JP4866518B2 - Suppository manufacturing method - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は直腸、尿道又は膣等に適用する坐剤およびその製造法に関する。特に高温保存条件において、変形やヒビ、ワレといった品質劣化が起こさないなどの優れた耐熱性を有し、且つ適用された部位では、崩壊性と薬物放出性に優れた坐剤及び坐剤の製造法に関するものである。
【０００２】
【従来の技術】
坐剤は、直腸、尿道又は膣等に投与される固形薬剤であり、体温で軟化又は溶融するか、粘液に溶解し、粘膜から薬物を体内に吸収させる。
また、痔疾用薬等の局所用坐剤では、坐剤基剤である油脂が排便時の潤滑剤として働き、症状の悪化を抑えている。
市販坐剤の多くは、ハードファット、イソカカオ脂等の油脂性基剤を用いており、体温付近で軟化又は溶融させるために融点を体温以下に設定している。
このために保存条件としては、通常冷所（１５℃以下）、高くても３０℃以下といった管理温度や坐剤先端部を下向きとして立てて保存するといった注意が必要で、他の製剤に比べて保存上の制約が多い。
夏場や搬送途上の車中等、坐剤が長時間高温にさらされる環境では、上記保存条件内で管理するのはかなり困難であり、特に患者の手元に渡った後の良好な管理は難しく、当然の事ながら変形やヒビ、ワレと言った品質劣化の問題が生じる。
一方、マクロゴール等を用いた坐剤は、局所の粘液に溶解することでその機能を果たすことから、その融点は高く設定されている。したがって、上記の油脂性基剤を用いた坐剤のような問題は生じにくいが、局所の粘液を吸収するため局所への物理的な刺激が強く、粘膜に充血や紅斑等を生じ、患者に苦痛を与えることがある。
【０００３】
【発明が解決しようとする課題】
このような状況において、本発明の課題は、高温保存条件においても変形やヒビ、ワレといった品質劣化を起こさず、適用部位では薬物の放出性、粘膜からの吸収性、安全性等に優れた坐剤およびその製造法を提供することにある。
【０００４】
【課題を解決するための手段】
このような状況のもと、本発明者らは溶融した油脂性基剤、薬物、界面活性剤、ショ糖を含む混合物を水と均一に混合するか、もしくは溶融した油脂性基剤、薬物、界面活性剤、ショ糖を含む均一な混合物を水と混合して連続相を油相から水相へ転相させ、乾燥、粉末化して圧縮成型することにより製造した坐剤が前記課題を解決することを知り、この知見を基にさらに研究を重ねて本発明を完成した。
すなわち、本発明は、
（１）油脂性基剤、薬物、ショ糖、水および界面活性剤を含んでなる混合物を油脂性基剤の融点以上の温度で混合し、乾燥後粉末とし、圧縮成型する坐剤の製造法、
（２）油脂性基剤に対するショ糖の重量比が１：０．６〜１．９であり、水の重量比が１：０．１５〜０．３７であり、界面活性剤の重量比が１：０．０１〜０．２０である請求項１記載の坐剤の製造法、
（３）ショ糖の含有量が坐剤全量に対し３０〜６０重量％である（１）または（２）記載の坐剤の製造法、
（４）水の使用量が坐剤全量に対し７〜１５重量％である（１）または（２）記載の坐剤の製造法、
（５）界面活性剤がＨＬＢ８〜１６のショ糖脂肪酸エステルである（１）または（２）記載の坐剤の製造法、
（６）界面活性剤の使用量が、坐剤全量に対し０．２〜５重量％である（１）または（２）記載の坐剤の製造法、
（７）油脂性基剤が融点１０〜４５℃を有するものである（１）または（２）記載の坐剤の製造法、
（８）油脂性基剤がカカオ脂、ラウリン脂、牛脂若しくは半合成品由来のハードファットの１種または２種以上の混合物、或いはそれに常温で液状であるヤシ油、パーム核油、ツバキ油、オリーブ油、大豆油、ゴマ油、トウモロコシ油、中鎖脂肪酸トリグリセライド、流動パラフィン若しくはミリスチン酸イソプロピルの１種または２種以上が添加されたものである（１）または（２）記載の坐剤の製造法、
（９）粉末が平均粒子径２０〜２０００μｍのものである（１）または（２）記載の坐剤の製造法、
（１０）薬物が副腎皮質ホルモン剤、局所麻酔剤、解熱鎮痛消炎剤、消炎・鎮痒・創傷治癒剤、ビタミン剤、サルファ剤、抗生物質、抗真菌剤、殺菌剤、血管収縮剤、抗ヒスタミン剤、麻薬、睡眠鎮静剤、抗不安剤、抗癲癇剤、興奮剤・覚せい剤、抗パーキンソン剤、中枢神経用剤、骨格筋弛緩剤、自律神経用剤、鎮痙剤、鎮暈剤、強心剤、不整脈用剤、利尿剤、血圧降下剤、冠血管拡張剤、末梢血管拡張剤、高脂血症用剤、呼吸促進剤、止瀉・整腸剤、消化性潰瘍治療剤、気管支拡張剤、アレルギー用剤、下剤、浣腸剤、利胆剤および各種ホルモン剤から選ばれた１種または２種以上である（１）記載の坐剤の製造法、
（１１）乾燥が減圧乾燥または凍結乾燥である（１）記載の坐剤の製造法、
である。
【０００５】
【発明の実施の形態】
本発明に用いられる油脂性基剤としては、たとえば、カカオ脂、ラウリン脂、牛脂若しくは半合成品由来のハードファットの１種または２種以上の混合物、或いはそれに常温（１５〜２５℃）で液状であるヤシ油、パーム核油、ツバキ油、オリーブ油、大豆油、ゴマ油、トウモロコシ油、中鎖脂肪酸トリグリセライド、流動パラフィン若しくはミリスチン酸イソプロピルの１種または２種以上が添加されたものがあげられるが、好ましくはハードファットである。
本発明に用いられる油脂性基剤は、その融点が通常１０〜４５℃、好ましくは２５〜３８℃に調整されたものが使用される。
本発明に用いられる水及びショ糖は医薬品に用いることができる品質のものであればどのようなものでもよい。
【０００６】
坐剤全量に対するショ糖の含有率の割合は３０〜６０重量％であるが、好ましくは３５〜５０重量％である。また、油脂性基剤に対するショ糖の重量比は１：０．６〜１．９で、好ましくは１：０．７５〜１．３５である。
坐剤全量に対する水の使用量は７〜１５重量％であるが、好ましくは８〜１２重量％である。また、油脂性基剤に対する水の重量比は１：０．１５〜０．３７であり、好ましくは１：０．１８〜０．３５である。
【０００７】
本発明に用いられる界面活性剤は、ＨＬＢが８〜１６の界面活性剤で、医薬に用いられるものであればよいが、好ましくは、ＨＬＢが９〜１５のショ糖脂肪酸エステルである。ショ糖脂肪酸エステルを構成する脂肪酸としては、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸などが挙げられるが、ステアリン酸エステルが好ましい。坐剤全量に対する界面活性剤の使用量は、通常０．２〜５重量％であるが、好ましくは、０．５〜３重量％である。また、油脂性基剤に対する界面活性剤の重量比は、１：０．０１〜０．２であり、好ましくは、１：０．０１〜０．１である。
本発明に用いられる薬物としては、たとえば副腎皮質ホルモン剤、局所麻酔剤、解熱鎮痛消炎剤、消炎・鎮痒・創傷治癒剤、ビタミン剤、サルファ剤、抗生物質、抗真菌剤、殺菌剤、血管収縮剤、抗ヒスタミン剤、麻薬、睡眠鎮静剤、抗不安剤、抗癲癇剤、興奮剤、覚せい剤、抗パーキンソン剤、中枢神経用剤、骨格筋弛緩剤、自律神経用剤、鎮痙剤、鎮暈剤、強心剤、不整脈用剤、利尿剤、血圧降下剤、冠血管拡張剤、末梢血管拡張剤、高脂血症用剤、呼吸促進剤、止瀉・整腸剤、消化性潰瘍治療剤、気管支拡張剤、アレルギー用剤、下剤、浣腸剤、利胆剤、各種ホルモン剤などが挙げられる。
薬物の使用量は、薬物の種類、疾病の種類、投与対象等により異なるので一概にはいえないが、通常坐剤に対し０．１〜１５重量％程度である。
【０００８】
本発明の坐剤には、より耐熱性を向上させるためにポリエチレンやポリグリセリン脂肪酸エステルを配合することができる。また必要によりさらに吸収調節剤、溶解補助剤、安定化剤、防腐剤、賦形剤、潤沢剤などの適量を配合してもよい。
本発明に用いることのできるポリエチレンは、エチレンを重合して得られるもので、その平均分子量は通常５００〜３０，０００程度、好ましくは１，０００〜５，０００程度である。
ポリエチレンの含有量は、坐剤用全量に対して１〜２０重量％であり、好ましくは３〜１５重量％である。
本発明に用いることのできるポリグリセリン脂肪酸エステルは、グリセリンを重合し脂肪酸によりエステル化して得られるものである。グリセリンの重合数は２〜１０程度、好ましくは４〜１０程度ものであり、脂肪酸数は１〜１０程度、好ましくは５〜１０程度である。その脂肪酸は特に限定されるものではないがステアリン酸が好ましい。ポリグリセリン脂肪酸エステルの具体例としては、例えばペンタステアリン酸テトラグリセリル、ペンタステアリン酸ヘキサグリセリル、ペンタステアリン酸デカグリセル、デカステアリン酸デカグリセリルが挙げられるが、これらに限定されるものではない。坐剤用基剤全量に対するポリグリセリン脂肪酸エステルの配合割合は、通常０．５〜１０重量％、好ましくは１〜７重量％である。また、油脂性基剤または油脂性基剤とポリグリセリン脂肪酸エステルの混合物に対するポリエチレンの重量比は、通常１：０．１０〜０．５、好ましくは１：０．０３〜０．３である。
【０００９】
本発明の坐剤の製造法は、たとえば坐剤用の油脂性基剤を５０〜１２０℃で溶融し、これに薬物、ショ糖、その他の配合物を加え、均一に混合したものを界面活性剤を分散又は溶解した水に徐々に加えてペースト状の乳化物とする。得られた乳化物はそのまま減圧乾燥するか、乳化物を冷却固化後、減圧乾燥または凍結乾燥するが、好ましくは乳化物を冷却固化させた後乾燥する。得られた板状固形物をそのまま、または適当な大きさに分割した後減圧下、油脂性基剤の融点以上の温度で、好ましくは８０℃以下の温度で乾燥させるかまたは凍結乾燥して、水分を５重量％以下、好ましくは３重量％以下とする。
得られた乾燥物をたとえば粉砕機により粉末化する。粉末の平均粒子径は通常２０〜２０００μｍ、好ましくは３００〜１５００μｍ程度である。
【００１０】
この粉末を圧縮成型機で坐剤として好ましい形状に圧縮成型する。圧縮圧は通常１００〜１５００ｋｇｆ／ｃｍ２、好ましくは２００〜１０００ｋｇｆ／ｃｍ２である。
得られた坐剤中の油脂性基剤とショ糖は、界面活性剤の存在下に互いに均一に入り交じると同時に、油脂およびショ糖とも、それぞれ溶融または溶解した状態から固化させたものであるのでそれぞれが立体的網目構造により連結した構造を有している。特にショ糖により形成される網目構造は、耐熱性および機械的強度に優れ、坐剤が高温や振動に晒されても変形やワレといった品質劣化を起こさない。
しかも本発明の坐剤を局所に投与した場合、粘液がショ糖の網目構造を崩壊させることにより、速やかに坐剤を崩壊させるので、薬物の放出が速く薬物の効果の発現も速い。
【００１１】
【実施例】
以下に実施例、比較例および試験例を挙げて本発明を具体的に説明する。なお「部」は断りのない限り「重量部」を意味する。
実施例１
処方
酢酸プレドニゾロン １．０部
ショ糖 ７００部
精製水 １７５部
ショ糖脂肪酸エステル（ＨＬＢ １１）※ １７．５部
エタノール １７．５部
ハードファット ８３９部
（※ ＤＫエステルＦ−１１０、第一工業製薬（株）製）
製法
ショ糖脂肪酸エステル（ＨＬＢ １１）、エタノールおよび６０℃に加温した精製水の混合物に６０℃に溶融したハードファット、ショ糖、酢酸プレドニゾロンの混合物を加え、よく混練してペースト状物の乳化物を得た。このペースト状物をシャーレに厚み５ｍｍ程度となるよう流し込み、１０℃に冷却して固化させた。固化物を６０℃で真空乾燥し、水分を３．０ｗ／ｗ％以下とした。乾燥物を−５℃の冷却下、コーミルで１０分間粉砕し、平均粒子径３５０〜５５０μｍの粉体を得た。得られた粉体を、１坐剤当り１７５０ｍｇとなるように手動式圧縮打錠機の金型に重填し、１０℃の環境温度下、８００Ｋｇｆ／ｃｍ２の圧力下に圧縮成形して、坐剤１００個を製造した。
【００１２】
比較例１
ハードファットを６０℃で溶融し、アルミニウム製の坐剤の型に流し込み、室温（２０〜２５℃）で冷却して、１７５０ｍｇ／個の坐剤１００個を製造した。
【００１３】
試験例１
実施例１および比較例１の坐剤を２５℃、２日放置後、それぞれ次の試験を行った。
試験項目と試験方法
１）変形試験（ｎ＝１０）
坐剤１０個を６０℃の温度で横に寝かせた状態で１時間放置し、その後２５℃の室温で１時間冷却したときの坐剤の外観を観察し、変形もしくはヒビが発生した坐剤の個数を数えた。
２）硬度試験（ｎ＝３）
エルウエカ(Erweka)社製坐剤硬度計により、３０℃（±１℃）における硬度測定を行った。すなわち、坐剤をあらかじめ３０℃（±１℃）に２日以上放置し、同温度に加温した室で硬度計の坐剤挿入具に坐剤の先端を上に向けて挿入し、その上へ懸垂金具をのせた。測定１分ごとに２００ｇの円盤のおもりを下方の台にのせていって、坐剤の崩壊時間を測定し、その値から硬度を求めた。
３）セトニカル法による液化又は崩壊時間の測定（ｎ＝３）
セトニカル（Setnikar）らの方法※により３７℃（±０．２℃）で坐剤が液化または崩壊し終わるまでの時間を測定した。
※Setnikar,W.H.et al.:J.Pharm.Sci.,51、566(1962)
４）ＤＳＣ法によるピーク頂点温度の測定
坐剤約３ｍｇをアルミニウムクリンプセルに入れ、窒素雰囲気下−２０℃から６０℃まで２℃／分で昇温し、示差走査熱量計ＤＳＣ６２００（セイコーインスツルメンツ（株））により示差走査熱量測定を行い、最大シフトを示したピーク頂点温度を融点として求めた。
それらの結果を表１に示した。
【００１４】
【表１】
表１から明らかなごとく、実施例１の坐剤は比較例１の坐剤に比べて耐熱性に優れ、セトニカル法においても速い崩壊時間を示した。実施例１の坐剤の３０℃における硬度は比較例１のものより低いが、０．６Ｋｇ以上あれば実用上全く問題はない。
【００１６】
実施例２
処方
酢酸プレドニゾロン １．０部
ショ糖 ７００部
ショ糖脂肪酸エステル（ＨＬＢ １１）※ １７．５部
精製水 １７５部
ハードファット ８５７．４部
（※ ＤＫエステルＦ−１１０ 第一工業製薬（株）製）
製法
６０℃に溶融したハードファット、ショ糖、酢酸プレドニゾロンの混合物を、ショ糖脂肪酸エステルおよび６０℃に加温した精製水の混合物に加え、よく混練してペースト状物を得た。このペースト状物をシャーレに厚み５ｍｍ程度となるよう流し込み、１０℃に冷却して固化させた。固化物を６０℃で真空乾燥し、水分を３．０ｗ／ｗ％以下とした。乾燥物を−５℃の冷却下、コーミルで１０分間粉砕し、得られた粉体を篩により粒子径８５０〜１４００μｍに粒径調整した。
得られた粉末を、１０℃の環境温度下、手動式圧縮打錠機により３００Ｋｇｆ／ｃｍ２の圧力下に圧縮成形して、１７５０ｍｇの坐剤１００個を製造した。
【００１７】
実施例３〜７
坐剤を製造するための成分とその重量部を〔表２〕に示した。これらの成分を用いて、実施例２と同様の操作により１７５０ｍｇの坐剤をそれぞれ１００個製造した。
【００１８】
【表２】
試験例２
実施例２〜７および比較例１で得られた坐剤各１０個を２０℃、４０℃、５０℃および６０℃の各温度で横に寝かせた状態で１時間または１日保存し、後にそのままの状態で、２０℃の室温に冷却したときの坐剤の外観を観察し、変形もしくはヒビが発生した坐剤の個数を数えた。
結果を〔表３〕に示した。
【００２０】
【表３】
〔表３〕から明らかなように、比較例１の坐剤は４０〜６０℃の高温保存においてすべて変形又はヒビが発生したのに対し、本発明の実施例２〜７の坐剤はいずれの条件下においても、変形又はヒビが全く発生しなかった。
【００２２】
【発明の効果】
本発明の坐剤は、従来法の溶融法による坐剤に比して、耐熱性に優れ、しかも直腸等の適用部位における崩壊時間が極めて早く、薬物放出性に優れるという効果を奏する。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a suppository applied to the rectum, urethra, vagina and the like and a method for producing the same. Production of suppositories and suppositories that have excellent heat resistance, such as deformation, cracks, cracks, etc., under high-temperature storage conditions, and excellent disintegration and drug release properties at the site where they are applied. It is about the law.
[0002]
[Prior art]
A suppository is a solid drug administered to the rectum, urethra, vagina, etc., and softens or melts at body temperature or dissolves in mucus to absorb the drug from the mucosa into the body.
In addition, in topical suppositories such as antiepileptic drugs, the fats and oils that are suppository bases act as lubricants during defecation and suppress the deterioration of symptoms.
Many of the commercially available suppositories use an oily base such as hard fat or isocaca butter, and the melting point is set below the body temperature in order to soften or melt the body suppository.
For this reason, as storage conditions, it is necessary to be careful to store in a cold place (15 ° C or lower), a controlled temperature such as 30 ° C or lower at the highest and the suppository tip part facing downward, compared to other preparations. There are many storage restrictions.
In an environment where the suppository is exposed to high temperatures for a long time, such as in the summer or in a car that is being transported, it is quite difficult to manage within the above-mentioned storage conditions. However, quality degradation problems such as deformation, cracks and cracks occur.
On the other hand, suppositories using macrogol or the like have a high melting point because they function by dissolving in local mucus. Therefore, problems such as suppositories using the above-mentioned oleaginous base are unlikely to occur, but local physical irritation is strong due to absorption of local mucus, resulting in hyperemia and erythema in the mucous membranes. May be painful.
[0003]
[Problems to be solved by the invention]
Under such circumstances, the problem of the present invention is that it does not cause quality deterioration such as deformation, cracks and cracks even under high-temperature storage conditions, and is excellent in drug release, mucosal absorption, safety, etc. at the application site. It is in providing an agent and its manufacturing method.
[0004]
[Means for Solving the Problems]
Under such circumstances, the present inventors uniformly mixed a mixture containing a molten oleaginous base, drug, surfactant, and sucrose with water, or a molten oleaginous base, drug, A suppository produced by mixing a uniform mixture containing a surfactant and sucrose with water to invert the continuous phase from the oil phase to the aqueous phase, drying, powdering and compression molding solves the above problems. Based on this knowledge, further research was repeated to complete the present invention.
That is, the present invention
(1) A method for producing a suppository in which a mixture comprising an oleaginous base, a drug, sucrose, water and a surfactant is mixed at a temperature equal to or higher than the melting point of the oleaginous base, dried and then powdered, and compression molded. ,
(2) The weight ratio of sucrose to the oily base is 1: 0.6 to 1.9, the weight ratio of water is 1: 0.15 to 0.37, and the weight ratio of the surfactant is The method for producing a suppository according to claim 1, wherein the ratio is 1: 0.01 to 0.20.
(3) The method for producing a suppository according to (1) or (2), wherein the sucrose content is 30 to 60% by weight based on the total amount of the suppository,
(4) The method for producing a suppository according to (1) or (2), wherein the amount of water used is 7 to 15% by weight based on the total amount of the suppository.
(5) The method for producing a suppository according to (1) or (2), wherein the surfactant is a sucrose fatty acid ester of HLB 8-16.
(6) The method for producing a suppository according to (1) or (2), wherein the amount of the surfactant used is 0.2 to 5% by weight based on the total amount of the suppository.
(7) The method for producing a suppository according to (1) or (2), wherein the oily base has a melting point of 10 to 45 ° C.
(8) Coconut butter, lauric butter, beef tallow, or a mixture of two or more hard fats derived from semi-synthetic products, or palm oil, palm kernel oil, camellia oil that is liquid at room temperature, A method for producing a suppository according to (1) or (2), wherein one or more of olive oil, soybean oil, sesame oil, corn oil, medium chain fatty acid triglyceride, liquid paraffin or isopropyl myristate are added,
(9) The method for producing a suppository according to (1) or (2), wherein the powder has an average particle size of 20 to 2000 μm,
(10) Drugs are corticosteroids, local anesthetics, antipyretic analgesic / anti-inflammatory agents, anti-inflammatory / antipruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, bactericides, vasoconstrictors, antihistamines, narcotics, Sleep sedative, anti-anxiety agent, antidepressant, stimulant / stimulant, anti-parkinsonian agent, central nervous system agent, skeletal muscle relaxant, autonomic nerve agent, antispasmodic agent, antipruritic agent, cardiotonic agent, arrhythmic agent, diuretic agent Antihypertensive agent, coronary vasodilator, peripheral vasodilator, hyperlipidemia agent, respiratory accelerator, antipruritic / intestinal agent, peptic ulcer treatment agent, bronchodilator, allergic agent, laxative, enema agent, (1) the method for producing a suppository according to (1), wherein the suppository is one or more selected from a bile agent and various hormone agents;
(11) The method for producing a suppository according to ( 1 ), wherein the drying is vacuum drying or freeze drying.
It is.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
As the oily base used in the present invention, for example, cacao butter, laurin butter, beef tallow or a mixture of two or more hard fats derived from semi-synthetic products, or a liquid at room temperature (15 to 25 ° C.) Coconut oil, palm kernel oil, camellia oil, olive oil, soybean oil, sesame oil, corn oil, medium chain fatty acid triglyceride, liquid paraffin or isopropyl myristate are added, A hard fat is preferable.
The oleaginous base used in the present invention is one whose melting point is usually adjusted to 10 to 45 ° C., preferably 25 to 38 ° C.
The water and sucrose used in the present invention may be of any quality that can be used for pharmaceuticals.
[0006]
The ratio of sucrose content to the total amount of suppository is 30 to 60% by weight, preferably 35 to 50% by weight. The weight ratio of sucrose to the oleaginous base is 1: 0.6 to 1.9, preferably 1: 0.75 to 1.35.
The amount of water used is 7-15% by weight, preferably 8-12% by weight, based on the total amount of suppository. The weight ratio of water to the oleaginous base is 1: 0.15 to 0.37, preferably 1: 0.18 to 0.35.
[0007]
The surfactant used in the present invention is a surfactant having an HLB of 8 to 16 and can be used for medicine, but is preferably a sucrose fatty acid ester having an HLB of 9 to 15. Examples of the fatty acid constituting the sucrose fatty acid ester include lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid, and stearic acid ester is preferable. The amount of the surfactant used relative to the total amount of the suppository is usually 0.2 to 5% by weight, preferably 0.5 to 3% by weight. The weight ratio of the surfactant to the oleaginous base is 1: 0.01 to 0.2, preferably 1: 0.01 to 0.1.
Examples of the drug used in the present invention include corticosteroids, local anesthetics, antipyretic analgesic / antiinflammatory agents, anti-inflammatory / antipruritic / wound healing agents, vitamins, sulfa drugs, antibiotics, antifungal agents, bactericides, and vasoconstrictors. , Antihistamines, narcotics, sleep sedatives, anxiolytics, antiepileptics, stimulants, stimulants, antiparkinsonian agents, central nervous system agents, skeletal muscle relaxants, autonomic nerve agents, antispasmodics, antipruritics, cardiotonics, arrhythmia Agents, diuretics, antihypertensive agents, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, respiratory accelerators, antipruritics / enteric agents, peptic ulcer treatment agents, bronchodilators, allergic agents, Laxatives, enemas, antibacterial agents, various hormonal agents and the like.
The amount of drug used varies depending on the type of drug, the type of disease, the subject of administration, etc., and cannot be generally stated, but is usually about 0.1 to 15% by weight based on the suppository.
[0008]
In the suppository of the present invention, polyethylene or polyglycerin fatty acid ester can be blended in order to further improve heat resistance. Further, if necessary, an appropriate amount such as an absorption regulator, a solubilizer, a stabilizer, an antiseptic, an excipient, or a lubricant may be added.
The polyethylene that can be used in the present invention is obtained by polymerizing ethylene, and its average molecular weight is usually about 500 to 30,000, preferably about 1,000 to 5,000.
The content of polyethylene is 1 to 20% by weight, preferably 3 to 15% by weight, based on the total amount for suppositories.
The polyglycerol fatty acid ester that can be used in the present invention is obtained by polymerizing glycerol and esterifying with a fatty acid. The polymerization number of glycerin is about 2 to 10, preferably about 4 to 10, and the number of fatty acids is about 1 to 10, preferably about 5 to 10. The fatty acid is not particularly limited, but stearic acid is preferred. Specific examples of the polyglyceryl fatty acid ester include, but are not limited to, tetraglyceryl pentastearate, hexaglyceryl pentastearate, decaglyceryl pentastearate, and decaglyceryl decastearate. The blending ratio of the polyglycerol fatty acid ester to the total amount of the suppository base is usually 0.5 to 10% by weight, preferably 1 to 7% by weight. Further, the weight ratio of polyethylene to the oleaginous base or the mixture of the oleaginous base and the polyglycerin fatty acid ester is usually 1: 0.10 to 0.5, preferably 1: 0.03 to 0.3.
[0009]
The method for producing the suppository of the present invention includes, for example, melting an oleaginous base for suppository at 50 to 120 ° C., adding a drug, sucrose, and other ingredients to this, and mixing the mixture uniformly to obtain a surfactant. The agent is gradually added to the dispersed or dissolved water to form a paste-like emulsion. The obtained emulsion is dried under reduced pressure as it is or after cooling and solidifying the emulsion, it is dried under reduced pressure or freeze drying. Preferably, the emulsion is cooled and solidified and then dried. The obtained plate-like solid as it is or after being divided into appropriate sizes, dried under reduced pressure at a temperature equal to or higher than the melting point of the oleaginous base, preferably at a temperature of 80 ° C. or lower, or freeze-dried, The water content is 5% by weight or less, preferably 3% by weight or less.
The obtained dried product is pulverized by, for example, a pulverizer. The average particle size of the powder is usually about 20 to 2000 μm, preferably about 300 to 1500 μm.
[0010]
This powder is compression molded into a preferred shape as a suppository with a compression molding machine. Compression pressure is usually 100~1500kgf / cm 2, preferably 200~1000kgf / cm 2.
The oleaginous base and sucrose in the suppository obtained are uniformly mixed with each other in the presence of a surfactant, and at the same time, both the fat and sucrose are solidified from a molten or dissolved state, respectively. Therefore, each has the structure connected by the three-dimensional network structure. In particular, the network structure formed by sucrose is excellent in heat resistance and mechanical strength, and does not cause quality deterioration such as deformation and cracking even when the suppository is exposed to high temperature and vibration.
In addition, when the suppository of the present invention is administered locally, mucus disintegrates the sucrose network structure, thereby rapidly disintegrating the suppository, so that the drug is released quickly and the effect of the drug is rapidly manifested.
[0011]
【Example】
The present invention will be specifically described below with reference to examples, comparative examples and test examples. “Parts” means “parts by weight” unless otherwise specified.
Example 1
Prednisolone acetate 1.0 parts Sucrose 700 parts Purified water 175 parts Sucrose fatty acid ester (HLB 11) * 17.5 parts Ethanol 17.5 parts Hard fat 839 parts ( * DK Ester F-110, Daiichi Kogyo Seiyaku ( Made by Co., Ltd.)
Manufacturing method A mixture of hard fat, sucrose and prednisolone acetate melted at 60 ° C. is added to a mixture of sucrose fatty acid ester (HLB 11), ethanol and purified water heated to 60 ° C., and kneaded well to emulsify the paste. I got a thing. This paste was poured into a petri dish to a thickness of about 5 mm and cooled to 10 ° C. to solidify. The solidified product was vacuum-dried at 60 ° C., and the water content was adjusted to 3.0 w / w% or less. The dried product was pulverized with a comil for 10 minutes under cooling at −5 ° C. to obtain a powder having an average particle size of 350 to 550 μm. The obtained powder was placed in a mold of a manual compression tableting machine so as to be 1750 mg per suppository, and compression-molded under an environmental temperature of 10 ° C. and a pressure of 800 kgf / cm 2 , 100 suppositories were produced.
[0012]
Comparative Example 1
The hard fat was melted at 60 ° C., poured into an aluminum suppository mold, and cooled at room temperature (20-25 ° C.) to produce 100 1750 mg / piece suppositories.
[0013]
Test example 1
The suppositories of Example 1 and Comparative Example 1 were allowed to stand at 25 ° C. for 2 days, and then subjected to the following tests.
Test items and test method 1) Deformation test (n = 10)
10 suppositories were laid down at 60 ° C. for 1 hour and then cooled at room temperature of 25 ° C. for 1 hour to observe the appearance of the suppository. Counted the number.
2) Hardness test (n = 3)
The hardness was measured at 30 ° C. (± 1 ° C.) with a suppository hardness meter manufactured by Erweka. That is, leave the suppository at 30 ° C. (± 1 ° C.) for 2 days or more in advance, and insert the suppository with the tip of the suppository facing upward into the suppository insert of the hardness meter in the room heated to the same temperature. A hanging bracket was placed. The weight of the suppository was measured by placing a weight of a 200 g disk on the lower table every minute of measurement, and the hardness was determined from the value.
3) Measurement of liquefaction or disintegration time by setonic method (n = 3)
The time until the suppository was completely liquefied or disintegrated at 37 ° C. (± 0.2 ° C.) was measured by the method * of Setnikar et al.
* Setnikar, WHet al .: J. Pharm. Sci., 51, 566 (1962)
4) Measurement of peak apex temperature by DSC method About 3 mg of suppository was placed in an aluminum crimp cell, heated from -20 ° C to 60 ° C at a rate of 2 ° C / minute under a nitrogen atmosphere, and a differential scanning calorimeter DSC6200 (Seiko Instruments Inc.) )), Differential scanning calorimetry was performed, and the peak apex temperature showing the maximum shift was determined as the melting point.
The results are shown in Table 1.
[0014]
[Table 1]
As is apparent from Table 1, the suppository of Example 1 was superior in heat resistance to the suppository of Comparative Example 1, and showed a fast disintegration time even in the setonic method. The hardness of the suppository of Example 1 at 30 ° C. is lower than that of Comparative Example 1, but there is no practical problem if it is 0.6 kg or more.
[0016]
Example 2
Prednisolone acetate 1.0 parts Sucrose 700 parts Sucrose fatty acid ester (HLB 11) * 17.5 parts Purified water 175 parts Hard fat 857.4 parts ( * DK ester F-110, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)
Production Method A mixture of hard fat, sucrose and prednisolone acetate melted at 60 ° C. was added to a mixture of sucrose fatty acid ester and purified water heated to 60 ° C. and kneaded well to obtain a paste. This paste was poured into a petri dish to a thickness of about 5 mm and cooled to 10 ° C. to solidify. The solidified product was vacuum-dried at 60 ° C., and the water content was adjusted to 3.0 w / w% or less. The dried product was pulverized with a comil for 10 minutes under cooling at −5 ° C., and the obtained powder was adjusted to a particle size of 850 to 1400 μm with a sieve.
The obtained powder was compression-molded under a pressure of 300 Kgf / cm 2 with a manual compression tableting machine at an environmental temperature of 10 ° C. to produce 100 1750 mg suppositories.
[0017]
Examples 3-7
The ingredients for preparing suppositories and their parts by weight are shown in [Table 2]. Using these components, 100 1750 mg suppositories were produced in the same manner as in Example 2.
[0018]
[Table 2]
Test example 2
Each of the 10 suppositories obtained in Examples 2 to 7 and Comparative Example 1 was stored for 1 hour or 1 day at 20 ° C., 40 ° C., 50 ° C. and 60 ° C. In this state, the appearance of the suppository when it was cooled to room temperature of 20 ° C. was observed, and the number of suppositories in which deformation or cracks occurred was counted.
The results are shown in [Table 3].
[0020]
[Table 3]
As apparent from [Table 3], all of the suppositories of Comparative Example 1 were deformed or cracked during high-temperature storage at 40 to 60 ° C., whereas any of the suppositories of Examples 2 to 7 of the present invention Even under the conditions, no deformation or cracking occurred.
[0022]
【Effect of the invention】
The suppository of the present invention is superior in heat resistance and has an effect that the disintegration time at the application site such as the rectum is extremely fast and excellent in drug release compared to a suppository obtained by the conventional melting method.
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001288313A JP4866518B2 (en) | 2001-09-21 | 2001-09-21 | Suppository manufacturing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001288313A JP4866518B2 (en) | 2001-09-21 | 2001-09-21 | Suppository manufacturing method |
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| Publication Number | Publication Date |
|---|---|
| JP2003095921A JP2003095921A (en) | 2003-04-03 |
| JP4866518B2 true JP4866518B2 (en) | 2012-02-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2001288313A Expired - Fee Related JP4866518B2 (en) | 2001-09-21 | 2001-09-21 | Suppository manufacturing method |
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| JP4549036B2 (en) * | 2003-06-03 | 2010-09-22 | 小川香料株式会社 | Sucrose fatty acid ester-containing granulated powder and method for producing the powder |
| JP5279343B2 (en) * | 2007-05-25 | 2013-09-04 | 第一三共ヘルスケア株式会社 | Suppository formulation composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS62267238A (en) * | 1986-05-15 | 1987-11-19 | R P Shiila- Kk | Production of insulin suppository |
| JP2718087B2 (en) * | 1988-09-08 | 1998-02-25 | 大正製薬株式会社 | Long-acting suppository |
| JPH0776527A (en) * | 1993-06-28 | 1995-03-20 | Hayashibara Biochem Lab Inc | Semi-solid preparation and production thereof |
| JP3638299B2 (en) * | 1993-11-16 | 2005-04-13 | 大日本製薬株式会社 | Sustained release suppository and method for producing the same |
| EP0748630B1 (en) * | 1994-12-29 | 2002-04-03 | Mochida Pharmaceutical Co., Ltd. | Ulinastatin-containing suppository |
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