JP2010241798A - Sildenafil citrate-containing oral liquid formulation and vessel containing the liquid formulation - Google Patents
Sildenafil citrate-containing oral liquid formulation and vessel containing the liquid formulation Download PDFInfo
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- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 title claims abstract description 29
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Abstract
Description
本発明は、シルデナフィルクエン酸塩を含有する、主として、陰茎勃起機能不全治療用又は改善のための、保存安定性および使用上便宜性に優れた内服液剤及びその液剤含有容器に関する。 The present invention relates to a liquid preparation containing sildenafil citrate mainly for treatment or improvement of penile erection dysfunction and excellent in storage stability and convenience in use, and a container containing the liquid preparation.
ホスホジエステラーゼ（以下、ＰＤＥと称す）はサイクリックＡＭＰ（以下、ｃＡＭＰと称す）やサイクリックＧＭＰ（以下、ｃＧＭＰと称す）のリン酸エステルを加水分解する酵素であり、これまでに１１種のＰＤＥが存在することが判っている。細胞の機能が損なわれた状態では多くの場合、ＰＤＥ活性が亢進しており、結果的にｃＧＭＰやｃＡＭＰが不足した状態になることが推定され、ＰＤＥを阻害する薬剤はこれらを増加させるのに有用である。 Phosphodiesterase (hereinafter referred to as PDE) is an enzyme that hydrolyzes cyclic AMP (hereinafter referred to as cAMP) and cyclic GMP (hereinafter referred to as cGMP) phosphate esters. I know it exists. In many cases, the PDE activity is increased in the state in which the cell function is impaired, and it is presumed that cGMP and cAMP are deficient as a result, and drugs that inhibit PDE increase these. Useful.
ＰＤＥの１種であるＰＤＥ５については陰茎海綿体や肺組織に豊富に存在する酵素であり、陰茎勃起不全や肺高血圧症に関与することが知られている。勃起の機序については、これまでの公知文献を統合すると、以下のように説明できる。 PDE5, which is a type of PDE, is an enzyme that is abundant in the corpus cavernosum and lung tissue, and is known to be involved in penile erectile dysfunction and pulmonary hypertension. The mechanism of erection can be explained as follows by integrating known literatures so far.
性的刺激により、陰茎海綿体にある末梢神経の神経型一酸化窒素合成酵素（ｎＮＯＳ）によって生成した一酸化窒素（ＮＯ）が、陰茎海綿体のグアニル酸シクラーゼを活性化してｃＧＭＰが合成される。ｃＧＭＰ濃度上昇とともに陰茎海綿体の平滑筋が弛緩して陰茎動脈から血液が流入してくる。陰茎海綿体への血液流入により陰茎体積・寸法の増大と、内圧上昇による陰茎硬化が惹起される。これに伴い陰茎静脈が圧迫されるようになり陰茎海綿体からの血液流出も抑制され、勃起が完結する。その後、射精の完了又は性的刺激の減弱によってＮＯ供給が途絶えてくると、陰茎海綿体に存在するＰＤＥ５によりｃＧＭＰが分解され、陰茎動脈からの血液流入が止まり、やがて勃起前の状態に戻る。 By sexual stimulation, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) in peripheral nerves in the penile cavernous body activates guanylate cyclase in the penile cavernous body to synthesize cGMP. . As the cGMP concentration rises, the smooth muscle of the cavernous cavernous body relaxes and blood flows from the penile artery. The blood inflow into the penile cavernous body causes an increase in penis volume and size, and penile hardening due to an increase in internal pressure. As a result, the penile veins are compressed, blood outflow from the cavernous corpus cavernosum is suppressed, and the erection is completed. Thereafter, when the supply of NO is interrupted due to completion of ejaculation or attenuation of sexual stimulation, cGMP is decomposed by PDE5 present in the cavernous corpus cavernosum, blood inflow from the penile artery is stopped, and the state before the erection is eventually restored.
一方、ストレス等による交感神経の緊張による陰茎動脈収縮による海綿体血液流入の遮断、陰茎海綿体におけるｎＮＯＳ活性低下やグアニル酸シクラーゼ活性の低下、ＰＤＥ５活性の亢進、等のいずれか又はこれらが複合して起こると、陰茎が勃起しなかったり、勃起しても持続しなかったりして、性交が行えなくなる。このような病態を勃起不全、勃起機能障害あるいは勃起障害と言うが、心理的な配慮から、英名Erectile Dysfunctionの略名表示である「ＥＤ」なる表現が広く用いられるようになっている。 On the other hand, blockage of cavernous blood inflow due to penile arterial contraction due to sympathetic nerve tension due to stress, etc., a decrease in nNOS activity or a decrease in guanylate cyclase activity, an increase in PDE5 activity, etc. If this happens, the penis will not erection, or it will not persist after erection, making it impossible to have intercourse. Such a pathological condition is called erectile dysfunction, erectile dysfunction, or erectile dysfunction. For psychological considerations, the expression “ED”, which is an abbreviation for the English name Erectile Dysfunction, is widely used.
近年、ＰＤＥ５阻害剤が見いだされ、ＥＤ治療に革命がもたらされた。これは、陰茎海綿体のｃＧＭＰ分解酵素であるＰＤＥ５の活性を阻害し、陰茎の末梢ＮＯ神経によってもたらされる陰茎海綿体内のｃＧＭＰ量を維持・増大させ、陰茎海綿体内圧上昇（勃起）状態を持続させるものである（例えば、非特許文献１参照）。このＰＤＥ５阻害剤はＥＤに悩む患者の大部分を救った。 In recent years, PDE5 inhibitors have been found and revolutionized ED treatment. This inhibits the activity of PDE5, a cGMP-degrading enzyme in the corpus cavernosum, maintains and increases the amount of cGMP in the corpus cavernosum caused by peripheral NO nerves in the penis, and maintains the increased intracavernosal pressure (erection) state (For example, refer nonpatent literature 1). This PDE5 inhibitor saved the majority of patients suffering from ED.
現在まで、数種類のＰＤＥ５阻害剤が発売されているが、いずれも固形製剤（錠剤）であり、液剤に関する技術はほとんど知られておらず、これまでに、シルデナフィルメタンスルホン酸塩の鼻内投与用水溶液剤が開示されているのみである（特許文献１参照）。しかし、これは内服用の液剤ではない。 To date, several types of PDE5 inhibitors have been put on the market, but all are solid preparations (tablets), and little is known about techniques related to liquids. To date, for intranasal administration of sildenafil methanesulfonate Only an aqueous solution is disclosed (see Patent Document 1). However, this is not an internal solution.
特許文献２には、シルデナフィルクエン酸塩配合製剤の剤型として錠剤、カプセル、溶液、懸濁液、軟膏、スプレー、クリーム、ゲル等が記載されている。しかし、同文献中には、溶液又は懸濁液の具体的な製剤例や製造技術等について一切開示されていない（特許文献２参照）。 Patent Document 2 describes tablets, capsules, solutions, suspensions, ointments, sprays, creams, gels, and the like as dosage forms of sildenafil citrate combination formulations. However, this document does not disclose any specific formulation example or production technique of a solution or suspension (see Patent Document 2).
これまでに、ＰＤＥ５阻害剤含有内服液剤については技術情報が全く存在しなかったが、本発明者らは、ＰＤＥ５阻害剤含有内服液剤の有用性に着目して、長年に渡り鋭意研究を行ってきた。 So far, there has been no technical information about PDE5 inhibitor-containing internal liquids, but the present inventors have conducted intensive research for many years focusing on the usefulness of PDE5 inhibitor-containing internal liquids. It was.
すなわち、本発明者らは、特に、ＰＤＥ５阻害剤の使用形態を考慮した場合には、通常の固形剤とは異なる事情により剤形を液剤とすることにより、特別に服用の便宜性が向上するであろうことに着目して、安定性に優れたＰＤＥ５阻害剤含有内服液剤の研究を行い、本発明を完成させた。 That is, the present inventors, in particular, taking into account the usage form of the PDE5 inhibitor, makes the dosage form a liquid agent under circumstances different from that of a normal solid agent, so that the convenience of taking is particularly improved. Focusing on the fact that this would be the case, the present inventors completed the present invention by investigating a PDE5 inhibitor-containing internal solution with excellent stability.
また、通常、内服液剤では、固形剤と異なり、その剤の安定性を確保するのが困難なため、非常に限られた薬剤でのみ内服液剤が使用され得ることが知られている。その点でも、本発明の内服液剤は、その安定性が非常に優れていることに大きな特徴といえる。さらに、様々な容器に充填して保存し、使用可能であるから有用である。 In general, it is known that an internal liquid preparation can be used only with a very limited drug because it is difficult to ensure the stability of the internal liquid preparation, unlike a solid preparation. In that respect, the internal liquid preparation of the present invention can be said to be a great feature in that its stability is very excellent. Furthermore, it is useful because it can be stored in various containers.
服用便宜性、さらには容器廃棄時のプライバシー等を鑑みると、容器本体および蓋は樹脂容器であることが好ましく、また、つまみ部をねじ切ることで飲み口部を開口させるようにした１回飲み切りの使い捨てタイプのポリエチレン製容器であれば一層好ましいことも本発明の特徴である。 In view of convenience for taking, and privacy at the time of disposal of the container, the container body and the lid are preferably resin containers, and the drinking part is opened by screwing the knob part. It is also a feature of the present invention that it is more preferable if it is a disposable disposable polyethylene container.
通常、ポリエチレン製容器は、透明であり、ガラス瓶等容器に比べて酸素透過性が高く、長期保存安定性を確保するためには窒素ガス置換下で充填し、かつ脱酸素剤と共に包装袋に密封されることが一般的である。 In general, polyethylene containers are transparent, have higher oxygen permeability than glass bottles and other containers, are filled under nitrogen gas replacement to ensure long-term storage stability, and sealed in a packaging bag with an oxygen scavenger. It is common to be done.
すなわち、本発明の課題は、ＰＤＥ５阻害剤を内服液剤にすることが果たして可能かどうか、また、内容物（液剤）のみならず、その収納容器の材質、保存条件等、いかなる条件のもとで理想的なＰＤＥ５阻害剤の内服液剤が得られるかを解明し、ひいては、安定性が優れた陰茎勃起機能不全治療用又は改善用の液剤を提供し、かつ、実使用に便利な構造と材料の容器を提供することである。 That is, the problem of the present invention is whether it is possible to make a PDE5 inhibitor into an internal solution, and not only the contents (liquid) but also the material of the storage container, storage conditions, etc. Elucidating whether an ideal oral solution of PDE5 inhibitor can be obtained. As a result, it is possible to provide a liquid for treating or improving penile erectile dysfunction with excellent stability, and a structure and material convenient for practical use. Is to provide a container.
本発明者らは、かかる課題を解明かつ解決するために、まずシルデナフィルクエン酸塩含有液剤について鋭意研究を進めてきた。その結果、クエン酸でｐＨ調整した場合には内服液剤として好ましい酸性領域において室温（２５℃）状態で保存すると数週間以内に結晶が析出してしまい製剤的に不安定であることを見出した。さらに検討を進めてゆくなかで、クエン酸以外のｐＨ調整剤を用いて、特定のｐＨ範囲内で内服液剤を製造すれば、極めて安定なシルデナフィルクエン酸塩含有内服液剤が得られることを見出した。 In order to elucidate and solve such problems, the present inventors have made extensive studies on a liquid solution containing sildenafil citrate. As a result, when the pH was adjusted with citric acid, it was found that when it was stored at room temperature (25 ° C.) in an acidic region preferable as an internal solution, crystals were precipitated within a few weeks and the formulation was unstable. While further studying, it was found that if an internal liquid preparation was produced within a specific pH range using a pH adjusting agent other than citric acid, an extremely stable sildenafil citrate-containing internal liquid preparation could be obtained. .
また、本発明の液剤が安定剤を添加しなくても、また、特に遮光保存を要せず、さらに、ガス透過バリア性を考慮しない材質の収容容器であっても、充分な保存安定性が実現できるという驚くべき結果も見出した。 In addition, even if the liquid agent of the present invention does not contain a stabilizer, it does not require light-shielding storage, and even a container containing a material that does not take gas permeability barrier properties into consideration, sufficient storage stability is obtained. We have also found a surprising result that it can be realized.
さらに、かかる知見をもとに、使用上および廃棄便宜性を兼ね備えた、つまみ部をねじ切ることで飲み口部を開口させるようにしたポリエチレン製の飲み切り・使い捨てタイプの容器に当該液剤を充填した、シルデナフィルクエン酸塩含有内服液剤容器仕様が可能であることも見出し、本発明を完成するに至った。 In addition, based on this knowledge, the liquid agent is filled into a single-use / disposable container made of polyethylene that has a mouthpiece opening by screwing the knob, which has both convenience in use and disposal. The present inventors have also found that a sildenafil citrate-containing internal liquid container specification is possible, and have completed the present invention.
すなわち、本発明は、以下に記すとおりである。
（１）シルデナフィルクエン酸塩と、クエン酸以外のｐＨ調製剤を含有し、かつ保存料を含有しないことを特徴とする内服液剤。
本発明として、好適には、
（２）ｐＨ調整剤が、乳酸、酒石酸、リンゴ酸又は水酸化ナトリウムである、上記（１）に記載の内服液剤、
（３）内服液剤のｐＨが、２．５〜４．５である、上記（１）−（２）から選択されるいずれか１項に記載の内服液剤、
（４）内服液剤のｐＨが、３．０〜４．０である、上記（１）−（２）から選択されるいずれか１項に記載の内服液剤、
（５）さらに、甘味料及び／又は香料を含有する、上記（１）−（４）から選択されるいずれか１項に記載の内服液剤、
（６）陰茎勃起機能不全治療用又は改善のための、上記（１）−（５）から選択されるいずれか１項に記載の内服液剤、
（７）樹脂性容器に充填されてなることを特徴とする、上記（１）−（５）から選択されるいずれか１項に記載の内服液剤、
（８）樹脂性容器がポリエチレン製容器である、上記（７）に記載の内服液剤、
（９）樹脂性容器が、つまみ部をねじ切ることで飲み口部を開口させるようにした樹脂製容器である、上記（７）又は（８）に記載の内服液剤
（１０）樹脂性容器が、使い捨て、かつ、飲み切りタイプの樹脂性容器である、上記（７）−（９）から選択されるいずれか１項に記載の内服液剤、及び
（１１）固形製剤よりも薬効が早く発現することを特徴とする、上記（１）−（１０）から選択されるいずれか１項に記載の内服液剤である。
That is, the present invention is as described below.
(1) An oral solution characterized by containing sildenafil citrate and a pH adjusting agent other than citric acid and containing no preservative.
As the present invention, preferably,
(2) The internal liquid preparation according to (1), wherein the pH adjuster is lactic acid, tartaric acid, malic acid or sodium hydroxide,
(3) The internal liquid preparation according to any one of (1) to (2), wherein the internal liquid preparation has a pH of 2.5 to 4.5,
(4) The internal liquid preparation according to any one of (1) to (2), wherein the internal liquid preparation has a pH of 3.0 to 4.0,
(5) The internal liquid preparation according to any one of (1) to (4), further comprising a sweetener and / or a fragrance,
(6) The internal liquid preparation according to any one of (1) to (5), which is used for the treatment or improvement of penile erection dysfunction,
(7) The internal liquid preparation according to any one of (1) to (5), which is filled in a resinous container,
(8) The internal liquid preparation according to (7), wherein the resinous container is a polyethylene container,
(9) The internal liquid medicine (10) resinous container according to (7) or (8) above, wherein the resinous container is a resin container in which the drinking mouth part is opened by threading the knob part. It is a disposable and swallowable type resinous container, and the medicinal effect develops earlier than the internal liquid preparation according to any one of (7) to (9) selected from the above (7) to (9) and the solid preparation The internal liquid preparation according to any one of (1) to (10), which is characterized by the above.
本発明の液剤は、安定剤を添加しなくても極めて安定なシルデナフィルクエン酸塩含有内服液剤である。また、安定性が優れ、かつ、必要に応じて適宜容器が選択できることを特徴とする服用に便利な陰茎勃起機能不全治療用又は改善用の内服液剤であるため有用である。 The liquid preparation of the present invention is a sildenafil citrate-containing internal liquid preparation that is extremely stable without the addition of a stabilizer. In addition, it is useful because it is an internal solution for treatment or improvement of penile erection dysfunction, which is excellent in stability and can be appropriately selected as needed.
「陰茎勃起機能不全治療」とは、何らかの原因により、性交に必要とされるほどの陰茎勃起が発現しなかったり、いったん勃起しても持続せず正常な性交渉が行えなかったりする病気又は症状を治癒させることを意味し、「陰茎勃起機能不全改善」とは、このような病気又は症状を軽減或いは抑制させることをいう。 “Penis erection dysfunction treatment” is a disease or symptom that, for some reason, penile erection does not occur to the extent necessary for sexual intercourse, or it does not persist even after erection and normal sexual intercourse cannot be performed. The term “improvement of penile erection dysfunction” means to reduce or suppress such a disease or symptom.
シルデナフィルクエン酸塩は公知の化合物であり市販されているため入手できる。また、ｐＨ調整剤はクエン酸以外であれば特に限定されないが、例えば、乳酸、酒石酸、リンゴ酸及び水酸化ナトリウム等のｐＨ調製剤は医薬品添加物辞典２００５に収載されている。 Sildenafil citrate is a known compound and is commercially available. The pH adjuster is not particularly limited as long as it is other than citric acid. For example, pH adjusters such as lactic acid, tartaric acid, malic acid and sodium hydroxide are listed in the Pharmaceutical Additives Dictionary 2005.
「ｐＨ調整剤」とは、通常、添加物辞典等に記載されているｐＨ調整剤であるが、好適には、リンゴ酸、乳酸、酒石酸、酢酸、フマル酸、コハク酸、マレイン酸、アジピン酸、水酸化ナトリウム等であり、さらに好適には、リンゴ酸、乳酸、水酸化ナトリウム又は酒石酸である。 “PH adjuster” is usually a pH adjuster described in an additive dictionary or the like, and preferably malic acid, lactic acid, tartaric acid, acetic acid, fumaric acid, succinic acid, maleic acid, adipic acid Sodium hydroxide, and more preferably malic acid, lactic acid, sodium hydroxide or tartaric acid.
内服液剤のｐＨは、好適には、２．５〜４．５であり、さらに好適には、３．０〜４．０である。 The pH of the internal solution is preferably 2.5 to 4.5, and more preferably 3.0 to 4.0.
「甘味料」とは、通常、食品として使用されている甘味料であるが、好適には、一般的甘味料としてブドウ糖、果糖、白糖等であり、糖アルコ−ルとして還元麦芽糖水アメ、キシリト−ル、ソルビト−ル、エリスリトール等であり、人口甘味料としてアセスルファムＫ、スクラロ−ス、アスパルテーム、ステビア等である。 The “sweetener” is a sweetener usually used as a food. Preferably, glucose, fructose, sucrose, etc. are used as general sweeteners, and reduced maltose water candy, xylitol is used as a sugar alcohol. -Such as acesulfame K, sclarose, aspartame, stevia, etc. as artificial sweeteners.
「保存料」、「香料」とは、一般に、食品添加物辞典に記載されている保存料、香料である。 “Preservatives” and “fragrances” are generally preservatives and fragrances described in the food additive dictionary.
本発明の液剤の１日投与量における、シルデナフィルクエン酸塩の含有量は１ｍｇ〜１２０ｍｇであり、好ましくは、５ｍｇ〜７０ｍｇである。 The content of sildenafil citrate in the daily dose of the liquid preparation of the present invention is 1 mg to 120 mg, preferably 5 mg to 70 mg.
これらを１日１回、性行為の約１時間前に服用する。また、肺動脈性肺高血圧症の場合は当該量を３回に分けて服用する。なお、液剤の容量は特に限定されないが、１回当たりの液量は１００ｍＬ以下が望ましく、５０ｍＬ以下が更に望ましい。 Take these once a day, approximately 1 hour before sexual activity. In the case of pulmonary arterial hypertension, take this amount in three divided doses. The volume of the liquid agent is not particularly limited, but the amount of liquid per one time is preferably 100 mL or less, and more preferably 50 mL or less.
本発明の液剤には、服用性および嗜好性を持たせるために、さらに甘味料及び／又は香料を適量含有させることができる。 The liquid preparation of the present invention may further contain an appropriate amount of sweeteners and / or fragrances in order to provide ingestion and palatability.
本発明の液剤には、服用性および嗜好性を持たせるために、さらに甘味料及び／又は香料を適量含有させることができる。 The liquid preparation of the present invention may further contain an appropriate amount of sweeteners and / or fragrances in order to provide ingestion and palatability.
さらに、本発明の内服液剤の収納容器は、服用シーンの便宜、および、廃棄時の便宜を兼ね備えるために、つまみ部をねじ切ることで飲み口部を開口させるようにしたポリエチレン製の飲み切り・使い捨てタイプの容器であることが望ましい。かかる容器は、例えば、通常のブローフィルシール（ＢＦＳ）成型機を用いて成型される。ＢＦＳ成型は、樹脂容器を成型機で成型し、直ちに薬液を充填・密封する。 Furthermore, the container for internal use liquid preparations of the present invention is a polyethylene swallow-up / opening-out part that has a mouth part opened by screwing a knob part for the convenience of taking a scene and the convenience of disposal. A disposable container is desirable. Such a container is molded using, for example, a normal blow fill seal (BFS) molding machine. In BFS molding, a resin container is molded by a molding machine, and immediately filled with a chemical solution and sealed.
本発明の実施例等を以下に記載するが、本発明は、これらに限定されるものではない。
（比較例１）
精製水にシルデナフィルクエン酸塩を溶解させた後、クエン酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ３．０の液剤を調製した。
（比較例２）
精製水にシルデナフィルクエン酸塩を溶解させた後、クエン酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ４．０の液剤を調製した。
（比較例３）
精製水にシルデナフィルクエン酸塩を溶解させた後、クエン酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ５．０の液剤を調製した。
Examples of the present invention will be described below, but the present invention is not limited thereto.
(Comparative Example 1)
Sildenafil citrate was dissolved in purified water, and then a citric acid solution was added to prepare a solution of 25 mg / 20 mL, pH 3.0 as sildenafil.
(Comparative Example 2)
Sildenafil citrate was dissolved in purified water, and then a citric acid solution was added to prepare a solution of 25 mg / 20 mL, pH 4.0 as sildenafil.
(Comparative Example 3)
Sildenafil citrate was dissolved in purified water, and then a citric acid solution was added to prepare a 25 mg / 20 mL, pH 5.0 solution as sildenafil.
（実施例１）
精製水にシルデナフィルクエン酸塩を溶解させた後、乳酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ３．０および３．５の液剤を調製した。
（実施例２）
精製水にシルデナフィルクエン酸塩を溶解させた後、酒石酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ３．０および３．５の液剤を調製した。
（実施例３）
精製水にシルデナフィルクエン酸塩を溶解させた後、リンゴ酸溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ３．０および３．５の液剤を調製した。
（実施例４）
精製水にシルデナフィルクエン酸塩を溶解させた後、水酸化ナトリウム溶液を加えて、シルデナフィルとして２５ｍｇ／２０ｍＬ、ｐＨ４．０の液剤を調製した。
Example 1
Sildenafil citrate was dissolved in purified water, and then a lactic acid solution was added to prepare liquids of 25 mg / 20 mL, pH 3.0 and 3.5 as sildenafil.
(Example 2)
Sildenafil citrate was dissolved in purified water, and then a tartaric acid solution was added to prepare 25 mg / 20 mL, pH 3.0 and 3.5 solutions as sildenafil.
Example 3
Sildenafil citrate was dissolved in purified water, and then a malic acid solution was added to prepare liquids of 25 mg / 20 mL, pH 3.0 and 3.5 as sildenafil.
Example 4
After dissolving sildenafil citrate in purified water, a sodium hydroxide solution was added to prepare a solution of 25 mg / 20 mL, pH 4.0 as sildenafil.
＜試験例１＞液剤安定性試験１
（１）被験物質
シルデナフィルクエン酸塩は市販の医療用バイアグラ錠（登録商標，ファイザー製）を抽出した後、再度クエン酸塩としてから使用した。
ｐＨ調整剤のクエン酸は市販の和光純薬工業株式会社製のものを使用した。
（２）試験方法
比較例１−３で得た液剤を透明ガラス瓶に入れて、各温度条件のもとで保管し、一定期間にわたり性状を観察した。
（３）試験結果
結果を表１に示す。４０℃以上の保存条件でのシルデナフィルの含量は、いずれのｐＨにおいても９７％以上であり、極めて良好な保存安定性が得られることが判明した。その一方で、室温２５℃保存では５日から３週間で結晶が析出した。
<Test Example 1> Solution stability test 1
(1) Test substance Sildenafil citrate was extracted from a commercially available Viagra tablet (registered trademark, manufactured by Pfizer) and then used again as citrate.
The citric acid used as a pH adjuster was commercially available from Wako Pure Chemical Industries.
(2) Test method The liquid agent obtained in Comparative Example 1-3 was put in a transparent glass bottle, stored under each temperature condition, and the property was observed over a certain period.
(3) Test results The results are shown in Table 1. The content of sildenafil under storage conditions of 40 ° C. or higher was 97% or higher at any pH, and it was found that very good storage stability was obtained. On the other hand, crystals were precipitated in 5 to 3 weeks when stored at room temperature of 25 ° C.
（表１）
保存条件 比較例１（ｐＨ３） 比較例２（ｐＨ４） 比較例３（ｐＨ５）
―――――――――――――――――――――――――――――――――――
２５℃ ３週間で結晶析出 ５日間で結晶析出 １週間で結晶析出
４０℃ ８週間で変化なし ８週間で変化なし ８週間で変化なし
５０℃ ８週間で変化なし ８週間で変化なし ８週間で変化なし
６０℃ ６週間で変化なし ６週間で変化なし ６週間で変化なし
―――――――――――――――――――――――――――――――――――
表１の結果より、シルデナフィルクエン酸塩を、クエン酸を用いてｐＨ調製した液剤は、室温保存では結晶が析出してしまうため利用できないことが判明した。
(Table 1)
Storage conditions Comparative example 1 (pH 3) Comparative example 2 (pH 4) Comparative example 3 (pH 5)
―――――――――――――――――――――――――――――――――――
Crystallization at 25 ° C for 3 weeks Crystallization at 5 days Crystallization at 1 week Crystallization at 1 week 40 ° C No change at 8 weeks No change at 8 weeks 50 ° C No change at 8 weeks No change at 8 weeks Change at 8 weeks None 60 ℃ No change in 6 weeks No change in 6 weeks No change in 6 weeks ―――――――――――――――――――――――――――――――― ―――
From the results in Table 1, it was found that a solution prepared by adjusting the pH of sildenafil citrate with citric acid cannot be used because crystals precipitate when stored at room temperature.
＜試験例２＞液剤安定性試験２
（１）被験物質
シルデナフィルクエン酸塩は市販の医療用バイアグラ錠（登録商標，ファイザー製）を抽出した後、再度クエン酸塩としてから使用した。
ｐＨ調整剤の乳酸は市販の株式会社武蔵野化学研究所製のものを、また、酒石酸、リンゴ酸および水酸化ナトリウムは市販の和光純薬工業株式会社製のものを使用した。
（２）試験方法
試験例１で得られた室温での保存結果を鑑み、更に過酷な低温条件下での安定性試験を実施することにした。
実施例１−４で得た液剤を透明ガラス瓶に入れて、各温度条件のもとで保管し、一定期間にわたり性状を観察した。
（３）試験結果
結果を表２に示す。全ての温度範囲、保存条件でのシルデナフィルの含量は、いずれのｐＨにおいても対開始時９８％以上であり、極めて良好な保存安定性が得られることが判明した。
<Test Example 2> Solution stability test 2
(1) Test substance Sildenafil citrate was extracted from a commercially available Viagra tablet (registered trademark, manufactured by Pfizer) and then used again as citrate.
The pH adjuster lactic acid used was a commercially available product from Musashino Chemical Research Co., Ltd., and tartaric acid, malic acid and sodium hydroxide used were commercially available products from Wako Pure Chemical Industries, Ltd.
(2) Test Method In view of the storage result at room temperature obtained in Test Example 1, it was decided to conduct a stability test under more severe low temperature conditions.
The liquid agent obtained in Example 1-4 was put in a transparent glass bottle, stored under each temperature condition, and the property was observed over a certain period.
(3) Test results The results are shown in Table 2. The content of sildenafil in all temperature ranges and storage conditions was 98% or more at the start of each pH, and it was found that very good storage stability was obtained.
（表２）
実施例１ 実施例２ 実施例３ 実施例４
条件 ｐＨ３及び３．５ ｐＨ３及び３．５ ｐＨ３及び３．５ ｐＨ４
―――――――――――――――――――――――――――――――――――――――
５℃ ２ケ月で変化なし ２ケ月で変化なし ２ケ月で変化なし ２ケ月で変化なし
４０℃ １５週で変化なし １５週で変化なし １５週で変化なし １５週で変化なし
５０℃ ８週で変化なし ８週で変化なし ８週で変化なし ８週で変化なし
６０℃ ６週で変化なし ６週で変化なし ６週で変化なし ６週で変化なし
―――――――――――――――――――――――――――――――――――――――
表２の結果より、シルデナフィルクエン酸塩を、クエン酸以外のｐＨ調製剤で調整した液剤は、保存料を要さず、保存安定性の極めて優れた液剤となることが判明した。
(Table 2)
Example 1 Example 2 Example 3 Example 4
Conditions pH 3 and 3.5 pH 3 and 3.5 pH 3 and 3.5 pH 4
―――――――――――――――――――――――――――――――――――――――
No change in 2 months No change in 2 months No change in 2 months 40 ° C No change in 15 weeks No change in 15 weeks No change in 15 weeks No change in 15 weeks 50 ° C Change in 8 weeks None No change in 8 weeks No change in 8 weeks No change in 8 weeks 60 ° C No change in 6 weeks No change in 6 weeks No change in 6 weeks No change in 6 weeks ―――――――――――― ―――――――――――――――――――――――――――
From the results shown in Table 2, it was found that a solution prepared by adjusting sildenafil citrate with a pH adjusting agent other than citric acid does not require a preservative and becomes a solution with extremely excellent storage stability.
＜試験例３＞液剤安定性試験３
（１）被験物質および容器
シルデナフィルクエン酸塩は市販の医療用バイアグラ錠（登録商標，ファイザー製）を抽出した後、再度クエン酸塩としてから使用した。
リンゴ酸（和光純薬工業株式会社製）を使用して、ｐＨを３．５に調製した液剤（実施例３）を作製した。
各液剤は市販の、透明ガラス瓶、褐色ガラス瓶、完全遮光したガラス瓶、透明ＰＥＴ瓶、半透明ＰＰ（ポリプロピレン）瓶、半透明ＰＥ（ポリエチレン）瓶、透明ＰＥＮ（ポリエチレンナフタレート）瓶にそれぞれ充填した。
（２）試験方法
それぞれの容器に充填された各液剤は、３５００Ｌｕｘ／ｈｒの光安定性試験機に入れて光安定性試験を実施した。照射３４３時間後（１２０万Ｌｕｘ・ｈｒ）の時点で液剤の性状を観察した。
（３）試験結果
性状の変化を調べた結果を表３に、ｐＨの変化を調べた結果を表４に、シルデナフィルの含量の変化を調べた結果を表５にそれぞれ示す。いずれの条件においても、極めて良好な保存安定性が、窒素ガス置換下でない通常の充填条件の下で得られることが判明した。
<Test Example 3> Solution stability test 3
(1) Test substance and container Sildenafil citrate was used after extracting commercially available medical Viagra tablets (registered trademark, manufactured by Pfizer) and then again as citrate.
Using malic acid (manufactured by Wako Pure Chemical Industries, Ltd.), a solution (Example 3) having a pH adjusted to 3.5 was prepared.
Each liquid agent was filled in a commercially available transparent glass bottle, brown glass bottle, completely light-shielded glass bottle, transparent PET bottle, translucent PP (polypropylene) bottle, translucent PE (polyethylene) bottle, and transparent PEN (polyethylene naphthalate) bottle.
(2) Test method Each liquid agent filled in each container was put in a 3500 Lux / hr light stability tester and subjected to a light stability test. The properties of the solution were observed at 343 hours after irradiation (1,200,000 Lux · hr).
(3) Test results Table 3 shows the results of examining changes in properties, Table 4 shows the results of examining changes in pH, and Table 5 shows the results of examining changes in the content of sildenafil. Under either condition, it has been found that very good storage stability is obtained under normal filling conditions not under nitrogen gas replacement.
（表３）性状の変化
容器 実施例３（ｐＨ３．５）
――――――――――――――――――――――
透明ガラス瓶 無色透明のまま変化なし
褐色ガラス瓶 無色透明のまま変化なし
ガラス瓶完全遮光 無色透明のまま変化なし
透明ＰＥＴ瓶 無色透明のまま変化なし
半透明ＰＰ瓶 無色透明のまま変化なし
半透明ＰＥ瓶 無色透明のまま変化なし
透明ＰＥＮ瓶 無色透明のまま変化なし
――――――――――――――――――――――
(Table 3) Change in properties Container Example 3 (pH 3.5)
――――――――――――――――――――――
Transparent glass bottle
Brown glass bottle
Glass bottle complete shading colorless and transparent, no change
Transparent PET bottle
Translucent PP bottle
Translucent PE bottle
Clear PEN bottle
――――――――――――――――――――――
（表４）ｐＨの変化
容器 実施例３（ｐＨ３．５）
――――――――――――――――――――――
透明ガラス瓶 １０２．５％
褐色ガラス瓶 １０４．１％
ガラス瓶完全遮光 １０６．５％
透明ＰＥＴ瓶 １０２．５％
半透明ＰＰ瓶 １００．９％
半透明ＰＥ瓶 １０２．８％
透明ＰＥＮ瓶 １０４．７％
――――――――――――――――――――――
ｐＨ変化（％）＝１００×（照射後ｐＨ値／初期ｐＨ値）
(Table 4) Change in pH Container Example 3 (pH 3.5)
――――――――――――――――――――――
Transparent glass bottle 102.5%
Brown glass bottle 104.1%
Glass bottle complete shading 106.5%
Transparent PET bottle 102.5%
Translucent PP bottle 100.9%
Translucent PE bottle 102.8%
Clear PEN bottle 104.7%
――――――――――――――――――――――
pH change (%) = 100 × (pH value after irradiation / initial pH value)
（表５）シルデナフィルの含量変化
容器 実施例３（ｐＨ３．５）
――――――――――――――――――――――
透明ガラス瓶 ９７．６％
褐色ガラス瓶 ９７．６％
ガラス瓶完全遮光 ９８．７％
透明ＰＥＴ瓶 ９９．７％
半透明ＰＰ瓶 ９８．２％
半透明ＰＥ瓶 ９８．８％
透明ＰＥＮ瓶 ９９．７％
――――――――――――――――――――――
含量変化（％）＝１００×（照射後含量ｍｇ／初期含量ｍｇ）
(Table 5) Content change of sildenafil Container Example 3 (pH 3.5)
――――――――――――――――――――――
Clear glass bottle 97.6%
Brown glass bottle 97.6%
Glass bottle complete shading 98.7%
Transparent PET bottle 99.7%
Translucent PP bottle 98.2%
Translucent PE bottle 98.8%
Clear PEN bottle 99.7%
――――――――――――――――――――――
Content change (%) = 100 × (mg after irradiation / mg initial content)
本発明の液剤は、安定剤を添加しなくても極めて安定なシルデナフィルクエン酸塩含有内服液剤である。また、安定性が優れ、かつ、必要に応じて適宜容器が選択できることを特徴とする服用に便利な陰茎勃起機能不全治療用又は改善用の内服液剤であるため有用である。
The liquid preparation of the present invention is a sildenafil citrate-containing internal liquid preparation that is extremely stable without the addition of a stabilizer. In addition, it is useful because it is an internal solution for treatment or improvement of penile erection dysfunction, which is excellent in stability and can be appropriately selected as needed.
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