本発明は霧化電子送達製品に用いられる霧化溶液に関し、電子送達製品分野に属する。The present invention relates to atomizing solutions for use in atomized electronic delivery products, and belongs to the field of electronic delivery products.
アナバシンは、化学構造及び物理的および化学的性質においてニコチンと多くの類似点があり、容易に霧化または加熱されてエアロゾルを形成する。また、生理学的効果においてもニコチンに類似しており、脳内のニコチン性アセチルコリン受容体（ｎＡＣｈＲｓ）に選択的に作用して、生理学的効果を発揮する。アナバシンは、構造、物理化学的特性、および生理学的メカニズムにおいてニコチンに類似しているため、喫煙者にニコチンと同様の体験効果をもたらすことができる。霧化電子送達製品におけるアナバシンが単独で応用されることはまだ発見されていない。Anabasine has many similarities to nicotine in chemical structure and physical and chemical properties and is easily atomized or heated to form an aerosol. It is also similar to nicotine in its physiological effects, and exerts its physiological effects by selectively acting on nicotinic acetylcholine receptors (nAChRs) in the brain. Anabasine is similar to nicotine in structure, physicochemical properties, and physiological mechanisms, and thus can provide smokers with similar experiential effects as nicotine. The application of anabasine alone in an atomized electronic delivery product has not yet been discovered.
本発明は、霧化電子送達製品に用いられる霧化溶液を提供し、霧化溶液は、アナバシン、発煙剤、エッセンス、水を含有して、電子霧化装置を介してアナバシンの人体への効果的な送達を実現し、ニコチンと同様の体験をもたらして、現在の霧化電子送達製品に新たなオプション形態を提供することを目的とする。The present invention provides an atomization solution used in an atomization electronic delivery product, the atomization solution containing anabasine, a fuming agent, an essence, and water, and the effect of anabasine on the human body through an electronic atomization device. The goal is to deliver a nicotine-like delivery experience and provide a new option to current atomized electronic delivery products.
本発明の上記の目的を達成するために、本発明は、以下の技術的技術案を提供する：
本発明は霧化電子送達製品に用いられる霧化溶液であって、上記霧化溶液がアナバシンを含むことを特徴とする霧化溶液を提供する。In order to achieve the above objectives of the present invention, the present invention provides the following technical solutions:
The present invention provides an atomized solution for use in an atomized electron delivery product, wherein the atomized solution comprises anabasine.
好ましくは、前記アナバシンは遊離形態で使用される。Preferably, said anabasine is used in free form.
好ましくは、前記アナバシンは（－）－Ｓ－アナバシン、（－）－Ｒ－アナバシン又は（±）－アナバシンを含む。Preferably, the anabasine comprises (-)-S-anabasine, (-)-R-anabasine or (±)-anabasine.
好ましくは、前記霧化溶液は、アナバシン１～１０質量％、発煙剤８０～８５質量％、エッセンス０～３質量％、余量の水を含む。Preferably, the atomized solution contains 1-10% by weight of anabasine, 80-85% by weight of a fuming agent, 0-3% by weight of essence, and a surplus of water.
アナバシンは分子量が小さく、容易に揮発するので、発煙剤はアナバシンの放出をさらに促進し、本発明は霧化溶液の中にアナバシンを添加して人体へのアナバシンの効果的な送達を実現し、ニコチンに同様の体験をもたらすことができて、電子タバコの健康への害を減らす。Since anabasine has a small molecular weight and is easily volatile, the fuming agent can further promote the release of anabasine, and the present invention adds anabasine into the atomized solution to realize the effective delivery of anabasine to the human body, It can provide a nicotine-like experience and reduce the health harm of e-cigarettes.
また、本発明に使用されるアナバシンは遊離形態であるため（即ち、塩を形成するために様々な有機酸を添加することない）、低毒性、低刺激性、酸を添加して塩を形成する必要がなく、霧化溶液を調製するプロセスがシンプルであり、霧化電子送達製品における使用中、顕著なスロートヒットを生じず、霧化電子送達製品を使用する際に、消費者のより良い体験を確保する。さらに、遊離形態のアナバシンは、高い転移率、体内の組織を容易に透過し受容体標的に作用しやすい、迅速的に生理学的効果が発揮されるという利点がある。Additionally, since the anabasine used in the present invention is in free form (i.e., without the addition of various organic acids to form salts), it has low toxicity, low irritation, and the ability to form salts with the addition of acids. The process of preparing the atomized solution is simple and does not result in significant throat hits during use in atomized e-delivery products, making it easier for consumers to use the atomized e-delivery products. Secure the experience. In addition, the free form of anabasine has the advantages of a high rate of metastasis, easy penetration of body tissues and action on receptor targets, and rapid onset of physiological effects.
実施例の結果は、ＣＥＴＩ８ Ｖ３．０電子タバコ機器を使用して喫煙し、固定喫煙時間は３秒、喫煙頻度は３０秒、喫煙量は５５ｍＬであり、霧化蒸気型電子タバコにおけるアナバシンの放出量は５０～２００μｇ／ｐｕｆｆ（標準的な喫煙モードでのエアロゾルの各パフ中のアルカロイドの質量）に達し、さまざまな消費者のニーズに応える。The results of the example show that the CETI8 V3.0 electronic cigarette device was used to smoke, the fixed smoking time was 3 seconds, the smoking frequency was 30 seconds, the smoking volume was 55 mL, and the release of anabasine in the atomized vapor type electronic cigarette was The amount reaches 50-200 μg/puff (mass of alkaloid in each puff of aerosol in standard smoking mode), meeting different consumer needs.
アナバシンとニコチンの急性および亜急性吸入毒性評価の結果は、アナバシンのヒト吸入許容量は３．７５ｍｇ／ｋｇ／ｄａｙに達し、ニコチンの吸入許容量は１．１３ｍｇ／ｋｇ／ｄａｙに達したことから、ニコチンと比較して、アナバシンは人体に対するバイオセーフティが高く、霧化電子送達製品でニコチン代替品として使用可能である。The results of the acute and subacute inhalation toxicity evaluation of anabasine and nicotine showed that the tolerable inhalation amount for anabasine in humans reached 3.75 mg/kg/day, and the tolerable inhalation amount for nicotine reached 1.13 mg/kg/day. , compared to nicotine, anabasine has higher biosafety for humans and can be used as a nicotine replacement in atomized electronic delivery products.
本発明は霧化電子送達製品に用いられる霧化溶液を提供する。The present invention provides atomizing solutions for use in atomized electronic delivery products.
本発明では、前記霧化溶液は、好ましくは発煙剤、エッセンス、水を更に含む。In the present invention, the atomized solution preferably further contains a fuming agent, essence, and water.
本発明は前記混合のプロセスに特別な制限がなく、各成分を均一に混合できればよい。本発明は、酸を添加して塩を形成することがなしで、霧化溶液を調製するプロセスはシンプルであり、霧化電子送達製品での使用はスロートヒットを生じることがなく、霧化電子送達製品を使用する際に、消費者のより良い体験を確保する。In the present invention, there is no particular restriction on the mixing process as long as each component can be mixed uniformly. The present invention provides a simple process for preparing atomized solutions without the addition of acids to form salts, no throat hits for use in atomized electronic delivery products, and Ensuring a better experience for consumers when using delivery products.
本発明では、前記霧化溶液は、好ましくは、アナバシン１～１０質量％、発煙剤８０～８５質量％、エッセンス０～３質量％、水を含む。In the present invention, the atomized solution preferably contains 1 to 10% by weight of anabasine, 80 to 85% by weight of a fuming agent, 0 to 3% by weight of essence, and water.
前記霧化溶液は、アナバシンを質量パーセントで１～１０質量％含有し、好ましくは、３～７質量％であり、更に好ましくは３～５質量％である。本発明の実施例では、具体的に３質量％又は５質量％である。本発明では、前記アナバシンは（－）－Ｓ－アナバシン、（－）－Ｒ－アナバシン又は（±）－アナバシンの一つ又は複数である。The atomized solution contains anabasine in a mass percentage of 1 to 10% by weight, preferably 3 to 7% by weight, and more preferably 3 to 5% by weight. In the examples of the present invention, it is specifically 3% by mass or 5% by mass. In the present invention, the anabasine is one or more of (-)-S-anabasine, (-)-R-anabasine or (±)-anabasine.
本発明によって提供される霧化溶液は、発煙剤を８０～８５質量％含有し、好ましくは８１～８５質量％であり、より好ましくは８３～８５質量％である。本発明の実施例では、具体的に８４質量％又は８５質量％である。本発明では、前記発煙剤は、好ましくは、グリセロールおよび／またはプロピレングリコールであり、より好ましくはグリセロールおよびプロピレングリコールである。本発明では、前記発煙剤がグリセロールおよびプロピレングリコールである場合、前記グリセロールとプロピレングリコールの質量比は、好ましくは（０．５～３）：１であり、より好ましくは（１～１．５）：１である。本発明では、前記発煙剤はアナバシンの放出を更に促進できる。The atomized solution provided by the present invention contains 80-85% by weight of smoke generating agent, preferably 81-85% by weight, more preferably 83-85% by weight. In the examples of the present invention, it is specifically 84% by mass or 85% by mass. In the present invention, the smoke generating agent is preferably glycerol and/or propylene glycol, more preferably glycerol and propylene glycol. In the present invention, when the smoke generating agent is glycerol and propylene glycol, the mass ratio of the glycerol to propylene glycol is preferably (0.5 to 3):1, more preferably (1 to 1.5). :1. In the present invention, the fuming agent can further promote the release of anabasine.
本発明によって提供される霧化溶液にはエッセンス０～３質量％が含まれ、好ましくは１～３質量％であり、より好ましくは２～３質量％である。本発明の実施例では、具体的に３質量％である。本発明では、前記エッセンスは植物抽出物又は合成香料である。本発明は前記エッセンスの具体的なタイプについて特に制限されず、当業者は必要に応じて選択することができる。The atomized solution provided by the present invention contains 0-3% by weight of essence, preferably 1-3% by weight, more preferably 2-3% by weight. In the example of the present invention, it is specifically 3% by mass. In the present invention, the essence is a plant extract or a synthetic fragrance. The present invention is not particularly limited to the specific type of the essence, and those skilled in the art can select it as necessary.
本発明によって提供される霧化溶液には水が含まれる。The atomized solution provided by the present invention includes water.
本発明では、前記霧化電子送達製品は、好ましくは、電子タバコが含まれる。In the present invention, said atomized electronic delivery product preferably comprises an electronic cigarette.
本発明は、応用方法について特別な要件を有さず、霧化溶液を直接加熱及び霧化してエアロゾルを生成することができる。The present invention has no special requirements on the application method, and the atomized solution can be directly heated and atomized to generate an aerosol.
アナバシンは分子量が小さく、容易に揮発するので、ネブライザーはアナバシンの放出をさらに促進し、本発明は霧化溶液の中にアナバシンを添加して人体へのアナバシンの効果的な送達を実現し、ニコチンに同様の体験をもたらすことができて、電子タバコの健康への害を減らす。Since anabasine has a small molecular weight and is easily volatilized, the nebulizer can further promote the release of anabasine, and the present invention adds anabasine into the atomized solution to realize the effective delivery of anabasine to the human body, and the nicotine can bring you a similar experience and reduce the health harm of e-cigarettes.
本発明によって提供される霧化溶液およびその調製方法およびその調製方法、並びに霧化電子送達製品での応用は実施例を参照しながら詳細に説明するが、本発明の保護範囲を限定するものとして解釈してはいけない。The atomized solution and its preparation method and its application in atomized electronic delivery products provided by the present invention will be described in detail with reference to examples, but as limiting the protection scope of the present invention. Don't interpret it.
実施例１
４５ｍｇの（±）－アナバシンを１２７５ｍｇの発煙剤（グリセロール：プロピレングリコール＝６：４の質量比）、４５ｍｇのエッセンス（ストロベリーエッセンス：ミントエッセンス＝１：１の質量比）、および１３５ｍｇの水と混合して霧化溶液を作成し、電子霧化装置で霧化溶液を加熱及び霧化してエアロゾルを生成する。Example 1
45 mg of (±)-anabasine was mixed with 1275 mg of smoke agent (glycerol: propylene glycol = 6:4 mass ratio), 45 mg of essence (strawberry essence: mint essence = 1:1 mass ratio), and 135 mg of water. An atomized solution is created by heating and atomizing the atomized solution using an electronic atomization device to generate an aerosol.
ＣＥＴＩ８Ｖ３．０電子タバコ喫煙機でテストを行い、ＣＯＲＥＳＴＡが推奨する電子タバコ喫煙モード（固定吸引持続時間は３秒、吸引頻度は３０秒、吸引量は５５ｍＬ、方形波吸引曲線）を採用し、ケンブリッジフィルターによってエアロゾルの総粒子状物質を捕捉してＧＣ－ＦＩＤ分析した結果、霧化電子装置におけるアナバシンの放出量は１０５μｇ／ｐｕｆｆに達した。Tested with CETI8V3.0 electronic cigarette smoking machine, adopted the electronic cigarette smoking mode recommended by CORESTA (fixed suction duration 3 seconds, suction frequency 30 seconds, suction volume 55mL, square wave suction curve), Cambridge As a result of capturing the total particulate matter of the aerosol by a filter and performing GC-FID analysis, the amount of anabasine released in the atomization electronic device reached 105 μg/puff.
実施例２
１００ｍｇの（±）－アナバシンを１６００ｍｇの発煙剤（グリセロール：プロピレングリコール＝６：４の質量比）、６０ｍｇのエッセンス（ストロベリーエッセンス：ミントエッセンス＝１：１の質量比）、および２４０ｍｇの水と混合して霧化溶液を作成し、電子霧化装置で霧化溶液を加熱及び霧化してエアロゾルを生成する。Example 2
100 mg of (±)-anabasine was mixed with 1600 mg of smoke agent (glycerol:propylene glycol = 6:4 mass ratio), 60 mg of essence (strawberry essence: mint essence = 1:1 mass ratio), and 240 mg of water. An atomized solution is created by heating and atomizing the atomized solution using an electronic atomization device to generate an aerosol.
ＣＥＴＩ８Ｖ３．０電子タバコ喫煙機でテストを行い、ＣＯＲＥＳＴＡが推奨する電子タバコ喫煙モード（固定吸引持続時間は３秒、吸引頻度は３０秒、吸引量は５５ｍＬ、方形波吸引曲線）を採用し、ケンブリッジフィルターによってエアロゾルの総粒子状物質を捕捉してＧＣ－ＦＩＤ分析した結果、霧化電子装置におけるアナバシンの放出量は１２４μｇ／ｐｕｆｆに達した。Tested with CETI8V3.0 electronic cigarette smoking machine, adopted the electronic cigarette smoking mode recommended by CORESTA (fixed suction duration 3 seconds, suction frequency 30 seconds, suction volume 55mL, square wave suction curve), Cambridge As a result of capturing the total particulate matter of the aerosol by a filter and performing GC-FID analysis, the amount of anabasine released in the atomization electronic device reached 124 μg/puff.
実施例３
１００ｍｇの（±）－アナバシンを１６００ｍｇの発煙剤（グリセロール：プロピレングリコール＝５：５の質量比）、６０ｍｇのエッセンス（ストロベリーエッセンス：紅茶：ミントエッセンス＝１：１：１の質量比）、および２４０ｍｇの水と混合して霧化溶液を作成し、電子霧化装置で霧化溶液を加熱及び霧化してエアロゾルを生成する。Example 3
100 mg of (±)-anabasine, 1600 mg of smoke agent (glycerol: propylene glycol = 5:5 mass ratio), 60 mg of essence (strawberry essence: black tea: mint essence = 1:1:1 mass ratio), and 240 mg water to create an atomized solution, and an electronic atomizer heats and atomizes the atomized solution to produce an aerosol.
ＣＥＴＩ８Ｖ３．０電子タバコ喫煙機でテストを行い、ＣＯＲＥＳＴＡが推奨する電子タバコ喫煙モード（固定吸引持続時間は３秒、吸引頻度は３０秒、吸引量は５５ｍＬ、方形波吸引曲線）を採用し、ケンブリッジフィルターによってエアロゾルの総粒子状物質を捕捉してＧＣ－ＦＩＤ分析した結果、霧化電子装置におけるアナバシンの放出量は１２０μｇ／ｐｕｆｆに達した。Tested with CETI8V3.0 electronic cigarette smoking machine, adopted the electronic cigarette smoking mode recommended by CORESTA (fixed suction duration 3 seconds, suction frequency 30 seconds, suction volume 55mL, square wave suction curve), Cambridge As a result of capturing the total particulate matter of the aerosol by a filter and performing GC-FID analysis, the amount of anabasine released in the atomization electronic device reached 120 μg/puff.
実施例４
４５ｍｇの（－）－Ｓ－アナバシンを１２７５ｍｇの発煙剤（グリセロール：プロピレングリコール＝６：４の質量比）、４５ｍｇのエッセンス（ストロベリーエッセンス：ミントエッセンス＝１：１の質量比）、および１３５ｍｇの水と混合して霧化溶液を作成し、電子霧化装置で霧化溶液を加熱及び霧化してエアロゾルを生成する。Example 4
45 mg of (-)-S-anabasine, 1275 mg of smoke agent (glycerol: propylene glycol = 6:4 mass ratio), 45 mg of essence (strawberry essence: mint essence = 1:1 mass ratio), and 135 mg of water. An atomized solution is created by mixing with the atomized solution, and the atomized solution is heated and atomized using an electronic atomization device to generate an aerosol.
ＣＥＴＩ８Ｖ３．０電子タバコ喫煙機でテストを行い、ＣＯＲＥＳＴＡが推奨する電子タバコ喫煙モード（固定吸引持続時間は３秒、吸引頻度は３０秒、吸引量は５５ｍＬ、方形波吸引曲線）を採用し、ケンブリッジフィルターによってエアロゾルの総粒子状物質を捕捉してＧＣ－ＦＩＤ分析した結果、霧化電子装置におけるアナバシンの放出量は１１０μｇ／ｐｕｆｆに達した。Tested with CETI8V3.0 electronic cigarette smoking machine, adopted the electronic cigarette smoking mode recommended by CORESTA (fixed suction duration 3 seconds, suction frequency 30 seconds, suction volume 55mL, square wave suction curve), Cambridge As a result of capturing the total particulate matter of the aerosol by a filter and performing GC-FID analysis, the amount of anabasine released in the atomization electronic device reached 110 μg/puff.
実施例５
４５ｍｇの（－）－Ｒ－アナバシンを１２７５ｍｇの発煙剤（グリセロール：プロピレングリコール＝６：４の質量比）、４５ｍｇのエッセンス（ストロベリーエッセンス：ミントエッセンス＝１：１の質量比）、および１３５ｍｇの水と混合して霧化溶液を作成し、電子霧化装置で霧化溶液を加熱及び霧化してエアロゾルを生成する。Example 5
45 mg of (-)-R-anabasine, 1275 mg of smoke agent (glycerol: propylene glycol = 6:4 mass ratio), 45 mg of essence (strawberry essence: mint essence = 1:1 mass ratio), and 135 mg of water. An atomized solution is created by mixing with the atomized solution, and the atomized solution is heated and atomized using an electronic atomization device to generate an aerosol.
ＣＥＴＩ８Ｖ３．０電子タバコ喫煙機でテストを行い、ＣＯＲＥＳＴＡが推奨する電子タバコ喫煙モード（固定吸引持続時間は３秒、吸引頻度は３０秒、吸引量は５５ｍＬ、方形波吸引曲線）を採用し、ケンブリッジフィルターによってエアロゾルの総粒子状物質を捕捉してＧＣ－ＦＩＤ分析した結果、霧化電子装置におけるアナバシンの放出量は１０８μｇ／ｐｕｆｆに達した。Tested with CETI8V3.0 electronic cigarette smoking machine, adopted the electronic cigarette smoking mode recommended by CORESTA (fixed suction duration 3 seconds, suction frequency 30 seconds, suction volume 55mL, square wave suction curve), Cambridge As a result of capturing the total particulate matter of the aerosol by a filter and performing GC-FID analysis, the amount of anabasine released in the atomization electronic device reached 108 μg/puff.
性能試験：
ＳＤラットの急性吸入毒性試験により、アナバシジン（ＡＮＡ）のエアロゾル吸入の半数致死量（ＬＣ５０）及び無毒性量（ＮＯＡＥＬ）を計算し、ニコチン（ＮＩＣ）急性吸入毒性の結果と比較した。急性吸入毒性試験結果に基づいて、ＡＮＡの亜急性毒性試験をさらに実施し、ＡＮＡが気道から動物の体内に入った後の呼吸器組織および全身への損傷および危害の程度を評価し、霧化電子送達製品におけるＡＮＡの応用のために安全性評価を提供する。performance test:
Through the acute inhalation toxicity test in SD rats, the half-lethal dose (LC50) and no observed adverse effect level (NOAEL) of aerosol inhalation of anabasidine (ANA) were calculated and compared with the results of nicotine (NIC) acute inhalation toxicity. Based on the acute inhalation toxicity test results, we further conducted subacute toxicity tests of ANA to evaluate the degree of damage and harm to respiratory tissues and the whole body after ANA enters the animal body through the respiratory tract, and Provides a safety evaluation for the application of ANA in electronic delivery products.
１．材料と方法
１．１試験される物質
純度９８％以上、淡黄色の油性液体であるＡＮＡ；純度９５％以上、黄色の油性液体であるＮＩＣ；プロピレングリコール（ＰＧ）；植物性グリセリン（ＶＧ）。1. Materials and Methods 1.1 Substances Tested ANA, a pale yellow oily liquid with a purity of 98% or more; NIC, a yellow oily liquid with a purity of 95% or more; Propylene Glycol (PG); Vegetable Glycerin (VG).
１．２供試品の調製及び試験グループ分け
空白の対照グループ（Ｓｈａｍ Ｃｏｎｔｒｏｌ）は空気を吸入し；陰性対照グループ（Ｖｅｈｉｃｌｅ Ｃｏｎｔｒｏｌ）供試品を質量比ＰＧ：ＶＧ＝５０：５０に従って調製し；１％ＡＮＡは質量比ＡＮＡ：ＰＧ：ＶＧ＝１：４９．５：４９．５に従って調製し；５％ＡＮＡは質量比ＡＮＡ：ＰＧ：ＶＧ＝５：４７．５：４７．５に従って調製し；１０％ＡＮＡは質量比ＡＮＡ：ＰＧ：ＶＧ＝１０：４５：５５に従って調製し；１５％ＡＮＡは質量比ＡＮＡ：ＰＧ：ＶＧ＝１５：４２．５：４２．５に従って調製し；２０％ＡＮＡは質量比ＡＮＡ：ＰＧ：ＶＧ＝２０：４０：４０に従って調製する。１％ＮＩＣは質量比ＮＩＣ：ＰＧ：ＶＧ＝１：４９．５：４９．５に従って調製し；３％ＮＩＣは質量比ＮＩＣ：ＰＧ：ＶＧ＝３：４８．５：４８．５に従って調製し；５％ＮＩＣは質量比ＮＩＣ：ＰＧ：ＶＧ＝５：４７．５：４７．５に従って調製し；１０％ＮＩＣは質量比ＮＩＣ：ＰＧ：ＶＧ＝１０：４５：５５に従って調製した。1.2 Preparation of test samples and test grouping Blank control group (Sham Control) inhales air; negative control group (Vehicle Control) test samples are prepared according to the mass ratio PG:VG=50:50; 1% ANA was prepared according to the mass ratio ANA:PG:VG=1:49.5:49.5; 5% ANA was prepared according to the mass ratio ANA:PG:VG=5:47.5:47.5; 10% ANA was prepared according to the mass ratio ANA:PG:VG = 10:45:55; 15% ANA was prepared according to the mass ratio ANA:PG:VG = 15:42.5:42.5; 20% ANA was prepared according to the mass ratio ANA:PG:VG = 15:42.5:42.5; Prepared according to mass ratio ANA:PG:VG=20:40:40. 1% NIC was prepared according to the mass ratio NIC:PG:VG=1:49.5:49.5; 3% NIC was prepared according to the mass ratio NIC:PG:VG=3:48.5:48.5; 5% NIC was prepared according to the mass ratio NIC:PG:VG=5:47.5:47.5; 10% NIC was prepared according to the mass ratio NIC:PG:VG=10:45:55.
１．３実験動物と飼育環境
ＳＰＦグレードのＳＤラットは雄と雌が半分ずつである。動物を導入した後、順応性検査を行い、順応期間中ケージあたり２匹の動物がおり、順応時間は１２〜１３日導入当日は健康診断を行い、体重を測定した。飼料は滅菌されたフルバリューの栄養粉末であり、飲水は自由であり、動物室の温度は２０〜２５℃、湿度は４５％〜７０％、光周期は１日１２時間の明期と１２時間の暗期で自動的にコントロールされる。1.3 Experimental animals and breeding environment SPF grade SD rats are half male and half female. After introducing the animals, an acclimatization test was performed, and there were two animals per cage during the acclimatization period, and the acclimatization time was 12〜13 days.On the day of introduction, a health check was performed and body weight was measured. The diet was sterile, full-value nutritional powder, drinking water was available ad libitum, the temperature of the animal room was 20〜25°C, the humidity was 45%〜70%, and the photoperiod was 12 hours per day. It is automatically controlled with a light period and a 12-hour dark period.
１．４試験機器
ＨＲＨ－ＢＡＧ１衝撃式液体エアロゾル発生器、ＨＲＨ－ＭＮＥ３０２６小動物単一濃度口腔鼻暴露システム、北京慧栄和科技有限公司；３３２１医薬品エアロゾル粒径分析システム、米国ＴＳＩ会社。1.4 Test equipment HRH-BAG1 impact liquid aerosol generator, HRH-MNE3026 small animal single concentration oral-nasal exposure system, Beijing Huironghe Technology Co., Ltd.; 3321 pharmaceutical aerosol particle size analysis system, US TSI company.
１．５急性毒性試験
ＯＥＣＤ化学物質試験ガイドの急性吸入毒性試験（ＮＯ．４０３、２００９）の要件を参照して、雄と雌のラット５匹ずつ、動物をそれぞれＨＲＨ－ＭＮＥ３０２６小動物単一濃度鼻暴露システムリテーナー内に入れて、リテーナを毒ガスチャーバーに取り付け、次に、毒ガスチャーバーを密閉し、ラットを空白の対照グループ（Ｓｈａｍ Ｃｏｎｔｒｏｌ）、陰性対照グループ（Ｖｅｈｉｃｌｅ Ｃｏｎｔｒｏｌ）、４つのＡＮＡ供試品エアロゾル（５ｍｇ／Ｌ）及び４つのＮＩＣ供試品エアロゾル（５ｍｇ／Ｌ）に曝露し、曝露して中毒時間は４時間である。中毒期間中臨床観察を行い、各グループ動物の死亡、生存数をそれぞれ統計する。生き残ったラットを１４日間継続的に観察する。ＡＮＡ及びＮＩＣガスの吸入性ＬＣ５０およびＮＯＡＥＬ値をそれぞれ計算する。1.5 Acute toxicity test Referring to the requirements of acute inhalation toxicity test (NO.403, 2009) of the OECD Test Guide for Chemicals, five male and five female rats were each tested using HRH-MNE3026 Small Animal Single Concentration Nose. The exposure system was placed inside the retainer, the retainer was attached to the poison gas chamber, the poison gas chamber was then sealed, and the rats were placed in a blank control group (Sham Control), a negative control group (Vehicle Control), and four ANA test samples. sample aerosol (5 mg/L) and four NIC sample aerosols (5 mg/L), and the exposure time of intoxication is 4 hours. Clinical observations will be made during the intoxication period, and the numbers of dead and surviving animals in each group will be counted. Surviving rats are continuously observed for 14 days. Calculate the respirability LC50 and NOAEL values for ANA and NIC gases, respectively.
１．６亜急性毒性試験
ＡＮＡ急性毒性試験の総合評価に基づき、最大暴露量としてＡＮＡ吸入性ＮＯＡＥＬを使用し、体重に応じて、ランダムに以下の５つのグループに分け、空白の対照グループ（Ｓｈａｍ Ｃｏｎｔｒｏｌ）、陰性対照グループ（Ｖｅｈｉｃｌｅ Ｃｏｎｔｒｏｌ）及びＡＮＡの高、中、低用量グループで、各グループに１０匹の動物、雄と雌は半分ずつである。グループ内の動物の体重は、グループの平均体重の±２０％を超えず、動物をそれぞれＨＲＨ－ＭＮＥ３０２６小動物単一濃度鼻暴露システムリテーナーに入れ、リテーナを毒ガスチャーバーに取り付けた後、毒ガスチャーバーを密閉し、毎日１回、２８日にわたって曝露して中毒させる。1.6 Subacute Toxicity Test Based on the comprehensive evaluation of the ANA acute toxicity test, the ANA inhalable NOAEL was used as the maximum exposure dose, and randomly divided into the following five groups according to body weight, a blank control group (Sham Control), negative control group (Vehicle Control), and ANA high, medium, and low dose groups, 10 animals in each group, half male and half female. The body weight of the animals in a group does not exceed ±20% of the average body weight of the group, each animal is placed in an HRH-MNE3026 Small Animal Single Concentration Nasal Exposure System Retainer, and the retainer is attached to a poison gas char bar. sealed and exposed once a day for 28 days to cause poisoning.
臨床症状の観察：２８日間の鼻吸入暴露期間中、実験動物の刺激、罹患率、死亡率を観察し、動物の体重と摂餌量を定期的に測定した。Observation of clinical symptoms: During the 28-day nasal inhalation exposure period, the experimental animals were observed for irritation, morbidity, and mortality, and the animals' body weights and food intake were measured regularly.
病理学的検査：実験の最後に、生き残ったすべての動物に対して肉眼解剖学を実施した。解剖時に、呼吸器系および代謝系（肺、肝臓、腎臓など）を含む動物を徹底的かつ丁寧な目視検査し、各動物の肉眼的病理学的変化を詳細に記録した。Pathological examination: At the end of the experiment, gross anatomy was performed on all surviving animals. At the time of necropsy, the animals were thoroughly and carefully visually inspected, including the respiratory and metabolic systems (lungs, liver, kidneys, etc.), and the gross pathological changes of each animal were recorded in detail.
１．７データ処理と結果分析
各グループの数、症状、死、生存及び肉眼解剖学および組織病理学的検査における病変の発生頻度を統計し、異なるグループと性別の上記各項目の発生率及び異なる時間の体重平均値及び標準偏差を計算する。1.7 Data processing and result analysis The number, symptoms, death, survival and incidence of lesions in gross anatomy and histopathological examination in each group were statisticized, and the incidence of each of the above items in different groups and genders and the differences Calculate the time weight mean and standard deviation.
２．試験結果
２．１ＮＩＣ吸入急性毒性試験
曝露期間中の中毒用チャーバーのエアロゾル濃度、ＮＩＣ吸入線量、および粒径分布を表１に示す。2. Test Results 2.1 NIC Inhalation Acute Toxicity Test Table 1 shows the aerosol concentration, NIC inhalation dose, and particle size distribution of the poisoning charver during the exposure period.
注：表１では、ＭＭＡＤはエアロゾル質量の空気力学的直径の中央値であり、ＧＳＤは幾何標準偏差である。Note: In Table 1, MMAD is the median aerodynamic diameter of the aerosol mass and GSD is the geometric standard deviation.
臨床症状の観察：ＮＩＣにおけるエアロゾル吸入線量は８７ｍｇ／ｋｇ、４３．５ｍｇ／ｋｇ、２６．１ｍｇ／ｋｇ、８．７ｍｇ／ｋｇであり、曝露中毒期間中の死亡動物と瀕死動物はそれぞれ９２．７％、６７．３％、１０．６％、２．５％に達した（図１を参照）。実験終了し、異常な変化がないまで、非死亡動物を１４日間継続的に観察した。Observation of clinical symptoms: The aerosol inhalation doses at NIC were 87 mg/kg, 43.5 mg/kg, 26.1 mg/kg, and 8.7 mg/kg, and the dead and moribund animals during the exposure toxicity period were 92.7 mg/kg, respectively. %, 67.3%, 10.6%, and 2.5% (see Figure 1). Non-dead animals were continuously observed for 14 days until the experiment ended and there were no abnormal changes.
吸入用量とラット死亡率の統計によると、非線形フィッティングにはＧｒａｐｈｐａｄ Ｐｒｉｓｍ ９．０を使用し（図２）、計算されたＳＤラットのＮＩＣエアロゾル吸入ＬＣ５０値は３７．８ｍｇ／ｋｇであり、ＳＤラットにおけるＮＩＣエアロゾル吸入ＮＯＡＥＬ用量は７．１４ｍｇ／ｋｇ／日であり、人間の等価線量（ＨＥＤ）換算係数に従って計算されたＨＥＤ値は、１．１３ｍｇ／ｋｇ／日である。According to the statistics of inhalation dose and rat mortality, using Graphpad Prism 9.0 for non-linear fitting (Fig. 2), the calculated NIC aerosol inhalation LC50 value for SD rats was 37.8 mg/kg; The NIC aerosol inhalation NOAEL dose in is 7.14 mg/kg/day, and the HED value calculated according to the human equivalent dose (HED) conversion factor is 1.13 mg/kg/day.
２．２ＡＮＡ吸入急性毒性試験
曝露期間中の中毒用チャーバーのエアロゾル濃度、ＡＮＡ吸入線量、および粒径分布を表２に示す。2.2 ANA Inhalation Acute Toxicity Test Table 2 shows the aerosol concentration, ANA inhalation dose, and particle size distribution of the poisoning charver during the exposure period.
臨床症状の観察：ＡＮＡにおけるエアロゾル吸入線量は１７４ｍｇ／ｋｇ、１３０ｍｇ／ｋｇ、８７ｍｇ／ｋｇ、４３．５ｍｇ／ｋｇであり、曝露中毒期間中の死亡動物と瀕死動物はそれぞれ８４．３％、５２．０％、６．０％、１．５％に達した（図３を参照）。実験終了し、異常な変化がないまで、非死亡動物を１４日間継続的に観察した。Observation of clinical symptoms: The aerosol inhalation doses in ANA were 174 mg/kg, 130 mg/kg, 87 mg/kg, and 43.5 mg/kg, and the percentage of dead and moribund animals during the exposure toxicity period was 84.3% and 52.5%, respectively. reached 0%, 6.0%, and 1.5% (see Figure 3). Non-dead animals were continuously observed for 14 days until the experiment ended and there were no abnormal changes.
吸入用量とラット死亡率の統計によると、非線形フィッティングにはＧｒａｐｈｐａｄ Ｐｒｉｓｍ ９．０を使用し（図４）、計算されたＳＤラットのＡＮＡエアロゾル吸入ＬＣ５０値は１２５ｍｇ／ｋｇである。ＳＤラットにおけるＡＮＡエアロゾル吸入最大用量は２３．６ｍｇ／ｋｇ／日であり、人間の等価線量（ＨＥＤ）換算係数に従って計算されたＨＥＤ値は、３．７５ｍｇ／ｋｇ／日である。According to the inhalation dose and rat mortality statistics, using Graphpad Prism 9.0 for non-linear fitting (Figure 4), the calculated ANA aerosol inhalation LC50 value for SD rats is 125 mg/kg. The maximum inhaled ANA aerosol dose in SD rats is 23.6 mg/kg/day, and the HED value calculated according to the human equivalent dose (HED) conversion factor is 3.75 mg/kg/day.
２．２亜急性毒性試験
暴露期間内、中毒用チャーバー内のＡＮＡエアロゾルの最大吸入用量はＮＯＡＥＬ（２３．６ｍｇ／ｋｇ／日）であり、１日１回、毎回６３分間中毒させた。ＡＮＡエアロゾル濃度、吸入線量、および粒径分布を表３に示した。2.2 Subacute Toxicity Test During the exposure period, the maximum inhaled dose of ANA aerosol in the poisoning char bar was NOAEL (23.6 mg/kg/day), and poisoning was performed once a day for 63 minutes each time. The ANA aerosol concentration, inhalation dose, and particle size distribution are shown in Table 3.
臨床症状の観察：亜急性吸入毒性評価は、２８日間の投与期間中、雄と雌の試験ラットの体重（図５～６）、摂餌量（図７～８）および臓器重量（表４～５）の変化には、各線量グループで統計的に有意な差（Ｐ＞０．０５）がなかった。Observation of clinical symptoms: Subacute inhalation toxicity evaluation was performed on body weight (Figures 5-6), food intake (Figures 7-8) and organ weights (Tables 4-8) of male and female test rats during the 28-day administration period. There was no statistically significant difference (P>0.05) in the change in 5) in each dose group.
気管支肺胞洗浄液：
雄及び雌の試験ラットの各線量グループの気管支肺胞洗浄液におけるＡＭ（肺胞マクロファージ）、ＭＯＮＯ（単球）、Ｌｙｍ（リンパ球）およびＮｅｕｔ（好中球）、ＴＰ（総タンパク質）、ＡＬＰ（アルカリホスファターゼ）、ＬＤＨ（乳酸デヒドロゲナーゼ）などを検出し、対照グループと比べた結果統計的に有意な差（Ｐ＞０．０５）がなかった。検出データは表６と７を参照する。Bronchoalveolar lavage fluid:
AM (alveolar macrophages), MONO (monocytes), Lym (lymphocytes) and Neut (neutrophils), TP (total protein), ALP ( Alkaline phosphatase), LDH (lactate dehydrogenase), etc. were detected, and when compared with the control group, there was no statistically significant difference (P>0.05). See Tables 6 and 7 for detection data.
血液学指標
異なる線量グループの雄と雌の実験動物に対して血液学的検査が行われた結果、統計的に有意な差（Ｐ＞０．０５）がなかった。検出データは表８と９を参照する。Hematology Indicators Hematology tests were performed on male and female experimental animals in different dose groups, and the results showed no statistically significant differences (P>0.05). See Tables 8 and 9 for detection data.
組織病理学的検査：
試験が終わった後、実験動物の組織をスライスし、肝臓、心臓、脾臓、肺、腎臓、その他の組織を病理学的検査のためにＨＥで染色した（図９、倍率１００倍）、対象グループ（ｓｈａｍ ｃｏｎｔｒｏｌ と ｖｅｈｉｃｌｅ ｃｏｎｔｒｏｌ）および高線量群（１０％ＡＮＡ）動物組織にいずれも明らかな病理学的変化は見られなかった。Histopathological examination:
After the test was finished, the tissues of the experimental animals were sliced, and the liver, heart, spleen, lung, kidney, and other tissues were stained with HE for pathological examination (Fig. 9, 100x magnification), and the target group No obvious pathological changes were observed in the animal tissues of the (sham control and vehicle control) and high-dose groups (10% ANA).
以上より、ラットの異なるグループ間で体重、食物摂取、臓器重量などに統計的に有意な差はなく（Ｐ＞０．０５）、血液、尿、気管支肺胞洗浄液、および組織病理学的検査などにおいて、いずれも試験される物質に関連する異常な変化は見られなかった。From the above, there were no statistically significant differences in body weight, food intake, organ weight, etc. between different groups of rats (P>0.05), and blood, urine, bronchoalveolar lavage fluid, and histopathological examination. No abnormal changes related to the substances tested were observed in any of the tests.
ヒトの等価線量（ＨＥＤ）換算によると、ヒトＡＮＡの吸入ＨＥＤ値は３．７５ｍｇ／ｋｇ／日と計算され、ヒトＮＩＣの吸入ＨＥＤ値は１．１３ｍｇ／ｋｇ／日だった。ＳＤラットにおけるＡＮＡとＮＩＣの吸入暴露毒性結果を総合的に比較すると、エアロゾル電子送達製品でのＡＮＡの使用はＮＩＣの使用よりも高い。これは、アナバシンは毒性の低い安全性が高い活性添加剤であり、霧化電子送達製品に適用できることを示している。According to human equivalent dose (HED) conversion, the inhaled HED value for human ANA was calculated to be 3.75 mg/kg/day, and the inhaled HED value for human NIC was 1.13 mg/kg/day. Comprehensive comparison of inhalation exposure toxicity results of ANA and NIC in SD rats shows that the use of ANA in aerosol electronic delivery products is higher than that of NIC. This indicates that anabasine is a safe active additive with low toxicity and can be applied in atomized electronic delivery products.
上記は、本発明の好ましい実施形態にすぎず、指摘しなければならないことは、当業者にとって、本発明の原理から逸脱することなく、いくつかの改善および修正ができ、これらの改善および修正も本発明の保護範囲に見なされるべきである。The above are only preferred embodiments of the invention, and it must be pointed out that a person skilled in the art will be able to make several improvements and modifications without departing from the principles of the invention. shall be considered within the protection scope of the present invention.
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