JP5823592B2 - Formulation with improved stability - Google Patents
Formulation with improved stability Download PDFInfo
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- JP5823592B2 JP5823592B2 JP2014209601A JP2014209601A JP5823592B2 JP 5823592 B2 JP5823592 B2 JP 5823592B2 JP 2014209601 A JP2014209601 A JP 2014209601A JP 2014209601 A JP2014209601 A JP 2014209601A JP 5823592 B2 JP5823592 B2 JP 5823592B2
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- olanzapine
- mixed
- fluidizing agent
- related substances
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- 239000000203 mixture Substances 0.000 title claims description 24
- 238000009472 formulation Methods 0.000 title claims description 21
- 239000000126 substance Substances 0.000 claims description 58
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 46
- 229960005017 olanzapine Drugs 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 35
- 229930064664 L-arginine Natural products 0.000 claims description 35
- 235000014852 L-arginine Nutrition 0.000 claims description 35
- 235000012239 silicon dioxide Nutrition 0.000 claims description 29
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 24
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 22
- 239000001095 magnesium carbonate Substances 0.000 claims description 22
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 22
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 229920002678 cellulose Polymers 0.000 claims description 15
- 239000001913 cellulose Substances 0.000 claims description 14
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims description 6
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- 230000001687 destabilization Effects 0.000 claims description 3
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 claims 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 24
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- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
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- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
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- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- UDYRPJABTMRVCX-UHFFFAOYSA-J dimagnesium;carbonate;dihydroxide Chemical compound [OH-].[OH-].[Mg+2].[Mg+2].[O-]C([O-])=O UDYRPJABTMRVCX-UHFFFAOYSA-J 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、流動化剤により不安定化するオランザピンの製剤組成物にアルカリ性添加剤を配合することで、保存安定性を改善することに関する。 The present invention relates to improving storage stability by adding an alkaline additive to a pharmaceutical composition of olanzapine that is destabilized by a fluidizing agent.
医薬品の経口投与製剤には、液剤、散剤、顆粒剤、錠剤、カプセル剤等種々の剤形が存在する。その中で、製造性や服用性に優れるため最も繁用されるのは錠剤である。さらに、近年では易服用性を目的とする口腔内崩壊錠が多数開発され、上市されている。
口腔内崩壊錠の製法は、凍結乾燥による鋳型錠、湿潤顆粒を成形後に乾燥する湿製錠、低圧成形錠を加湿後乾燥する方法など様々あるが、最近ではコスト面などから特殊装置でなく既存の造粒機や打錠機を用いて口腔内崩壊錠を製する方法が増えている。
There are various dosage forms such as liquids, powders, granules, tablets, capsules and the like for oral pharmaceutical preparations. Among them, tablets are most frequently used because of their excellent manufacturability and dosage. In recent years, many orally disintegrating tablets have been developed and marketed for easy administration.
There are various methods for producing orally disintegrating tablets such as freeze-dried mold tablets, wet tablets that dry after forming wet granules, and low-pressure formed tablets that are dried after humidification. There are an increasing number of methods for producing orally disintegrating tablets using a granulator or tableting machine.
口腔内崩壊錠が求められる例には、高血圧治療剤、糖尿病治療剤、認知症治療剤など、嚥下能力の低下した高齢者を主な対象とする疾患があり、服用時のつかえ感を軽減する目的が挙げられる。そのほか、統合失調症や双極性障害等の精神疾患における治療剤においても、服用を拒む患者に介助者が速やかに投薬・嚥下させるのに有用とされる(非特許文献1)。 Examples that require orally disintegrating tablets include diseases mainly targeted at the elderly with reduced swallowing ability, such as antihypertensive agents, antidiabetic agents, and dementia agents. The purpose is listed. In addition, it is also useful for a caregiver to quickly administer and swallow a patient who refuses to take a therapeutic agent for psychiatric disorders such as schizophrenia and bipolar disorder (Non-patent Document 1).
統合失調症及び双極性障害の治療薬であるオランザピンは、イーライ・リリー社よりジプレキサ(登録商標)としてフィルムコート錠、ザイディス(登録商標)錠、細粒及び筋注の4剤形が発売されている。この中で、ザイディス錠は上述の凍結乾燥による鋳型錠に相当する。ザイディス錠は口腔内において数秒で溶解するため、本疾患の剤形として優れる半面、製造には特殊な装置を要するほか、製剤が非常にもろく取り扱いにくいといった課題がある。特許文献1にはオランザピンの口腔内崩壊錠を湿製錠方式で製する方法が開示されているが、これも一般的装置では製造できないうえ、平均硬度も3kpと十分でない。 Olanzapine, a treatment for schizophrenia and bipolar disorder, is available in four dosage forms from Eli Lilly as Zyprexa (registered trademark): film-coated tablets, Zydis (registered trademark) tablets, fine granules and intramuscular injections. Yes. Among these, Zydis tablets correspond to the above-mentioned template tablets by freeze-drying. Since Zydis tablets dissolve in the oral cavity within a few seconds, it is excellent as a dosage form for this disease. On the other hand, a special device is required for production, and the preparation is extremely fragile and difficult to handle. Patent Document 1 discloses a method of producing an orally disintegrating tablet of olanzapine by a wet tableting method, but this cannot be produced by a general apparatus, and the average hardness is not sufficient at 3 kp.
また、オランザピンの製剤化には安定性に関する課題もある。特許文献2には、オランザピンがある種の添加剤との接触により褪色し、高温、高湿条件ではそれが加速するため、錠剤にフィルムコーティングを施すことで美観を維持する方法が開示されている。特許文献3には、アルカリ性賦形剤を用いるとオランザピンの安定性に負の効果をもたらすが、事前にオランザピンを単離剤と十分に混合しておけば分解が抑制されるほか、機能性ポリマーで錠剤をコーティングすることでも錠剤の着色及びアルカリ性賦形剤による不安定化を改善できることが開示されている。しかし、これらはいずれも普通錠の安定化方策である。口腔内崩壊錠は一般に錠剤硬度が低く摩損しやすいことから、フィルムコーティングを適用すると操作中に錠剤の欠けなどを生じ外観を損ねやすいほか、被膜の存在が口腔内崩壊性を落とすことにもつながり、困難と予想される。 Olanzapine formulation also has stability issues. Patent Document 2 discloses a method of maintaining aesthetics by applying a film coating to tablets because olanzapine fades by contact with certain additives and accelerates under high temperature and high humidity conditions. . In Patent Document 3, the use of an alkaline excipient has a negative effect on the stability of olanzapine. However, if olanzapine is sufficiently mixed with an isolating agent in advance, decomposition is suppressed, and a functional polymer is also disclosed. It is disclosed that coating tablets with can also improve tablet coloration and destabilization by alkaline excipients. However, these are all measures for stabilizing ordinary tablets. Orally disintegrating tablets generally have low tablet hardness and are easily worn away, so the application of a film coating tends to cause chipping of the tablet during operation and damage the appearance, and the presence of a coating also reduces the disintegration property in the oral cavity. Expected to be difficult.
そのため、特殊でない一般的装置で製造ができ、かつ安定性や物理的品質に優れたオランザピンの口腔内崩壊錠が求められていた。 Therefore, there has been a demand for an oranzapine orally disintegrating tablet that can be produced by a general device that is not special and that is excellent in stability and physical quality.
なお、特許文献4には、水分と接触すると崩壊する、炭酸マグネシウムヘビーを含有する速崩壊型の製剤が開示され、オランザピンを含有する口腔分散性錠剤が例示されているが、安定性には言及していない。 Patent Document 4 discloses a rapidly disintegrating preparation containing magnesium carbonate heavy that disintegrates when contacted with moisture, and an oral dispersible tablet containing olanzapine is exemplified, but mentions stability. Not done.
普通錠を得る一般的な方法で口腔内崩壊錠を製する場合、流通上及び取扱い上支障のない錠剤硬度に加え、服用性に優れた速やかな崩壊をいかに両立させるかが課題となる。その中で、比較的簡便な方法としては、シリカ系(ケイ酸類)に代表される流動化剤を配合することで高い硬度と速崩壊性を両立できることが知られている。口腔内崩壊錠の主たる賦形剤として繁用される糖アルコールまたは糖類などは流動性が劣るため、造粒時の流動性を改善するのにも都合が良い。しかし、流動化剤にはしばしば薬物の分解を促進する課題がある。オランザピンも原薬単独は非常に安定であるが、口腔内崩壊錠を製するに当たり賦形剤の流動性を改善する目的で流動化剤を検討したところ、熱、湿度及び光照射のいずれでも顕著に類縁物質が増加することが分かった。 When an orally disintegrating tablet is produced by a general method for obtaining a normal tablet, in addition to tablet hardness that does not hinder distribution and handling, a problem is how to achieve both rapid disintegration with excellent dosing properties. Among them, as a relatively simple method, it is known that high hardness and quick disintegration can be achieved by blending a fluidizing agent typified by silica (silicic acid). Since sugar alcohols or sugars frequently used as the main excipients for orally disintegrating tablets have poor fluidity, they are also convenient for improving fluidity during granulation. However, fluidizing agents often have the task of promoting drug degradation. Olanzapine is also very stable with the drug substance alone, but when making an orally disintegrating tablet, we investigated a fluidizing agent for the purpose of improving the fluidity of excipients. It was found that related substances increased.
オランザピンの口腔内崩壊錠の検討において、造粒時の賦形剤等の流動性確保と、得られる錠剤の硬度及び速崩壊性を両立するには流動化剤の配合が好ましいことから、安定化する方法につき検討した。その結果、アルカリ性添加剤を配合することで、流動化剤の配合に伴う類縁物質の増加を明らかに抑制できることを見出し、本発明を完成するに至った。これは特許文献3でアルカリ性賦形剤がオランザピンの安定性に負の効果をもたらすという結果と相反しており、意外な効果であった。 In studying orally disintegrating tablets of olanzapine, stabilization of the fluidizing agent is preferable in order to achieve both the fluidity of excipients during granulation and the hardness and rapid disintegration of the resulting tablets. We examined how to do it. As a result, it has been found that by adding an alkaline additive, an increase in related substances accompanying the addition of a fluidizing agent can be clearly suppressed, and the present invention has been completed. This was contrary to the result that the alkaline excipient had a negative effect on the stability of olanzapine in Patent Document 3, and was an unexpected effect.
すなわち本発明は、流動化剤により不安定化するオランザピンの製剤組成物にアルカリ性添加剤を配合することで、保存安定性を改善した製剤である。 That is, the present invention is a preparation with improved storage stability by blending an alkaline additive into a pharmaceutical composition of olanzapine that is destabilized by a fluidizing agent.
本発明によれば、アルカリ性添加剤を配合することで、流動化剤による類縁物質の増加を抑制することができ、一般的な方法で製造可能で、安定性や物理的品質にも優れたオランザピンの口腔内崩壊錠をはじめとするオランザピンの経口製剤を提供することができる。 According to the present invention, by adding an alkaline additive, olanzapine which can suppress an increase in related substances due to a fluidizing agent, can be produced by a general method, and has excellent stability and physical quality. Oranzapine oral preparations, including orally disintegrating tablets, can be provided.
流動化剤による安定性の低下をアルカリ性添加剤の配合により改善した本発明の一例であるオランザピン口腔内崩壊錠は、その他の成分として賦形剤、崩壊剤、結合剤、滑沢剤などを加え、普通錠を得る一般的な方法で製造できる。 Olanzapine orally disintegrating tablet, which is an example of the present invention in which the decrease in stability due to a fluidizing agent is improved by the addition of an alkaline additive, includes excipients, disintegrants, binders, lubricants and the like as other components. It can be produced by a general method for obtaining ordinary tablets.
流動化剤は、軽質無水ケイ酸、含水二酸化ケイ素、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム、タルクなどのシリカ系の流動化剤のほか、結晶セルロース、結晶セルロース・カルメロースナトリウムなどが例示される。この中で、流動性改善効果や崩壊補助効果の点で好ましいのはシリカ系流動化剤、さらに好ましくは軽質無水ケイ酸が挙げられる。なお、流動化剤により不安定化する、あるいは安定性が低下するとは、これを配合しない処方と比べ、熱、湿度、光照射により主薬由来の類縁物質が増える状態を指し、安定化あるいは安定性を改善するとは、アルカリ性添加剤を配合しない処方に比べ同様の類縁物質が低減する状態を指す。(改行なし) なお、流動化剤は医薬品の承認申請上、賦形剤に区分される場合もあるが、本発明の目的はこれらがオランザピン製剤中に存在することによる安定性の低下をアルカリ性添加剤の配合で改善したことにあるため、承認申請上の配合目的に関わらず、前記に例示された流動化剤が配合されたオランザピン製剤が本発明の対象となる。 Fluidizers include light silicic anhydride, hydrous silicon dioxide, calcium silicate, magnesium metasilicate aluminate, synthetic aluminum silicate, talc and other silica-based fluidizers, crystalline cellulose, crystalline cellulose and carmellose sodium Etc. are exemplified. Among these, a silica-based fluidizing agent is preferable from the viewpoint of fluidity improving effect and disintegration assisting effect, and light anhydrous silicic acid is more preferable. In addition, destabilization or decrease in stability due to a fluidizing agent refers to a state in which related substances derived from the active ingredient increase due to heat, humidity, or light irradiation compared to a prescription that does not contain this, stabilizing or stability "Improving" refers to a state in which similar substances are reduced as compared with a formulation not containing an alkaline additive. (No line breaks) Note that fluidizing agents may be categorized as excipients in the application for drug approval, but the purpose of the present invention is to add a decrease in stability due to the presence of these in the olanzapine formulation. Therefore, an olanzapine preparation containing the above-described fluidizing agent is an object of the present invention, regardless of the purpose of the approval application.
流動化剤の配合量は、多いほど錠剤硬度や崩壊補助効果が高まるが、薬物の安定性を低下させる成分であるため、製剤中の0.1〜10重量%が好ましく、より好ましくは0.5〜5重量%、さらに好ましくは1〜3重量%である。 As the blending amount of the fluidizing agent increases, the tablet hardness and the disintegration assisting effect increase, but since it is a component that lowers the stability of the drug, 0.1 to 10% by weight in the preparation is preferable, and more preferably 0. 5 to 5% by weight, more preferably 1 to 3% by weight.
流動化剤による安定性低下を改善するために使用するアルカリ性添加剤としては、ポリリン酸ナトリウム、メタリン酸ナトリウムなどのアルカリ金属塩や、酸化マグネシウム、炭酸カルシウム、沈降炭酸カルシウム、炭酸マグネシウムなどのアルカリ土類金属またはマグネシウムの塩、あるいはL−アルギニン、オルニチンなどの塩基性アミノ酸が例示される。この中で、好ましくはアルカリ土類金属またはマグネシウムの塩及び塩基性アミノ酸、さらに好ましくは炭酸マグネシウム及びL−アルギニンが挙げられる。これらは2種以上を組み合わせても良い。 Alkaline additives used to improve stability degradation due to fluidizing agents include alkali metal salts such as sodium polyphosphate and sodium metaphosphate, and alkaline earth such as magnesium oxide, calcium carbonate, precipitated calcium carbonate and magnesium carbonate. Examples thereof include basic metal or magnesium salts, or basic amino acids such as L-arginine and ornithine. Among them, preferred are alkaline earth metal or magnesium salts and basic amino acids, and more preferred are magnesium carbonate and L-arginine. Two or more of these may be combined.
アルカリ性添加剤の配合量は多いほど安定性改善に有効であるが、添加剤の種類によっては崩壊遅延を生じることから、製剤物性への影響も考慮すると好ましくは製剤中の0.05〜10重量%であり、さらに好ましくは0.1〜5重量%である。 The larger the amount of the alkaline additive is, the more effective for improving the stability. However, depending on the type of additive, it may cause a delay in disintegration. %, More preferably 0.1 to 5% by weight.
賦形剤は、特に限定されるものではないが、口腔内崩壊錠を製するのに適したものとしてD−マンニトール、エリスリトール、ソルビトールなどの糖アルコール、乳糖、マルトースなどの糖類、リン酸水素カルシウムなどの無機塩類やセルロース類などが例示される。この中で、好ましくは糖アルコール、さらに好ましくはD−マンニトールが挙げられる。これらは2種以上を組み合わせても良い。 Excipients are not particularly limited, but suitable for producing orally disintegrating tablets include sugar alcohols such as D-mannitol, erythritol and sorbitol, sugars such as lactose and maltose, calcium hydrogen phosphate Examples thereof include inorganic salts such as cellulose and celluloses. Among these, sugar alcohol is preferable, and D-mannitol is more preferable. Two or more of these may be combined.
賦形剤の配合量は、他の成分の配合量を優先した後の重量調整にはなるが、製剤中の50重量%以上が好ましく、さらに好ましくは70重量%以上である。 The blending amount of the excipient is a weight adjustment after giving priority to the blending amount of other components, but is preferably 50% by weight or more, more preferably 70% by weight or more in the preparation.
崩壊剤は、特に限定されるものではないが、クロスポビドン、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、カルメロースカルシウム、カルメロース、デンプングリコール酸ナトリウム、部分アルファー化デンプン、デンプンなどが例示される。この中で、好ましくはクロスポビドン、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、デンプングリコール酸ナトリウム、さらに好ましくはクロスポビドン及び低置換度ヒドロキシプロピルセルロースが挙げられる。これらは2種以上を組み合わせても良い。 The disintegrant is not particularly limited, and crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, carmellose, sodium starch glycolate, partially pregelatinized starch, starch and the like are exemplified. . Among these, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium starch glycolate, more preferably crospovidone and low-substituted hydroxypropylcellulose are preferable. Two or more of these may be combined.
崩壊剤の配合量は、多いほど錠剤の崩壊を速やかにできるが、湿度の高い条件に保存した際に膨張して錠剤硬度を低下させるなど負の影響もあることから、好ましくは1〜20重量%、さらに好ましくは5〜15重量%である。 The larger the amount of disintegrant added, the faster the tablet can disintegrate, but it also has negative effects such as swelling when stored under high humidity conditions and lowering the tablet hardness. %, More preferably 5 to 15% by weight.
結合剤は、特に限定されるものではないが、トウモロコシデンプン、バレイショデンプン、コムギデンプン、デキストリン、部分アルファー化デンプン、アルファー化デンプンなどのデンプン系結合剤、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、コポリビドン、ポリビニルアルコールなどの水溶性合成高分子が例示される。この中で、好ましくはデンプン系、さらに好ましくはトウモロコシデンプンが挙げられる。 The binder is not particularly limited, but starch-based binders such as corn starch, potato starch, wheat starch, dextrin, partially pregelatinized starch, pregelatinized starch, hydroxypropylcellulose, hypromellose, povidone, copolyvidone, polyvinyl A water-soluble synthetic polymer such as alcohol is exemplified. Among these, preferably starch-based, and more preferably corn starch.
結合剤の配合量は、多いほど錠剤硬度が高く、少ないほど速崩壊性には有利になるが、製剤中の1〜5重量%が好ましく、さらに好ましくは1.5〜2.5重量%である。 The larger the binder content, the higher the tablet hardness, and the lower the amount, the more advantageous for quick disintegration. However, the amount is preferably 1 to 5% by weight, more preferably 1.5 to 2.5% by weight in the preparation. is there.
滑沢剤は、特に限定されるものではないが、ステアリン酸マグネシウム、フマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステルが例示される。この中で、好ましくはステアリン酸マグネシウム及びフマル酸ステアリルナトリウムが挙げられる。 The lubricant is not particularly limited, and examples thereof include magnesium stearate, sodium stearyl fumarate, calcium stearate, talc, and sucrose fatty acid ester. Among these, magnesium stearate and sodium stearyl fumarate are preferable.
滑沢剤の配合量は、多いほどスティッキング等の打錠障害回避に有利であるが、その半面で疎水性に基づく崩壊遅延を生じることから、製剤中の0.1〜5重量%が好ましく、さらに好ましくは0.5〜2重量%である。ただし、外部滑沢装置を使用する場合はごく少量でも必要とする機能を満たすことができる。 The larger the blending amount of the lubricant, the more advantageous for avoiding tableting troubles such as sticking, but on the other hand, it causes disintegration delay based on hydrophobicity, so 0.1 to 5% by weight in the preparation is preferable. More preferably, it is 0.5 to 2% by weight. However, when an external lubrication device is used, the required function can be satisfied even with a very small amount.
そのほか、必要に応じて甘味剤、矯味剤、着色剤、コーティング剤、香料などを配合することもできる。 In addition, a sweetener, a corrigent, a coloring agent, a coating agent, a fragrance | flavor, etc. can also be mix | blended as needed.
口腔内崩壊錠の製造方法は、特に限定されるものではないが、薬物と賦形剤、流動化剤、崩壊剤等を流動層造粒機、撹拌造粒機、乾式造粒機などの一般的造粒装置を用いて造粒する方法が例示される。この中で、好ましくは流動層造粒法が挙げられる。アルカリ性物質は造粒時に粉末として添加するのでも良く、結合液に溶解または分散して添加しても良い。その後、造粒によって得た顆粒に滑沢剤を混合し、打錠機を用いて打錠すれば、普通錠と同様の方法で簡便に口腔内崩壊錠を得ることができる。 The method for producing the orally disintegrating tablet is not particularly limited, but the drug and excipient, fluidizing agent, disintegrating agent, etc. are generally used such as fluidized bed granulator, stirring granulator, dry granulator, etc. An example is a method of granulating using an automatic granulator. Among these, a fluidized bed granulation method is preferable. The alkaline substance may be added as a powder during granulation, or may be added after being dissolved or dispersed in a binding solution. Then, if a lubricant is mixed with the granule obtained by granulation and tableting is performed using a tableting machine, an orally disintegrating tablet can be easily obtained in the same manner as a normal tablet.
本発明はオランザピンの口腔内崩壊錠に限定されるものではなく、流動化剤により不安定化するオランザピンの経口製剤であれば適用することができる。また、各添加剤の種類や配合量も、求める製剤品質に応じて変更でき、上記に例示した範囲に限らない。 The present invention is not limited to olanzapine orally disintegrating tablets, and can be applied to any oral preparation of olanzapine that is destabilized by a fluidizing agent. Moreover, the kind and compounding quantity of each additive can also be changed according to the formulation quality to request | require, and are not restricted to the range illustrated above.
本発明の好適な実施形態について、オランザピンの口腔内崩壊錠の例を以下に説明する。 An example of an olanzapine orally disintegrating tablet will be described below with respect to a preferred embodiment of the present invention.
比較例1〜3:流動化剤を配合し、アルカリ性添加剤を配合しない例
D−マンニトール(三菱商事フードテック製、マンニットP)、軽質無水ケイ酸(日本アエロジル製、アエロジル(登録商標)200)、アスパルテーム(味の素製、味の素KKアスパルテーム)を混合後、ピンミル(ホソカワミクロン製、ファインインパクトミル100UPZ)で14000回転にて粉砕した。これに低置換度ヒドロキシプロピルセルロース(信越化学工業製、L−HPC(登録商標)LH22)、クロスポビドン(ISP製、ポリプラスドン(登録商標)XL−10)及びオランザピンを混合し、トウモロコシデンプン(日澱化学製、トウモロコシデンプンST−C)の水分散液を加熱して得た糊液を用いて流動層造粒機(パウレック製、MP−01)にて2800錠スケールで造粒した。得られた顆粒にステアリン酸マグネシウム(日油製、ステアリン酸マグネシウムS)を混合後、ロータリー式打錠機(菊水製作所製、VIRG0518SS2AZ)で打錠して、表1に示す配合の製剤を得た。錠剤は1錠中にオランザピンを5mg含み、質量を160mg、形状はφ8.0mm、9.5Rとした。
Comparative Examples 1 to 3: Example in which a fluidizing agent is blended and no alkaline additive is blended D-mannitol (manufactured by Mitsubishi Corporation Foodtech, Mannit P), light anhydrous silicic acid (manufactured by Nippon Aerosil, Aerosil (registered trademark) 200) ) And aspartame (manufactured by Ajinomoto Co., Inc., Ajinomoto KK Aspartame) were mixed and then pulverized at 14,000 revolutions with a pin mill (manufactured by Hosokawa Micron, Fine Impact Mill 100UPZ). Low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH22), crospovidone (ISP, polyplastidone (registered trademark) XL-10) and olanzapine were mixed with this, and corn starch ( Using a paste obtained by heating an aqueous dispersion of corn starch ST-C (manufactured by Nippon Star Chemical Co., Ltd.), granulation was performed on a 2800 tablet scale using a fluidized bed granulator (manufactured by Paulek, MP-01). Magnesium stearate (manufactured by NOF Corporation, magnesium stearate S) was mixed with the obtained granules, and then tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho, VIRG0518SS2AZ) to obtain a preparation having the composition shown in Table 1. . The tablet contained 5 mg of olanzapine in one tablet, the mass was 160 mg, and the shape was φ8.0 mm, 9.5R.
打錠圧650、750、800、850、950kgf/杵で得た各配合の製剤について、10錠の錠剤硬度(硬度計:シュロイニゲル製8M)と6錠の崩壊時間(崩壊試験器:富山産業製NT-60H、試験条件:水、37℃)を測定した結果、図1のように軽質無水ケイ酸の配合量が多いほど、一定錠剤硬度における崩壊時間は短くなった。 For each formulation obtained with tableting pressures of 650, 750, 800, 850, and 950 kgf / kg, tablet hardness of 10 tablets (hardness meter: Schleunigel 8M) and disintegration time of 6 tablets (disintegration tester: manufactured by Toyama Sangyo Co., Ltd.) NT-60H, test conditions: water, 37 ° C.) As a result, the disintegration time at a constant tablet hardness was shortened as the amount of light anhydrous silicic acid was increased as shown in FIG.
比較例1〜3の製剤は口腔内崩壊錠としての物性は問題なかったため、安定性を調査した。高密度ポリエチレン(HDPE)製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出した。以下に示す高速液体クロマトグラフィ(HPLC)条件で類縁物質総量を測定した結果、図2に示すように軽質無水ケイ酸の配合量が多いほど類縁物質量は増加しやすく、特に湿度の影響を顕著に受け、許容できる品質ではなかった。
(HPLCによる類縁物質測定条件)
装置:LC−2010CHT(島津製作所)
検出器:紫外吸光光度計(220nm)
カラム:オクチルジイソプロピルシリル化シリカゲル
カラム温度:35℃
移動相:30mMドデシル硫酸ナトリウム水溶液にリン酸3.3mLを加え、25%(w/v)水酸化ナトリウム水溶液でpHを2.5に調整し、1Lとする(A液)。A液520mLにアセトニトリル480mLを混合し、B液とする。また、A液300mLにアセトニトリル700mLを混合し、C液とする。B液とC液を以下の時間で濃度勾配制御する。
時間(分) 移動相B液 移動相C液
0〜20 100→0 0→100
20〜25 0 100
25〜27 0→100 100→0
27〜35 100 0
流量:約1.5mL/分(オランザピンの保持時間を約13分に調整する)
注入量:20μL
Since the preparations of Comparative Examples 1 to 3 had no problem as physical properties as orally disintegrating tablets, the stability was investigated. After filling 100 tablets in a high density polyethylene (HDPE) container, store it in a thermostatic oven at 40 ° C and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time I took it out. As a result of measuring the total amount of related substances under the following high performance liquid chromatography (HPLC) conditions, as shown in FIG. 2, the amount of related substances tends to increase as the amount of light anhydrous silicic acid increases. It was not acceptable quality.
(Related substances measurement conditions by HPLC)
Equipment: LC-2010CHT (Shimadzu Corporation)
Detector: UV absorption photometer (220nm)
Column: Octyl diisopropylsilylated silica gel Column temperature: 35 ° C
Mobile phase: 3.3 mL of phosphoric acid is added to a 30 mM sodium dodecyl sulfate aqueous solution, and the pH is adjusted to 2.5 with a 25% (w / v) aqueous sodium hydroxide solution to 1 L (solution A). Mix 520 mL of acetonitrile with 520 mL of A solution to make B solution. Moreover, 700 mL of acetonitrile is mixed with 300 mL of A solution to prepare C solution. Concentration control is performed for the B liquid and the C liquid at the following times.
Time (minutes) Mobile phase B liquid Mobile phase C liquid 0-20 100 → 0 0 → 100
20-25 0 100
25-27 0 → 100 100 → 0
27-35 100 0
Flow rate: About 1.5 mL / min (Adjust olanzapine retention time to about 13 minutes)
Injection volume: 20 μL
比較例4、実施例1、実施例2:軽質無水ケイ酸に炭酸マグネシウムを併用した例
比較例4は、D−マンニトール470.9g及び軽質無水ケイ酸11.5gを混合後、ピンミルで粉砕したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水581.7gにトウモロコシデンプン18.0g及びショ糖脂肪酸エステル(第一工業製薬製、DKエステル(登録商標)SS)0.28gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例1は、D−マンニトール452.9g及び軽質無水ケイ酸11.5gを混合後、ピンミルで粉砕したのち361.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水364.7gにトウモロコシデンプン12.0g、ショ糖脂肪酸エステル0.18g及び炭酸マグネシウム(協和化学工業製、炭酸マグネシウム)23.1gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例2は、D−マンニトール452.9g、軽質無水ケイ酸11.5g及び炭酸マグネシウム18.0gを混合後、ピンミルで粉砕したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、比較例4で調製した糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Comparative Example 4, Example 1, Example 2: Example in which magnesium carbonate was used in combination with light anhydrous silicic acid In Comparative Example 4, 470.9 g of D-mannitol and 11.5 g of light anhydrous silicic acid were mixed and then pulverized with a pin mill. Thereafter, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. In this, 18.0 g of corn starch and 0.28 g of sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd., DK Ester (registered trademark) SS) were dispersed in 581.7 g of purified water, and the paste solution 242. 7g was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 1, 452.9 g of D-mannitol and 11.5 g of light anhydrous silicic acid were mixed and then pulverized by a pin mill, and 361.2 g was weighed, to which 14.0 g of olanzapine, low substituted hydroxypropylcellulose 31. 9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 23.1 g of magnesium carbonate (magnesium carbonate, manufactured by Kyowa Chemical Industry Co., Ltd.) were dispersed in 364.7 g of purified water, and the paste solution 242. 7g was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 2, 452.9 g of D-mannitol, 11.5 g of light anhydrous silicic acid, and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Comparative Example 4. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
打錠圧650、750、800、850、950kgf/杵で得た各配合の製剤について、10錠の錠剤硬度と6錠の崩壊時間の関係を図3に示したが、炭酸マグネシウムは錠剤の硬度及び崩壊性にほとんど影響を与えなかった。 FIG. 3 shows the relationship between the tablet hardness of 10 tablets and the disintegration time of 6 tablets for each formulation obtained at tableting pressures of 650, 750, 800, 850, and 950 kgf / kg. Magnesium carbonate is the tablet hardness. And had little effect on disintegration.
比較例4及び実施例1〜2の製剤は口腔内崩壊錠としての物性は問題なかったため、安定性を調査した。HDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図4に示すように比較例4の製剤は類縁物質が増加しやすいのに対し、炭酸マグネシウムを配合した実施例1及び2は明らかに類縁物質の増加が抑制されていた。特に、湿度の高い条件での安定性改善効果は大きかった。また、炭酸マグネシウムは造粒時に粉末で添加しても、結合液に分散して添加しても、安定性改善効果は同等であった。 Since the preparations of Comparative Example 4 and Examples 1 and 2 had no problem with the physical properties as an orally disintegrating tablet, the stability was investigated. After filling 100 tablets into a container made of HDPE, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with a desiccant) and open (no lid), and remove it after a certain period of time to remove related substances. It was measured. As a result, as shown in FIG. 4, in the preparation of Comparative Example 4, the number of related substances tends to increase, whereas in Examples 1 and 2 containing magnesium carbonate, the increase in related substances was clearly suppressed. In particular, the effect of improving the stability under high humidity conditions was great. Further, the effect of improving the stability was the same whether magnesium carbonate was added as a powder during granulation or dispersed in a binder solution.
実施例3、実施例4:炭酸マグネシウムの配合量を変動させた例
安定性向上に対する炭酸マグネシウム量の影響を調査するため、実施例3、実施例4として各々1mg/錠、10mg/錠とした製剤を調製した。
実施例3は、D−マンニトール467.3g、軽質無水ケイ酸11.5g及び炭酸マグネシウム3.6gを混合後、ピンミルで粉砕したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水581.7gにトウモロコシデンプン18.0g及びショ糖脂肪酸エステル0.27gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例4は、D−マンニトール434.9g、軽質無水ケイ酸11.5g及び炭酸マグネシウム36.0gを混合後、ピンミルで粉砕したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、実施例3で調製した糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Examples 3 and 4: Examples in which the amount of magnesium carbonate was varied In order to investigate the effect of the amount of magnesium carbonate on stability improvement, each of Examples 3 and 4 was 1 mg / tablet and 10 mg / tablet, respectively. A formulation was prepared.
In Example 3, 467.3 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 3.6 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. To this, 18.0 g of corn starch and 0.27 g of sucrose fatty acid ester were dispersed in 581.7 g of purified water, and 242.7 g of paste liquid obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 4, 434.9 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 36.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 375.2 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Example 3. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図5に示すように比較例4と比べて、炭酸マグネシウムの配合量が1mg/錠(実施例3)であっても類縁物質の増加が抑制されていた。特に、湿度の高い条件での安定性改善効果は大きかった。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 5, as compared with Comparative Example 4, even when the compounding amount of magnesium carbonate was 1 mg / tablet (Example 3), an increase in related substances was suppressed. In particular, the effect of improving the stability under high humidity conditions was great.
比較例5、実施例5:ケイ酸カルシウムにL−アルギニンを併用した例
流動化剤にケイ酸カルシウム、アルカリ性添加剤にL-アルギニンを用い、安定性を比較した。
比較例5は、D−マンニトール473.8g及びケイ酸カルシウム(富田製薬製、フローライト(登録商標)RE)8.6gを混合後、ピンミルで粉砕したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水1066.5gにトウモロコシデンプン33.0g及びショ糖脂肪酸エステル0.51gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例5は、D−マンニトール1253.3g、ケイ酸カルシウム23.8g及びクロスポビドン49.5gを混合後、ピンミルで粉砕したのち412.7gを秤量した。これを流動層造粒機に投入し、精製水432.0gにL−アルギニン(和光純薬工業製、試薬特級)18.0gを溶解して得た水溶液385.0gを噴霧した。得られた粉末389.2gにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9gを混合して流動層造粒機に投入した。これに、精製水824.1gにトウモロコシデンプン25.5g及びショ糖脂肪酸エステル0.39gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Comparative Example 5, Example 5: Example in which L-arginine was used in combination with calcium silicate The stability was compared using calcium silicate as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 5 was prepared by mixing 473.8 g of D-mannitol and 8.6 g of calcium silicate (made by Tomita Pharmaceutical Co., Ltd., FLORITE (registered trademark) RE), pulverizing with a pin mill, and weighing 375.2 g. 14.0 g, 31.9 g of low-substituted hydroxypropyl cellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 33.0 g of corn starch and 0.51 g of sucrose fatty acid ester were dispersed in 1066.5 g of purified water, and 242.7 g of paste solution obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 5, 1253.3 g of D-mannitol, 23.8 g of calcium silicate, and 49.5 g of crospovidone were mixed and then ground by a pin mill, and 412.7 g was weighed. This was put into a fluidized bed granulator, and 385.0 g of an aqueous solution obtained by dissolving 18.0 g of L-arginine (manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 432.0 g of purified water was sprayed. Olanzapine 14.0 g and low-substituted hydroxypropylcellulose 31.9 g were mixed with 389.2 g of the obtained powder and charged into a fluidized bed granulator. To this, 25.5 g of corn starch and 0.39 g of sucrose fatty acid ester were dispersed in 824.1 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図6に示すように比較例5と比べて、L−アルギニンを配合した実施例5は類縁物質の増加が抑制されていた。特に、気密条件での安定性改善効果は大きかった。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 6, compared to Comparative Example 5, Example 5 containing L-arginine inhibited the increase in related substances. In particular, the effect of improving stability under airtight conditions was great.
実施例6〜7:軽質無水ケイ酸にL−アルギニンを併用した例
流動化剤に軽質無水ケイ酸、アルカリ性添加剤に実施例5よりも少ない量のL−アルギニンを用い、安定性を比較した。
実施例6は、D−マンニトール859.3g及び軽質無水ケイ酸21.1gを混合後、ピンミルで粉砕したのち373.5gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水310.0gにトウモロコシデンプン9.6g、ショ糖脂肪酸エステル0.15g及びL−アルギニン0.7gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品394.0gにステアリン酸マグネシウム6.0gを混合後、ロータリー式打錠機で打錠した。
実施例7は、実施例6で得たD−マンニトール及び軽質無水ケイ酸の粉砕品を373.0g秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水309.0gにトウモロコシデンプン9.6g、ショ糖脂肪酸エステル0.15g及びL−アルギニン1.5gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品394.0gにステアリン酸マグネシウム6.0gを混合後、ロータリー式打錠機で打錠した。
Examples 6 to 7: Examples in which L-arginine was used in combination with light anhydrous silicic acid, light anhydrous silicic acid was used as a fluidizing agent, and L-arginine in an amount smaller than that in Example 5 was used as an alkaline additive, and the stability was compared. .
In Example 6, after mixing D-mannitol (859.3 g) and light anhydrous silicic acid (21.1 g) and pulverizing with a pin mill, 373.5 g was weighed, to which olanzapine (14.0 g), low-substituted hydroxypropylcellulose 31. 9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 9.6 g of corn starch, 0.15 g of sucrose fatty acid ester and 0.7 g of L-arginine were dispersed in 310.0 g of purified water, and granulated by spraying 242.7 g of paste obtained by heating. . 6.0 g of magnesium stearate was mixed with 394.0 g of the obtained granulated product, and then tableted with a rotary tableting machine.
In Example 7, 373.0 g of the pulverized product of D-mannitol and light anhydrous silicic acid obtained in Example 6 was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropyl cellulose, and crospovidone 14. 0 g was mixed and charged into a fluidized bed granulator. In this, 9.6 g of corn starch, 0.15 g of sucrose fatty acid ester and 1.5 g of L-arginine are dispersed in 309.0 g of purified water, and 242.7 g of paste obtained by heating is sprayed and granulated. . 6.0 g of magnesium stearate was mixed with 394.0 g of the obtained granulated product, and then tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図7に示すように比較例4と比べて、少量のL−アルギニンを配合した実施例6〜7は類縁物質の増加が抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 7, as compared with Comparative Example 4, Examples 6 to 7 in which a small amount of L-arginine was blended suppressed the increase in related substances.
実施例8〜11:軽質無水ケイ酸に炭酸マグネシウムとL−アルギニンを併用した例
流動化剤に軽質無水ケイ酸、アルカリ性添加剤に炭酸マグネシウムとL−アルギニンを併用し、安定性を比較した。
実施例8は、D−マンニトール452.2g、軽質無水ケイ酸11.5g及び炭酸マグネシウム18.0gを混合後、ピンミルで粉砕したのち374.6gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水386.9gにトウモロコシデンプン12.0g、ショ糖脂肪酸エステル0.18g及びL−アルギニン0.92gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例9は、D−マンニトール451.4g、軽質無水ケイ酸11.5g及び炭酸マグネシウム18.0gを混合後、ピンミルで粉砕したのち374.1gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水386.0gにトウモロコシデンプン12.0g、ショ糖脂肪酸エステル0.18g及びL−アルギニン1.8gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例10は、D−マンニトール450.7g、軽質無水ケイ酸11.5g及び炭酸マグネシウム18.0gを混合後、ピンミルで粉砕したのち373.5gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水385.0gにトウモロコシデンプン12.0g、ショ糖脂肪酸エステル0.18g及びL−アルギニン2.8gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例11は、D−マンニトール449.3g、軽質無水ケイ酸11.5g及び炭酸マグネシウム18.0gを混合後、ピンミルで粉砕したのち372.4gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水383.2gにトウモロコシデンプン12.0g、ショ糖脂肪酸エステル0.18g及びL−アルギニン4.6gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Examples 8 to 11: Examples in which magnesium carbonate and L-arginine were used in combination with light anhydrous silicic acid, light anhydrous silicic acid was used in combination with a fluidizing agent, and magnesium carbonate and L-arginine were used in combination in an alkaline additive, and the stability was compared.
In Example 8, 452.2 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and then 374.6 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 0.92 g of L-arginine were dispersed in 386.9 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 9, 451.4 g of D-mannitol, 11.5 g of light anhydrous silicic acid, and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 374.1 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this solution, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 1.8 g of L-arginine were dispersed in 386.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 10, 45.7 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and 373.5 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. In this, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 2.8 g of L-arginine were dispersed in 385.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 11, 449.3 g of D-mannitol, 11.5 g of light anhydrous silicic acid and 18.0 g of magnesium carbonate were mixed and then pulverized with a pin mill, and then 372.4 g was weighed, to which 14.0 g of olanzapine, low substitution Hydroxypropyl cellulose 31.9 g and crospovidone 14.0 g were mixed and charged into a fluidized bed granulator. To this, 12.0 g of corn starch, 0.18 g of sucrose fatty acid ester and 4.6 g of L-arginine were dispersed in 383.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. . The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図8に示すように、炭酸マグネシウムのみを配合した実施例2と比べてL−アルギニンを併用した実施例8〜11は、L−アルギニンの配合量増加に従って類縁物質の増加が抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 8, in Examples 8 to 11 in which L-arginine was used in combination with Example 2 in which only magnesium carbonate was added, an increase in related substances was suppressed as the amount of L-arginine was increased. It was.
比較例6、実施例12:結晶セルロースにL−アルギニンを併用した例
流動化剤に結晶セルロース、アルカリ性添加剤にL-アルギニンを用い、安定性を比較した。
比較例6は、D−マンニトール(三菱商事フードテック製、マンニットC)693.8g及び結晶セルロース(旭化成ケミカルズ製、セオラス(登録商標)UF711)94.1gを混合後、JP30号ふるいで篩過したのち372.4gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水543.2gにトウモロコシデンプン16.8gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例12は、比較例6と同じ粉体成分を流動層造粒機に投入し、精製水536.7gにトウモロコシデンプン16.8g及びL−アルギニン(味の素製)6.5gを分散し加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Comparative Example 6, Example 12: Example in which L-arginine is used in combination with crystalline cellulose Stability was compared using crystalline cellulose as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 6 was prepared by mixing 693.8 g of D-mannitol (manufactured by Mitsubishi Corporation Foodtech, Mannit C) and 94.1 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corp., Theolas (registered trademark) UF711), and sieving with a JP 30 sieve. Thereafter, 372.4 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 16.8 g of corn starch was dispersed in 543.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 12, the same powder component as in Comparative Example 6 was put into a fluidized bed granulator, and 16.8 g of corn starch and 6.5 g of L-arginine (Ajinomoto Co.) were dispersed in 536.7 g of purified water and heated. Then, 242.7 g of the paste liquid obtained was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図9に示すように比較例6と比べて、L−アルギニンを配合した実施例12は類縁物質の増加が抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 9, compared to Comparative Example 6, Example 12 containing L-arginine suppressed the increase in related substances.
比較例7、実施例13:結晶セルロース・カルメロースナトリウムにL−アルギニンを併用した例
流動化剤に結晶セルロース・カルメロースナトリウム、アルカリ性添加剤にL-アルギニンを用い、安定性を比較した。
比較例7及び実施例13は、表8の通り比較例6及び実施例12と比べ結晶セルロースを結晶セルロース・カルメロースナトリウム(旭化成ケミカルズ製、セオラスRC-A591NF)に替えた以外は同じ処方及び製法で製剤を得た。
Comparative Example 7 and Example 13: Crystalline cellulose / carmellose sodium combined with L-arginine Crystalline cellulose / carmellose sodium was used as the fluidizing agent, and L-arginine was used as the alkaline additive, and the stability was compared.
Comparative Example 7 and Example 13 have the same formulation and manufacturing method as in Table 8, except that the crystalline cellulose was replaced with crystalline cellulose / carmellose sodium (produced by Asahi Kasei Chemicals, Theolas RC-A591NF) as compared with Comparative Example 6 and Example 12. A formulation was obtained.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図10に示すように比較例7と比べて、L−アルギニンを配合した実施例13は類縁物質の増加が抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 10, compared to Comparative Example 7, Example 13 containing L-arginine suppressed the increase in related substances.
比較例8、実施例14:ケイ酸アルミニウムにL−アルギニンを併用した例
流動化剤にケイ酸アルミニウム、アルカリ性添加剤にL-アルギニンを用い、安定性を比較した。
比較例8は、D−マンニトール(マンニットC)769.1g及びケイ酸アルミニウム(和光純薬工業製、試薬)18.8gを混合後、JP30号ふるいで篩過したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水543.2gにトウモロコシデンプン16.8gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例14は、比較例8と同じ粉体成分を流動層造粒機に投入し、精製水536.7gにトウモロコシデンプン16.8g及びL−アルギニン(味の素製)6.5gを分散し加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Comparative Example 8, Example 14: Example in which L-arginine was used in combination with aluminum silicate Aluminum silicate was used as the fluidizing agent and L-arginine was used as the alkaline additive, and the stability was compared.
In Comparative Example 8, 769.1 g of D-mannitol (Mannit C) and 18.8 g of aluminum silicate (manufactured by Wako Pure Chemical Industries, Ltd., reagent) were mixed, and after sieving with JP30 sieve, 375.2 g was weighed. To this, 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and put into a fluidized bed granulator. To this, 16.8 g of corn starch was dispersed in 543.2 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 14, the same powder component as in Comparative Example 8 was charged into a fluidized bed granulator, and 16.8 g of corn starch and 6.5 g of L-arginine (manufactured by Ajinomoto) were dispersed in 536.7 g of purified water and heated. Then, 242.7 g of the paste liquid obtained was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図11に示すように比較例8と比べて、L−アルギニンを配合した実施例14は類縁物質の増加が大幅に抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 11, compared to Comparative Example 8, in Example 14 in which L-arginine was blended, the increase in related substances was significantly suppressed.
比較例9、実施例15:タルクにL−アルギニンを併用した例
流動化剤にタルク、アルカリ性添加剤にL-アルギニンを用い、安定性を比較した。
比較例9及び実施例15は、表10の通り比較例8及び実施例14と比べケイ酸アルミニウムをタルク(松村産業製、ハイ・フィラー(登録商標)♯17)に替えた以外は同じ処方及び製法で製剤を得た。
Comparative Example 9, Example 15: Example in which L-arginine was used in combination with talc Stability was compared using talc as the fluidizing agent and L-arginine as the alkaline additive.
Comparative Example 9 and Example 15 were the same as those in Comparative Example 8 and Example 14 except that aluminum silicate was replaced with talc (manufactured by Matsumura Sangyo, High Filler (registered trademark) # 17) as shown in Table 10. The preparation was obtained by the manufacturing method.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図12に示すように比較例9と比べて、L−アルギニンを配合した実施例15は類縁物質の増加が抑制されていた。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 12, compared to Comparative Example 9, Example 15 containing L-arginine suppressed the increase in related substances.
比較例10、実施例16〜17:軽質無水ケイ酸に酸化マグネシウムまたはポリリン酸ナトリウムを併用した例
流動化剤に軽質無水ケイ酸、アルカリ性添加剤に酸化マグネシウム(実施例16)またはポリリン酸ナトリウム(実施例17)を用い、安定性を比較した。
比較例10は、D−マンニトール(マンニットC)384.6g及び軽質無水ケイ酸9.4gを混合後、JP30号ふるいで篩過したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水776.0gにトウモロコシデンプン24.0gを分散し、加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例16は、D−マンニトール(マンニットC)369.9g、軽質無水ケイ酸9.4g及び酸化マグネシウム(和光純薬工業製、試薬特級)14.7gを混合後、JP30号ふるいで篩過したのち375.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、比較例10で調製した糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
実施例17は、D−マンニトール(マンニットC)369.9g及び軽質無水ケイ酸9.4gを混合後、JP30号ふるいで篩過したのち361.2gを秤量し、これにオランザピン14.0g、低置換度ヒドロキシプロピルセルロース31.9g、クロスポビドン14.0gを混合して流動層造粒機に投入した。これに、精製水291.9gにトウモロコシデンプン9.6g及びポリリン酸ナトリウム(和光純薬工業製、食品添加物)18.5gを分散し加熱して得た糊液242.7gを噴霧して造粒した。得られた造粒品395.0gにステアリン酸マグネシウム5.0gを混合後、ロータリー式打錠機で打錠した。
Comparative Example 10 and Examples 16 to 17: Examples of using light anhydrous silicic acid in combination with magnesium oxide or sodium polyphosphate Light anhydrous silicic acid as a fluidizing agent, magnesium oxide (Example 16) or sodium polyphosphate as an alkaline additive ( Example 17) was used to compare the stability.
In Comparative Example 10, 384.6 g of D-mannitol (Mannit C) and 9.4 g of light anhydrous silicic acid were mixed, and after sieving with JP 30 sieve, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 24.0 g of corn starch was dispersed in 776.0 g of purified water, and 242.7 g of a paste obtained by heating was sprayed and granulated. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
In Example 16, 369.9 g of D-mannitol (Mannit C), 9.4 g of light anhydrous silicic acid, and 14.7 g of magnesium oxide (made by Wako Pure Chemical Industries, Ltd., reagent grade) were mixed, and then sieved with a JP 30 sieve. Thereafter, 375.2 g was weighed, and 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose, and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. This was sprayed and granulated with 242.7 g of the paste prepared in Comparative Example 10. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
Example 17 was prepared by mixing 369.9 g of D-mannitol (Mannit C) and 9.4 g of light anhydrous silicic acid, and then sieving it with a JP 30 sieve, and weighing 361.2 g, to which 14.0 g of olanzapine, 31.9 g of low-substituted hydroxypropylcellulose and 14.0 g of crospovidone were mixed and charged into a fluidized bed granulator. To this, 299.6 g of purified water is sprayed with 242.7 g of paste obtained by dispersing 9.6 g of corn starch and 18.5 g of sodium polyphosphate (manufactured by Wako Pure Chemical Industries, Ltd., food additive) and heating. Grained. The obtained granulated product 395.0 g was mixed with magnesium stearate 5.0 g, and tableted with a rotary tableting machine.
得られた製剤をHDPE製容器に100錠充填したのち、40℃75%RH恒温恒湿器に気密(1gのアロフェン製乾燥剤付フタ)及び開放(フタなし)で保存して、一定期間後に取り出して類縁物質を測定した。その結果、図13に示すように比較例10と比べて、酸化マグネシウムを配合した実施例16及びポリリン酸ナトリウムを配合した実施例17のいずれも類縁物質の増加が抑制されていた。特に、湿度の高い条件での安定性改善効果は大きかった。 After filling the obtained formulation into 100 tablets in a HDPE container, store it in a thermostatic oven at 40 ° C. and 75% RH in airtight (1 g allophane lid with desiccant) and open (no lid), and after a certain period of time The related substances were taken out and measured. As a result, as shown in FIG. 13, as compared with Comparative Example 10, the increase in the related substances was suppressed in both Example 16 in which magnesium oxide was blended and Example 17 in which sodium polyphosphate was blended. In particular, the effect of improving the stability under high humidity conditions was great.
オランザピンは流動化剤の共存によって光照射でも類縁物質が増加することから、比較例4、実施例8〜11の製剤について光安定性試験(試験器:ナガノサイエンス製、LTL-200AS-14WC)を行った。製剤をシャーレ開放状態で保存し、25℃で白色ランプを毎時5000lux、総照度120万lux・hrとなるまで照射した。照射後に類縁物質を測定した結果を図14に示した。実施例8〜11のように、比較例4と比べL-アルギニンの併用量増加に伴って類縁物質量は抑制された。 Since olanzapine increases the number of related substances even when irradiated with light due to the coexistence of a fluidizing agent, the photostability test (tester: manufactured by Nagano Science Co., Ltd., LTL-200AS-14WC) was conducted on the preparations of Comparative Example 4 and Examples 8-11. went. The preparation was stored in an open petri dish and irradiated at 25 ° C. with a white lamp until 5000 lux / hour and a total illumination of 1.2 million lux · hr. The results of measuring related substances after irradiation are shown in FIG. As in Examples 8 to 11, the amount of related substances was suppressed as the combined amount of L-arginine was increased as compared with Comparative Example 4.
本発明によれば、流動化剤により不安定化するオランザピンの製剤組成物にアルカリ性添加剤を配合することで、熱、湿度及び光照射による類縁物質の増加を抑制することができ、一般的な方法で製造可能で、安定性や物理的品質にも優れた口腔内崩壊錠をはじめとするオランザピンの経口製剤を提供することができる。 According to the present invention, by adding an alkaline additive to the olanzapine pharmaceutical composition that is destabilized by a fluidizing agent, an increase in related substances due to heat, humidity, and light irradiation can be suppressed. It is possible to provide an oral preparation of olanzapine including an orally disintegrating tablet which can be produced by the method and is excellent in stability and physical quality.
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