JP5503939B2 - Azelastine hydrochloride-containing capsule - Google Patents
Azelastine hydrochloride-containing capsule Download PDFInfo
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- JP5503939B2 JP5503939B2 JP2009238800A JP2009238800A JP5503939B2 JP 5503939 B2 JP5503939 B2 JP 5503939B2 JP 2009238800 A JP2009238800 A JP 2009238800A JP 2009238800 A JP2009238800 A JP 2009238800A JP 5503939 B2 JP5503939 B2 JP 5503939B2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Description
本発明は、アゼラスチン塩酸塩含有カプセル剤、詳しくは充填液中のアゼラスチン塩酸塩の安定性および水分散性が改良されたカプセル剤に関する。 The present invention relates to an azelastine hydrochloride-containing capsule, and more particularly to a capsule having improved stability and water dispersibility of azelastine hydrochloride in a filling liquid.
アゼラスチン塩酸塩は、喘息を含むアレルギー性疾患の治療薬として長年使用されており、セルフメディケーションにおいても有用性の高い一般用医薬品抗アレルギー薬として販売されている。経口投与用の製剤としては１錠中アゼラスチン塩酸塩０．５ｍｇを含有する錠剤が市販されている。しかしながら錠剤、特に小型の錠剤において含量均一性を確保することは容易でない。この点はアゼラスチン塩酸塩の溶液を充填したカプセル剤として提供すれば克服される。アゼラスチン塩酸塩の溶液を用いてカプセル剤とした場合、アゼラスチン塩酸塩が経時的に安定であること、アゼラスチン塩酸塩を溶かした液状成分がカプセル剤皮に作用してカプセルの崩壊性に悪影響しないこと、およびアゼラスチン塩酸塩として水への分散性が良好であることが求められる。 Azelastine hydrochloride has been used for many years as a therapeutic agent for allergic diseases including asthma, and is marketed as an anti-allergic over-the-counter drug that is highly useful in self-medication. As a preparation for oral administration, a tablet containing 0.5 mg of azelastine hydrochloride per tablet is commercially available. However, it is not easy to ensure content uniformity in tablets, particularly small tablets. This can be overcome if provided as a capsule filled with a solution of azelastine hydrochloride. When capsules are prepared using azelastine hydrochloride solution, azelastine hydrochloride is stable over time, and liquid components in which azelastine hydrochloride is dissolved do not adversely affect the disintegration of the capsule by acting on the capsule skin And azelastine hydrochloride is required to have good dispersibility in water.
アゼラスチン塩酸塩の溶液を充填したカプセル剤に関する先行技術として特許文献１がある。ここではアゼラスチン塩酸塩をポリエチレングリコールに溶解し、軟カプセルに充填している。この先行技術は含量均一性の確保を目的としており、アゼラスチン塩酸塩の経時安定性やカプセル剤皮の崩壊性は考慮されていない。 There exists patent document 1 as a prior art regarding the capsule filled with the solution of azelastine hydrochloride. Here, azelastine hydrochloride is dissolved in polyethylene glycol and filled into soft capsules. This prior art is aimed at ensuring content uniformity, and does not take into account the temporal stability of azelastine hydrochloride and the disintegration property of capsule skin.
以上に鑑み、本発明の課題は、含量均一性が確保されていることは勿論のこと、アゼラスチン塩酸塩の経時安定性および水への分散性が高く、カプセル剤皮の崩壊性が悪影響されない、アゼラスチン塩酸塩溶液を充填したカプセル剤を提供することである。 In view of the above, the problem of the present invention is that the uniformity of content is ensured, as well as the stability over time of azelastine hydrochloride and dispersibility in water, and the disintegration property of the capsule skin is not adversely affected. It is to provide a capsule filled with azelastine hydrochloride solution.
本発明により、前記課題は抗酸化剤を添加したアゼラスチン塩酸塩溶液を充填したカプセル剤の提供によって解決される。 According to the present invention, the above problem is solved by providing a capsule filled with an azelastine hydrochloride solution to which an antioxidant is added.
第一の好ましい実施態様によれば、アゼラスチン塩酸塩はプロピレングリコール脂肪酸エステルおよび非イオン界面活性剤と、任意にプロピレングリコールおよび／またはポリエチレングリコールと中鎖脂肪酸トリグリセリドを含む混合液に溶解される。この場合の抗酸化剤はプロピレングリコール脂肪酸エステルに可溶な抗酸化剤である。 According to a first preferred embodiment, azelastine hydrochloride is dissolved in a mixture comprising propylene glycol fatty acid ester and nonionic surfactant and optionally propylene glycol and / or polyethylene glycol and medium chain fatty acid triglyceride. The antioxidant in this case is an antioxidant soluble in propylene glycol fatty acid ester.
第二の好ましい実施態様によれば、アゼラスチン塩酸塩は、プロピレングリコールと、クエン酸トリエチルと、中鎖脂肪酸トリグリセリドと、非イオン界面活性剤の混合液へ溶解される。この場合の抗酸化剤はプロピレングリコールに可溶な抗酸化剤、例えばエデト酸ナトリウムである。 According to a second preferred embodiment, azelastine hydrochloride is dissolved in a mixture of propylene glycol, triethyl citrate, medium chain fatty acid triglyceride and nonionic surfactant. The antioxidant in this case is an antioxidant soluble in propylene glycol, such as sodium edetate.
第三の好ましい実施態様によれば、アゼラスチン塩酸塩は、少割合の水を含むポリエチレングリコールへ溶解される。この場合、水溶性の抗酸化剤、例えば亜硫酸ナトリウムが添加される。 According to a third preferred embodiment, azelastine hydrochloride is dissolved in polyethylene glycol with a small proportion of water. In this case, a water-soluble antioxidant such as sodium sulfite is added.
アゼラスチン塩酸塩は水およびプロピレングリコールには良く溶ける。しかしながらこれらはカプセル剤皮を溶解または膨潤させるため単独ではカプセル充填用アゼラスチン塩酸塩の溶媒として使用することはできない。アゼラスチン塩酸塩が良く溶ける医薬品添加用に許容される他の溶媒としては、ポリエチレングリコール、セスキオレイン酸ソルビタンおよびプロピレングリコール脂肪酸エステルがある。このうちプロピレングリコール脂肪酸エステルは親水性が低く、単独では水分散性が求められるカプセル充填用アゼラスチン塩酸塩の溶媒としては不適切である。しかしながら非イオン界面活性剤と組合せて使用すれば水分散性を付与することが可能になる。好ましい非イオン界面活性剤の例は、ポリオキシエチレン硬化ヒマシ油、ポリオキシル３５ヒマシ油、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステルおよびポリソルベート８０を含む。溶媒としての役割も兼ねてセスキオレイン酸ソルビタンでもよい。 Azelastine hydrochloride is well soluble in water and propylene glycol. However, since these dissolve or swell the capsule skin, they cannot be used alone as a solvent for azelastine hydrochloride for capsule filling. Other acceptable solvents for drug addition in which azelastine hydrochloride is well soluble include polyethylene glycol, sorbitan sesquioleate and propylene glycol fatty acid esters. Among these, propylene glycol fatty acid ester has low hydrophilicity and is not suitable as a solvent for azelastine hydrochloride for capsule filling, which requires water dispersibility alone. However, when used in combination with a nonionic surfactant, water dispersibility can be imparted. Examples of preferred nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyl 35 castor oil, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester and polysorbate 80. Sorbitan sesquioleate may also be used as a solvent.
任意の成分としてプロピレングリコールおよび／またはポリエチレングリコールを含んでもよい。これらは水分散性を高める。溶液の粘度を調節するための中鎖脂肪酸トリグリセリドを含んでも良い。 Propylene glycol and / or polyethylene glycol may be included as an optional component. These increase the water dispersibility. Medium chain fatty acid triglycerides may be included to adjust the viscosity of the solution.
この場合アゼラスチン塩酸塩の溶液へ添加される抗酸化剤は、プロピレングリコール脂肪酸エステルに可溶な抗酸化剤である。好ましいこのタイプの抗酸化剤の例は、ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール（ＢＨＡ）、ｄ−α−トコフェロールおよびトコフェロール酢酸エステルのようなトコフェロールおよびそのエステルである。 In this case, the antioxidant added to the solution of azelastine hydrochloride is an antioxidant that is soluble in propylene glycol fatty acid ester. Examples of preferred antioxidants of this type are tocopherols and their esters such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), d-α-tocopherol and tocopherol acetate.
配合割合は、重量基準でアゼラスチン塩酸塩１部に対してプロピレングリコール脂肪酸エステル２０〜２００部、非イオン界面活性剤２０〜１００部の割合が好ましい。任意の成分は合計して１００部までである。抗酸化剤は０．１〜１０部の割合が好ましい。 The blending ratio is preferably 20 to 200 parts of propylene glycol fatty acid ester and 20 to 100 parts of nonionic surfactant with respect to 1 part of azelastine hydrochloride on a weight basis. The optional ingredients total up to 100 parts. The proportion of the antioxidant is preferably from 0.1 to 10 parts.
他の好ましい実施態様によれば、アゼラスチン塩酸塩はプロピレングリコールと、クエン酸トリエチルと、中鎖脂肪酸トリグリセリドおよび非イオン界面活性剤の混合液へ溶解される。この場合は非イオン界面活性剤および中鎖脂肪酸トリグリセリドの割合をプロピレングリコールより多くし、重量基準でアゼラスチン塩酸塩１部に対し、非イオン界面活性剤および中鎖脂肪酸トリグリセリドそれぞれ２０〜２００部、プロピレングリコールとクエン酸トリエチルの合計が１０〜８０部が好ましい。抗酸化剤はこの場合プロピレングリコールに可溶な抗酸化剤、例えばエデト酸ナトリウムであり、その割合は先の具体例と同じでよい。 According to another preferred embodiment, azelastine hydrochloride is dissolved in a mixture of propylene glycol, triethyl citrate, medium chain fatty acid triglyceride and nonionic surfactant. In this case, the proportion of the nonionic surfactant and the medium chain fatty acid triglyceride is higher than that of propylene glycol, and 20 parts by weight of each of the nonionic surfactant and the medium chain fatty acid triglyceride is 20 to 200 parts by weight based on 1 part of azelastine hydrochloride. The total of glycol and triethyl citrate is preferably 10 to 80 parts. The antioxidant is in this case an antioxidant soluble in propylene glycol, for example sodium edetate, the proportion of which may be the same as in the previous example.
さらなる好ましい具体例においては、アゼラスチン塩酸塩は少割合の水を含むポリエチレングリコールに溶解される。この場合水溶性の抗酸化剤、例えば亜硫酸ナトリウムが添加される。 In a further preferred embodiment, azelastine hydrochloride is dissolved in polyethylene glycol containing a small proportion of water. In this case, a water-soluble antioxidant such as sodium sulfite is added.
常温で液状のポリエチレングリコール、例えばマクロゴール２００、マクロゴール４００などが使用される。含水率は１％以下が好ましい。アゼラスチン塩酸塩はポリエチレングリコールに良く溶けるので、この具体例は小型のカプセル剤に適しており、重量基準でアゼラスチン塩酸塩１部に対し、５０〜１５０部の含水ポリエチレングリコールの割合でよい。 Polyethylene glycol that is liquid at room temperature, for example, Macrogol 200, Macrogol 400, or the like is used. The water content is preferably 1% or less. Since azelastine hydrochloride is well soluble in polyethylene glycol, this embodiment is suitable for small capsules, and may be in a proportion of 50-150 parts hydrous polyethylene glycol to 1 part azelastine hydrochloride on a weight basis.
本発明のカプセル剤は、軟カプセル剤であっても硬カプセル剤であってもよい。軟カプセル剤は、常法により、本発明の医薬組成物をゼラチン等の軟カプセル用の皮膜に充填することにより製造することができ、また硬カプセル剤は、液体充てんの常法により、本発明の医薬組成物をゼラチン等の硬カプセルに封入することにより製造することができる。 The capsule of the present invention may be a soft capsule or a hard capsule. Soft capsules can be produced by filling the pharmaceutical composition of the present invention into a film for soft capsules such as gelatin by a conventional method, and hard capsules can be produced by a conventional method for liquid filling. This pharmaceutical composition can be produced by encapsulating it in a hard capsule such as gelatin.
試験例１
アゼラスチン塩酸塩20mgを精密に量り、表１に示す各種溶解剤約4gを精密に量り加えた後、30分超音波処理し、試験開始時試料とした。同様に調製した試料をガラス瓶に封入し密栓して、50℃75%RHの環境で2週間保管し、保管後試料とした。試験開始時及び保管後の試料のアゼラスチン塩酸塩の含量をHPLCにより測定し、アゼラスチン塩酸塩の残存率を求めた。
Test example 1
20 mg of azelastine hydrochloride was precisely weighed, and about 4 g of various solubilizers shown in Table 1 were precisely weighed and then ultrasonically treated for 30 minutes to obtain a sample at the start of the test. A sample prepared in the same manner was sealed in a glass bottle, sealed, and stored in an environment of 50 ° C. and 75% RH for 2 weeks. The content of azelastine hydrochloride in the sample at the start of the test and after storage was measured by HPLC, and the residual rate of azelastine hydrochloride was determined.
結果
アゼラスチン塩酸塩と一般的な各種溶解剤の配合変化は表1のとおりとなった。プロピレングリコール、精製水に溶解したものは溶解性・残存率共に優れており、アゼラスチン塩酸塩の溶液状組成物としては有用性がある。しかし、プロピレングリコール及び精製水は、カプセル剤皮成分を溶解させてしまうため、本発明では利用が制限される。また、本発明で目的とするのは医薬組成物であり、吸収性を考慮した場合、水中への溶解性が確保されることが望ましい。そのため、親水性の低いプロピレングリコール脂肪酸エステルを単独で使用することは、本来の目的から逸し、他の界面活性剤の使用が必須条件となる。 Table 1 shows the changes in the composition of azelastine hydrochloride and various common solubilizers. Those dissolved in propylene glycol and purified water are excellent in solubility and residual rate, and are useful as a solution composition of azelastine hydrochloride. However, since propylene glycol and purified water dissolve the capsule skin component, its use is limited in the present invention. Moreover, it is a pharmaceutical composition aimed at in the present invention, and it is desirable that the solubility in water is ensured in consideration of absorbability. Therefore, the use of propylene glycol fatty acid ester having low hydrophilicity alone departs from the original purpose, and the use of other surfactants is an essential condition.
試験例２
表２に示す処方により、50℃4週間の保存試験を行ったところ、抗酸化剤を添加した試料はアゼラスチン塩酸塩の残存率が良好となった。
Test example 2
When a storage test was conducted at 50 ° C. for 4 weeks according to the formulation shown in Table 2, the sample to which the antioxidant was added had a good residual rate of azelastine hydrochloride.
試験例３
表３に示す処方について、崩壊性に与える影響を観察した。カプセル剤皮は、一般的な組成で直径10mmのシート状に作製した。カプセル剤皮を処方液中に漬込んだ状態で保管し、試料とした。崩壊性の観察は、日本薬局方崩壊試験に準じた。その結果、抗酸化剤を添加した試料はカプセル剤皮の不溶化が抑制された。
Test example 3
For the formulations shown in Table 3, the effect on disintegration was observed. The capsule skin was made into a sheet having a general composition and a diameter of 10 mm. The capsule skin was stored in a prescription solution and used as a sample. Observation of disintegration was according to the Japanese Pharmacopoeia disintegration test. As a result, insolubilization of the capsule skin was suppressed in the sample to which the antioxidant was added.
試験例４
表３に示した処方２とアゼラスチン塩酸塩含有の市販製剤について、溶出試験を実施した。具体的には、検体1個をとり、試験液に薄めたMcIlvaine緩衝液（pH4.0）900mLを用い、パドル法により、毎分50回転で試験を行った。規定時間で溶出液10mLをとり、HPLCにより、製剤単位中に含まれるアゼラスチン塩酸塩の表示含有量に対する溶出率を算出した。その結果、処方２はいずれの市販製剤と比較して速やかにアゼラスチン塩酸塩が溶出し、かつ良好な溶出性が得られた。結果を表４及び図１に示す。
Test example 4
The dissolution test was conducted on the commercial preparations containing Formulation 2 and azelastine hydrochloride shown in Table 3. Specifically, one test sample was taken, and the test was performed at 50 rpm with the paddle method using 900 mL of diluted McIlvaine buffer (pH 4.0) as the test solution. 10 mL of the eluate was taken at the specified time, and the dissolution rate relative to the indicated content of azelastine hydrochloride contained in the preparation unit was calculated by HPLC. As a result, in Formulation 2, azelastine hydrochloride was rapidly eluted as compared with any commercially available preparation, and good dissolution properties were obtained. The results are shown in Table 4 and FIG.
以下に実施例として処方例を挙げる。各処方においてアゼラスチンと溶解剤及び抗酸化剤は常法に従って溶解混合し溶液状医薬組成物得た。さらに該医薬組成物を常法により充填して、軟カプセル剤を製造した。 Examples of prescription are given below as examples. In each formulation, azelastine, a solubilizer and an antioxidant were dissolved and mixed according to a conventional method to obtain a solution-like pharmaceutical composition. Further, the pharmaceutical composition was filled by a conventional method to produce a soft capsule.
Claims (3)
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| JP2009238800A JP5503939B2 (en) | 2009-10-16 | 2009-10-16 | Azelastine hydrochloride-containing capsule |
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| JP2009238800A JP5503939B2 (en) | 2009-10-16 | 2009-10-16 | Azelastine hydrochloride-containing capsule |
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| JP2011084521A JP2011084521A (en) | 2011-04-28 |
| JP5503939B2 true JP5503939B2 (en) | 2014-05-28 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014010008A1 (en) * | 2012-07-09 | 2014-01-16 | 東洋カプセル株式会社 | Capsule-filling composition of candesartan cilexetil |
| CA2906008C (en) | 2013-03-13 | 2019-07-09 | Flatley Discovery Lab, Llc | Pyridazinone compounds and methods for the treatment of cystic fibrosis |
| JP6410408B2 (en) * | 2013-05-23 | 2018-10-24 | 東洋カプセル株式会社 | Oral capsule containing sodium loxoprofen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH05229947A (en) * | 1991-03-26 | 1993-09-07 | Tokai Capsule Kk | Azelastine hydrochloride soft capsule |
| JPH07196483A (en) * | 1993-11-25 | 1995-08-01 | Taisho Pharmaceut Co Ltd | Composition for pharmaceutical preparation improved in oral absorption |
| JP3557008B2 (en) * | 1994-08-05 | 2004-08-25 | 塩野義製薬株式会社 | Hard gelatin capsule in which denaturation is prevented and method for producing the same |
| JPH0977663A (en) * | 1995-07-07 | 1997-03-25 | Nippon Kayaku Co Ltd | Flutamide composition |
| JP2003055254A (en) * | 2001-08-17 | 2003-02-26 | Toyo Capsule Kk | Cyclosporin preparation for oral administration |
| WO2004010974A2 (en) * | 2002-07-31 | 2004-02-05 | Pharmacia Corporation | Gelatin capsule exhibiting reduced cross-linking |
| JP2005075804A (en) * | 2003-09-03 | 2005-03-24 | Toyo Capsule Kk | Medicinal composition including menatetrenone |
| US20050249802A1 (en) * | 2004-05-06 | 2005-11-10 | The Procter & Gamble Company | Softgel encapsulated pharmaceutical compositions comprising concentrated active ingredients |
| MX2007006233A (en) * | 2004-11-24 | 2007-11-23 | Medpointe Healthcare Inc | Compositions comprising azelastine and methods of use thereof. |
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