet surface, if necessary, and can be sugar-coated with sugar. Examples of coating agents that can be used in such film coating include hypromellose, hydroxypropyl cellulose, ethyl cellulose, polyacrylates and polymethacrylates (Eudragit (R)).
本発明組成物は、剤型、エスシタロプラムの含有量、患者の状態、体重、年齢等によって異なるが、例えば、１日１回〜数回または１日〜数日間の間隔でヒトなどに、例えば抗うつ剤として投与することができる。 The composition of the present invention may vary depending on the dosage form, the content of escitalopram, the condition of the patient, body weight, age, etc. It can be administered as a depressant.
以下に実施例や試験例などを掲げて本発明を説明するが、本発明はこれら実施例により何ら限定されるものではない。 EXAMPLES The present invention will be described by listing examples and test examples below, but the present invention is not limited by these examples.
＜安定性試験＞
（１）光安定性試験
光安定性試験は、ＡＴＬＡＳ社製の光安定性試験装置（型番：ＳＵＮＴＥＳＴ ＸＬＳ＋）を用いて、総照度１２０万ｌｘ（ルクス）・ｈｒの照射条件で行った。<Stability test>
(1) Photostability test The photostability test was conducted under an irradiation condition of a total illuminance of 1.2 million lx (lux) · hr using a light stability test apparatus manufactured by ATLAS (model number: SUNTEST XLS +).
（２）熱安定性試験
熱安定性試験は、４０℃相対湿度７５％ＲＨの開放条件下において、１ヶ月間保存することにより行った。(2) Thermal Stability Test The thermal stability test was conducted by storing for 1 month under open conditions of 40 ° C. and 75% RH.
（３）類縁物質の測定方法
試料溶液の各類縁物質（類縁１、類縁２）および総類縁物質の量は、ＨＰＬＣ法で測定した。そして、各類縁物質または総類縁物質の量を、ＨＰＬＣのエスシタロプラムに由来する全ピーク面積中の各類縁物質または総類縁物質のピーク面積の割合（％）で表した。本測定に使用した試料溶液、およびＨＰＬＣの測定条件は、以下の通りである。なお、各類縁物質は、それぞれ下記の構造を有する。また、総類縁物質とは、類縁１および類縁２を含むすべての不純物を合わせたものである。(3) Measurement Method of Related Substances The amount of each related substance (analog 1, relative 2) and total related substances in the sample solution was measured by the HPLC method. Then, the amount of each related substance or total related substance was expressed as a percentage (%) of the peak area of each related substance or total related substance in the total peak area derived from escitalopram in HPLC. The sample solution used for this measurement and the measurement conditions of HPLC are as follows. Each related substance has the following structure, respectively. In addition, total related substances are all impurities including affinity 1 and affinity 2 in combination.
〔試料溶液〕
錠剤（１個）または顆粒（１個）に、下記移動相Ａを２０ｍＬ加えて振り混ぜて超音波処理した。得られた液を孔径０．４５μｍ以下のメンブランフィルターでろ過し、初めのろ液５ｍＬを除き、次のろ液１０ｍＬを試料溶液とした。[Sample solution]
To tablets (1 piece) or granules (1 piece), 20 mL of the following mobile phase A was added, shaken, and sonicated. The resulting solution was filtered with a membrane filter with a pore size of 0.45 μm or less to remove 5 mL of the first filtrate, and 10 mL of the next filtrate was used as a sample solution.
〔ＨＰＬＣ測定条件〕
検出器：紫外吸光光度計（測定波長：２３７ｎｍ）
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５μｍの液体クロマトグラフ用オクタデシルシリカゲルを充填したもの。
カラム温度：４５℃付近の一定温度
移動相Ａ：ｐＨ３．０のリン酸塩緩衝液／アセトニトリル混液（１７：３）
移動相Ｂ：アセトニトリル／ｐＨ３．０のリン酸塩緩衝液（４：１）
移動相の送液：移動相Ａ及び移動相の混合比を適宜調整し、濃度勾配制御する。
流量：毎分１．０ｍＬ[HPLC measurement conditions]
Detector: Ultraviolet absorptiometer (measurement wavelength: 237 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm filled with 5 μm octadecyl silica gel for liquid chromatography.
Column temperature: constant temperature around 45 ° C. Mobile phase A: pH 3.0 phosphate buffer / acetonitrile mixed solution (17: 3)
Mobile phase B: acetonitrile / pH 3.0 phosphate buffer (4: 1)
Transfer of mobile phase: The mixing ratio of mobile phase A and mobile phase is appropriately adjusted, and concentration gradient control is performed.
Flow rate: 1.0 mL per minute
［試験例１］ 酸化鉄含有の効果（平均粒子径Ｄ５０が１５μｍの場合）
表１、２の前段に示す処方に従い、平均粒子径Ｄ５０が１５μｍエスシタロプラムシュウ酸塩および各添加剤を混合し、直接打錠することによって試験用素錠を得た。そして、各試験用素錠について、光安定性試験を行った。その試験結果を表１、２の後段に示す。Test Example 1 Effect of Containing Iron Oxide (When Average Particle Size D 50 is 15 μm)
According to the formulation shown in preceding Tables 1 and 2, the average particle diameter D 50 of a mixture of 15μm escitalopram oxalate and each additive, to give a plain tablet test by direct tableting. And the light stability test was done about each uncoated tablet for a test. The test results are shown in the latter part of Tables 1 and 2.
表１、２に示す結果から明らかな通り、酸化鉄を含む錠剤は、酸化鉄を含まない錠剤あるいは酸化鉄の代わりに酸化チタンを含む錠剤よりも光安定性に優れていた。 As evident from the results shown in Tables 1 and 2, the tablets containing iron oxide were superior in light stability to tablets containing no iron oxide or tablets containing titanium oxide instead of iron oxide.
［試験例２］ 酸化鉄含有の効果（平均粒子径Ｄ５０が４０μｍの場合）
表３、４の前段に示す処方に従い、試験例１に記載の製法と同様にして、試験用素錠を得た。そして、各試験用素錠について、光安定性試験を行った。その試験結果を表３、４の後段に示す。[Test Example 2] Effect of containing iron oxide (when the average particle size D 50 is 40 μm)
According to the prescription shown in the front | former stage of Table 3, 4, it carried out similarly to the manufacturing method of Experiment 1, and obtained the uncoated tablet for a test. And the light stability test was done about each uncoated tablet for a test. The test results are shown in the latter part of Tables 3 and 4.
表３、４に示す結果から明らかな通り、酸化鉄を含む錠剤は、酸化鉄を含まない錠剤あるいは酸化鉄の代わりに酸化チタンを含む錠剤よりも光安定性に優れていた。 As apparent from the results shown in Tables 3 and 4, the tablets containing iron oxide were superior in light stability to tablets containing no iron oxide or tablets containing titanium oxide instead of iron oxide.
［試験例３］ 原薬の粒子径の効果（非コーティング顆粒の安定性）
表５ないし表６の前段に示す処方に従い、平均粒子径Ｄ５０が１５μｍ、４０μｍ、または１８０μｍのエスシタロプラムシュウ酸塩、Ｄ−マンニトール、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに着色剤（黄色三二酸化鉄、三二酸化鉄、または酸化チタン）を水に分散させた分散液、または分散させない液を加えて、造粒し、乾燥させ、整粒して、試験用整粒末（素顆粒）を得た。そして、各試験用素顆粒について、光安定性試験を行った。その試験結果を表５ないし表６の後段に示す。[Test Example 3] Effect of particle size of drug substance (stability of non-coated granules)
According to the formulation shown in the front part of Tables 5 to 6, while mixing escitalopram oxalate, D-mannitol, croscarmellose sodium and hydroxypropyl cellulose having an average particle diameter D 50 of 15 μm, 40 μm or 180 μm, A dispersion in which a coloring agent (yellow ferric oxide, ferric oxide, or titanium oxide) is dispersed in water, or a non-dispersed liquid is added, granulated, dried and sized, and the particle size adjusted for testing. Obtained (elementary granules). And the light stability test was done about each elementary particle for a test. The test results are shown in the latter part of Tables 5 to 6.
表５、表６に示す結果から明らかな通り、平均粒子径Ｄ５０が１８０μｍのものに比べ、１５μｍ、および４０μｍものを含む顆粒は、光安定性に優れていた。As apparent from the results shown in Tables 5 and 6, the granules containing 15 μm and 40 μm had excellent photostability as compared with those having an average particle diameter D 50 of 180 μm.
［試験例４］ 原薬の粒子径の効果（コーティング粒子からなる錠剤の安定性）
表７、８に示す処方に従い、平均粒子径Ｄ５０が１５μｍ、４０μｍ、または１８０μｍのエスシタロプラムシュウ酸塩、Ｄ−マンニトール、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに着色剤（黄色三二酸化鉄、三二酸化鉄、または酸化チタン）を水に分散させた分散液、または分散させない液を加えて、造粒し、乾燥させ、整粒して、核粒子を調製した。別途、精製水と無水エタノールの混合液にエチルセルロース（被覆剤）を溶解させた溶解液に、タルクを分散させて被覆液を調製した。Test Example 4 Effect of Particle Size of Drug Substance (Stability of Tablet Composed of Coated Particles)
According to the formulation shown in Tables 7 and 8, while mixing escitalopram oxalate, D-mannitol, croscarmellose sodium, and hydroxypropyl cellulose having an average particle diameter D 50 of 15 μm, 40 μm, or 180 μm, a coloring agent ( A dispersion in which yellow ferric oxide, ferric oxide or titanium oxide was dispersed in water, or a liquid not dispersed was added, granulated, dried and sized to prepare core particles. Separately, talc was dispersed in a solution in which ethyl cellulose (coating agent) was dissolved in a mixture of purified water and absolute ethanol to prepare a coating solution.
上記核粒子を流動層造粒機に入れ、これに上記被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング粒子）を調製した。かかるコーティング粒子、Ｄ−マンニトール、結晶セルロース、軽質無水ケイ酸、クロスカルメロースナトリウム、タルク、ステアリン酸マグネシウムを混合し、打錠することにより、試験用素錠を得た。そして、各試験用素錠について、光安定性試験を行った。その試験結果を表７、８の各後段に示す。 The core particles were placed in a fluid bed granulator, and the coating solution was sprayed thereon, dried, and sized to obtain a sized powder (coated particles). The coated particles, D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, and magnesium stearate were mixed and tableted to obtain a plain tablet for test. And the light stability test was done about each uncoated tablet for a test. The test results are shown in the latter part of Tables 7 and 8.
表７、表８に示す結果から明らかな通り、平均粒子径Ｄ５０が１８０μｍのものに比べ、１５μｍ、および４０μｍものを含むコーティング粒子から得られた錠剤は、光安定性に優れていた。As is clear from the results shown in Tables 7 and 8, the tablets obtained from the coated particles containing 15 μm and 40 μm had excellent light stability, as compared with those having an average particle diameter D 50 of 180 μm.
［試験例５］ エチルセルロース被覆の効果（熱安定性、マンニトール含有）
表９に示す処方に従い、平均粒子径Ｄ５０が１５μｍのエスシタロプラムシュウ酸塩、Ｄ−マンニトール、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに三二酸化鉄を水に分散させた分散液を加えて造粒し、乾燥させ、整粒して、核粒子を調製した。実施例５７を除き、別途、精製水と無水エタノールの混合液に被覆剤（エチルセルロース、ヒプロメロース、またはアミノアルキルメタクリレートコポリマーＥ）を溶解させた溶解液に、タルクを分散させて被覆液を調製した。Test Example 5 Effect of Ethyl Cellulose Coating (Thermal Stability, Containing Mannitol)
Dispersion where iron trioxide is dispersed in water while mixing escitalopram oxalate having an average particle size D 50 of 15 μm, D-mannitol, croscarmellose sodium and hydroxypropyl cellulose according to the formulation shown in Table 9 The solution was added, granulated, dried and sized to prepare core particles. A talc was dispersed in a solution in which a coating agent (ethyl cellulose, hypromellose or aminoalkyl methacrylate copolymer E) was dissolved in a mixture of purified water and absolute ethanol separately, except for Example 57, to prepare a coating.
実施例５７を除き、上記核粒子を流動層造粒機に入れ、これに上記被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング粒子）を調製した。かかるコーティング粒子または非コーティング顆粒（核粒子）、Ｄ−マンニトール、結晶セルロース、軽質無水ケイ酸、クロスカルメロースナトリウム、タルク、ステアリン酸マグネシウムを混合し、打錠することにより、試験用素錠を得た。そして、各試験用素錠について、熱安定性試験を行った。その試験結果を表１０に示す。 Except for Example 57, the above core particles were placed in a fluid bed granulator, sprayed with the above coating solution, dried, and sized to obtain a sized powder (coated particles). Such coated particles or uncoated granules (core particles), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate are mixed and tableted to obtain a plain tablet for test. The And the heat stability test was done about each uncoated tablet for a test. The test results are shown in Table 10.
表１０に示す結果から明らかな通り、核粒子をエチルセルロースで被覆したコーティング粒子から得られた錠剤は、核粒子を他の被覆剤で被覆したコーティング粒子または被覆剤で被覆しない粒子から得られた錠剤よりも熱安定性に優れていた。 As apparent from the results shown in Table 10, the tablets obtained from the coated particles in which the core particles are coated with ethylcellulose are tablets obtained from the coated particles in which the core particles are coated with the other coating or the particles not coated with the coating. Thermal stability was better than that.
［試験例６］ エチルセルロース被覆の効果（熱安定性、乳糖含有）
表１１に示す処方に従い、平均粒子径Ｄ５０が１５μｍのエスシタロプラムシュウ酸塩、乳糖水和物、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに三二酸化鉄を水に分散させた分散液を加えて造粒し、乾燥させ、整粒して、核粒子を調製した。実施例６６を除き、別途、精製水と無水エタノールの混合液に被覆剤（エチルセルロース）を溶解させた溶解液に、タルクを分散させて被覆液を調製した。Test Example 6 Effect of Ethyl Cellulose Coating (Heat Stability, Lactose Containing)
Iron trioxide was dispersed in water while mixing escitalopram oxalate having an average particle size D 50 of 15 μm, lactose hydrate, croscarmellose sodium and hydroxypropyl cellulose according to the formulation shown in Table 11 The dispersion was added, granulated, dried and sized to prepare core particles. Talc was dispersed in a solution in which a coating agent (ethyl cellulose) was dissolved in a mixture of purified water and absolute ethanol separately, except for Example 66, to prepare a coating solution.
実施例６６を除き、上記核粒子を流動層造粒機に入れ、これに上記被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング粒子）を調製した。かかるコーティング顆粒または非コーティング顆粒（核粒子）、Ｄ−マンニトール、結晶セルロース、軽質無水ケイ酸、クロスカルメロースナトリウム、タルク、ステアリン酸マグネシウムを混合し、打錠することにより、試験用素錠を得た。そして、各試験用素錠について、熱安定性試験を行った。その試験結果を表１２に示す。 Except for Example 66, the core particles were placed in a fluid bed granulator, sprayed with the coating solution, dried, and sized to obtain sized powder (coated particles). The coated granules or uncoated granules (core particles), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate are mixed and tableted to obtain a plain tablet for testing. The And the heat stability test was done about each uncoated tablet for a test. The test results are shown in Table 12.
表１２に示す結果から明らかな通り、核粒子をエチルセルロースで被覆したコーティング粒子から得られた錠剤は、被覆剤で被覆しない粒子から得られた錠剤よりも熱安定性に優れていた。 As is clear from the results shown in Table 12, the tablets obtained from the coated particles in which the core particles were coated with ethylcellulose were superior in thermal stability to the tablets obtained from the particles not coated with the covering agent.
［試験例７］ エチルセルロース被覆の効果（熱安定性、結晶セルロース含有）
表１３に示す処方に従い、平均粒子径Ｄ５０が１５μｍのエスシタロプラムシュウ酸塩、結晶セルロース、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに三二酸化鉄を水に分散させた分散液を加えて造粒し、乾燥させ、整粒して、核粒子を調製した。実施例７３を除き、別途、精製水と無水エタノールの混合液に被覆剤（エチルセルロース）を溶解させた溶解液に、タルクを分散させて被覆液を調製した。Test Example 7 Effect of Ethyl Cellulose Coating (Thermal Stability, Containing Crystalline Cellulose)
A dispersion in which ferric oxide is dispersed in water while mixing escitalopram oxalate having an average particle size D 50 of 15 μm, crystalline cellulose, croscarmellose sodium and hydroxypropyl cellulose according to the formulation shown in Table 13 Was granulated, dried and sized to prepare core particles. Talc was dispersed in a solution obtained by separately dissolving a coating agent (ethyl cellulose) in a mixture of purified water and absolute ethanol except for Example 73 to prepare a coating solution.
実施例７３を除き、上記核粒子を流動層造粒機に入れ、これに上記被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング顆粒）を調製した。かかるコーティング顆粒または非コーティング顆粒（核粒子）、Ｄ−マンニトール、結晶セルロース、軽質無水ケイ酸、クロスカルメロースナトリウム、タルク、ステアリン酸マグネシウムを混合し、打錠することにより、試験用素錠を得た。そして、各試験用素錠について、熱安定性試験を行った。その試験結果を表１４に示す。 Except for Example 73, the core particles were placed in a fluid bed granulator, sprayed with the coating solution, dried, and sized to obtain a sized powder (coated granules). The coated granules or uncoated granules (core particles), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate are mixed and tableted to obtain a plain tablet for testing. The And the heat stability test was done about each uncoated tablet for a test. The test results are shown in Table 14.
表１４に示す結果から明らかな通り、核粒子をエチルセルロースで被覆したコーティング顆粒から得られた錠剤は、被覆剤で被覆しない粒子から得られた錠剤よりも熱安定性に優れていた。 As apparent from the results shown in Table 14, the tablets obtained from the coated granules in which the core particles were coated with ethylcellulose were superior in thermal stability to the tablets obtained from the particles not coated with the covering agent.
また、図１から明らかな通り、核粒子の賦形剤としてマンニトールまたは結晶セルロースを含有するものから得られた錠剤は、核粒子の賦形剤として乳糖を含有するものから得られた錠剤よりも熱安定性に優れていた。 Also, as is apparent from FIG. 1, the tablets obtained from those containing mannitol or crystalline cellulose as an excipient for core particles are better than the tablets obtained from those containing lactose as an excipient for core particles. It was excellent in heat stability.
［実施例７４］
表１５に示す処方に従い、平均粒子径Ｄ５０が１５μｍのエスシタロプラムシュウ酸塩、Ｄ−マンニトール、クロスカルメロースナトリウム、およびヒドロキシプロピルセルロースを混合しつつ、これに着色剤（黄色三二酸化鉄）を水に分散させた分散液を加えて、造粒し、乾燥させ、整粒して、核粒子を調製した。別途、精製水にヒプロメロースを溶解させた溶解液に、タルクを分散させて中間層被覆液を調製した。[Example 74]
According to the formulation shown in Table 15, while mixing escitalopram oxalate having an average particle size D 50 of 15 μm, D-mannitol, croscarmellose sodium, and hydroxypropyl cellulose, a coloring agent (yellow ferric oxide) is added thereto The dispersion dispersed in the above was added, granulated, dried and sized to prepare core particles. Separately, talc was dispersed in a solution in which hypromellose was dissolved in purified water to prepare an interlayer coating solution.
上記核粒子を流動層造粒機に入れ、これに上記中間層被覆液を噴霧し、乾燥させ、整粒して、整粒末（中間層粒子）を調製した。別途、精製水と無水エタノールの混合液に被覆剤（エチルセルロース）を溶解させた溶解液に、タルクを分散させてエチルセルロース被覆液を調製した。
上記整粒末（中間層粒子）を流動層造粒機に入れ、これに上記エチルセルロース被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング粒子）を調製した。The core particles were placed in a fluid bed granulator, the middle layer coating solution was sprayed thereon, dried, and sized to obtain a sized powder (middle layer particles). Separately, talc was dispersed in a solution in which a coating agent (ethyl cellulose) was dissolved in a mixture of purified water and absolute ethanol, to prepare an ethyl cellulose coating solution.
The above sized powder (intermediate layer particles) was placed in a fluid bed granulator, the above ethyl cellulose coating liquid was sprayed thereon, dried, and sized to obtain sized powder (coated particles).
［実施例７５］
表１６に示す処方に従い、平均粒子径Ｄ５０が１５μｍのエスシタロプラムシュウ酸塩およびヒドロキシプロピルセルロースを精製水と無水エタノールの混合液に溶解させた溶解液に、タルクおよび黄色三二酸化鉄を分散させて被覆液を調整した。Ｄ−マンニトール球状顆粒を流動層造粒機に入れ、これに上記被覆液を噴霧し、乾燥させ、整粒して、整粒末（核粒子）を調製した。別途、精製水と無水エタノールの混合液に被覆剤（エチルセルロース）を溶解させた溶解液に、タルクを分散させてエチルセルロース被覆液を調製した。
上記整粒末（核粒子）を流動層造粒機に入れ、これに上記エチルセルロース被覆液を噴霧し、乾燥させ、整粒して、整粒末（コーティング粒子）を調製した。[Example 75]
Talc and yellow ferric trioxide are dispersed in a solution in which escitalopram oxalate having an average particle size D 50 of 15 μm and hydroxypropyl cellulose are dissolved in a mixture of purified water and absolute ethanol according to the formulation shown in Table 16 The coating solution was adjusted. D-mannitol spherical granules were placed in a fluid bed granulator, sprayed with the coating solution, dried, and sized to obtain sized granules (core particles). Separately, talc was dispersed in a solution in which a coating agent (ethyl cellulose) was dissolved in a mixture of purified water and absolute ethanol, to prepare an ethyl cellulose coating solution.
The above sized powder (core particles) was placed in a fluid bed granulator, the above ethyl cellulose coating liquid was sprayed onto this, dried, and sized to obtain sized powder (coated particles).
本発明組成物は、保存安定性が担保されているから、医薬品として有用である。 The composition of the present invention is useful as a pharmaceutical because its storage stability is secured.
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