JP2019006829A - Escitalopram pharmaceutical composition - Google Patents
Escitalopram pharmaceutical composition Download PDFInfo
- Publication number
- JP2019006829A JP2019006829A JP2018195514A JP2018195514A JP2019006829A JP 2019006829 A JP2019006829 A JP 2019006829A JP 2018195514 A JP2018195514 A JP 2018195514A JP 2018195514 A JP2018195514 A JP 2018195514A JP 2019006829 A JP2019006829 A JP 2019006829A
- Authority
- JP
- Japan
- Prior art keywords
- escitalopram
- pharmaceutical composition
- coating
- tablets
- salt
- 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
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- 229960004341 escitalopram Drugs 0.000 title claims abstract description 37
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- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- 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
- A61K31/335—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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- 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
Abstract
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 that ensures storage stability as a pharmaceutical product.
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 the general name for the S form of citalopram, and the chemical name: (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 -Carbonitrile). This has a selective serotonin reuptake inhibitory action (SSRI), and its oxalate salt (see the structural formula below) is marketed as an antidepressant under a trade name such as Lexapro (registered trademark, Lexapro). .
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 invention regarding the pharmaceutical composition of escitalopram, patent document 1 and 2 can be mentioned, for example.
In Patent Document 1, an object is to develop a pharmaceutical dosage form for escitalopram oxalate having high bioavailability and minimizing impurities generated during production, and the problem is an average of less than 100 μm. An invention solved by making escitalopram oxalate having a particle size and a granular material containing at least one filler is described. Patent Document 1 describes that it is preferable to use titanium oxide as a pigment (see paragraph [0037]), but other specific pigments including Examples are not specifically mentioned. In addition, various film forming agents that can be usually used in the pharmaceutical field are exemplified, and cellulose derivatives are also exemplified. 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 a large crystalline particle of escitalopram oxalate suitable for direct compression and a method for producing the same. Such crystalline particles have an average particle size (D 50 ) and a particle size of at least 40 μm.
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 with reduced unpleasant taste such as bitter taste, which contains a drug-containing granule obtained by coating a drug mixed with an excipient with ethyl cellulose. However, there is no description regarding 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 that contains escitalopram or a salt thereof as an active ingredient and that has storage stability (light stability, heat stability) as a pharmaceutical product.
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 have included iron oxide in the pharmaceutical composition of escitalopram, and the average particle size (D 50 ) of escitalopram is 40 μm or less, and a mixture containing the escitalopram particles and mannitol. The present invention was completed by finding that the above-mentioned problems can be solved by granulating the powder. Furthermore, the inventors have found that the above problem can also be solved by coating the core particles containing escitalopram and an excipient with ethyl cellulose, thereby completing the present 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 [1] or [2] above, wherein the salt is oxalate.
[4] The escitalopram or a salt thereof has an average particle diameter D 50 of less 40 [mu] m, and characterized in that it is contained within the granules containing D- mannitol, the above-mentioned [1] to [3] Pharmaceutical composition as described in any one of these.
[5] Any one of the above-mentioned [1] to [4], comprising granules having a coating layer containing ethylcellulose outside the core particles containing the escitalopram or a salt thereof and an excipient. A pharmaceutical composition according to 1.
[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 [1] to [6] above, 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 having a coating layer containing ethyl cellulose on the outside of a core particle containing escitalopram or a salt thereof and an excipient.
[10] The granule according to [9] above, 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 a 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.
The escitalopram or a salt thereof according to the present invention (hereinafter also referred to simply as “escitalopram”) is a known compound, and can be easily produced or obtained. The escitalopram may be a particle or a 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 a salt with an organic acid and a salt with an inorganic acid. Examples of the salt with an organic acid include salts with oxalic acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. . Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Of these, salts with oxalic acid are preferred. Such salts 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 of 40 μm or less or in the range of 5 to 40 μm, and more preferably has an average particle size in the range of 10 to 40 μm. Here, the “average particle diameter” is a volume average particle diameter, and means a particle diameter (D 50 , median diameter) at which the cumulative distribution from the smaller one becomes 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, but the amount of escitalopram is suitably in the range of 1-50 mg, and in the range of 5-20 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 Containing Iron Oxide The composition of the present invention preferably contains iron oxide. Inclusion of iron oxide can improve the light stability.
The iron oxide is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include yellow iron sesquioxide, iron sesquioxide, brown iron oxide, and black iron oxide. Among these, yellow iron sesquioxide and iron sesquioxide are preferable.
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 is suitably in the range of 0.01 to 15% by mass, The range of 10% by mass is preferable, and the range of 0.1 to 5% by mass is more preferable. If it is less than 0.01% by mass, sufficient storage stability may not be obtained. If it exceeds 15% by mass, the powder physical properties may be deteriorated and 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 Form and Additives Examples of the unit form (formulation) of the composition of the present invention include tablets, capsules, granules, fine granules, and powders. Of these, tablets are preferred. Examples of such tablets include ordinary tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, enteric tablets, matrix tablets, orally disintegrating tablets, sustained-release tablets, dispersible tablets, chewable tablets, tongues, and the like. Mention may be made of tablets, troches and chewable tablets. The tablet hardness is not particularly limited, but is 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 pharmaceutically acceptable additives in addition to the above-mentioned iron oxide, if necessary. Examples of such additives include, but are not limited to, excipients, disintegrants or disintegration promoters, binders, lubricants or fluidizing agents (anti-adhesion agents), coating agents, plasticizers, colorants, taste masking, and the like. Agents, preservatives, dispersants, fragrances. 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 additives include excipients such as D-mannitol, lactose, crystalline cellulose, corn starch, agar, gelatin, precipitated calcium carbonate, calcium hydrogen phosphate, sucrose; carboxymethyl cellulose, carboxymethyl cellulose calcium, low substitution Degrading agents or disintegration accelerators such as hydroxypropylcellulose, sodium croscarmellose, sodium carboxymethyl starch, calcium carbonate, sodium carbonate, corn starch, carmellose calcium, crospovidone; sodium carboxymethylcellulose, methylcellulose, hypromellose, gelatin, polyvinyl Binding agents such as pyrrolidone, polyvinyl alcohol and povidone; colloidal silica, talc, magnesium stearate, Lubricants or fluidizing agents such as calcium allate, stearic acid, hydrous silicon dioxide, light anhydrous silicic acid, macrogol; methylcellulose, ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, phthalate Coating agents such as hydroxypropylmethylcellulose acid, polyacrylate and polymethacrylate (Eudragid (registered trademark)), polyvinylpyrrolidone, polyvinyl acetate phthalate, shellac; plasticizers such as polyethylene glycol, triatin, glycerin fatty acid ester, liquid paraffin; titanium oxide And coloring 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, it is preferable that the total escitalopram-related substance after storage for 1 month under an open condition of 40 ° C. and a relative humidity of 75% is 0.2% by weight or less. What is 0.15 weight% or less is more preferable. What is 0.1 weight% or less is still more preferable.
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. Production method of the composition of the present invention The composition of the present invention can be produced by a conventional method according to the dosage form employed.
For example, tablets are made into a powder mixture by adding excipients, disintegrants, etc., and then added with a dispersion in which coloring agents are dispersed, and granulated (for example, wet granulation) to be granulated or slugged. , Dried and sized, and then added with an excipient, a disintegrant, a lubricant and the like, and then compressed (compressed). The 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。
In the manufacturing method of this invention composition (tablet), it is preferable to include the process of granulating the mixture containing the escitalopram particle | grains and mannitol in the range whose average particle diameter is 40 micrometers or less or 5-40 micrometers. The average particle diameter of the escitalopram particles in such a production method is more preferably in the range of 10 to 40 μm. The 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 improving 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 the coating layer which contains an ethyl cellulose on the outer side of the core particle containing an escitalopram and an excipient | filler. Examples of the excipient include the same as those described above, but D-mannitol and crystalline cellulose are preferable. The composition of the present invention produced by such a production method is particularly excellent in improving thermal 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 granule can be produced by a conventional method. Specifically, for example, each compounding component is mixed, granulated (for example, wet granulation), sized and dried to produce the core particles, and the core particles are usually coated with a coating agent containing ethyl cellulose. It can be manufactured by coating by the method. An intermediate coating layer may be provided between the core particle and the coating layer containing ethylcellulose.
The core particles can include iron oxide and the like. Moreover, talc, iron oxide, etc. can be included 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 above-mentioned granule having a coating layer containing the core particles and ethyl cellulose, an excipient, a lubricant and the like are added and mixed, and then compressed (compressed) by a conventional method to obtain the composition (tablet) of the present invention. 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 agent on the tablet surface as necessary, and can be sugar-coated with sugars. Examples of the coating agent that can be used in such film coating include hypromellose, hydroxypropyl cellulose, ethyl cellulose, polyacrylate, and polymethacrylate (Eudragid (registered trademark)).
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 varies depending on the dosage form, the content of escitalopram, the patient's condition, body weight, age, etc., for example, once to several times a day or at an interval of 1 day to several days, 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。 Hereinafter, the present invention will be described with reference to examples and test examples, but the present invention is not limited to 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) Light Stability Test The light stability test was performed using an ATLAS light stability tester (model number: SUNTEST XLS +) under irradiation conditions of a total illumination of 1,200,000 lx (lux) · hr.
（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 performed by storing for one month under an open condition of 40 ° C. and a relative humidity of 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) Measuring method of related substances The amount of each related substance (related 1, related 2) and total related substances in the sample solution was measured by HPLC. 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 of HPLC. The sample solution used for this measurement and the measurement conditions of HPLC are as follows. Each related substance has the following structure. Further, the total related substance is a combination of all impurities including the related 1 and related 2.
〔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]
20 mL of the following mobile phase A was added to tablets (1) or granules (1) and shaken and sonicated. The obtained liquid was filtered through a membrane filter having a pore size of 0.45 μm or less, 5 mL of the first filtrate was removed, 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: UV absorptiometer (measurement wavelength: 237 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecyl silica gel for liquid chromatography.
Column temperature: constant temperature around 45 ° C. Mobile phase A: pH 3.0 phosphate buffer / acetonitrile mixture (17: 3)
Mobile phase B: Acetonitrile / pH 3.0 phosphate buffer (4: 1)
Mobile phase liquid feed: The mixing ratio of mobile phase A and mobile phase is adjusted as appropriate to control the concentration gradient.
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] Iron oxide-containing effect (when the average particle diameter D 50 of 15 [mu] m)
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 is apparent from the results shown in Tables 1 and 2, 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] iron oxide-containing effect (when the average particle diameter D 50 of 40 [mu] m)
According to the prescription shown in the front stage of Tables 3 and 4, in the same manner as in the production method described in Test Example 1, test plain tablets were obtained. 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 is apparent from the results shown in Tables 3 and 4, the tablets containing iron oxide were superior in light stability to the tablets not containing iron oxide or the 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 drug substance particle size (stability of uncoated granules)
Table 5 or in accordance with the formulation shown in front of the table 6, 15 [mu] m average particle diameter D 50, 40 [mu] m or escitalopram oxalate of 180 [mu] m,, D-mannitol, while mixing sodium croscarmellose, and hydroxypropyl cellulose, in which Add a dispersion with or without dispersing a colorant (yellow ferric oxide, ferric oxide, or titanium oxide), granulate, dry, sizing, and test sized powder (Elementary granule) was obtained. And the light stability test was done about each elementary granule 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 is clear from the results shown in Tables 5 and 6, the granules containing 15 μm and 40 μm had excellent light stability compared to 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 drug substance particle size (stability of tablets made of coated particles)
According to the formulation shown in Table 7, 8, 15 [mu] m average particle diameter D 50, 40 [mu] m or escitalopram oxalate of 180 [mu] m,, D-mannitol, while mixing sodium croscarmellose, and hydroxypropyl cellulose, to which a coloring agent ( A dispersion liquid in which yellow iron sesquioxide, iron sesquioxide, or titanium oxide) was dispersed in water or a liquid that was not dispersed was added, granulated, dried, and sized to prepare core particles. Separately, talc was dispersed in a solution obtained by dissolving ethyl cellulose (coating agent) in a mixed solution 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 said core particle was put into the fluidized-bed granulator, the said coating liquid was sprayed on this, it was made to dry and sized, and the sized powder (coating particle) was prepared. The coated particles, D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, and magnesium stearate were mixed and tableted to obtain a test tablet. And the light stability test was done about each uncoated tablet for a test. The test results are shown in the subsequent stages 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 apparent from the results shown in Tables 7 and 8, the tablets obtained from the coating particles containing 15 μm and 40 μm were superior in light stability compared to 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 coating with ethyl cellulose (thermal stability, containing mannitol)
According to the formulation shown in Table 9, the average particle diameter D 50 of 15μm of escitalopram oxalate, D- mannitol, while mixing the croscarmellose sodium, and hydroxypropyl cellulose, and this is dispersed ferric oxide in aqueous dispersion The liquid was added, granulated, dried, and sized to prepare core particles. Except for Example 57, separately, talc was dispersed in a solution obtained by dissolving a coating agent (ethyl cellulose, hypromellose, or aminoalkyl methacrylate copolymer E) in a mixed solution of purified water and absolute ethanol to prepare a coating solution.
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 put into a fluidized bed granulator, and the above coating solution was sprayed, dried and sized to prepare a sized powder (coating particles). By mixing such coated particles or uncoated granules (core particles), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate and tableting, an uncoated tablet for testing is obtained. It was. And the thermal 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 is apparent from the results shown in Table 10, tablets obtained from coated particles in which core particles are coated with ethyl cellulose are tablets obtained from coated particles in which core particles are coated with another coating agent or particles not coated with a coating agent. The heat 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 coating with ethyl cellulose (heat stability, containing lactose)
According to the formulation shown in Table 11, while mixing escitalopram oxalate having an average particle size D 50 of 15 μm, lactose hydrate, croscarmellose sodium, and hydroxypropylcellulose, iron sesquioxide was dispersed in water. The dispersion liquid was added, granulated, dried, and sized to prepare core particles. Except for Example 66, separately, a coating solution was prepared by dispersing talc in a solution obtained by dissolving a coating agent (ethyl cellulose) in a mixed solution of purified water and absolute ethanol.
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 Example 66, the said core particle was put into the fluidized-bed granulator, the said coating liquid was sprayed on this, and it dried and sized, and prepared the sized powder (coating particle). This coated granule or uncoated granule (core particle), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate are mixed and tableted to obtain an uncoated tablet for testing. It was. And the thermal 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 apparent from the results shown in Table 12, the tablets obtained from the coated particles in which the core particles were coated with ethyl cellulose were superior in thermal stability to the tablets obtained from the particles not coated with the coating 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 coating with ethyl cellulose (thermal stability, containing crystalline cellulose)
According to the formulation shown in Table 13, the average particle diameter D 50 of 15μm of escitalopram oxalate, crystalline cellulose, while mixing the croscarmellose sodium, and hydroxypropyl cellulose, which in dispersion of ferric oxide was dispersed in water Was added, granulated, dried, and sized to prepare core particles. Except for Example 73, separately, a coating solution was prepared by dispersing talc in a solution obtained by dissolving a coating agent (ethyl cellulose) in a mixed solution of purified water and absolute ethanol.
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 Example 73, the said core particle was put into the fluidized-bed granulator, and the said coating liquid was sprayed on this, and it dried and sized, and prepared the sized powder (coating granule). This coated granule or uncoated granule (core particle), D-mannitol, crystalline cellulose, light anhydrous silicic acid, croscarmellose sodium, talc, magnesium stearate are mixed and tableted to obtain an uncoated tablet for testing. It was. And the thermal 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 is apparent from the results shown in Table 14, the tablets obtained from the coated granules in which the core particles were coated with ethyl cellulose were superior in thermal stability to the tablets obtained from the particles not coated with the coating 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。 Further, as is apparent from FIG. 1, tablets obtained from those containing mannitol or crystalline cellulose as the core particle excipient are more than tablets obtained from those containing lactose as the core particle excipient. Excellent thermal 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 diameter D 50 of 15 μm, D-mannitol, croscarmellose sodium, and hydroxypropylcellulose, a coloring agent (yellow ferric oxide) is mixed with water. The dispersion liquid dispersed in was added, granulated, dried, and sized to prepare core particles. Separately, talc was dispersed in a solution obtained by dissolving hypromellose in purified water to prepare an intermediate layer 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 put in a fluidized bed granulator, and the intermediate layer coating solution was sprayed onto the core particles, dried and sized to prepare a sized powder (intermediate layer particles). Separately, talc was dispersed in a solution obtained by dissolving a coating agent (ethylcellulose) in a mixed solution of purified water and absolute ethanol to prepare an ethylcellulose coating solution.
The sized powder (intermediate layer particles) was put in a fluidized bed granulator, and the ethyl cellulose coating solution was sprayed onto the dried powder, dried and sized to prepare sized powder (coating 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]
According to the formulation shown in Table 16, talc and yellow ferric oxide were dispersed in a solution obtained by dissolving escitalopram oxalate and hydroxypropyl cellulose having an average particle size D 50 of 15 μm in a mixture of purified water and absolute ethanol. The coating solution was adjusted. D-mannitol spherical granules were put in a fluidized bed granulator, and the above coating solution was sprayed onto the granules, dried and sized to prepare sized powder (core particles). Separately, talc was dispersed in a solution obtained by dissolving a coating agent (ethylcellulose) in a mixed solution of purified water and absolute ethanol to prepare an ethylcellulose coating solution.
The above sized powder (core particles) was put into a fluidized bed granulator, and the ethyl cellulose coating solution was sprayed on this, dried and sized to prepare a sized powder (coating 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 the storage stability is ensured.
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| JP2020114355A (en) * | 2019-01-18 | 2020-07-30 | 株式会社大一商会 | Game machine |
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| JP7391521B2 (en) * | 2019-03-12 | 2023-12-05 | 東和薬品株式会社 | Pharmaceutical composition for treating erectile dysfunction |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009519969A (en) * | 2005-12-14 | 2009-05-21 | ハー・ルンドベック・アクチエゼルスカベット | Escitalopram modified-release and pulse-release formulations |
| JP2011126906A (en) * | 2004-02-20 | 2011-06-30 | Eisai R & D Management Co Ltd | Medicinal preparation containing warfarin potassium and method for producing the same |
| JP2011520798A (en) * | 2008-05-07 | 2011-07-21 | へクサル アーゲー | Granules containing escitalopram oxalate |
| US20110196032A1 (en) * | 2005-05-20 | 2011-08-11 | Ashish Gogia | Pharmaceutical Dosage Form of an Antidepressant |
| JP2015147821A (en) * | 2015-05-29 | 2015-08-20 | 大日本住友製薬株式会社 | Composition improved in light stability |
| JP2015178482A (en) * | 2014-03-20 | 2015-10-08 | 日医工株式会社 | Pharmaceutical preparation containing rosuvastatin |
| CN106176691A (en) * | 2016-08-31 | 2016-12-07 | 齐鲁制药有限公司 | A kind of molten membrane of escitalopram oxalate mouth and preparation method thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR200400189T2 (en) * | 2001-07-31 | 2004-12-21 | H.Lundbeck A/S | Crystalline composition containing escitalopram. |
| US7834201B2 (en) | 2005-06-22 | 2010-11-16 | H. Lundbeck A/S | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
| TWI347942B (en) | 2005-06-22 | 2011-09-01 | Lundbeck & Co As H | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
| WO2008104880A2 (en) | 2007-03-01 | 2008-09-04 | Aurobindo Pharma Limited | Stable solid dosage forms of an antidepressant |
| US20090048336A1 (en) | 2007-08-17 | 2009-02-19 | Naveen Kumar Kolla | Escitalopram oxalate powders |
| WO2009135646A2 (en) | 2008-05-05 | 2009-11-12 | Farmaprojects, Sa | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
| GR20080100696A (en) | 2008-10-23 | 2010-05-13 | Genepharm �.�. | Taste masked dosage form of pharmaceutically aceptable salt of escitalopram |
| US20160008375A1 (en) * | 2013-03-01 | 2016-01-14 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical formulations comprising quetiapine and escitalopram |
| WO2018190294A1 (en) | 2017-04-10 | 2018-10-18 | 東和薬品株式会社 | Medicinal composition comprising escitalopram |
-
2018
- 2018-04-09 WO PCT/JP2018/014919 patent/WO2018190294A1/en active Application Filing
- 2018-04-09 JP JP2018540506A patent/JP6423133B1/en active Active
- 2018-08-10 JP JP2018151122A patent/JP7051638B2/en active Active
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011126906A (en) * | 2004-02-20 | 2011-06-30 | Eisai R & D Management Co Ltd | Medicinal preparation containing warfarin potassium and method for producing the same |
| US20110196032A1 (en) * | 2005-05-20 | 2011-08-11 | Ashish Gogia | Pharmaceutical Dosage Form of an Antidepressant |
| JP2009519969A (en) * | 2005-12-14 | 2009-05-21 | ハー・ルンドベック・アクチエゼルスカベット | Escitalopram modified-release and pulse-release formulations |
| JP2011520798A (en) * | 2008-05-07 | 2011-07-21 | へクサル アーゲー | Granules containing escitalopram oxalate |
| JP2015178482A (en) * | 2014-03-20 | 2015-10-08 | 日医工株式会社 | Pharmaceutical preparation containing rosuvastatin |
| JP2015147821A (en) * | 2015-05-29 | 2015-08-20 | 大日本住友製薬株式会社 | Composition improved in light stability |
| CN106176691A (en) * | 2016-08-31 | 2016-12-07 | 齐鲁制药有限公司 | A kind of molten membrane of escitalopram oxalate mouth and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020114357A (en) * | 2019-01-18 | 2020-07-30 | 株式会社大一商会 | Game machine |
| JP2020114353A (en) * | 2019-01-18 | 2020-07-30 | 株式会社大一商会 | Game machine |
| JP2020114355A (en) * | 2019-01-18 | 2020-07-30 | 株式会社大一商会 | Game machine |
| JP2020114356A (en) * | 2019-01-18 | 2020-07-30 | 株式会社大一商会 | Game machine |
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