JP2016210702A - Salivation accelerator for percutaneous salivary gland administration - Google Patents
Salivation accelerator for percutaneous salivary gland administration Download PDFInfo
- Publication number
- JP2016210702A JP2016210702A JP2015093486A JP2015093486A JP2016210702A JP 2016210702 A JP2016210702 A JP 2016210702A JP 2015093486 A JP2015093486 A JP 2015093486A JP 2015093486 A JP2015093486 A JP 2015093486A JP 2016210702 A JP2016210702 A JP 2016210702A
- Authority
- JP
- Japan
- Prior art keywords
- salivary
- muscarinic receptor
- receptor agonist
- secretion promoter
- transdermal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
本発明は、唾液分泌促進剤に関する。より詳細には、本発明は、有効成分を皮膚表面から吸収させて大唾液分泌腺に送達する経皮唾液腺投与用の唾液分泌促進剤に関する。 The present invention relates to a salivary secretion promoter. More specifically, the present invention relates to a salivary secretion promoter for transdermal salivary gland administration that absorbs an active ingredient from the skin surface and delivers it to the major salivary gland.
唾液は主に耳下腺、顎下腺、舌下腺などの唾液腺から分泌されており、1日の唾液分泌量は成人で約500−600ミリリットルと報告されている。唾液は、消化液として作用するほか、口腔粘膜の乾燥を防ぐことによる保護や洗浄、口腔から侵入する微生物の殺菌作用、う蝕の予防、食物摂取の易化の作用を有することが知られている。大唾液腺(耳下腺、顎下腺、舌下腺)のほかに口腔粘膜下のいたるところに小唾液腺が存在する。 Saliva is mainly secreted from salivary glands such as the parotid gland, submandibular gland and sublingual gland, and daily saliva secretion is reported to be about 500-600 milliliters in adults. Saliva is known to act as a digestive fluid, as well as protect and cleanse by preventing dryness of the oral mucosa, bactericidal action of microorganisms entering the oral cavity, prevention of caries, and facilitating food intake. Yes. In addition to the major salivary glands (parotid gland, submandibular gland, sublingual gland), there are small salivary glands everywhere under the oral mucosa.
一般的に、安静時10分間での唾液分泌量が1mL以下の場合に、唾液分泌低下があると考えられ、唾液分泌量が50%程度まで減少すると口腔乾燥症の自覚症状が生じると言われている。短期間の発症では口腔内乾燥による不快感、咀嚼障害、味覚異常のような症状を生じ、また発症が長期間に及ぶ場合にはう蝕、歯周病、舌苔、口臭、口内炎、舌痛症、嚥下障害、構音障害などの重度の症状を生じ、QOLの低下を引き起こす。また、シェーグレン症候群が口腔乾燥症を伴うことが知られおり、その診断基準のひとつに唾液分泌量低下(ガムテスト10分間で10mL以下、またはサクソンテスト2分間2g以下)があり、かつ唾液腺シンチグラフィーにて機能低下の所見が定められている。 In general, it is considered that saliva secretion is reduced when saliva secretion in resting 10 minutes is 1 mL or less, and subjective symptoms of xerostomia are said to occur when saliva secretion decreases to about 50%. ing. Symptoms such as discomfort due to dry mouth, mastication disorders, and taste abnormalities occur in the short-term onset, and caries, periodontal disease, tongue coating, bad breath, stomatitis, glossodynia, etc. Cause severe symptoms such as dysphagia and dysarthria, causing a decrease in QOL. It is also known that Sjogren's syndrome is associated with xerostomia, and one of the diagnostic criteria is a decrease in salivary secretion (10 mL or less for gum test for 10 minutes or 2 g or less for saxon test for 2 minutes), and salivary gland scintigraphy The findings of functional decline are established.
従来、口腔乾燥症に対しては、ピロカルピン塩酸塩やセビメリン塩酸塩などのムスカリン受容体作動薬を有効成分とする内服薬が販売されている。
非特許文献1および2には、ピロカルピンは内服することで唾液分泌促進作用があることが報告されている。
特許文献1ならびに非特許文献3および4には、セビメリンは内服することで唾液分泌促進作用があることが報告されている。
Conventionally, for xerostomia, oral medicines containing muscarinic receptor agonists such as pilocarpine hydrochloride and cevimeline hydrochloride as active ingredients have been marketed.
Non-Patent Documents 1 and 2 report that pilocarpine has a salivary secretion promoting action when taken internally.
Patent Document 1 and Non-Patent Documents 3 and 4 report that cevimeline has a salivary secretion promoting action when taken internally.
しかしながら、これらの有効成分を内服薬として服用して有効に作用させようとすると、内服後に消化管から体内に取り込まれ血中に循環させた後に唾液腺に送達しなければならず、また、有効成分の血中濃度および組織濃度が急激に上昇したあと急激に降下するため副作用が発現する濃度の範囲まで血中濃度が上昇し、また、目的の作用を奏功する有効血中濃度や有効組織濃度の範囲にとどまる時間が短くなるという問題があった。
そのため、内服薬投与による療法では、投与時から効果が現れるまでに時間がかかり、副作用発生の回避が困難となり、また、服用頻度を多くする必要があった。
However, if these active ingredients are taken as internal medicines to be effective, they must be taken into the body from the digestive tract after internal use and then circulated in the blood before being delivered to the salivary glands. The blood concentration rises to the range where the side effect appears because the blood concentration and tissue concentration rapidly rise and then fall, and the range of effective blood concentration and effective tissue concentration that achieves the desired effect There was a problem that the time to stay in was shortened.
For this reason, in the therapy using the internal medicine, it takes time from the time of administration until the effect appears, and it is difficult to avoid the side effects, and it is necessary to increase the frequency of administration.
本発明者らは、短時間で効果が現れ、有効成分の血中濃度を副作用が発現する濃度未満に抑制しつつ唾液腺組織濃度を有効組織濃度に到達させることを目的として鋭意検討した結果、特定の可溶化剤に溶解した有効成分を大唾液腺表面皮膚から経皮投与することによりかかる課題を解決し得ることを見出し、本発明を完成するに至った。 As a result of diligent investigation for the purpose of achieving the salivary gland tissue concentration to the effective tissue concentration while suppressing the blood concentration of the active ingredient to less than the concentration at which side effects appear, the present inventors have found an effect in a short time. The present inventors have found that this problem can be solved by transdermally administering the active ingredient dissolved in the solubilizing agent from the surface skin of the major salivary gland, thereby completing the present invention.
すなわち、本発明は、
[1]ムスカリン受容体作動薬とn−ブタノールまたはプロピレングリコールを含有する、経皮唾液腺投与用の唾液分泌促進剤;
[2]ムスカリン受容体作動薬の配合量が唾液分泌促進剤の全重量に対して0.1〜50重量%である、上記[1]記載の経皮唾液腺投与用の唾液分泌促進剤;
[3]ムスカリン受容体作動薬がピロカルピン、セビメリンおよび製薬学的に許容されるそれらの塩から選択される、上記[1]または[2]記載の経皮唾液腺投与用の唾液分泌促進剤;
[4]リニメント剤、ローション剤、外用エアゾール剤、ポンプスプレー剤、軟膏剤、クリーム剤およびゲル剤よりなる群から選択される剤形である、上記[1]〜[3]のいずれか1に記載の経皮唾液腺投与用の唾液分泌促進剤;
[5]テープ剤およびパップ剤よりなる群から選択される剤形である、上記[1]〜[3]のいずれか1に記載の経皮唾液腺投与用の唾液分泌促進剤;
[6]ムスカリン受容体作動薬の速放作用を特徴とする、上記[1]〜[5]のいずれか1に記載の経皮唾液腺投与用の唾液分泌促進剤
を提供する。
That is, the present invention
[1] A salivary secretion promoter for transdermal salivary gland administration, comprising a muscarinic receptor agonist and n-butanol or propylene glycol;
[2] The saliva secretion promoter for transdermal salivary gland administration according to the above [1], wherein the compounding amount of the muscarinic receptor agonist is 0.1 to 50% by weight with respect to the total weight of the saliva secretion promoter;
[3] The salivary secretion promoter for transdermal salivary gland administration according to the above [1] or [2], wherein the muscarinic receptor agonist is selected from pilocarpine, cevimeline and pharmaceutically acceptable salts thereof;
[4] In any one of the above [1] to [3], which is a dosage form selected from the group consisting of a liniment, a lotion, an external aerosol, a pump spray, an ointment, a cream and a gel The salivary secretion promoter for transdermal salivary gland administration as described;
[5] The salivary secretion promoter for transdermal salivary gland administration according to any one of [1] to [3], which is a dosage form selected from the group consisting of a tape agent and a cataplasm;
[6] The salivary secretion promoter for transdermal salivary gland administration according to any one of the above [1] to [5], characterized by an immediate release action of a muscarinic receptor agonist.
本発明によれば、適用後早期に効果が現れ、副作用が抑制され、投与頻度を少なく抑えられる薬剤により、口腔内乾燥症およびそれから派生する二次的な疾患および症状の発症を予防または治療することができる。 According to the present invention, the onset of xerostomia and secondary diseases and symptoms derived therefrom is prevented or treated with a drug that exhibits effects early after application, suppresses side effects, and reduces administration frequency. be able to.
本発明は第1の態様において、経皮唾液腺投与用の唾液分泌促進剤を提供する。
本発明の唾液分泌促進剤は、ムスカリン受容体作動薬とn−ブタノールまたはプロピレングリコールを含有する。
In a first aspect, the present invention provides a salivary secretion promoter for transdermal salivary gland administration.
The salivary secretion promoter of the present invention contains a muscarinic receptor agonist and n-butanol or propylene glycol.
ムスカリン受容体作動薬は、アセチルコリン受容体に属する代謝調節型のムスカリン受容体に作用する薬剤であり、M1〜M5の受容体サブタイプに非選択的に作用する薬剤とそれぞれに選択的に作用する薬剤が存在する。唾液腺の細胞にはムスカリン受容体(M3)が発現しており、唾液はこの受容体を介して分泌されている。 Muscarinic receptor agonists are drugs that act on metabolically regulated muscarinic receptors belonging to the acetylcholine receptor, and selectively act on drugs that act non-selectively on M1-M5 receptor subtypes. The drug is present. Muscarinic receptor (M3) is expressed in salivary gland cells, and saliva is secreted through this receptor.
本発明の唾液分泌促進剤に使用するムスカリン受容体作動薬は、M1〜M5の受容体サブタイプに非選択的または選択的に作用してムスカリン受容体を活性化させることができる成分であり、例えば、M3受容体受容体に作用するピロカルピン、セビメリン、アセチルコリン、カルバコール、ベタネコール、メタコリン、アセクリジン、タルサクリジン、アレコリンおよび製薬学的に許容されるそれらの塩などが挙げられる。製薬学的に許容される塩としては、例えば、塩酸、硫酸、リン酸、酢酸、酒石酸などの無機酸もしくは有機酸の塩;ナトリウム、カリウムなどのアルカリ金属塩;カルシウムなどのアルカリ土類金属塩;アンモニア、トリエチルアミン、ピリジンなどの有機アンモニウム塩などが挙げられる。このなかでも、ピロカルピン若しくはセビメリンが好ましく、さらにはピロカルピン塩酸塩若しくはセビメリン塩酸塩が最も好ましい。ムスカリン受容体作動薬の含有量は、唾液分泌促進剤の重量に対して0.1〜50重量%、好ましくは1〜40重量%、より好ましくは3〜40重量%である。 The muscarinic receptor agonist used for the salivary secretion promoter of the present invention is a component capable of activating the muscarinic receptor by acting non-selectively or selectively on the M1-M5 receptor subtype, Examples thereof include pilocarpine acting on the M3 receptor receptor, cevimeline, acetylcholine, carbachol, betanecol, methacholine, aceclidine, talsaclidine, arecoline, and pharmaceutically acceptable salts thereof. Examples of the pharmaceutically acceptable salt include salts of inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and tartaric acid; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium An organic ammonium salt such as ammonia, triethylamine or pyridine. Of these, pilocarpine or cevimeline is preferable, and pilocarpine hydrochloride or cevimeline hydrochloride is most preferable. The content of the muscarinic receptor agonist is 0.1 to 50% by weight, preferably 1 to 40% by weight, more preferably 3 to 40% by weight, based on the weight of the salivary secretion promoter.
本発明の唾液分泌促進剤を軟膏剤、クリーム剤、ゲル剤といった塗布剤として適用する場合には、ムスカリン受容体作動薬の含有量は、唾液分泌促進剤の重量に対して0.1〜40重量%、好ましくは1〜30重量%、より好ましくは3〜20重量%である。テープ剤またはパップ剤といった貼付剤として適用する場合には、ムスカリン受容体作動薬の含有量は、唾液分泌促進剤の重量に対して1〜50重量%、好ましくは10〜40重量%、より好ましくは20〜40重量%である。 When the saliva secretion promoter of the present invention is applied as a coating agent such as an ointment, cream, or gel, the content of the muscarinic receptor agonist is 0.1 to 40% by weight based on the weight of the saliva secretion promoter. , Preferably 1 to 30% by weight, more preferably 3 to 20% by weight. When applied as a patch such as a tape or a poultice, the content of the muscarinic receptor agonist is 1 to 50% by weight, preferably 10 to 40% by weight, more preferably based on the weight of the salivary secretion promoter. Is 20-40% by weight.
また、本発明の唾液分泌促進剤に可溶化剤として使用するn−ブタノールまたはプロピレングリコールは、上記したムスカリン受容体作動薬および他の成分を溶解または分散し、かつ、皮膚表面に適用した場合にムスカリン受容体作動薬を唾液腺まで速放できる媒体であり、例えばn−ブタノールまたはプロピレングリコールなどが挙げられる。経皮投与の医薬品では一般的に適用してから効果が得られるまでに1時間から6時間程度のタイムラグがあることが知られているが、口腔乾燥は飲食や日常会話といったQOLに大きな影響を与えることから、速放できる媒体とすることは非常に重要である。一方、エタノールやグリセリンをn−ブタノールまたはプロピレングリコールの合計量よりも多く配合するとn−ブタノールやプロピレングリコールのもつ経皮吸収促進効果を阻害する可能性があることから好ましくない。人体に適用する製剤におけるエタノールおよびグリセリンの合計量は、n−ブタノールおよびプロピレングリコールの合計量よりも少ないことが好ましく、2分の1以下の量であることがより好ましく、10分の1量以下であることが最も好ましい。 Further, n-butanol or propylene glycol used as a solubilizer in the salivary secretion promoter of the present invention dissolves or disperses the above-described muscarinic receptor agonist and other components, and is applied to the skin surface. A medium that can release a muscarinic receptor agonist quickly to the salivary glands, such as n-butanol or propylene glycol. It is known that there is a time lag of about 1 to 6 hours from the time it is applied to drugs for transdermal administration, but dry mouth has a major impact on quality of life such as eating and drinking and daily conversation. Therefore, it is very important to use a medium that can be released quickly. On the other hand, if ethanol or glycerin is added in a larger amount than the total amount of n-butanol or propylene glycol, it is not preferable because it may inhibit the percutaneous absorption promoting effect of n-butanol or propylene glycol. The total amount of ethanol and glycerin in the preparation applied to the human body is preferably less than the total amount of n-butanol and propylene glycol, more preferably half or less, and one-tenth or less. Most preferably.
また、本発明の唾液分泌促進剤に使用する可溶化剤は、上記したn−ブタノールまたはプロピレングリコールのほか、静置型フランツセルを用いた透過性試験においてムスカリン受容体作動薬の短時間での透過性(速放性)が認められた可溶化剤とすることができる。好ましくは、37℃に保温した静置型フランツセルに装着したMerck Millipore社製Strat−MTMなどのヒト皮膚モデル膜におけるムスカリン受容体作動薬の透過速度が3時間後で200μg/cm2/hr以上であることができる可溶化剤とすることができる。 Further, the solubilizer used in the salivary secretion promoter of the present invention may be a permeation of a muscarinic receptor agonist in a short time in a permeability test using a stationary Franz cell in addition to the above-described n-butanol or propylene glycol. The solubilizer can be used as a solubilizing agent (fast release). Preferably, the permeation rate of a muscarinic receptor agonist is 200 μg / cm 2 / hr or more after 3 hours in a human skin model membrane such as Merct Millipore Strat-M TM attached to a stationary Franz cell kept at 37 ° C. Solubilizers that can be
静置型フランツセルおよびStrat−MTMなどのヒト皮膚モデル膜は、薬剤経皮吸収性のin vitro評価で使用することが確立されている器具である(Biopharm. Drug Disps. 33:pp.218-228 (2012)、Pharmazie, 66:pp.849-852 (2011))。本フランツセルを用いて有効成分の透過を促進する可溶化剤の検討が多く報告されている(International Journal of Biological Macromolecules 61(2013)26-32)。一般的にヒト皮膚モデル膜の有効成分の透過速度は100μg/cm2/hr以下であり、可溶化剤の検討で200μg/cm2/hr以上に上げることが可能である。 Human skin model membranes such as stationary Franz cells and Strat-M ™ are devices that have been established for use in in vitro evaluation of drug transdermal absorbability (Biopharm. Drug Disps. 33: pp. 218- 228 (2012), Pharmazie, 66: pp.849-852 (2011)). Many studies on solubilizing agents that promote permeation of active ingredients using this Franz cell have been reported (International Journal of Biological Macromolecules 61 (2013) 26-32). In general, the permeation rate of the active ingredient of the human skin model membrane is 100 μg / cm 2 / hr or less, and can be increased to 200 μg / cm 2 / hr or more by examining the solubilizer.
本発明の唾液分泌促進剤は、大唾液腺表面の皮膚から経皮投与することを特徴とする。詳しくは、大唾液腺には、顎の奥の喉付近にある顎下腺、舌の付け根の真下付近にある舌下腺および、もみあげの下部付近から耳たぶ周囲付近にある耳下腺の3つが存在する。効果的に薬剤を唾液腺に投与する方法として、顎下腺および耳下腺に適用する場合は顎の下部と下顎骨の下顎角付近から首にかけての皮膚、耳下腺に適用する場合はもみ上げの下付近から耳たぶの周囲にかけての皮膚に本願発明の経皮唾液腺投与用の唾液分泌促進剤を貼付もしくは塗布する。中でも顎下腺および舌下腺付近の皮膚に適用すると、シェーグレン症候群や唾液腺腫瘍の場合に他部位への適用に比べ有効に作用させる可能性が高いことからより好ましい。 The salivary secretion promoter of the present invention is characterized by being transdermally administered from the skin on the surface of the major salivary gland. Specifically, there are three major salivary glands: the submandibular gland near the throat behind the jaw, the sublingual gland near the base of the tongue, and the parotid gland near the earlobe from the bottom of the side of the side To do. As an effective method of administering drugs to the salivary glands, when applied to the submandibular gland and parotid gland, the skin from the lower jaw and near the lower jaw angle of the mandible to the neck, and when applied to the parotid gland The salivary secretion promoter for transdermal salivary gland administration of the present invention is affixed or applied to the skin from near the bottom to the periphery of the earlobe. In particular, it is more preferable to apply to the skin near the submandibular gland and the sublingual gland because it has a higher possibility of acting more effectively in the case of Sjogren's syndrome or salivary gland tumors than in other sites.
本発明の唾液分泌促進剤は、リニメント剤、ローション剤、外用エアゾール剤、ポンプスプレー剤、軟膏剤、クリーム剤およびゲル剤などの経皮投与用の剤形とすることができる。また、本発明の唾液分泌促進剤は、テープ剤およびパップ剤などの経皮投与用の剤形とすることができる。 The saliva secretion-promoting agent of the present invention can be made into dosage forms for transdermal administration such as liniment, lotion, external aerosol, pump spray, ointment, cream and gel. Moreover, the saliva secretion promoter of this invention can be made into dosage forms for transdermal administration, such as a tape agent and a poultice.
貼付して使用する剤形であるテープ剤およびパップ剤は、薬剤浸透の観点で他剤形と比較し長時間にわたり効果を持続させるという利点があるが、大唾液腺表面皮膚、とくに耳下腺や顎下腺付近の皮膚に貼付した場合、貼付物が他人の目に入り易く目立つため、外出時など人目が気になる状況においては使い勝手が悪い。一方で、軟膏剤、クリーム剤、ゲル剤といった塗布剤は、塗布後の滞留性は貼付する場合には劣るものの、外出時に目立たずに適用することができるという利点がある。両方の剤形があることで、たとえば就寝時と外出時など、生活スタイルに合わせて異なる製剤を選ぶことが可能となる。 Tapes and poultices, which are pasted and used, have the advantage of sustaining the effect over a long period of time compared to other dosage forms in terms of drug penetration, but the surface skin of the major salivary glands, especially the parotid gland and When it is applied to the skin near the submandibular gland, the adhesive sticks easily into other people's eyes, so it is inconvenient in situations where people are concerned about it, such as when going out. On the other hand, coating agents such as ointments, creams, and gels have the advantage that they can be applied inconspicuously when going out, although the retention after application is poor when applied. By having both dosage forms, it becomes possible to select different preparations according to lifestyle, for example, at bedtime and when going out.
また、本発明の唾液分泌促進剤には、上記した剤形に応じ、本発明の効果を損なわない範囲内で、医薬品または医薬部外品に通常使用される基剤、基剤マトリックス、油剤、界面活性剤、増粘剤、樹脂成分、湿潤剤などの任意の成分を含有させることができる。 In addition, the salivary secretion promoter of the present invention is a base, base matrix, oil, ordinarily used for pharmaceuticals or quasi-drugs, as long as the effects of the present invention are not impaired, according to the above-mentioned dosage form. Arbitrary components such as a surfactant, a thickener, a resin component, and a wetting agent can be contained.
基剤の例としては、ワセリン、パラフィン、シリコーン、プラスチベース、親水ワセリン、精製ラノリン、加水ラノリン、カルボキシビニルポリマー、ポリアクリル酸、メチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、ポリエチレンオキサイド、ポリアクリルアミド、アルギン酸ナトリウム、ゼラチン、アラビアゴム、トラガカントゴム、グアガム、キサンタンガム、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、乳酸、ラウリン酸、オレイン酸、リノール酸、リノレン酸、スクアレン、スクアラン、スチレンイソプレンスチレンブロック共重合体、スチレンブタジエンブロック共重合体、ポリイソブチレン、生ゴム、ポリイソプレン、ポリブテンなどが挙げられる。 Examples of bases include petrolatum, paraffin, silicone, plastibase, hydrophilic petrolatum, purified lanolin, hydrolyzed lanolin, carboxyvinyl polymer, polyacrylic acid, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, sodium alginate, gelatin , Gum arabic, gum tragacanth, guar gum, xanthan gum, isopropyl myristate, isopropyl palmitate, lactic acid, lauric acid, oleic acid, linoleic acid, linolenic acid, squalene, squalane, styrene isoprene styrene block copolymer, styrene butadiene block copolymer , Polyisobutylene, raw rubber, polyisoprene, polybutene and the like.
また、油剤の例としては、セチルアルコール、イソステアリルアルコール、イソステアリン酸、オレイン酸、ソルビトール、エチレングリコール、ポリエチレングリコール、ミリスチン酸ミリスチル、ラウリン酸ヘキシル、オレイン酸デシル、ミリスチン酸イソプロピル、モノステアリン酸グリセリル、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、リノール酸、ステアリン酸、乳酸ラウリル、オレイン酸オレイル、アジピン酸ジイソプロピル、セバシン酸ジイソプロピル、モノカプリル酸グリセリン、モノイソオクタン酸エチレングリコール、アーモンド油、オリーブ油、ツバキ油、パーシック油、ハッカ油、ダイズ油、ゴマ油、シンク油、綿実油、トウモロコシ油、サフラワー油、ヤシ油、ユーカリ油、ヒマシ油、硬化ヒマシ油、大豆レシチン、スクワレン、dlまたはl−メントール、l−メントン、リモネン、ピネン、ピペリトン、テルピネン、テルピノレン、テルピノール、カルベオール、dl−カンフル、N−メチル−2−ピロリドン、流動パラフィンなどが挙げられる。 Examples of oils include cetyl alcohol, isostearyl alcohol, isostearic acid, oleic acid, sorbitol, ethylene glycol, polyethylene glycol, myristyl myristate, hexyl laurate, decyl oleate, isopropyl myristate, glyceryl monostearate, Capric acid, lauric acid, myristic acid, palmitic acid, linoleic acid, stearic acid, lauryl lactate, oleyl oleate, diisopropyl adipate, diisopropyl sebacate, glyceryl monocaprylate, ethylene glycol monoisooctanoate, almond oil, olive oil, camellia Oil, persic oil, peppermint oil, soybean oil, sesame oil, sink oil, cottonseed oil, corn oil, safflower oil, palm oil, eucalyptus oil, castor oil, hydrogenated castor , Soybean lecithin, squalene, dl or l- menthol, l- menthone, limonene, pinene, piperitone, terpinene, terpinolene, terpineol, carveol, dl-camphor, N- methyl-2-pyrrolidone, liquid paraffin and the like.
また、界面活性剤の例としては、アニオン性界面活性剤、カチオン性界面活性剤、ノニオン性界面活性剤および両イオン性界面活性剤を用いることができる。例えば、脂肪酸塩、アルキル硫酸塩、ポリオキシエチレンアルキルエーテル硫酸塩、アルキルスルホコハク酸塩、ポリオキシエチレンスルホコハク酸塩、アルキルエーテルカルボン酸塩などのアニオン性界面活性剤;塩化ステアリルトリメチルアンモニウム、塩化オレイルトリメチルアンモニウム、塩化セチルトリメチルアンモニウム、塩化ジステアリルジメチルアンモニウムなどのカチオン性界面活性剤;ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル、グリセリン脂肪酸エステルなどのノニオン性界面活性剤;モノアルキルジメチルアミノ酢酸ベタイン、モノ脂肪酸アミドピロピルジメチルアミノ酢酸ベタイン、N−脂肪酸アシル―N―カルボキシメチル―N―ヒドロキシエチルエチレンジアミン塩、ジメチルアルキルグリシン、レシチンなどの両イオン性界面活性剤が挙げられる。 As examples of the surfactant, an anionic surfactant, a cationic surfactant, a nonionic surfactant, and an amphoteric surfactant can be used. For example, anionic surfactants such as fatty acid salts, alkyl sulfates, polyoxyethylene alkyl ether sulfates, alkyl sulfosuccinates, polyoxyethylene sulfosuccinates, alkyl ether carboxylates; stearyl trimethyl ammonium chloride, oleyl trimethyl chloride Cationic surfactants such as ammonium, cetyltrimethylammonium chloride, distearyldimethylammonium chloride; polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, Nonionic surfactants such as propylene glycol fatty acid esters and glycerin fatty acid esters; monoalkyldimethylaminoacetic acid betaines; Roh fatty amides pyromellitic pills acid betaine, N- fatty acyl -N- carboxymethyl -N- hydroxyethyl ethylenediamine salt, dimethyl alkyl glycine, the zwitterionic surfactant such as lecithin and the like.
また、増粘剤または樹脂成分の例としては、ポリアクリル酸ナトリウム、エチレン−アクリル酸共重合体、ビニルピロリドン系ポリマー、ビニルアルコール−ビニルピロリドン共重合体、アクリルアミド系ポリマー、アクリル酸メタクリル酸共重合体、ポリオキシエチレン−ポリオキシプロピレン共重合体、ポリアクリルアミド、カルボキシビニルポリマー、ポリビニルアルコール、セルロースエーテル、カチオン化グアガム、プルラン、ゼラチン、キサンタンガム、カラギーナン、グアガム、アラビアガム、カラヤガム、トラガカントガム、ジェランガム、セルロース、結晶セルロース、アルギン酸、デキストランなどが挙げられる。なお、ポリアクリル酸またはポリアクリル酸ナトリウムなどの水性高分子化合物を使用する場合は、架橋反応し得るアルミニウム化合物として活性アルミナ、合成ケイ酸アルミニウム、水酸化アルミニウムなどを使用することができる。また、脂溶性高分子化合物としては天然ゴム、イソプレンゴム、ポリイソブチレンゴム、スチレンブタジエンゴム、スチレンイソプレンスチレンブロック共重合体、スチレンブタジエンスチレンブロック共重合体、(メタ)アクリル酸エステル共重合体、シリコーン樹脂、ロジン、ポリブテン、ラノリン、ワセリン、プラスチベース、ミツロウ、固形パラフィンなどが挙げられる。 Examples of thickeners or resin components include sodium polyacrylate, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer, acrylamide polymer, acrylic acid methacrylic acid copolymer. Copolymer, polyoxyethylene-polyoxypropylene copolymer, polyacrylamide, carboxyvinyl polymer, polyvinyl alcohol, cellulose ether, cationized guar gum, pullulan, gelatin, xanthan gum, carrageenan, guar gum, gum arabic, karaya gum, tragacanth gum, gellan gum, cellulose , Crystalline cellulose, alginic acid, dextran and the like. When an aqueous polymer compound such as polyacrylic acid or sodium polyacrylate is used, activated alumina, synthetic aluminum silicate, aluminum hydroxide, or the like can be used as an aluminum compound that can undergo a crosslinking reaction. The fat-soluble polymer compounds include natural rubber, isoprene rubber, polyisobutylene rubber, styrene butadiene rubber, styrene isoprene styrene block copolymer, styrene butadiene styrene block copolymer, (meth) acrylic acid ester copolymer, silicone. Resins, rosin, polybutene, lanolin, petrolatum, plastibase, beeswax, solid paraffin and the like.
湿潤剤の例としては、アクリル酸デンプン、グリセリン、ポリエチレングリコール、ソルビトール、マルチトール、メタノール、プロピルアルコール、イソプロピルアルコールなどの脂肪族アルコール類;オクタンジオール、エチレングリコール、ポリエチレングリコール、D−ソルビトールなどの脂肪族多価アルコール類;ベンジルアルコールなどの芳香脂肪族アルコール類;トリメチルグリシンなどが挙げられる。 Examples of wetting agents include fatty alcohols such as starch acrylate, glycerin, polyethylene glycol, sorbitol, maltitol, methanol, propyl alcohol, isopropyl alcohol; fats such as octanediol, ethylene glycol, polyethylene glycol, D-sorbitol Aromatic polyhydric alcohols; araliphatic alcohols such as benzyl alcohol; trimethylglycine and the like.
酸化防止剤の例としては、アスコルビン酸、エリソルビン酸、パルミチン酸アスコルビン酸、亜硫酸水素ナトリウム、エデト酸ナトリウム、エデト酸4ナトリウム、乾燥亜硫酸ナトリウム、クエン酸、クエン酸ナトリウム、酢酸トコフェロール、dl−α−トコフェロール、ジクロルイソシアヌル酸カリウム、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、大豆レシチン、ピロ亜硫酸ナトリウム、ベンゾトリアゾール、ペンタエリスリル−テトラキス[3−(3,5−ジ−t−ブチル−4−ヒドロキシフェニル)プロピオネート]、没食子酸プロピル、2−メルカプトベンズイミダゾールなどが挙げられる。 Examples of antioxidants include ascorbic acid, erythorbic acid, ascorbic palmitate, sodium bisulfite, sodium edetate, tetrasodium edetate, dry sodium sulfite, citric acid, sodium citrate, tocopherol acetate, dl-α- Tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, soy lecithin, sodium pyrosulfite, benzotriazole, pentaerythryl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) Propionate], propyl gallate, 2-mercaptobenzimidazole and the like.
本発明の唾液分泌促進剤は、前記した経皮投与に適した剤形に周知の技術を用いて製剤化することができる。
本発明の唾液分泌促進剤は、耳下腺、顎下腺または耳下腺などの大唾液腺付近の皮膚表面に適用して投与する経皮唾液腺投与用の唾液分泌促進剤である。本発明の唾液分泌促進剤中のムスカリン受容体作動薬は大唾液腺を直接刺激することにより、ムスカリン受容体作動薬の血中濃度を抑えつつ大唾液腺における有効組織濃度を達成することができる。したがって、本発明の唾液分泌促進剤は、副作用の発現を抑えつつ大唾液腺に局所的かつ短時間のうちに奏功して、唾液の分泌量を増加させることができる。
The saliva secretion-promoting agent of the present invention can be formulated into a dosage form suitable for transdermal administration using a well-known technique.
The salivary secretion promoter of the present invention is a salivary secretion promoter for transdermal salivary gland administration that is applied to the skin surface near the major salivary glands such as the parotid gland, submandibular gland or parotid gland. The muscarinic receptor agonist in the salivary secretion promoter of the present invention can achieve an effective tissue concentration in the major salivary gland while suppressing the blood concentration of the muscarinic receptor agonist by directly stimulating the major salivary gland. Therefore, the salivary secretion-promoting agent of the present invention is effective in the large salivary gland locally and in a short time while suppressing the occurrence of side effects, and can increase the secretion amount of saliva.
本発明の唾液分泌促進剤は、1日当たり1回、所定の身体部位の皮膚に適用する。従来の服用する型の唾液分泌促進剤は血中で全身循環した一部が唾液腺を刺激して唾液の分泌を促進していたが、本発明の唾液分泌促進剤は実質的に血中を経ることなく大唾液腺に局所的に到達するため、短時間のうちに効力が現れ、また効力に持続性がある。 The saliva secretion promoter of the present invention is applied to the skin of a predetermined body part once a day. The conventional type of salivary secretion-promoting agent to be taken has partly circulated in the blood to stimulate the salivary gland to promote saliva secretion. However, the salivary secretion-promoting agent of the present invention substantially passes through the blood. Since it reaches the major salivary glands locally without any effect, the effect appears in a short time and the effect is persistent.
試験例1
可溶化剤のスクリーニング
ヒト皮膚モデル膜(商品名Strat-M、Merck Millipore)を装着した静置型フランツセル(拡散面積約0.636cm2)を用いて、種々の可溶化剤によるムスカリン受容体作動薬のin vitro皮膚透過性試験を行った。37℃に保温したフランツセルのレシーバー相(容量約15mL)に、レシーバー液(生理食塩水)を満たした。ヒト皮膚モデル膜をフランツセルのジョイント部にセットし、中央部に種々の可溶化剤で調製したムスカリン受容体作動薬、ピロカルピン塩酸塩(1%(w/w)、200μL)をドナー相に添加し、フランツセル内を37℃に保ち、試験を開始した。経時的に一定量のレシーバー液をサンプリングし、同量のレシーバー液(生理食塩水)を補充した。採取したレシーバー液に含まれるピロカルピンの量を高速液体クロマトグラフィー(機器名:Alliance HPLC system(Waters)、カラム:Chromolith Performance RP-18e(Merck Millipore)、温度:25℃、溶離:リン酸バッファー(pH=3)/メタノール=980/20、検出条件:214 nm)で測定した。24時間後に透過した結果を以下の表1に示す。
Test example 1
Screening of solubilizers Using a stationary Franz cell (diffusion area approximately 0.636 cm 2 ) equipped with a human skin model membrane (trade name Strat-M, Merck Millipore), muscarinic receptor agonists with various solubilizers In vitro skin permeability test was performed. A receiver solution (saline) was filled in a receiver phase (capacity: about 15 mL) of Franz cell kept at 37 ° C. Place human skin model membrane in Franz cell joint and add muscarinic receptor agonist, pilocarpine hydrochloride (1% (w / w), 200μL) prepared with various solubilizing agents to the donor phase in the center Then, the inside of the Franz cell was kept at 37 ° C., and the test was started. A certain amount of receiver solution was sampled over time, and the same amount of receiver solution (saline) was replenished. The amount of pilocarpine contained in the collected receiver solution was analyzed by high performance liquid chromatography (instrument name: Alliance HPLC system (Waters), column: Chromolith Performance RP-18e (Merck Millipore), temperature: 25 ° C, elution: phosphate buffer (pH = 3) / Methanol = 980/20, detection condition: 214 nm). The permeation results after 24 hours are shown in Table 1 below.
表1に示すように、可溶化剤のうちプロピレングリコールおよびn−ブタノールはピロカルピンを透過させたが、精製水、エタノールおよび濃グリセリンは透過させることができないことが示された。 As shown in Table 1, propylene glycol and n-butanol among the solubilizers permeated pilocarpine, but purified water, ethanol and concentrated glycerin could not permeate.
試験例2
可溶化剤による経時的透過性試験
試験例1と同じヒト皮膚モデル膜およびフランツセルを用いて、可溶化剤によるピロカルピン塩酸塩およびセビメリン塩酸塩の経時的なin vitro皮膚透過性試験を行った。その結果を以下の表2および表3に示す。
Test example 2
Time-course permeability test with solubilizer Using the same human skin model membrane and Franz cell as in Test Example 1, an in vitro skin permeability test of pilocarpine hydrochloride and cevimeline hydrochloride with a solubilizer was performed. The results are shown in Table 2 and Table 3 below.
表2および表3に示すように、プロピレングリコールおよびn−ブタノールは試験開始後3時間には多量のピロカルピンおよびセビメリンを透過させることが示された。 As shown in Tables 2 and 3, propylene glycol and n-butanol were shown to permeate large amounts of pilocarpine and cevimeline 3 hours after the start of the test.
これらの結果より、プロピレングリコールおよびn−ブタノールは、適用後短時間のうちにムスカリン受容体作動薬を大唾液腺まで送達できることが示された。
したがって、可溶化剤としてプロピレングリコールまたはn−ブタノールを用いた経皮唾液腺投与用の唾液分泌促進剤は、適用後早期に効果が現れ、副作用が抑制され、投与頻度を少なく抑えられる薬剤を提供することが示された。
From these results, it was shown that propylene glycol and n-butanol can deliver a muscarinic receptor agonist to the great salivary gland within a short time after application.
Therefore, a salivary secretion promoter for transdermal salivary gland administration using propylene glycol or n-butanol as a solubilizing agent provides a drug that is effective early after application, has side effects suppressed, and can be administered less frequently. It was shown that.
本発明の唾液分泌促進剤を以下の処方例に従って公知の製法により調製した。 The salivary secretion promoter of the present invention was prepared by a known production method according to the following formulation example.
実施例1〜32の唾液分泌促進剤は、耳下腺、顎下腺または舌下腺などの大唾液腺付近の皮膚表面に適用後早期にムスカリン受容体作動薬の血中濃度を抑えつつ大唾液腺における有効組織濃度を達成することができた。その結果として、実施例1〜32の唾液分泌促進剤は、多汗や胃腸障害などの副作用の発現を抑えつつ大唾液腺に局所的かつ早期に奏功して、唾液の分泌量を増加させることができた。 The salivary secretion promoters of Examples 1 to 32 are applied to the skin surface near the major salivary glands such as the parotid gland, the submandibular gland or the sublingual gland while suppressing the blood concentration of the muscarinic receptor agonist early after application. The effective tissue concentration in can be achieved. As a result, the salivary secretion promoters of Examples 1 to 32 can increase the amount of saliva secreted locally and early in the great salivary gland while suppressing the occurrence of side effects such as hyperhidrosis and gastrointestinal disorders. did it.
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