JP5483679B2 - Olopatadine solid preparation and method for producing olopatadine tablet - Google Patents
Olopatadine solid preparation and method for producing olopatadine tablet Download PDFInfo
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- JP5483679B2 JP5483679B2 JP2009168061A JP2009168061A JP5483679B2 JP 5483679 B2 JP5483679 B2 JP 5483679B2 JP 2009168061 A JP2009168061 A JP 2009168061A JP 2009168061 A JP2009168061 A JP 2009168061A JP 5483679 B2 JP5483679 B2 JP 5483679B2
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- Prior art keywords
- olopatadine
- solid preparation
- preparation according
- tablet
- present
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、オロパタジン固形製剤に関する。より詳しくは、安定性の高いオロパタジン固形製剤および安定性の高いオロパタジン錠剤の製造方法に関する。 The present invention relates to an olopatadine solid preparation. More specifically, the present invention relates to a highly stable olopatadine solid preparation and a method for producing a highly stable olopatadine tablet.
近年、生活環境の変化、食生活の変化、抗原に対する過剰暴露、遺伝などを原因としたアレルギー疾患が急増している。アレルギー疾患とは、特定の抗原に対して、免疫反応が過剰に起こる疾患の総称であり、例えば、喘息、花粉症などのアレルギー性鼻炎、蕁麻疹、アトピー性皮膚炎、などが挙げられる。 In recent years, there has been a rapid increase in allergic diseases caused by changes in the living environment, changes in dietary habits, excessive exposure to antigens, inheritance, and the like. An allergic disease is a general term for diseases in which an immune reaction occurs excessively with respect to a specific antigen, and examples thereof include allergic rhinitis such as asthma and hay fever, urticaria, and atopic dermatitis.
このようなアレルギー疾患の治療効果を示す物質として、オロパタジンが知られている（特許文献１）。オロパタジンは、喘息、花粉症などのアレルギー性鼻炎、蕁麻疹、皮膚疾患に伴うそう痒(湿疹・皮膚炎、痒疹、皮膚そう痒症、尋常性乾癬、多形滲出性紅斑)、などに有効であることが報告されている（特許文献２）。 Olopatadine is known as a substance showing the therapeutic effect of such allergic diseases (Patent Document 1). Olopatadine is effective for allergic rhinitis such as asthma and hay fever, urticaria, pruritus associated with skin diseases (eczema / dermatitis, prurigo, cutaneous pruritus, psoriasis vulgaris, polymorphic exudative erythema), etc. It has been reported (Patent Document 2).
現在、オロパタジン製剤は、錠剤の形態で市販されているが、オロパタジンは、光による不安定性や、経口投与用の医薬品製剤の製造に多用される賦形剤、崩壊剤、結合剤および滑沢剤等の添加物の添加により保存時に経時的に分解されることが知られており、現在市販されている錠剤も、光安定性を向上させるためにフィルムで被覆されているのが実情である。 Currently, olopatadine is marketed in the form of tablets, but olopatadine is an instability due to light and excipients, disintegrants, binders and lubricants frequently used in the production of pharmaceutical preparations for oral administration. It is known that it degrades over time when stored due to the addition of additives such as these, and the current situation is that tablets on the market are also coated with a film in order to improve light stability.
オロパタジン製剤の安定性を高める技術として、特許文献３には、乳糖および結晶セルロースをベースとした処方に、セルロース誘導体を添加することにより、オロパタジン製剤の安定性を高める技術が提案されている。
As a technique for improving the stability of an olopatadine preparation,
また、特許文献４には、パウダーコーティング法により、所定の核被覆層でオロパタジン固形製剤をコーティングすることにより、光安定性等の保存安定性を高める技術が提案されている。 Patent Document 4 proposes a technique for improving storage stability such as light stability by coating an olopatadine solid preparation with a predetermined core coating layer by a powder coating method.
更に、特許文献５には、オロパタジン素製剤１００重量部に対して０．６重量部以上の遮光剤を含有する皮膜またはカプセルで、オロパタジン固形製剤を被覆することにより、光安定性等の保存安定性を高める技術が提案されている。
Furthermore,
通常、オロパタジン錠剤は、オロパタジンに各種添加剤を混合し、造粒した後、乾燥して打錠するという、間接打錠法（乾式圧縮法、湿式圧縮法）を用いて製造される。錠剤の製造方法としては、間接打錠法の他に、造粒を行うことなく打錠を行う直接打錠法（直接圧縮法）があるが、オロパタジン錠剤の製造において、直接打錠法（直接圧縮法）が用いられたという報告はない。 Usually, olopatadine tablets are produced by using an indirect tableting method (dry compression method, wet compression method) in which various additives are mixed with olopatadine, granulated, and then dried and tableted. In addition to the indirect tableting method, there is a direct tableting method (direct compression method) in which tableting is performed without granulation. In the production of olopatadine tablets, the direct tableting method (direct There is no report that the compression method was used.
直接打錠法（直接圧縮法）を用いて錠剤を製造する場合には、適切な賦形剤を使用しなければ、硬度が不足したり、崩壊性が悪くなったりする場合があるため、賦形剤の選択は非常に重要である。例えば、特許文献６には、直接打錠用賦形剤として最も優れているものは、結晶セルロースであるとの報告がある。
When tablets are manufactured using the direct compression method (direct compression method), the hardness may be insufficient or the disintegration may deteriorate unless an appropriate excipient is used. The choice of form is very important. For example,
前述の通り、オロパタジン製剤は、高いアレルギー疾患治療効果を示す一方で、製剤としての安定性が低いという問題がある。この問題に対し、前記のような様々な技術が提案されているが、得られるオロパタジン錠剤の光安定性・苛酷安定性等は、充分なものではなかった。これは、前記の通り、市販されているオロパタジン製剤が、フィルムで被覆されたフィルムコーティング錠であることからもうかがえる。 As described above, the olopatadine preparation has a problem of low stability as a preparation while exhibiting a high therapeutic effect on allergic diseases. Various techniques as described above have been proposed for this problem, but the resulting olopatadine tablet has not been satisfactory in light stability, severe stability, and the like. This can be explained by the fact that the commercially available olopatadine preparation is a film-coated tablet coated with a film as described above.
そこで、本発明では、オロパタジン製剤の良好な溶出性を維持したまま、安定性を向上させる新規な技術を提供することを主目的とする。 Therefore, the main object of the present invention is to provide a novel technique for improving the stability while maintaining the good dissolution property of the olopatadine preparation.
本発明者らは、オロパタジン固形製剤の安定性を向上させるために鋭意研究を行った結果、従来、必須とされていた賦形剤について、発想を全く転換することにより、従来にない安定性を示すオロパタジン固形製剤を見出し、本発明を完成させるに至った。 As a result of diligent research to improve the stability of olopatadine solid preparations, the present inventors have changed the way of thinking about excipients, which have been considered essential in the past, to achieve unprecedented stability. The olopatadine solid preparation shown was found to complete the present invention.
即ち、本発明では、まず、オロパタジン、糖類、崩壊剤を含み、
結晶セルロースを含まず、
直接圧縮法により製造されるオロパタジン固形製剤を提供する。
従来、オロパタジン製剤の安定性向上には、結晶セルロースが必須と考えられていたが（特許文献３）、本発明においては、敢えて結晶セルロースを含有させないことにより、オロパタジン製剤の安定性を向上させることが見出された。
本発明に係るオロパタジン固形製剤の具体的な剤型は特に限定されないが、本発明においては特に、錠剤とすることが好ましい。
本発明に係るオロパタジン固形製剤の剤型を錠剤とする場合、その製造方法としては、直接打錠法を用いることが好ましい。
本発明に係るオロパタジン固形製剤に用いる糖類の種類も、本発明の効果を損なわなければ特に限定されないが、本発明では特に、乳糖を用いることが好ましい。
また、本発明に係るオロパタジン固形製剤に用いる崩壊剤の種類も、本発明の効果を損なわなければ特に限定されないが、本発明では特に、セルロース誘導体を用いることが好ましい。
この場合、セルロース誘導体の種類も、本発明の効果を損なわなければ特に限定されないが、本発明では特に、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）を用いることが好ましい。
That is, in the present invention, first, olopatadine, saccharides, disintegrant,
Does not contain crystalline cellulose
An olopatadine solid preparation produced by a direct compression method is provided.
Conventionally, crystalline cellulose has been considered essential for improving the stability of olopatadine preparations (Patent Document 3), but in the present invention, the stability of olopatadine preparations is improved by not intentionally containing crystalline cellulose. Was found.
The specific dosage form of the olopatadine solid preparation according to the present invention is not particularly limited, but in the present invention, a tablet is particularly preferable.
When the dosage form of the olopatadine solid preparation according to the present invention is used as a tablet, it is preferable to use a direct tableting method as its production method.
The type of saccharide used in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired. In the present invention, it is particularly preferable to use lactose.
Further, the type of disintegrant used in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired. In the present invention, it is particularly preferable to use a cellulose derivative.
In this case, the type of the cellulose derivative is not particularly limited as long as the effects of the present invention are not impaired, but in the present invention, it is particularly preferable to use low-substituted hydroxypropyl cellulose (L-HPC).
本発明では、次に、オロパタジン、糖類、崩壊剤を含み、結晶セルロースを含まない原料粉末混合体を、直接打錠する工程を少なくとも行うオロパタジン錠剤の製造方法を提供する。
本発明に係る製造方法では、結晶セルロースを用いずに、直接打錠法を行うにも関わらず、製造されるオロパタジン錠剤の安定性を高めることが可能であり、硬度や崩壊性等の物性が良好な錠剤を得ることができる。
Next, the present invention provides a method for producing an olopatadine tablet comprising at least a step of directly compressing a raw material powder mixture containing olopatadine, a saccharide and a disintegrant and not containing crystalline cellulose.
In the production method according to the present invention, it is possible to increase the stability of the produced olopatadine tablet despite the direct tableting method without using crystalline cellulose, and the physical properties such as hardness and disintegration are improved. Good tablets can be obtained.
本発明によれば、オロパタジン製剤の良好な溶出性を維持したまま、安定性を飛躍的に向上させることが可能である。 According to the present invention, it is possible to dramatically improve the stability while maintaining the good dissolution property of the olopatadine preparation.
以下、本発明を実施するための好適な形態について詳細に説明する。なお、以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。 Hereinafter, preferred embodiments for carrying out the present invention will be described in detail. In addition, embodiment described below shows an example of typical embodiment of this invention, and, thereby, the range of this invention is not interpreted narrowly.
＜オロパタジン固形製剤＞
本発明に係るオロパタジン固形製剤は、オロパタジン、糖類、崩壊剤を含み、結晶セルロースを含まないことを特徴とする。前述の通り、従来の技術常識からすると、オロパタジン固形製剤を製造するには、賦形剤として結晶セルロースが第一選択されるのが当然である（特許文献６参照）。現に、オロパタジン製剤の安定性を高めるために、結晶セルロース賦形剤として用いることが公知技術となっている（特許文献３参照）。このように、結晶セルロースは、医薬品の安定性に影響を及ぼす報告はほとんどなく、結晶セルロースは良好な賦形剤として医薬品に多用されているものである。
<Olopatadine solid formulation>
The olopatadine solid preparation according to the present invention contains olopatadine, a saccharide, and a disintegrant, and is characterized by not containing crystalline cellulose. As described above, from the conventional technical common sense, it is natural that crystalline cellulose is first selected as an excipient to produce an olopatadine solid preparation (see Patent Document 6). In fact, in order to increase the stability of olopatadine preparations, it has become a known technique to be used as a crystalline cellulose excipient (see Patent Document 3). Thus, crystalline cellulose has almost no reports affecting the stability of pharmaceuticals, and crystalline cellulose is frequently used in pharmaceuticals as a good excipient.
しかしながら、本発明者らは、オロパタジン固形製剤に結晶セルロースを用いたところ、意外にも安定性の低下が見られること、逆に、オロパタジン固形製剤においては結晶セルロースを用いないことにより、安定性が向上することを見出した。以下、本発明に係るオロパタジン固形製剤に含有する各成分、および剤型などについて詳細に説明する。 However, when the present inventors used crystalline cellulose in the olopatadine solid preparation, the stability was unexpectedly reduced, and conversely, in the olopatadine solid preparation, the stability was improved by not using crystalline cellulose. I found it to improve. Hereinafter, each component, dosage form, and the like contained in the olopatadine solid preparation according to the present invention will be described in detail.
（１）オロパタジン
オロパタジンは、（Ｚ）−１１−（３−ジメチルアミノプロピリデン）−６、１１−ジヒドロジベンズ〔ｂ、ｅ〕オキセピン−２−酢酸であって、（Ｅ）−１１−（３−ジメチルアミノプロピリデン）−６、１１−ジヒドロジベンズ〔ｂ、ｅ〕オキセピン−２−酢酸・塩酸塩の一般名である。その製造および薬理学的活性は、前記特許文献２に記載されているが、喘息、花粉症などのアレルギー性鼻炎、蕁麻疹、皮膚疾患に伴うそう痒(湿疹・皮膚炎、痒疹、皮膚そう痒症、尋常性乾癬、多形滲出性紅斑)などに有効な物質であり、本発明に係るオロパタジン固形製剤においても、このオロパタジンを有効成分として含有する。
(1) Olopatadine Olopatadine is (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid, and (E) -11- ( 3-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid / hydrochloride is a general name. Although its production and pharmacological activity are described in
本発明で使用する「オロパタジン」とは、遊離塩基形およびその製薬学的に許容可能な酸付加塩を広く包含する。ここで、「付加塩」とは、オロパタジン、並びにその塩類が形成できる溶媒和物も広く包含し、溶媒和物としては、例えば、アルコレート類などを挙げることができる。オロパタジンの溶解度は、このような塩の生成で増加し、それらは塩基形と適当な酸との反応により得ることができる。 As used herein, “olopatadine” broadly encompasses the free base form and pharmaceutically acceptable acid addition salts thereof. Here, the “addition salt” widely includes olopatadine and solvates that can be formed by the salts thereof, and examples of the solvates include alcoholates. The solubility of olopatadine increases with the formation of such salts, which can be obtained by reaction of the base form with a suitable acid.
塩を形成する無機酸の例としては、塩酸、臭素酸、硫酸、リン酸、ナトリウム−オルトリン酸塩、カリウム水素硫酸塩などが挙げられる。 Examples of inorganic acids that form salts include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, sodium orthophosphate, potassium hydrogensulfate, and the like.
また、塩を形成する有機酸の例としては、モノ、ジ、トリカルボン酸、などが挙げられる。これらの酸の例としては、例えば、酢酸、グリコール酸、乳酸、ピルビン酸、マロン酸、コハク酸、グルタル酸、フマル酸、リンゴ酸、酒石酸、クエン酸、アスコルビン酸、マレイン酸、ヒドロキシマレイン酸、安息香酸、ヒドロキシ安息香酸、フェニル酢酸、桂皮酸、サリチル酸、２−フェノキシ安息香酸、などが挙げられる。塩を形成するその他の有機酸としては、メタンスルホン酸、２−ヒドロキシエタンスルホン酸の様なスルホン酸を挙げることができる。 Examples of the organic acid that forms a salt include mono-, di-, and tricarboxylic acids. Examples of these acids include, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, Examples include benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, and the like. Examples of other organic acids that form salts include sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
これらの塩及び基本化合物は、水和形態、或いは実質的に無水の形態で存在する。酸塩は、水性溶液または水性−アルコール溶液、或いは適当な酸を含むその他の適当な溶媒に、遊離の塩基を溶解し、溶液を蒸発させて単離するか、または、塩の直接分離又は溶液の濃縮によって得る事のできるいずれかの場合において、遊離の塩基を有機溶媒で反応させる様な一般的な方法によって調製することができる。 These salts and basic compounds exist in hydrated or substantially anhydrous forms. The acid salt can be isolated by dissolving the free base in an aqueous solution or aqueous-alcohol solution or other suitable solvent containing a suitable acid and evaporating the solution or by direct salt separation or solution. In any case that can be obtained by concentrating, the free base can be prepared by general methods such as reacting with an organic solvent.
（２）糖類
本発明に係るオロパタジン固形製剤には、賦形剤として糖類を用いる。本発明に係るオロパタジン固形製剤に用いることが可能な糖類の種類は、本発明の効果を損なわなければ特に限定されず、医薬製剤に用いることができる糖類を、１種または２種以上自由に選択して用いることができる。
(2) Sugars In the olopatadine solid preparation according to the present invention, sugars are used as excipients. The kind of saccharide that can be used in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, and one or more saccharides that can be used in the pharmaceutical preparation can be freely selected. Can be used.
本発明では特に、後述の実施例で示すように、糖類中でも乳糖を用いることで、オロパタジン固形製剤の安定性を高めることができることが見出された。本発明に係るオロパタジン固形製剤に用いることが可能な乳糖とは、α−含水乳糖、α−無水乳糖、β−無水乳糖の全てを含み、一般的に医薬品として使用しうるグレートのものであれば、自由に選択して用いることが可能である。 In the present invention, it has been found that the stability of an olopatadine solid preparation can be enhanced by using lactose among saccharides, as shown in Examples described later. Lactose that can be used in the olopatadine solid preparation according to the present invention includes all of α-hydrated lactose, α-anhydrolactose, and β-anhydrolactose, and is generally a great one that can be used as a pharmaceutical product. It is possible to select and use freely.
本発明に係るオロパタジン固形製剤における糖類の含有量は、本発明の効果を損なわなければ自由に設計することができるが、２０〜９５質量％とすることが好ましく、３５〜９０質量％とすることがより好ましい。 The content of saccharide in the olopatadine solid preparation according to the present invention can be freely designed as long as the effects of the present invention are not impaired, but it is preferably 20 to 95% by mass, and preferably 35 to 90% by mass. Is more preferable.
（３）崩壊剤
本発明に係るオロパタジン固形製剤には、固形製剤の崩壊を促進させるために、崩壊剤を配合する。本発明に係るオロパタジン固形製剤に用いることが可能な崩壊剤の種類は、本発明の効果を損なわなければ特に限定されず、医薬製剤に用いることができる崩壊剤を、１種又は２種以上自由に選択して用いることができる。例えば、クロスポビドン、ポビドン、各種セルロース誘導体などが挙げられる。
(3) Disintegrant In the olopatadine solid preparation according to the present invention, a disintegrant is blended in order to promote disintegration of the solid preparation. The type of disintegrant that can be used in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, and one or more disintegrants that can be used in the pharmaceutical preparation are freely selected. Can be selected and used. For example, crospovidone, povidone, various cellulose derivatives and the like can be mentioned.
この中でも特に本発明においては、セルロース誘導体を用いることで、後述の実施例で示すように、オロパタジン固形製剤の安定性を高めることができることが見出された。本発明に係るオロパタジン固形製剤に用いることが可能なセルロース誘導体の種類は、本発明の効果を損なわなければ特に限定されず、医薬製剤に用いることができるセルロース誘導体を、１種又は２種以上自由に選択して用いることができる。例えば、メチルセルロース、エチルセルロース、カルボキシルメチルセルロース、カルボキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシエチルセルロース、ヒプロメロースなどが挙げられ、単糖類であるグルコースが多数重合し高分子を形成して多糖類として存在するセルロースの水酸基の一部または全部がエステル化あるいはエーテル化されたセルロースから誘導されるものを挙げることができる。この中でも特に本発明においては、安定性を最も満足させる崩壊剤として、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）を用いることが好ましい。 Among these, in particular, in the present invention, it was found that by using a cellulose derivative, the stability of the olopatadine solid preparation can be enhanced as shown in Examples described later. The kind of the cellulose derivative that can be used in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, and one or more cellulose derivatives that can be used in the pharmaceutical preparation can be freely used. Can be selected and used. For example, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hypromellose, etc., a large number of monosaccharide glucoses form a polymer to form a polysaccharide There may be mentioned those in which some or all of the hydroxyl groups of cellulose are derived from cellulose esterified or etherified. Among these, particularly in the present invention, it is preferable to use low-substituted hydroxypropyl cellulose (L-HPC) as a disintegrant that satisfies the stability most.
本発明に係るオロパタジン固形製剤における崩壊剤の含有量は、本発明の効果を損なわなければ自由に設計することができるが、１〜３０質量％とすることが好ましく、５〜２０質量％とすることがより好ましい。１質量％未満では、投与時に固形製剤の崩壊を十分に促進させることができない場合があり、逆に、３０質量％を超えると、錠剤が大型化する場合があるからである。 The content of the disintegrant in the olopatadine solid preparation according to the present invention can be freely designed as long as the effects of the present invention are not impaired, but it is preferably 1 to 30% by mass, and preferably 5 to 20% by mass. It is more preferable. If the amount is less than 1% by mass, the disintegration of the solid preparation may not be sufficiently promoted at the time of administration. Conversely, if it exceeds 30% by mass, the tablet may be enlarged.
（４）その他添加剤
本発明に係るオロパタジン固形製剤には、本発明の効果を損なわない範囲で、水溶性薬剤に通常使用されている種々の添加剤、例えば、賦形剤、滑沢剤、流動化剤、結合剤、粘稠剤、緩衝剤、保存剤、酸化防止剤(抗酸化剤)、等張化剤、コーティング剤、矯味剤、溶解補助剤、基剤、分散剤、安定化剤、着色剤、香料、清涼化剤などを使用して公知の方法により製剤化することができる。以下、代表的な添加剤について、具体例を示す。
(4) Other additives In the olopatadine solid preparation according to the present invention, various additives usually used for water-soluble drugs, for example, excipients, lubricants, and the like, within a range not impairing the effects of the present invention. Fluidizers, binders, thickeners, buffers, preservatives, antioxidants (antioxidants), isotonic agents, coating agents, corrigents, solubilizers, bases, dispersants, stabilizers , And can be formulated by a known method using a coloring agent, a fragrance, a cooling agent, and the like. Specific examples of typical additives are shown below.
例えば、賦形剤としては、アラビアゴム末、アルファー化デンプン、カゼインナトリウム、カルボキシメチルスターチナトリウム、含水二酸化ケイ素、カンテン、キシリトール、クロスカルメロースナトリウム、D-マンニトール、マルチトール、マルトース水和物、無水リン酸水素カルシウム、トウモロコシデンプン、軽質無水ケイ酸、精製白糖、ソルビトール、ポビドン、マクロゴール等を１種又は２種以上自由に選択して用いることができる。 Examples of excipients include gum arabic powder, pregelatinized starch, sodium caseinate, sodium carboxymethyl starch, hydrous silicon dioxide, agar, xylitol, croscarmellose sodium, D-mannitol, maltitol, maltose hydrate, anhydrous One or more kinds of calcium hydrogen phosphate, corn starch, light anhydrous silicic acid, purified sucrose, sorbitol, povidone, macrogol and the like can be freely selected and used.
例えば、滑沢剤としては、カカオ脂、カルナウバロウ、含水二酸化ケイ素、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、硬化油、フマル酸ステアリルナトリウムなどを１種又は２種以上自由に選択して用いることができる。例えば、流動化剤としては、含水二酸化ケイ素、軽質無水ケイ酸、タルクなどを１種又は２種以上自由に選択して用いることができる。 For example, as the lubricant, cacao butter, carnauba wax, hydrous silicon dioxide, stearic acid, magnesium stearate, calcium stearate, hydrogenated oil, sodium stearyl fumarate and the like can be freely selected and used. it can. For example, as the fluidizing agent, hydrous silicon dioxide, light anhydrous silicic acid, talc and the like can be freely selected and used.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な結合剤としては、水溶性高分子が好ましく、例えば、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシブチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコールなどを、１種又は２種以上自由に選択して用いることができる。 For example, as a binder that can be used in the olopatadine solid preparation according to the present invention, a water-soluble polymer is preferable. For example, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxy One or more kinds of propylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like can be freely selected and used.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な溶解補助剤としては、ポリオキシエチレンソルビタンモノオレエート、ポリオキシエチレンソルビタンモノパルミテート、ポリオキシエチレンソルビタンモノラウレート等のポリオキシエチレンソルビタンモノ脂肪酸エステル類、ポリオキシエチレンモノステアレート、ポリオキシエチレンモノオレエート、ポリオキシエチレンモノパルミテート等のポリオキシエチレンモノ脂肪酸エステル類、ポリオキシエチレンラウリルエーテル等のポリオキシエチレンアルコールエーテル、ポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油等の親水性の非イオン性界面活性剤、トロメタモール、ポリビニルピロリドン及びマクロゴールなどを、１種又は２種以上自由に選択して用いることができる。 For example, as a solubilizing agent that can be used in the olopatadine solid preparation according to the present invention, polyoxyethylene sorbitan such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, etc. Mono fatty acid esters, polyoxyethylene monostearate, polyoxyethylene monooleate, polyoxyethylene mono fatty acid esters such as polyoxyethylene monopalmitate, polyoxyethylene alcohol ethers such as polyoxyethylene lauryl ether, polyethylene glycol , Hydrophilic nonionic surfactant such as polyoxyethylene hydrogenated castor oil, trometamol, polyvinylpyrrolidone, macrogol, etc. It can be used.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な保存剤としては、パラオキシ安息香酸エステル類、亜硫酸塩類（亜硫酸ナトリウム、ピロ亜硫酸ナトリウム等）、リン酸塩類（リン酸ナトリウム、ポリリン酸カルシウム、ポリリン酸ナトリウム、メタリン酸ナトリウム等）、アルコール類（クロロブタノール、ベンジルアルコール等）、塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、クレゾール、クロロクレゾール、デヒドロ酢酸、デヒドロ酢酸ナトリウム、糖類などを、１種又は２種以上自由に選択して用いることができる。本発明に係るオロパタジン固形製剤における保存剤の濃度は、本発明の効果を損なわなければ特に限定されないが、０．０５％〜１％とするのが好ましく、０．１％〜０．５％とするのがより好ましく、そして約０．２％とするのが最も好ましい。 For example, preservatives that can be used in the olopatadine solid preparation according to the present invention include paraoxybenzoates, sulfites (sodium sulfite, sodium pyrosulfite, etc.), phosphates (sodium phosphate, calcium polyphosphate, polyphosphorus). 1 or 2 kinds of alcohol (sodium acid, sodium metaphosphate, etc.), alcohols (chlorobutanol, benzyl alcohol, etc.), benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorocresol, dehydroacetic acid, sodium dehydroacetate, saccharides, etc. More than one species can be freely selected and used. The concentration of the preservative in the olopatadine solid preparation according to the present invention is not particularly limited as long as the effect of the present invention is not impaired, but is preferably 0.05% to 1%, and 0.1% to 0.5%. More preferably, and most preferably about 0.2%.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な酸化防止剤(抗酸化剤)としては、亜硫酸塩類（亜硫酸ナトリウム、亜硫酸水素ナトリウム等）、ロンガリット、エリソルビン酸、Ｌ−アスコルビン酸、システイン、チオグリセロール、ブチルヒドロキシアニゾール、ジブチルヒドロキシトルエン、没食子酸プロピル、アスコルビン酸パルミテート、ｄｌ−α−トコフェロールなどを、１種又は２種以上自由に選択して用いることができる。 For example, as an antioxidant (antioxidant) that can be used in the olopatadine solid preparation according to the present invention, sulfites (sodium sulfite, sodium bisulfite, etc.), Rongalite, erythorbic acid, L-ascorbic acid, cysteine, One kind or two or more kinds of thioglycerol, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbyl palmitate, dl-α-tocopherol can be freely selected and used.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な矯味料としては、ショ糖、グルコースシロップ等の糖類、マンニトール、ソルビトール、キシリトール等の糖アルコール、シクラメートナトリウム、サッカリンナトリウム、アスパルテーム、スクラロース、アセスルファムカリウム、ステビア等の合成甘味料、グリチルリチン及びその塩類、及びハチミツ、ソーマチン、アマチャ末、アミノ酢酸、レモン油、オレンジ油等の精油などを、１種又は２種以上自由に選択して用いることができる。 For example, as a flavoring agent that can be used in the olopatadine solid preparation according to the present invention, sugars such as sucrose and glucose syrup, sugar alcohols such as mannitol, sorbitol, and xylitol, cyclamate sodium, saccharin sodium, aspartame, sucralose, acesulfame Synthetic sweeteners such as potassium and stevia, glycyrrhizin and its salts, and essential oils such as honey, thaumatin, amacha powder, aminoacetic acid, lemon oil, orange oil, etc. it can.
例えば、本発明に係るオロパタジン固形製剤に用いることが可能な香料又は清涼化剤としては、テルペン類（例えば、アネトール、オイゲノール、カンフル、ゲラニオール、シネオール、ボルネオール、メントール、リモネン、リュウノウ、精油（ウイキョウ油、クールミント油、ケイヒ油、スペアミント油、ハッカ水、ハッカ油、ペパーミント油、ベルガモット油、ユーカリ油、ローズ油など））などを、１種又は２種以上自由に選択して用いることができる。 For example, as a fragrance or a refreshing agent that can be used in the olopatadine solid preparation according to the present invention, terpenes (for example, anethole, eugenol, camphor, geraniol, cineol, borneol, menthol, limonene, ryuunou, essential oil (fennel oil) ), Mint oil, cinnamon oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.), etc.) can be freely selected and used.
その他、製薬学的に許容可能なシクロデキストリンまたはその誘導体を添加することにより、活性成分の水溶解度を増加させることも可能である。 In addition, it is also possible to increase the aqueous solubility of the active ingredient by adding a pharmaceutically acceptable cyclodextrin or a derivative thereof.
（５）剤型について
本発明に係るオロパタジン固形製剤は、固形であれば、その剤型は特に限定されず、公知の方法で自由に設計することができる。例えば、散剤、顆粒剤、錠剤、カプセル剤、丸剤などが挙げられる。本発明では特に、錠剤とすることが好ましい。
(5) About dosage form If the olopatadine solid preparation which concerns on this invention is solid, the dosage form will not be specifically limited, It can design freely by a well-known method. For example, powders, granules, tablets, capsules, pills and the like can be mentioned. In the present invention, a tablet is particularly preferable.
本発明に係るオロパタジン固形製剤の剤型を錠剤とする場合、従来のオロパタジン錠剤のように、いわゆる造粒工程を経た後に打錠する間接打錠法（乾式圧縮法、湿式圧縮法）を用いて製造することもできるが、本発明においては、後述の製造方法に記載する通り、直接打錠法（直接圧縮法）を用いて製造することが好ましい。 When the dosage form of the olopatadine solid preparation according to the present invention is used as a tablet, an indirect tableting method (dry compression method, wet compression method) in which tableting is performed after a so-called granulation process, as in the case of conventional olopatadine tablets, is used. Although it can also be manufactured, in the present invention, as described in the manufacturing method described later, it is preferable to manufacture using a direct tableting method (direct compression method).
直接打錠法（直接圧縮法）は、錠剤の各構成成分をただ単に混合するだけで圧縮成形に付する極めて簡便な製造方法であるため、製造時のコストや時間の削減に貢献する。また、製造工程中に水分などの添加をしていないので、錠剤の構成成分の安定性などにおいても好ましい製剤方法である。一方、製剤学分野では、錠剤の硬度や溶出性を向上させるためには、造粒工程を経た後に打錠する間接打錠法（顆粒圧縮法）を用いることが有効であるということが技術常識である。 The direct tableting method (direct compression method) is a very simple manufacturing method in which each component of the tablet is simply mixed and subjected to compression molding, and thus contributes to the reduction of manufacturing cost and time. In addition, since no moisture is added during the production process, it is a preferable preparation method in terms of stability of the components of the tablet. On the other hand, in the field of pharmaceutical sciences, it is effective to use an indirect tableting method (granule compression method) in which tableting is performed after a granulation step in order to improve tablet hardness and dissolution. It is.
しかしながら、本発明に係るオロパタジン固形製剤においては、前述した各成分を含有させ、且つ、結晶セルロースを含有させないことで、直接打錠法（直接圧縮法）を用いて錠剤を製造した場合であっても、十分な錠剤硬度と十分な溶出性を備え、光や熱などに対する安定性が向上したオロパタジン錠剤を製造することに成功した。 However, in the olopatadine solid preparation according to the present invention, it is a case where a tablet is produced using the direct compression method (direct compression method) by containing the above-described components and not containing crystalline cellulose. However, we have succeeded in producing olopatadine tablets with sufficient tablet hardness and sufficient dissolution properties, and improved stability against light and heat.
このように、本発明に係るオロパタジン固形製剤は、その剤型を錠剤とした場合にも、十分な錠剤硬度を備え、光や熱などに対する安定性も高いため、裸錠の状態でも十分な効果を発揮するが、薬物の放出の制御、薬物の味のマスキング、より確実な遮光、プロテクト(他の賦形剤との接触防止など)、防湿などの目的のために、その表面を１層または２層以上、コーティングすることも可能である。 As described above, the olopatadine solid preparation according to the present invention has sufficient tablet hardness and high stability against light, heat, etc. even when the dosage form is a tablet. However, the surface may be a single layer for purposes such as controlling the release of the drug, masking the taste of the drug, more reliable light shielding, protection (such as preventing contact with other excipients), and moisture. Two or more layers can be coated.
本発明に係るオロパタジン固形製剤に用いるコーティング剤は、本発明の効果を損なわなければ特に限定されず、公知のコーティング剤を１種または２種以上選択して用いることができる。例えば、水溶性高分子、水不溶性高分子、腸溶性高分子、胃溶性高分子、疎水性有機化合物などのコーティング剤を使用することができる。 The coating agent used for the olopatadine solid preparation according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, and one or more known coating agents can be selected and used. For example, coating agents such as water-soluble polymers, water-insoluble polymers, enteric polymers, gastric polymers, and hydrophobic organic compounds can be used.
より具体的には、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース(ヒプロメロース)などの水溶性セルロースエーテル、ポリビニルピロリドン、ポリビニルアルコールなどの水溶性ポリビニル誘導体、ポリエチレングリコール、ポリプロピレングリコールなどのアルキレンオキシド重合体等の水溶性高分子、エチルセルロースなどの水不溶性セルロースエーテル、アクリル酸エチル・メタクリル酸メチル・メタクリル酸塩化トリメチルアンモニウムエチル共重合体等の水不溶性高分子、ヒドロキシプロピルメチルセルロースアセテートサクシネート、スチレン・アクリル酸共重合体、アクリル酸メチル・アクリル酸共重合体、アクリル酸メチル・メタクリル酸共重合体、酢酸ビニル・マレイン酸無水物共重合体、スチレン・マレイン酸無水物共重合体、ポリビニルアルコールフタレート、ポリビニルアセタールフタレートなどの腸溶性高分子、ポリビニルアセタールジエチルアミノアセテートなどの胃溶性ポリビニル誘導体、メタアクリル酸メチル・メタクリル酸ブチル・メタクリル酸ジメチルアミノエチル共重合体等の胃溶性高分子などを挙げることができる。 More specifically, water-soluble cellulose ethers such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), water-soluble polyvinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol, and alkylene oxide polymers such as polyethylene glycol and polypropylene glycol. Water-soluble polymers, water-insoluble cellulose ethers such as ethyl cellulose, water-insoluble polymers such as ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer, hydroxypropyl methylcellulose acetate succinate, styrene / acrylic acid copolymer Polymer, methyl acrylate / acrylic acid copolymer, methyl acrylate / methacrylic acid copolymer, vinyl acetate / maleic anhydride Copolymers, styrene / maleic anhydride copolymers, enteric polymers such as polyvinyl alcohol phthalate and polyvinyl acetal phthalate, gastric polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / methacrylic acid Examples thereof include gastric polymers such as dimethylaminoethyl copolymer.
このコーティング層には、上記のようなコーティング剤成分のほか、必要に応じて着色剤、隠蔽剤、可塑剤、滑沢剤などの種々の添加剤を更に含有させることができる。 In addition to the coating agent component as described above, the coating layer may further contain various additives such as a colorant, a hiding agent, a plasticizer, and a lubricant as necessary.
着色剤としては、例えば、食用色素、レーキ色素、カラメル、カロチン、アナット、コチニール、三二酸化鉄などに加えて、レーキ色素とシロップを主体とした不透明着色剤オパラックス（ＯＰＡＬＵＸ）などを挙げることができる。より具体的には、食用赤色２号、３号、黄色４号、５号、緑色３号、青色１号、２号、紫１号などの食用アルミニウムレーキ、アナット（ベニノキ由来の天然色素）、カルミン（カルミン酸アルミニウム塩）、パールエッセンス（グアニンを主成分とする）などを使用することができる。 Examples of the colorant include edible pigments, lake pigments, caramel, carotene, anat, cochineal, iron sesquioxide and the like, and opaque pigment opalax (OPALUX) mainly composed of lake pigment and syrup. . More specifically, edible aluminum lakes such as edible red No. 2, No. 3, yellow No. 4, No. 5, green No. 3, blue No. 1, No. 2, purple No. 1, etc., anat (natural pigment derived from Beninoki), Carmine (aluminum carmate), pearl essence (based on guanine) and the like can be used.
隠蔽剤としては、二酸化チタン(酸化チタン)、タルク、沈降炭酸カルシウム、リン酸水素カルシウム、硫酸カルシウムなどを挙げることできる。 Examples of the masking agent include titanium dioxide (titanium oxide), talc, precipitated calcium carbonate, calcium hydrogen phosphate, and calcium sulfate.
可塑剤としては、ジエチルフタレート、ジブチルフタレート、ブチルフタリルブチルグリコレートなどのフタル酸誘導体のほか、シリコン油、クエン酸トリエチル、アセチルクエン酸トリエチル、トリアセチン、プロピレングリコール、ポリエチレングリコール、セタノール、モノステアリン酸グリセリン、ショ糖脂肪酸エステル、ポリソルベートなどを挙げることができる。 Plasticizers include phthalic acid derivatives such as diethyl phthalate, dibutyl phthalate, and butyl phthalyl butyl glycolate, as well as silicone oil, triethyl citrate, triethyl acetyl citrate, triacetin, propylene glycol, polyethylene glycol, cetanol, and monostearic acid. Examples thereof include glycerin, sucrose fatty acid ester, polysorbate and the like.
滑沢剤としては、ステアリン酸マグネシウム、タルク、合成ケイ酸マグネシウム、微粒子性酸化ケイ素、などを挙げることができる。また、光沢化剤としては、カルナウバロウ、軽質無水ケイ酸、ステアリン酸、タルク、パラフィン、マクロゴール、ミツロウ、モノステアリン酸グリセリン、流動パラフィンなどを挙げることができる。 Examples of the lubricant include magnesium stearate, talc, synthetic magnesium silicate, and particulate silicon oxide. Examples of the brightening agent include carnauba wax, light anhydrous silicic acid, stearic acid, talc, paraffin, macrogol, beeswax, glyceryl monostearate, liquid paraffin, and the like.
本発明に係るオロパタジン固形製剤の剤型を錠剤とする場合、その錠剤の種類は特に限定されず、例えば、内服錠に限らず、バッカル錠、舌下錠、チュアブル錠などの口腔錠として製剤することも可能である。 When the dosage form of the olopatadine solid preparation according to the present invention is a tablet, the type of the tablet is not particularly limited. For example, it is formulated as an oral tablet such as a buccal tablet, sublingual tablet, chewable tablet, etc. It is also possible.
以上説明した本発明に係るオロパタジン固形製剤の引張強度は、０．５ＭＰａ以上、好ましくは約０．８ＭＰａ以上、より好ましくは約１ＭＰａ以上である。また、第十五改正日本薬局方崩壊試験（試験液：水）による崩壊時間は、好ましくは５分以下、より好ましくは２分以下であり、口腔内速崩壊性製剤とした場合の口腔内崩壊時間は、好ましくは約６０秒以下、より好ましくは約３０秒以下、最も好ましくは約２０秒以下である。 The tensile strength of the olopatadine solid preparation according to the present invention described above is 0.5 MPa or more, preferably about 0.8 MPa or more, more preferably about 1 MPa or more. In addition, the disintegration time according to the 15th revised Japanese Pharmacopoeia disintegration test (test solution: water) is preferably 5 minutes or less, more preferably 2 minutes or less. The time is preferably about 60 seconds or less, more preferably about 30 seconds or less, and most preferably about 20 seconds or less.
＜オロパタジン錠剤の製造方法＞
本発明に係るオロパタジン錠剤の製造方法は、オロパタジン、糖類、崩壊剤を含み、結晶セルロースを含まない原料粉末混合体を、直接打錠する工程を少なくとも行う方法である。前述した通り、本発明においては、前記各成分を含有させ、且つ、結晶セルロースを含有させないことで、直接打錠法（直接圧縮法）を採用した場合であっても、得られたオロパタジン錠剤は、十分な錠剤硬度と十分な溶出性を備え、光や熱などに対する安定性が非常に高いことを特徴とする。
<Method for producing olopatadine tablet>
The manufacturing method of the olopatadine tablet which concerns on this invention is the method of performing at least the process of directly tableting the raw material powder mixture which contains olopatadine, saccharides, and a disintegrating agent, and does not contain crystalline cellulose. As described above, in the present invention, the obtained olopatadine tablet contains the above components and does not contain crystalline cellulose, so that the obtained olopatadine tablet can be used even when the direct tableting method (direct compression method) is adopted. It is characterized by having sufficient tablet hardness and sufficient dissolution properties, and very high stability to light and heat.
また、本発明に係る製造方法が採用する直接打錠法（直接圧縮法）は、極めて簡便な製造方法であるため、製造時のコストや時間を大幅に削減することができる。また、製造工程中に水分などの添加をしていないので、間接打錠法（顆粒圧縮法）を採用する場合に比べ、錠剤の構成成分の安定性などを向上させることができる。 In addition, the direct tableting method (direct compression method) employed by the production method according to the present invention is a very simple production method, and thus the cost and time during production can be greatly reduced. In addition, since no moisture or the like is added during the production process, the stability of the components of the tablet can be improved as compared with the case of employing the indirect tableting method (granular compression method).
具体的な打錠には、一般的な錠剤の成型または造粒に用いられる装置を、自由に選択して用いることができる。例えば、単発錠剤機、ロータリー式錠剤機などを用いることができる。 For specific tableting, an apparatus used for general tablet molding or granulation can be freely selected and used. For example, a single tablet machine or a rotary tablet machine can be used.
本発明に係る製造方法における打錠の際の成型圧力は、本発明の効果が損なわれない限り特に限定されず、自由に設定することができる。通常は、３〜１６０Ｋｇ／ｃｍ２（２．９４×１０５〜１．５７×１０７Ｐａ）、好ましくは５〜１３０Ｋｇ／ｃｍ２（４．９０×１０５〜１．２７×１０７Ｐａ）、より好ましくは８〜５０Ｋｇ／ｃｍ２（７．８４×１０５〜４．９０×１０６Ｐａ）程度である。 The molding pressure at the time of tableting in the production method according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, and can be freely set. Usually, 3 to 160 kg / cm 2 (2.94 × 10 5 to 1.57 × 10 7 Pa), preferably 5 to 130 kg / cm 2 (4.90 × 10 5 to 1.27 × 10 7 Pa). More preferably, it is about 8-50 kg / cm < 2 > (7.84 * 10 < 5 > -4.90 * 10 < 6 > Pa).
本発明に係る製造方法における打錠時の温度は、本発明の効果が損なわれない限り特に限定されず、自由に設定することができる。本発明では、用いる糖類粒子が溶解又は溶融しない程度に設定することが好ましく、通常室温（例えば２０〜３０℃程度）で行えば十分である。 The temperature at the time of tableting in the production method according to the present invention is not particularly limited as long as the effect of the present invention is not impaired, and can be freely set. In this invention, it is preferable to set to the grade which the saccharide particle to be used does not melt | dissolve or melt | dissolve, and it is enough to carry out normally at room temperature (for example, about 20-30 degreeC).
以下、実施例に基づいて本発明を更に詳細に説明する。なお、以下に説明する実施例は、本発明の代表的な実施例の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。 Hereinafter, the present invention will be described in more detail based on examples. In addition, the Example demonstrated below shows an example of the typical Example of this invention, and, thereby, the range of this invention is not interpreted narrowly.
＜実験１．結晶セルロースの必要性の検討＞
本実験では、結晶セルロースを用いたオロパタジン固形製剤と、結晶セルロースを用いないオロパタジン固形製剤とについて、安定性の比較検討を行った。
<
In this experiment, the stability of olopatadine solid preparation using crystalline cellulose and olopatadine solid preparation not using crystalline cellulose were compared.
（１）実施例１
以下の方法で、実施例１に係るオロパタジン固形製剤を得た。
Ａ．まず、オロパタジン塩酸塩５．０ｍｇ、乳糖９５．０５ｍｇ及び崩壊剤（カルボキシメチルセルロース）１１．５０ｍｇを混合し、ポリビニルアルコール水溶液２．３０ｍｇを用いて造粒した後、十分乾燥して造粒物を得た。
Ｂ．次に、Ａで得られた造粒物にステアリン酸マグネシウム１．１５ｍｇを混合し、錠用末を得た。
Ｃ．Ｂで得られた錠用末を、１錠１１５ｍｇになるように打錠し、実施例１に係るオロパタジン固形製剤を得た。
(1) Example 1
The olopatadine solid preparation according to Example 1 was obtained by the following method.
A. First, 5.0 mg of olopatadine hydrochloride, 95.05 mg of lactose and 11.50 mg of disintegrant (carboxymethylcellulose) are mixed, granulated using 2.30 mg of polyvinyl alcohol aqueous solution, and then sufficiently dried to obtain a granulated product. It was.
B. Next, 1.15 mg of magnesium stearate was mixed with the granulated product obtained in A to obtain a powder for tablets.
C. The tablet powder obtained in B was tableted to give 1 tablet of 115 mg, and the olopatadine solid preparation according to Example 1 was obtained.
（２）実施例２
造粒時に用いたポリビニルアルコール水溶液の代わりにヒドロキシプロピルセルロース水溶液２．３０ｍｇを用いた以外は、実施例１と同様の方法で実施例２に係るオロパタジン固形製剤を得た。
(2) Example 2
An olopatadine solid preparation according to Example 2 was obtained in the same manner as in Example 1 except that 2.30 mg of a hydroxypropylcellulose aqueous solution was used instead of the polyvinyl alcohol aqueous solution used at the time of granulation.
（３）実施例３
カルボキシメチルセルロースの代わりにクロスカルメロースナトリウム１１．５０ｍｇを用いた以外は、実施例１と同様の方法で実施例３に係るオロパタジン固形製剤を得た。
(3) Example 3
An olopatadine solid preparation according to Example 3 was obtained in the same manner as in Example 1, except that 11.50 mg of croscarmellose sodium was used instead of carboxymethylcellulose.
（４）実施例４
造粒時に用いたポリビニルアルコール水溶液の代わりにヒドロキシプロピルセルロース水溶液２．３０ｍｇを用いた以外は、実施例３と同様の方法で実施例４に係るオロパタジン固形製剤を得た。
(4) Example 4
An olopatadine solid preparation according to Example 4 was obtained in the same manner as in Example 3 except that 2.30 mg of hydroxypropylcellulose aqueous solution was used instead of the polyvinyl alcohol aqueous solution used at the time of granulation.
（５）実施例５
カルボキシメチルセルロースの代わりに低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）１１．５０ｍｇを用いた以外は、実施例１と同様の方法で実施例５に係るオロパタジン固形製剤を得た。
(5) Example 5
An olopatadine solid preparation according to Example 5 was obtained in the same manner as in Example 1 except that 11.50 mg of low-substituted hydroxypropylcellulose (L-HPC) was used instead of carboxymethylcellulose.
（６）実施例６
造粒時に用いたポリビニルアルコール水溶液の代わりにヒドロキシプロピルセルロース水溶液２．３０ｍｇを用いた以外は、実施例５と同様の方法で実施例６に係るオロパタジン固形製剤を得た。
(6) Example 6
The olopatadine solid preparation according to Example 6 was obtained in the same manner as in Example 5 except that 2.30 mg of hydroxypropylcellulose aqueous solution was used instead of the polyvinyl alcohol aqueous solution used at the time of granulation.
（７）比較例１
市販の先発製剤（アレロック（登録商標））のフィルムコーティングをカッターで剥離し素錠としたものを、比較例１として用いた。なお、比較例１に係るオロパタジン固形製剤の配合組成は、下記表１に示す。
(7) Comparative Example 1
A comparative example 1 was prepared by peeling off a film coating of a commercially available original preparation (Allelock (registered trademark)) with a cutter to form an uncoated tablet. The composition of the olopatadine solid preparation according to Comparative Example 1 is shown in Table 1 below.
以上のように製造した実施例１〜６および比較例１に係るオロパタジン固形製剤について、安定性試験を行った。具体的には、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合を測定した。なお、安定性が高ければ、オロパタジン塩酸塩の類縁物質の割合は小さい値となる。 A stability test was performed on the olopatadine solid preparations according to Examples 1 to 6 and Comparative Example 1 produced as described above. Specifically, the ratio of the related substances of olopatadine hydrochloride when measured under severe conditions (60 ° C., 75% RH, 3 days) was measured. In addition, if stability is high, the ratio of the related substance of olopatadine hydrochloride will become a small value.
結果を下記の表１および図１に示す。合わせて表１には、比較を容易にするために、各オロパタジン固形製剤の配合組成を記載した。 The results are shown in Table 1 below and FIG. In addition, Table 1 shows the composition of each olopatadine solid preparation for easy comparison.
表１および図１に示す通り、結晶セルロースを用いた比較例１にくらべ、結晶セルロースを用いない実施例１〜６は、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合が顕著に低いことが分かった。即ち、オロパタジン固形製剤には、結晶セルロースを含有させないことにより、安定性が向上することが実証された。 As shown in Table 1 and FIG. 1, in comparison with Comparative Example 1 using crystalline cellulose, Examples 1 to 6 using no crystalline cellulose were left under severe conditions (60 ° C., 75% RH, 3 days). The proportion of olopatadine hydrochloride related substances was found to be significantly lower. That is, it was demonstrated that the stability of olopatadine solid preparation is improved by not containing crystalline cellulose.
＜実験２．打錠法の検討＞
本実験では、間接打錠法（顆粒圧縮法）を用いた場合と、直接打錠法（直接圧縮法）を用いた場合について、得られたオロパタジン錠剤の安定性を比較検討した。オロパタジン固形製剤として、前記実験１で製造した実施例１〜６に係るオロパタジン固形製剤と、下記の方法で製造した実施例７〜１５に係るオロパタジン固形製剤を用いた。
<
In this experiment, the stability of the obtained olopatadine tablets was compared for the case of using the indirect tableting method (granular compression method) and the case of using the direct tableting method (direct compression method). As the olopatadine solid preparation, the olopatadine solid preparation according to Examples 1 to 6 produced in
（１）実施例７
以下の方法で、実施例７に係るオロパタジン固形製剤を得た。
Ａ．まず、オロパタジン塩酸塩５．０ｍｇ、乳糖９５．０５ｍｇ及び崩壊剤（カルボキシメチルセルロース）１１．５０ｍｇを混合した。
Ｂ．次に、Ａで得られた混合物にステアリン酸マグネシウム１．１５ｍｇを混合し、錠用末を得た。
Ｃ．Ｂで得られた錠用末を、１錠１１５ｍｇになるように打錠し、実施例７に係るオロパタジン固形製剤を得た。
(1) Example 7
The olopatadine solid preparation according to Example 7 was obtained by the following method.
A. First, 5.0 mg of olopatadine hydrochloride, 95.05 mg of lactose and 11.50 mg of disintegrant (carboxymethylcellulose) were mixed.
B. Next, 1.15 mg of magnesium stearate was mixed with the mixture obtained in A to obtain a powder for tablets.
C. The tablet powder obtained in B was tableted to give 1 tablet of 115 mg, and the olopatadine solid preparation according to Example 7 was obtained.
（２）実施例８
カルボキシメチルセルロースの代わりにクロスカルメロースナトリウム１１．５０ｍｇを用いた以外は、実施例７と同様の方法で実施例８に係るオロパタジン固形製剤を得た。
(2) Example 8
An olopatadine solid preparation according to Example 8 was obtained in the same manner as in Example 7, except that 11.50 mg of croscarmellose sodium was used instead of carboxymethylcellulose.
（３）実施例９
カルボキシメチルセルロースの代わりに低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）１１．５０ｍｇを用いた以外は、実施例７と同様の方法で実施例９に係るオロパタジン固形製剤を得た。
(3) Example 9
An olopatadine solid preparation according to Example 9 was obtained in the same manner as in Example 7, except that 11.50 mg of low-substituted hydroxypropylcellulose (L-HPC) was used instead of carboxymethylcellulose.
（４）実施例１０
カルボキシメチルセルロースの代わりにカルボキシメチルスターチナトリウム１１．５０ｍｇを用いた以外は、実施例７と同様の方法で実施例１０に係るオロパタジン固形製剤を得た。
(4) Example 10
An olopatadine solid preparation according to Example 10 was obtained in the same manner as in Example 7, except that 11.50 mg of sodium carboxymethyl starch was used instead of carboxymethylcellulose.
（５）実施例１１
カルボキシメチルセルロースの代わりにクロスポビドン１１．５０ｍｇを用いた以外は、実施例７と同様の方法で実施例１１に係るオロパタジン固形製剤を得た。
(5) Example 11
An olopatadine solid preparation according to Example 11 was obtained in the same manner as in Example 7, except that 11.50 mg of crospovidone was used instead of carboxymethylcellulose.
（６）実施例１２
カルボキシメチルセルロースの代わりにカルボキシメチルスターチナトリウム１１．５０ｍｇを用いた以外は、実施例１と同様の方法で実施例１２に係るオロパタジン固形製剤を得た。
(6) Example 12
An olopatadine solid preparation according to Example 12 was obtained in the same manner as in Example 1 except that 11.50 mg of sodium carboxymethyl starch was used instead of carboxymethylcellulose.
（７）実施例１３
造粒時に用いたポリビニルアルコール水溶液の代わりにヒドロキシプロピルセルロース水溶液２．３０ｍｇを用いた以外は、実施例１２と同様の方法で実施例１３に係るオロパタジン固形製剤を得た。
(7) Example 13
An olopatadine solid preparation according to Example 13 was obtained in the same manner as in Example 12, except that 2.30 mg of hydroxypropylcellulose aqueous solution was used instead of the polyvinyl alcohol aqueous solution used at the time of granulation.
（８）実施例１４
カルボキシメチルセルロースの代わりにクロスポビドン１１．５０ｍｇを用いた以外は、実施例１と同様の方法で実施例１４に係るオロパタジン固形製剤を得た。
(8) Example 14
An olopatadine solid preparation according to Example 14 was obtained in the same manner as in Example 1 except that 11.50 mg of crospovidone was used instead of carboxymethylcellulose.
（９）実施例１５
造粒時に用いたポリビニルアルコール水溶液の代わりにヒドロキシプロピルセルロース水溶液２．３０ｍｇを用いた以外は、実施例１４と同様の方法で実施例１５に係るオロパタジン固形製剤を得た。
(9) Example 15
An olopatadine solid preparation according to Example 15 was obtained in the same manner as in Example 14, except that 2.30 mg of hydroxypropylcellulose aqueous solution was used instead of the polyvinyl alcohol aqueous solution used at the time of granulation.
以上のように製造した実施例１〜１５に係るオロパタジン固形製剤について、安定性試験を行った。具体的には、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合、および、白色蛍光灯下（６０万Ｌｕｘ・ｈｒ、１２０万Ｌｕｘ・ｈｒ）に放置場合のオロパタジン塩酸塩の類縁物質の割合を測定した。 The stability test was done about the olopatadine solid formulation which concerns on Examples 1-15 manufactured as mentioned above. Specifically, the ratio of the related substances of olopatadine hydrochloride when left under severe conditions (60 ° C., 75% RH, 3 days), and under a white fluorescent lamp (600,000 Lux · hr, 1.2 million Lux · hr), the proportion of olopatadine hydrochloride related substances was measured.
結果を下記の表２〜６および図２〜６に示す。合わせて表２〜６には、比較を容易にするために、各オロパタジン固形製剤の配合組成および打錠法を記載した。なお、各表２〜６は、用いた崩壊剤の種類ごとに比較した結果である。 The results are shown in Tables 2-6 below and FIGS. In addition, Tables 2 to 6 show the blending composition and tableting method of each olopatadine solid preparation for easy comparison. In addition, each Table 2-6 is the result compared for every kind of used disintegrating agent.
表２〜６および図２〜６に示す通り、各崩壊剤ごとに安定性を比較した結果、間接打錠法（顆粒圧縮法）を用いた実施例１〜６、１２〜１５に比べ、直接打錠法（直接圧縮法）を用いた実施例７〜１１は、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合、および白色蛍光灯下（６０万Ｌｕｘ・ｈｒ、１２０万Ｌｕｘ・ｈｒ）に放置場合のオロパタジン塩酸塩の類縁物質の割合が低いことが分かった。即ち、オロパタジン固形製剤を製造する場合、直接打錠法（直接圧縮法）を用いることにより、安定性が向上することが実証された。 As shown in Tables 2 to 6 and FIGS. 2 to 6, as a result of comparing the stability of each disintegrant, as compared with Examples 1 to 6 and 12 to 15 using the indirect tableting method (granular compression method), Examples 7 to 11 using the tableting method (direct compression method) were the ratio of the related substances of olopatadine hydrochloride when left under severe conditions (60 ° C., 75% RH, 3 days), and white fluorescent lamp It was found that the ratio of the related substances of olopatadine hydrochloride when it was left under (600,000 Lux · hr, 1.2 million Lux · hr) was low. That is, when manufacturing an olopatadine solid preparation, it was demonstrated that stability is improved by using a direct tableting method (direct compression method).
＜実験３．結晶セルロースおよび打錠法の検討＞
前記実験２では、結晶セルロースを含有しないオロパタジン固形製剤について、その打錠法の違いによる安定性を比較し、直接打錠法が好適であることが見出された。そこで、実験３では、直接打錠法において、結晶セルロースの有無による安定性の違いについて検討した。オロパタジン固形製剤として、前記実験２で製造した実施例１０、１１に係るオロパタジン固形製剤と、下記の方法で製造した比較例２、３に係るオロパタジン固形製剤を用いた。
<
In
（１）比較例２
以下の方法で、比較例２に係るオロパタジン固形製剤を得た。
Ａ．まず、オロパタジン塩酸塩５．０ｍｇ、乳糖８０．５０ｍｇ、結晶セルロース１６．８５及び崩壊剤（カルボキシメチルスターチナトリウム）１１．５０ｍｇを混合した。
Ｂ．次に、Ａで得られた混合物にステアリン酸マグネシウム１．１５ｍｇを混合し、錠用末を得た。
Ｃ．Ｂで得られた錠用末を、１錠１１５ｍｇになるように打錠し、実施例７に係るオロパタジン固形製剤を得た。
(1) Comparative example 2
The olopatadine solid preparation according to Comparative Example 2 was obtained by the following method.
A. First, olopatadine hydrochloride 5.0 mg, lactose 80.50 mg, crystalline cellulose 16.85 and disintegrant (carboxymethyl starch sodium) 11.50 mg were mixed.
B. Next, 1.15 mg of magnesium stearate was mixed with the mixture obtained in A to obtain a powder for tablets.
C. The tablet powder obtained in B was tableted to give 1 tablet of 115 mg, and the olopatadine solid preparation according to Example 7 was obtained.
（２）比較例３
カルボキシメチルスターチナトリウムの代わりにクロスポビドン１１．５０ｍｇを用いた以外は、比較例２と同様の方法で比較例３に係るオロパタジン固形製剤を得た。
(2) Comparative Example 3
An olopatadine solid preparation according to Comparative Example 3 was obtained in the same manner as in Comparative Example 2, except that 11.50 mg of crospovidone was used instead of carboxymethyl starch sodium.
以上のように製造した実施例１０、１１および比較例２、３に係るオロパタジン固形製剤について、安定性試験を行った。具体的には、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合を測定した。 A stability test was performed on the olopatadine solid preparations according to Examples 10 and 11 and Comparative Examples 2 and 3 produced as described above. Specifically, the ratio of the related substances of olopatadine hydrochloride when measured under severe conditions (60 ° C., 75% RH, 3 days) was measured.
結果を下記の表７、８および図７、８に示す。合わせて表７および８には、比較を容易にするために、各オロパタジン固形製剤の配合組成および打錠法を記載した。なお、各表７および８は、用いた崩壊剤の種類ごとに比較した結果である。 The results are shown in Tables 7 and 8 below and FIGS. In addition, Tables 7 and 8 list the blending composition and tableting method of each olopatadine solid preparation for easy comparison. In addition, each Table 7 and 8 is the result compared for every kind of disintegrant used.
表７、８および図７、８に示す通り、各崩壊剤ごとに安定性を比較した結果、同一の打錠法（直接打錠法（直接圧縮法））を用いた場合であっても、結晶セルロースを含有する比較例２および３に比べ、結晶セルロースを含有しない実施例１０、１１は、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合が低いことが分かった。即ち、オロパタジン固形製剤を製造する場合、直接打錠法（直接圧縮法）を用いるだけでなく、結晶セルロースを含有させないことが、安定性向上に重要であることが実証された。 As shown in Tables 7 and 8 and FIGS. 7 and 8, as a result of comparing the stability of each disintegrant, even when the same tableting method (direct tableting method (direct compression method)) was used, Compared to Comparative Examples 2 and 3 containing crystalline cellulose, Examples 10 and 11 not containing crystalline cellulose were related substances of olopatadine hydrochloride when left under severe conditions (60 ° C., 75% RH, 3 days). It was found that the ratio of was low. That is, when manufacturing olopatadine solid preparations, it was demonstrated that not only the direct tableting method (direct compression method) but also the inclusion of crystalline cellulose is important for improving stability.
＜実験４．用いる糖類の検討＞
実験４では、本発明に係るオロパタジン固形製剤に用いる好適な糖類について検討した。具体的には、乳糖、精製白糖、ブドウ糖、還元麦芽糖水飴、マンニトールを用いた場合に、オロパタジン固形製剤の安定性の違いについて検討した。
<Experiment 4. Examination of sugars used>
In Experiment 4, saccharides suitable for the olopatadine solid preparation according to the present invention were examined. Specifically, when lactose, purified sucrose, glucose, reduced maltose starch syrup, and mannitol were used, differences in the stability of olopatadine solid preparations were examined.
（１）実施例１６
以下の方法で、実施例１６に係るオロパタジン固形製剤を得た。
Ａ．まず、オロパタジン塩酸塩５．０ｍｇ、乳糖９１．６０ｍｇ及びヒドロキシプロピルセルロース１７．２５ｍｇを混合した。
Ｂ．次に、Ａで得られた混合物にステアリン酸マグネシウム１．１５ｍｇを混合し、錠用末を得た。
Ｃ．Ｂで得られた錠用末を、１錠１１５ｍｇになるように打錠し、実施例１６に係るオロパタジン固形製剤を得た。
(1) Example 16
The olopatadine solid preparation according to Example 16 was obtained by the following method.
A. First, olopatadine hydrochloride 5.0 mg, lactose 91.60 mg and hydroxypropylcellulose 17.25 mg were mixed.
B. Next, 1.15 mg of magnesium stearate was mixed with the mixture obtained in A to obtain a powder for tablets.
C. The tablet powder obtained in B was tableted to give 1 tablet of 115 mg, and the olopatadine solid preparation according to Example 16 was obtained.
（２）実施例１７
乳糖の代わりに精製白糖９１．６０ｍｇを用いた以外は、実施例１６と同様の方法で実施例１７に係るオロパタジン固形製剤を得た。
(2) Example 17
An olopatadine solid preparation according to Example 17 was obtained in the same manner as in Example 16, except that 91.60 mg of purified sucrose was used instead of lactose.
（３）実施例１８
乳糖の代わりにブドウ糖９１．６０ｍｇを用いた以外は、実施例１６と同様の方法で実施例１８に係るオロパタジン固形製剤を得た。
(3) Example 18
An olopatadine solid preparation according to Example 18 was obtained in the same manner as in Example 16, except that 91.60 mg of glucose was used instead of lactose.
（４）実施例１９
乳糖の代わりに還元麦芽糖水飴９１．６０ｍｇを用いた以外は、実施例１６と同様の方法で実施例１９に係るオロパタジン固形製剤を得た。
(4) Example 19
An olopatadine solid preparation according to Example 19 was obtained in the same manner as in Example 16, except that 91.60 mg of reduced maltose starch syrup was used instead of lactose.
（５）実施例２０
乳糖の代わりにマンニトール９１．６０ｍｇを用いた以外は、実施例１６と同様の方法で実施例２０に係るオロパタジン固形製剤を得た。
(5) Example 20
An olopatadine solid preparation according to Example 20 was obtained in the same manner as in Example 16, except that 91.60 mg of mannitol was used instead of lactose.
以上のように製造した実施例１６〜２０に係るオロパタジン固形製剤について、安定性試験を行った。具体的には、苛酷条件下（６０℃、７５％ＲＨ、３日間および７日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合を測定した。 The stability test was done about the olopatadine solid formulation which concerns on Examples 16-20 manufactured as mentioned above. Specifically, the ratio of the related substances of olopatadine hydrochloride when measured under severe conditions (60 ° C., 75% RH, 3 days and 7 days) was measured.
結果を下記の表９および図９に示す。合わせて表９には、比較を容易にするために、各オロパタジン固形製剤の配合組成および打錠法を記載した。 The results are shown in Table 9 below and FIG. In addition, Table 9 shows the composition of each olopatadine solid preparation and the tableting method for easy comparison.
表９および図９に示す通り、糖類として乳糖を用いた実施例１６は、他の糖類を用いた実施例１７〜２０に比べ、苛酷条件下（６０℃、７５％ＲＨ、３日間および７日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合が顕著に低いことが分かった。即ち、本発明に係るオロパタジン固形製剤に用いる糖類としては、乳糖が好適であることが分かった。 As shown in Table 9 and FIG. 9, Example 16 using lactose as a saccharide was more severe under conditions (60 ° C., 75% RH, 3 days and 7 days) than Examples 17 to 20 using other saccharides. It was found that the proportion of olopatadine hydrochloride related substances when it was allowed to stand was significantly low. That is, it was found that lactose is suitable as the saccharide used in the olopatadine solid preparation according to the present invention.
＜実験５．用いる崩壊剤の検討＞
実験５では、本発明に係るオロパタジン固形製剤に用いる好適な崩壊剤について検討した。具体的には、カルボキシメチルセルロース、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルスターチナトリウム、クロスポビドンを用いた場合に、オロパタジン固形製剤の安定性の違いについて検討した。オロパタジン固形製剤として、前記実験２で製造した実施例７〜１１に係るオロパタジン固形製剤を用いた。
<
In
製造した各実施例７〜１１係るオロパタジン固形製剤について、安定性試験を行った。具体的には、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した場合のオロパタジン塩酸塩の類縁物質の割合、および、白色蛍光灯下（６０万Ｌｕｘ・ｈｒ、１２０万Ｌｕｘ・ｈｒ）に放置場合のオロパタジン塩酸塩の類縁物質の割合を測定した。 The stability test was done about the olopatadine solid formulation which concerns on each manufactured Examples 7-11. Specifically, the ratio of the related substances of olopatadine hydrochloride when left under severe conditions (60 ° C., 75% RH, 3 days), and under a white fluorescent lamp (600,000 Lux · hr, 1.2 million Lux · hr), the proportion of olopatadine hydrochloride related substances was measured.
結果を下記の表１０および図１０に示す。合わせて表１０には、比較を容易にするために、各オロパタジン固形製剤の配合組成および打錠法を記載した。 The results are shown in Table 10 below and FIG. In addition, Table 10 shows the composition of each olopatadine solid preparation and the tableting method for easy comparison.
表１０および図１０に示す通り、光安定性（６０万Ｌｕｘ・ｈｒ、１２０万Ｌｕｘ・ｈｒ）に関しては、それほどの違いがなかったが、高温高湿度下における安定性については、崩壊剤としてセルロース誘導体であるカルボキシメチルセルロース、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースを用いた場合の方が、カルボキシメチルスターチナトリウム、クロスポビドンを用いた場合に比べ、向上することが分かった。即ち、本発明に係るオロパタジン固形製剤に用いる崩壊剤としては、セルロース誘導体が好適であることが分かった。 As shown in Table 10 and FIG. 10, there was no significant difference in light stability (600,000 Lux · hr, 1.2 million Lux · hr), but the stability under high temperature and high humidity was cellulose as a disintegrant. It was found that the use of the derivatives carboxymethyl cellulose, croscarmellose sodium, and low-substituted hydroxypropyl cellulose improved compared to the use of carboxymethyl starch sodium and crospovidone. That is, it turned out that a cellulose derivative is suitable as a disintegrant used for the olopatadine solid preparation according to the present invention.
また、セルロース誘導体の中では、光安定性（６０万Ｌｕｘ・ｈｒ、１２０万Ｌｕｘ・ｈｒ）の観点から考えると、低置換度ヒドロキシプロピルセルロースが好適であることが分かった。 In addition, among cellulose derivatives, it was found that low-substituted hydroxypropylcellulose is preferable from the viewpoint of light stability (600,000 Lux · hr, 1.2 million Lux · hr).
＜実験６．溶出性の確認＞
実験６では、本発明に係るオロパタジン固形製剤の溶出性について確認した。オロパタジン固形製剤として、前記実験１〜３で製造した実施例１〜１５、比較例１〜３に係るオロパタジン固形製剤を用いた。
<
In
製造した各実施例１〜１５、比較例１〜３に係るオロパタジン固形製剤について、溶出試験を行った。具体的には、実施例１〜１５、比較例１〜３に係るオロパタジン固形製剤を各々１個を用いて、試験液として水９００ｍＬを用い、パドル法により、毎分５０回転で試験を行った。溶出試験開始５、１０、１５分後に、溶出液を１０ｍＬ以上とり、孔径０．４５μｍ以下のメンブランフィルターでろ過し、このろ液を試料溶液とした。別にオロパタジンを溶解した標準溶液を調製し、試料溶液及び標準溶液１０μＬにつき、次の条件で液体クロマトグラフィーにより試験を行い、オロパタジンピーク面積を求めた。
検出器：紫外吸光光度計（測定波長：２９９ｎｍ）
カラム：内径４．０ｍｍ、長さ２５ｃｍのステンレス管に、５μｍの液体クロマトグラフィー用オクチルシリル化シリカゲルを充てんした。
カラム温度：４０℃付近の一定温度
About the olopatadine solid formulation which concerns on each manufactured Examples 1-15 and Comparative Examples 1-3, the elution test was done. Specifically, using one olopatadine solid preparation according to each of Examples 1 to 15 and Comparative Examples 1 to 3, 900 mL of water was used as a test solution, and the test was performed at 50 revolutions per minute by the paddle method. . Five, ten and fifteen minutes after the start of the dissolution test, 10 mL or more of the eluate was taken and filtered through a membrane filter having a pore size of 0.45 μm or less, and this filtrate was used as a sample solution. Separately, a standard solution in which olopatadine was dissolved was prepared, and a sample solution and 10 μL of the standard solution were tested by liquid chromatography under the following conditions to determine the olopatadine peak area.
Detector: UV spectrophotometer (measurement wavelength: 299 nm)
Column: A stainless steel tube having an inner diameter of 4.0 mm and a length of 25 cm was filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C
また、各実施例１〜１５、比較例１〜３に係るオロパタジン固形製剤について、苛酷条件下（６０℃、７５％ＲＨ、３日間）に放置した後の溶出性についても、同様に溶出試験を行った。 In addition, for the olopatadine solid preparations according to Examples 1 to 15 and Comparative Examples 1 to 3, the dissolution test was conducted in the same manner for the dissolution properties after being left under severe conditions (60 ° C., 75% RH, 3 days). went.
結果を図１１〜１５に示す。なお、各図１１〜１５は、用いた崩壊剤の種類ごとに比較した結果である。 The results are shown in FIGS. In addition, each FIG. 11-15 is the result compared for every kind of used disintegrating agent.
図１１〜１５に示す通り、本発明係るオロパタジン固形製剤である実施例１〜１５は、従来のオロパタジン固形製剤である比較例１〜３と同様の溶出性を示すことが確認できた。即ち、本発明に係るオロパタジン製剤は、良好な溶出性を維持したまま、安定性が向上することが確認できた。 As shown to FIGS. 11-15, it has confirmed that Examples 1-15 which are olopatadine solid preparations which concern on this invention showed the same elution property as Comparative Examples 1-3 which are conventional olopatadine solid preparations. That is, it has been confirmed that the olopatadine formulation according to the present invention has improved stability while maintaining good dissolution properties.
本発明に係るオロパタジン固形製剤は、従来のオロパタジン固形製剤の溶出性を維持したまま、従来のオロパタジン固形製剤に比べて優れた硬度、光安定性などを有する。そのため、従来のオロパタジン固形製剤のように、コーティングなどの必要性が低いため、得られた製剤の小型化にも貢献し、更に、製造コスト、製造時間を著しく短縮することもできる。 The olopatadine solid preparation according to the present invention has excellent hardness, light stability and the like as compared with the conventional olopatadine solid preparation while maintaining the dissolution property of the conventional olopatadine solid preparation. Therefore, since the necessity of coating etc. is low like the conventional olopatadine solid formulation, it contributes also to size reduction of the obtained formulation, Furthermore, manufacturing cost and manufacturing time can also be shortened remarkably.
また、その製造方法も、直接打錠法（直接圧縮法）という簡便な方法を採用することが可能であるため、製造方法の面からも、製造コスト、製造時間の短縮へ貢献することができる。 Moreover, since the manufacturing method can employ a simple method called a direct tableting method (direct compression method), it can contribute to shortening of manufacturing cost and manufacturing time from the viewpoint of manufacturing method. .
Claims (7)
結晶セルロースを含まず、
直接圧縮法により製造されるオロパタジン固形製剤。 Contains olopatadine, sugars, disintegrants,
Does not contain crystalline cellulose
Olopatadine solid preparation produced by the direct compression method .
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