JP4979830B1 - Painless topical injection - Google Patents

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JP4979830B1
JP4979830B1 JP2011246946A JP2011246946A JP4979830B1 JP 4979830 B1 JP4979830 B1 JP 4979830B1 JP 2011246946 A JP2011246946 A JP 2011246946A JP 2011246946 A JP2011246946 A JP 2011246946A JP 4979830 B1 JP4979830 B1 JP 4979830B1
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重憲 青木
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

【課題】本発明は、痛みが少なく、かつ容易に実施できる注射用の外用剤を提供する
【解決手段】本発明は、脂肪族アルコールおよびＴＲＰＭ８受容体活性化チャンネルを刺激する物質を含む無痛注射用外用剤を提供する。また、脂肪族アルコール１００質量部に対し、ＴＲＰＭ８受容体活性化チャンネルを刺激する物質を１×１０−５〜１００質量部含む無痛注射用外用剤も提供する。さらに、脂肪族アルコール１００質量部に対し、更に水を１０〜２００質量部含む無痛注射用外用剤をも提供する
【選択図】図３
The present invention provides an external preparation for injection that is less painful and can be easily carried out. The present invention relates to painless injection containing a substance that stimulates fatty alcohol and a TRPM8 receptor activation channel. Provide topical preparations. In addition, an external preparation for painless injection containing 1 × 10 −5 to 100 parts by mass of a substance that stimulates the TRPM8 receptor activation channel with respect to 100 parts by mass of the aliphatic alcohol is also provided. Furthermore, an external preparation for painless injection containing 10 to 200 parts by mass of water with respect to 100 parts by mass of the aliphatic alcohol is also provided.

Description

本発明は、無痛注射に用いる外用剤に関するものである。   The present invention relates to an external preparation used for painless injection.

注射は治療、検査、予防接種などの医療の現場で多用されており、現在、医療行為の一つとして必要不可欠なものになっている。そして、今まで、注射は大なり小なり痛みを伴うのが当然とされ、注射の治療効果と比べれば多少の痛みは我慢すべきものとされてきた。しかし、老若男女を問わず注射に伴う痛みは不快であり、軽減できるに越したことはない。痛み故に、予防接種を受けないことなどになれば、患者が医療の恩恵を受ける上で障害となる。   Injections are frequently used in medical settings such as treatment, examination, and vaccination, and are now indispensable as a medical practice. And until now, it has been natural that injections are more or less painful, and some pain has been tolerated compared to the therapeutic effects of injections. However, the pain associated with injections is uncomfortable regardless of age or gender and has never been reduced. If the patient is not vaccinated because of pain, it will be an obstacle for the patient to benefit from medical care.

従来、注射時の痛みを緩和する方法として、痛みを軽減または無にする薬剤（以下「無痛化剤」という。）を注射液に混合して注射する方法や、人の痛覚の盲点に注射する方法などが提案されている。
例えば、特許文献１には、有効成分である生理活性タンパク質に、無痛化剤として少なくとも１種の糖類を混和し、かつｐＨを６．５〜７．４にして注射する、注射用製剤の投与時の疼痛を減少させる方法が提案されている。しかし、前記無痛化剤は、生理活性タンパク質に対して有効であるとしても、その他の薬効成分に対しても有効であるか否か不明である。
また、非特許文献１には、肩峰から肘頭に向かって垂直に下した線と、三角筋の下縁と交点の６ｍｍ下にすり鉢の底のような部位を痛覚の盲点として、その部位にワクチンを注射する方法が提案されている。しかしながら、該方法は、被接種者の皮下脂肪が厚い場合には上腕が一面に広く膨らんでいるため、痛覚の盲点を視覚的に捉えることができない場合があり、その場合は視覚に頼るとする方法であるから、ある程度の熟練が必要となる。
以上のことから、注射剤に無痛化剤を混合することや痛覚の盲点を視覚的に捉えることを行うことなく、例えば、無痛化剤を皮膚に塗布するだけで痛みを伴わずに注射することができれば、医療現場における前記長年の問題を解決できると期待される。 Conventional methods of relieving pain at the time of injection include injection of a drug that reduces or eliminates pain (hereinafter referred to as “analgesic agent”) into an injection solution, and injection to the blind spot of human pain. Methods have been proposed.
For example, Patent Document 1 discloses administration of an injectable preparation in which at least one saccharide as a soothing agent is mixed with a physiologically active protein, which is an active ingredient, and the pH is set to 6.5 to 7.4. Methods have been proposed to reduce time pain. However, it is unclear whether the soothing agent is effective against physiologically active proteins or other medicinal ingredients.
Further, Non-Patent Document 1 describes a site such as a line vertically dropped from the acromion toward the elbow and the bottom edge of the deltoid muscle and the bottom of the mortar as a blind spot of pain sensation. A method of injecting a vaccine has been proposed. However, in this method, when the subcutaneous fat of the inoculated person is thick, the upper arm is swollen over the entire surface, so it may not be possible to visually perceive the blind spot of pain. Since it is a method, a certain level of skill is required.
From the above, without injecting painless agents, for example, by simply applying the painless agent to the skin, without mixing the painless agent with the injection or visually perceiving blind spots in pain sensation If possible, it is expected that the long-standing problem in the medical field can be solved.

再表０２／０１１７５３号公報Table 02/011753

堺 春美、外１名、「無痛注射法による安全なインフルエンザ予防接種法の開発」、臨床とウイルス、Ｖｏｌ．３５、Ｎｏ．５、２００７、１２、４６１〜４７１頁美 Harumi, 1 other, “Development of safe influenza vaccination by painless injection”, Clinical and Virus, Vol. 35, no. 5, 2007, 12, 461-471.

したがって、本発明は、痛みが少なく、かつ容易に実施できる注射用の外用剤を提供することを目的とする。   Therefore, an object of the present invention is to provide an external preparation for injection that can be easily carried out with less pain.

本発明者は、患者が感じる注射の痛みを何とか軽減したいという医師としての思いから、痛みが少なく容易に実施できる注射に用いる外用剤を鋭意研究した結果、冷感覚を生じさせる特定物質を含む組成物を人体の特定の部位に塗布すると、痛みが軽減した注射を容易に行うことができることを見い出し、本発明の無痛注射用外用剤を完成するに至った。
すなわち、本発明は、以下の［１］〜［３］を提供する。
［１］上腕部に注射する場合において前腕部に塗布するための無痛注射用外用剤であって、メタノール、エタノール、イソプロパノールおよびノルマルプロパノールから選ばれる、少なくとも１種以上である脂肪族アルコール、並びに、メントールおよび下記（Ｉ）式の化合物の群から選ばれる、少なくとも１種以上であるＴＲＰＭ８受容体活性化チャンネルを刺激する物質を含む、無痛注射用外用剤。

Figure 0004979830
［２］前記脂肪族アルコール１００質量部に対し、前記ＴＲＰＭ８受容体活性化チャンネルを刺激する物質を１×１０−５〜１００質量部含む、前記［１］に記載の無痛注射用外用剤。
［３］前記脂肪族アルコール１００質量部に対し、更に水を１０〜２００質量部含む、前記［１］または［２］に記載の無痛注射用外用剤。
The present inventor, as a doctor who wants to alleviate the pain of injection felt by the patient, as a result of diligent research on external preparations used for injection that can be easily carried out with less pain, a composition containing a specific substance that causes a cold sensation It has been found that when an object is applied to a specific part of the human body, injection with reduced pain can be easily performed, and the external preparation for painless injection of the present invention has been completed.
That is, the present invention provides the following [1] to [ 3 ].
[1] An external preparation for painless injection for application to the forearm in the case of injection into the upper arm, which is at least one fatty alcohol selected from methanol, ethanol, isopropanol and normal propanol , and An analgesic external preparation for injection containing menthol and a substance that stimulates at least one TRPM8 receptor activation channel selected from the group of compounds of formula (I) below .
Figure 0004979830
 [2] with respect to the aliphatic alcohol 100 parts by mass, the TRPM8 comprises 1 × 10 -5 to 100 parts by mass of agents that stimulate receptor activation channels, painless injection external preparation according to [1].
[3] with respect to the aliphatic alcohol 100 parts by weight, further comprising 10 to 200 parts by weight of water, the [1] or painless injection external preparation according to [2].

Figure 0004979830
Figure 0004979830

本発明の無痛注射用外用剤を用いれば、痛みが低減した注射を容易に実施することができる。   If the external preparation for painless injection of the present invention is used, injection with reduced pain can be easily carried out.

破傷風トキソイドの予防接種の筋肉注射における、本発明の無痛注射用外用剤の効果を示す図である。It is a figure which shows the effect of the external preparation for painless injection of this invention in the intramuscular injection of the tetanus toxoid vaccination. 子宮頸がんの予防接種の筋肉注射における、本発明の無痛注射用外用剤の効果を示す図である。It is a figure which shows the effect of the external preparation for painless injection of this invention in the intramuscular injection of the vaccination of cervical cancer. インフルエンザの予防接種の皮下注射における、本発明の無痛注射用外用剤の効果を示す図である。It is a figure which shows the effect of the external preparation for painless injection of this invention in the subcutaneous injection of influenza vaccination. インフルエンザの予防接種の皮下注射において、本発明の無痛注射用外用剤を用いない場合の比較用の図である。It is a figure for the comparison in the case of not using the painless injection external preparation of this invention in the subcutaneous injection of influenza vaccination.

本発明の無痛注射用外用剤（以下「外用剤」という。）は、前記のとおり、脂肪族アルコールおよびＴＲＰＭ８受容体活性化チャンネルを刺激する物質を含むものである。
以下に、本発明の外用剤について、各含有成分および使用方法等に分けて詳細に説明する。 The external preparation for painless injection (hereinafter referred to as “external preparation”) of the present invention contains a fatty alcohol and a substance that stimulates the TRPM8 receptor activation channel as described above.
Hereinafter, the external preparation of the present invention will be described in detail for each of the components contained and the method of use.

１．脂肪族アルコール
本発明に用いる脂肪族アルコールは、塗布した部位から気化して気化熱を奪うことにより、該部位の温度を下げて冷感覚を生じさせるものであり、例えば、メタノール、エタノール、イソプロパノールおよびノルマルプロパノールから選ばれる、少なくとも１種以上が挙げられる。 1. Aliphatic alcohol The aliphatic alcohol used in the present invention is a substance that evaporates from an applied site and removes the heat of vaporization, thereby lowering the temperature of the site to produce a cold sensation. For example, methanol, ethanol, isopropanol and Examples include at least one selected from normal propanol.

２．ＴＲＰＭ８受容体活性化チャンネルを刺激する物質
本発明に用いるＴＲＰＭ８受容体活性化チャンネルを刺激する物質（以下「チャンネル刺激物質」という。）は、前記脂肪族アルコールとは異なり、塗付した部位の温度を下げる効果はなく、その代りにＴＲＰＭ８受容体活性化チャンネルを刺激することにより、冷感覚を生じさせる効果を奏するものである。該チャンネル刺激物質として、例えば、メントールおよび下記の化学構造式により表される化合物の群から選ばれる、少なくとも１種以上が挙げられる。 2. Substance that Stimulates TRPM8 Receptor Activation Channel The substance that stimulates the TRPM8 receptor activation channel used in the present invention (hereinafter referred to as “channel stimulator”) is different from the aliphatic alcohol in that the temperature of the applied site There is no effect of lowering the temperature, and instead, stimulating the TRPM8 receptor activation channel produces the effect of generating a cold sensation. Examples of the channel stimulating substance include at least one selected from the group of compounds represented by menthol and the following chemical structural formula.

Figure 0004979830
Figure 0004979830

これらの中でも、メントール、イシリン、１−（２’−メトキシフェニル）−４−（３”−ニトロフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オン、１−フェニル−４−（３”−ニトロフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オン、１−（２’−メトキシフェニル）−４−（３”−クロロフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オン、１−フェニル−４−（３”−クロロフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オン、１−（２’−メチルフェニル）−４−（３”−ニトロフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オン、１−（２’−メトキシフェニル）−４−（３”−メトキシフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オンまたは１−フェニル−４−（３”−メトキシフェニル）−１，２，３，６−テトラヒドロピリミジン−２−オンが好ましい。
これらの中でも、メントールおよびイシリンは入手が容易なため、より好ましい。さらに、メントールは、選択的にκオピオイド受容体を作動させることによる鎮痛作用も有しているため、特に好ましい。 Among these, menthol, icilin, 1- (2′-methoxyphenyl) -4- (3 ″ -nitrophenyl) -1,2,3,6-tetrahydropyrimidin-2-one, 1-phenyl-4- ( 3 "-nitrophenyl) -1,2,3,6-tetrahydropyrimidin-2-one, 1- (2'-methoxyphenyl) -4- (3" -chlorophenyl) -1,2,3,6-tetrahydro Pyrimidin-2-one, 1-phenyl-4- (3 ″ -chlorophenyl) -1,2,3,6-tetrahydropyrimidin-2-one, 1- (2′-methylphenyl) -4- (3 ″- Nitrophenyl) -1,2,3,6-tetrahydropyrimidin-2-one, 1- (2′-methoxyphenyl) -4- (3 ″ -methoxyphenyl) -1,2,3,6-tetrahydropyrimidine- 2-on Alternatively, 1-phenyl-4- (3 ″ -methoxyphenyl) -1,2,3,6-tetrahydropyrimidin-2-one is preferable.
Among these, menthol and icilin are more preferable because they are easily available. Furthermore, menthol is particularly preferable because it also has an analgesic action by selectively activating the kappa opioid receptor.

外用剤中のチャンネル刺激物質の含有量は、脂肪族アルコール１００質量部に対し１×１０−５〜１００質量部が好ましく、１×１０−４〜１０質量部がより好ましく、１×１０−３〜５質量部がさらに好ましい。該物質による冷感覚発生効果には、物質の種類や個人差などにより数百倍程度の差があるため一義的に決めにくいが、該値が１×１０−５質量部未満では冷感覚発生作用が十分でない場合があり、該値が１００質量部を超えると刺激が強すぎる場合がある。特に、メントールでは、脂肪族アルコール１００質量部に対し１×１０−２〜１００質量部が好ましく、０．１〜１０質量部がより好ましく、０．５〜５質量部がさらに好ましい。また、イシリンでは、脂肪族アルコール１００質量部に対し１×１０−５〜１質量部が好ましく、１×１０−４〜０．１質量部がより好ましく、１×１０−３〜１×１０−２質量部がさらに好ましい。 The content of the channel stimulator in the external preparation, 1 × 10 -5 to 100 weight parts preferably 100 parts by mass of an aliphatic alcohol, more preferably 1 × 10 -4 to 10 parts by weight, 1 × 10 -3 -5 mass parts is more preferable. The cold sensation generating effect by the substance is not easily determined because there is a difference of about several hundred times depending on the type of substance and individual differences, but if the value is less than 1 × 10 −5 parts by mass, the cold sensation generating action May not be sufficient, and when the value exceeds 100 parts by mass, stimulation may be too strong. In particular, in menthol, 1 * 10 <-2 > -100 mass parts is preferable with respect to 100 mass parts of aliphatic alcohol, 0.1-10 mass parts is more preferable, 0.5-5 mass parts is further more preferable. Further, in icilin, 1 × 10 -5 to 1 parts by weight is preferable with respect to 100 parts by weight fatty alcohol, more preferably 1 × 10 -4 to 0.1 part by weight, 1 × 10 -3 ~1 × 10 - 2 parts by mass is more preferred.

また、本発明の外用剤は、皮膚の感受性の高い個人に対して用いる場合、皮膚への刺激を緩和するために水で希釈して用いることができる。その場合は、水の含有量は、脂肪族アルコール１００質量部に対し１０〜２００質量部が好ましく、１５〜１５０質量部がより好ましく、２０〜１００質量部がさらに好ましい。該値が１０質量部未満では、刺激を緩和する効果が十分でない場合があり、該値が２００質量部を超えると、冷感覚発生効果が十分でない場合がある。なお、本発明に用いる水は特に制限されないが、衛生上、精製水が好ましい。
また、本発明の外用剤は他の薬液との誤用を防止するため着色して用いてもよい。その場合、青色１号、黄色4号等の染料を用いることができる。なお、本発明の効果を奏する限り、本発明の外用剤はその他の物質を含んでよい。 Moreover, when using the external preparation of this invention with respect to an individual with high skin sensitivity, in order to relieve the irritation | stimulation to skin, it can dilute and use. In that case, 10-200 mass parts is preferable with respect to 100 mass parts of aliphatic alcohol, and, as for content of water, 15-150 mass parts is more preferable, and 20-100 mass parts is further more preferable. If the value is less than 10 parts by mass, the effect of relaxing the stimulus may not be sufficient, and if the value exceeds 200 parts by mass, the effect of generating a cold sensation may not be sufficient. The water used in the present invention is not particularly limited, but purified water is preferred for hygiene purposes.
Further, the external preparation of the present invention may be colored and used in order to prevent misuse with other chemicals. In that case, dyes such as blue No. 1 and yellow No. 4 can be used. In addition, as long as the effect of the present invention is exhibited, the external preparation of the present invention may contain other substances.

３．本発明の外用剤の使用方法等
（１）外用剤の使用態様
該態様として、外用剤の皮膚への塗布、または噴霧が挙げられる。これらの中で、外用剤の使用の容易さや薬剤の損失の少なさから、塗布が好ましい。外用剤を塗布する場合は、外用剤を不織紙、不織布、脱脂綿などの繊維集合体に吸収して用いるのが好ましい。特に、衛生上、繊維集合体は脱脂綿が好ましい。 3. Usage method of external preparation of the present invention, etc. (1) Use aspect of external preparation As this aspect, application of the external preparation onto the skin or spraying can be mentioned. Among these, application is preferred because of the ease of use of external preparations and the small loss of drugs. When applying the external preparation, the external preparation is preferably absorbed into a fiber assembly such as nonwoven paper, non-woven fabric, or absorbent cotton. In particular, in terms of hygiene, the fiber assembly is preferably absorbent cotton.

（２）外用剤の使用方法
該方法として、例えば、（Ａ）注射する位置から離れた位置（以下「離隔位置」という。）に外用剤を塗布する方法、(Ｂ)注射する位置（例えば上腕部）に外用剤を塗布する方法、および、(Ｃ)前記（Ａ）の方法と（Ｂ）の方法を併用する方法等が挙げられる。なお、前記離隔位置として、例えば前腕部などが挙げられる。
以下に、これらの方法について具体的に説明する。
（Ａ）の方法は、外用剤（溶液）を含ませた脱脂綿を、離隔位置に当てて該溶液を塗布した後、自然に、または、該塗布部に息や空気を吹きかけて、外用剤の揮発分を揮発させる。この操作を複数回（好ましくは５〜６回程度）行い、さらにこの操作を繰り返している最中に、注射位置に注射する。
（Ｂ）の方法は、外用剤（溶液）を含ませた脱脂綿を、注射位置に当てて該溶液を塗布した後、自然に、または、該塗布部に息や空気を吹きかけて、外用剤の揮発分を揮発させる。この操作を複数回（好ましくは５〜６回程度）行った後に、注射位置に注射する。
（Ｃ）の方法は、注射位置と離隔位置の両方に外用剤を塗布して前記（Ａ）および（Ｂ）の方法に準じて、注射位置に注射する。
前記（Ａ）〜(Ｃ)の方法のいずれを用いても、注射時の痛みを軽減することができるが、特に（Ａ）の方法は、注射対象者が注射行為を除き単独で行うことができるため好適である。 (2) Method of using external preparation As the method, for example, (A) a method of applying the external preparation to a position away from the injection position (hereinafter referred to as “separated position”), (B) a position of injection (for example, upper arm) And (C) a method of using the method of (A) and the method of (B) in combination. In addition, as said separation position, a forearm part etc. are mentioned, for example.
Below, these methods are demonstrated concretely.
The method (A) is to apply the absorbent cotton containing the external preparation (solution) to the separation position, and then apply the solution naturally or by blowing breath or air on the application part. Volatile components are volatilized. This operation is performed a plurality of times (preferably about 5 to 6 times), and the injection is performed at the injection position while this operation is being repeated.
In the method (B), after the absorbent cotton containing the external preparation (solution) is applied to the injection position and the solution is applied, naturally or by spraying breath or air on the application portion, Volatile components are volatilized. After performing this operation a plurality of times (preferably about 5 to 6 times), the injection is performed at the injection position.
In the method (C), an external preparation is applied to both the injection position and the separation position, and injection is performed at the injection position according to the methods (A) and (B).
Although any of the methods (A) to (C) can be used to reduce pain at the time of injection, the method (A) can be performed by the person to be injected alone except for the injection action. This is preferable because it is possible.

４．本発明の外用剤による注射時の痛みの軽減に関する医学的考察
本発明者は、前記軽減のメカニズムに関し、以下の（i）〜（iv）を提案する。
（i）メカニズムの概要
痛覚を伝える神経には、痛覚を速く伝えるＡδ神経線維と遅く伝えるＣ神経線維の２種類があり、Ａδ神経線維は痛覚のほかに冷感覚や触覚も伝えることができる。そして、このＡδ神経線維に対して、本発明の外用剤による適切な冷感覚刺激を注射による痛み刺激に先行して与えると、冷感覚が痛覚に優先して知覚されるために、本発明において注射の痛覚が軽減したものと推察する。 4). Medical Consideration Regarding Relieving Pain During Injection by External Preparation of the Present Invention The present inventor proposes the following (i) to (iv) regarding the mechanism of the alleviation.
(I) Outline of mechanism There are two types of nerves that transmit pain sensation: A δ nerve fiber that transmits pain sensation fast and C nerve fiber that transmits pain sensation slowly. Then, when an appropriate cold sensation stimulus by the external preparation of the present invention is given to this Aδ nerve fiber prior to the pain stimulus by injection, the cold sensation is perceived in preference to the pain sensation. It is assumed that the pain of injection was reduced.

（ii）適切な冷感覚刺激について
次に、前記の適切な冷感覚刺激について説明する。
体温が２４〜３０℃の範囲にあると、０．５〜１℃程度のわずかな温度差でも人は感じることができる。そして、刺激温度が無関温度から著しく離れていない限り温度感覚の順応が生じる。ユニットの発火で見ると、３２℃から３０℃にしたとき、cold fiberの放電頻度は４倍にもなるが、１分後には一定値に落ち着く。したがって、３６℃の体温を数℃程度下げることは、冷感覚刺激として適切である。ちなみに、１５℃以下まで下げると冷感覚は痛覚となるため、極端に温度を下げることは適切ではない。この点については、冷水に浸しすぎると冷たさが痛みに変わる経験からも容易に理解できる。
また、適切な冷感覚刺激では順応も考慮に入れる必要がある。温覚の閾値は０．００１℃／ｓｅｃで、冷覚の閾値は０．００４℃／ｓｅｃであり、いずれも約３秒続いて順応する。１０〜４０℃の範囲では順応によって温度感覚はやがて消失する。したがって、痛覚刺激をブロックするための適切な冷覚刺激では、冷覚刺激を行った後、約３秒たったら復温し、再び冷覚刺激を行う必要がある。
よって、本発明において、外用剤の塗布と揮発の繰り返しの操作は、約３秒以内の間隔で行うのが好ましい。 (Ii) Appropriate cold sensory stimulation Next, the appropriate cold sensory stimulus will be described.
When the body temperature is in the range of 24 to 30 ° C, a person can feel even a slight temperature difference of about 0.5 to 1 ° C. As long as the stimulation temperature is not far from the indifferent temperature, the temperature sensation adapts. In terms of unit firing, when the temperature is changed from 32 ° C. to 30 ° C., the cold fiber discharge frequency is quadrupled, but settles to a constant value after 1 minute. Therefore, lowering the body temperature of 36 ° C. by several degrees is appropriate as a cold sensory stimulus. By the way, if the temperature is lowered to 15 ° C. or lower, the cold sensation becomes painful, so it is not appropriate to lower the temperature extremely. This point can be easily understood from the experience that the cold turns into pain when immersed in cold water too much.
Appropriate cold sensory stimuli also need to take adaptation into account. The threshold for warm sensation is 0.001 ° C./sec and the threshold for cold sensation is 0.004 ° C./sec, both of which adapt for about 3 seconds. In the range of 10 to 40 ° C., the temperature sensation eventually disappears due to adaptation. Therefore, in the case of an appropriate cold stimulus for blocking pain sensation, it is necessary to recover the temperature after about 3 seconds after performing the cold sensation and perform the cold sensation again.
Therefore, in this invention, it is preferable to perform the operation | movement of application | coating and volatilization of an external preparation at intervals within about 3 second.

（iii）外用剤が適切な冷感覚刺激を生じさせることについて
さらに、本発明の外用剤の各含有成分が、前記の適切な冷感覚刺激を生じさせることについて説明する。
本発明の外用剤は、前記のとおり、必須成分として脂肪族アルコールとチャンネル刺激物質を含む。このうち、脂肪族アルコールは、気化熱によって皮膚の温度を実際に低下させて冷感覚刺激を生じさせる。一方、チャンネル刺激物質は、皮膚に接触すると冷やりとした感覚を与える。この感覚は、実際に温度が低下するために生じるのではなく、冷感を引き起こすＴＲＰＭ８と呼ばれる受容体活性化チャンネルをチャンネル刺激物質が刺激することにより生じる。 (Iii) About an external preparation producing appropriate cold sensory stimulation Furthermore, it demonstrates that each content component of the external preparation of this invention produces the said appropriate cold sensory stimulus.
As described above, the external preparation of the present invention contains an aliphatic alcohol and a channel stimulating substance as essential components. Of these, fatty alcohols actually cause a cold sensory stimulus by actually lowering the skin temperature by heat of vaporization. On the other hand, channel stimulants give a cool sensation upon contact with the skin. This sensation does not occur because the temperature actually lowers, but is caused by the channel stimulator stimulating a receptor-activated channel called TRPM8 that causes a cold sensation.

（iv）その他
本発明の外用剤は、皮膚を撫でることによって触覚を刺激する。Ｃ神経線維は触覚を伝える。Gate control theoryで言われているように、触覚刺激は脊髄レベルで痛覚刺激をブロックしている。日常生活において、手をぶつけて痛い時に、人は無意識のうちに手を震わせている場合があるが、これは触覚を刺激することによって痛覚をブロックできることを経験上知っているため、無意識のうちに行っている。したがって、本発明の外用剤が痛みを軽減できる要素の一つに、触覚刺激も関与しているものと推察する。
また、（Ａ）や（Ｃ）の方法では、注射対象者が、注射よりも、外用剤を腕に塗布して適切に冷やすことに意識を集中させることにより、視床より下行性に痛みを抑制するメカニズムが作用しているものと推察する。俗にいう「気が紛れる」というものも、痛みを軽減することに一役買っているものと思われる。
なお、上腕部に注射するにもかかわらず、それとは別の位置にある前腕部に冷感覚刺激を与えて、痛みを軽減する効果がある点については、皮膚分節は上腕部と前腕部で異なっているが、これら末梢神経が腕神経叢で統合されて脊髄神経に伝わっていくので、冷感覚刺激もそれによって統合されるからであると推察する。 (Iv) Others The external preparation of the present invention stimulates the sense of touch by stroking the skin. C nerve fibers convey the sense of touch. As said in Gate control theory, tactile stimuli block painful stimuli at the spinal level. In everyday life, when a hand hits and hurts, a person may unconsciously shake his hand, but this is unconsciously because he knows from experience that pain can be blocked by stimulating the sense of touch. Is going to. Therefore, it is inferred that tactile stimulation is also involved in one of the factors that can reduce pain by the external preparation of the present invention.
In addition, in the methods (A) and (C), the injection target suppresses the pain descending from the thalamus by concentrating the consciousness on applying the external preparation to the arm and cooling it appropriately rather than the injection. It is presumed that the mechanism that acts is acting. The common sense of “distracting” seems to play a role in reducing pain.
Note that the skin segment differs between the upper arm and the forearm in that it has the effect of reducing the pain by giving a cold sensory stimulus to the forearm at a different position, even though it is injected into the upper arm. However, it is assumed that these peripheral nerves are integrated in the brachial plexus and transmitted to the spinal nerves, so that cold sensory stimulation is also integrated therewith.

１．外用剤を含む繊維集合体の調製
７０W/W％のエタノール水溶液１００質量部に対し、メントール０．５質量部（純エタノール１００質量部に対しては０．７質量部）および、溶液が着色する最小量の青色１号および黄色４号をそれぞれに含む外用剤を調製した。次に、該外用剤を脱脂綿に十分含ませて、外用剤を含む脱脂綿（繊維集合体）を調製した。 1. Preparation of fiber assembly containing external preparation 0.5 parts by mass of menthol (0.7 parts by mass with respect to 100 parts by mass of pure ethanol) and the solution are colored with respect to 100 parts by mass of 70 W / W% aqueous ethanol solution. External preparations each containing a minimum amount of Blue No. 1 and Yellow No. 4 were prepared. Next, the absorbent preparation was sufficiently contained in absorbent cotton to prepare absorbent cotton (fiber assembly) containing the external preparation.

２．注射の痛みの試験例１
前記脱脂綿と前記（Ａ）の方法を用いて、任意に抽出した注射対象者群に対し、破傷風トキソイドの予防接種（総数４５名）および子宮頸がんの予防接種（総数１７１名）の筋肉注射を行った。
注射後、注射対象者に、今までに受けた注射の痛みと比較した痛みの程度を聞き取り、痛みの程度に応じ６段階で評価した。これらの評価結果は、破傷風トキソイドの予防接種については表１と図１に、子宮頸がんの予防接種については表２と図２に示す。 2. Injection pain test example 1
Intramuscular injection of tetanus toxoid vaccination (total 45 patients) and cervical cancer vaccination (total 171 patients) to the injection target group arbitrarily extracted using the absorbent cotton and the method (A) Went.
After the injection, the subjects were asked about the degree of pain compared with the injection pain received so far, and evaluated according to the degree of pain in six levels. These evaluation results are shown in Table 1 and FIG. 1 for tetanus toxoid vaccination and in Table 2 and FIG. 2 for cervical cancer vaccination.

Figure 0004979830
Figure 0004979830

表１および図１に示すように、破傷風トキソイドの予防接種の筋肉注射において、本発明の外用剤を用いた群では、４５名中４３名（評価０〜２の割合は９６％）が以前の注射に比べ痛みが少ないと評価した。また、注射時の痛みを全く感じなかった者は、４５名中２７名（評価０の割合は６０％）にも達した。   As shown in Table 1 and FIG. 1, in the intramuscular injection of vaccination with tetanus toxoid, in the group using the external preparation of the present invention, 43 out of 45 patients (ratio of evaluation 0 to 2 was 96%) It was evaluated that there was less pain than injection. In addition, the number of persons who did not feel any pain at the time of injection reached 27 out of 45 persons (the ratio of 0 was 60%).

Figure 0004979830
Figure 0004979830

表２および図２に示すように、子宮頸がんの予防接種の筋肉注射において、本発明の外用剤を用いた群では、１７１名中１４５名（評価０〜２の割合は８５％）が以前の注射に比べて痛みが少ないと評価した。また、注射時の痛みを全く感じなかった者は、１７１名中１８名（評価０の割合は１０．５％）であった。ちなみに、子宮頸がん予防接種は痛みが強いことで知られており、女子高校生等の中には痛みのために倒れる者もいると言われている。   As shown in Table 2 and FIG. 2, in the intramuscular injection for vaccination of cervical cancer, in the group using the external preparation of the present invention, 145 out of 171 (ratio of evaluation 0 to 2 is 85%) The pain was rated less than the previous injection. In addition, 18 out of 171 persons did not feel any pain at the time of injection (rate of 0 was 10.5%). By the way, cervical cancer vaccination is known to be painful, and it is said that some high school girls and others fall down because of pain.

３．注射の痛み試験例２
次に、インフルエンザの予防接種の皮下注射について、本発明の外用剤を用いた群（総数４７名）と用いない群（総数４７名）での痛みの程度を、前記試験例１と同様の方法により評価した。これらの評価結果は、外用剤を用いた群では表３と図３に、用いない群では表３と図４に示した。 3. Injection pain test example 2
Next, for the subcutaneous injection of influenza vaccination, the degree of pain in the group using the external preparation of the present invention (total 47 persons) and the group not using it (total 47 persons) were determined in the same manner as in Test Example 1. It was evaluated by. These evaluation results are shown in Table 3 and FIG. 3 in the group using the external preparation and in Table 3 and FIG. 4 in the group not using it.

Figure 0004979830
Figure 0004979830

表３に示すように、本発明の外用剤を用いた群では、６９名中６８（評価０〜２の割合は９９％）が、従来の注射に比べて痛みが少ないと評価した。また、注射時の痛みを全く感じなかった者は６９名中２５名（評価０の割合は３６．２％）であった。
これに対し、外用剤を用いない群では、４７名中３０名（評価０の割合は６４％）が以前の注射に比べて痛みが少ないと評価した。 As shown in Table 3, in the group using the external preparation of the present invention, 68 out of 69 persons (ratio of evaluation 0 to 2 was 99%) was evaluated as having less pain compared to conventional injection. In addition, 25 out of 69 people who did not feel any pain at the time of injection (rate of 0 was 36.2%).
On the other hand, in the group that did not use external preparations, 30 out of 47 patients (the rate of evaluation 0 was 64%) were evaluated as less painful than the previous injection.

以上示したように、本発明の無痛注射用外用剤は、注射剤の種類および注射の態様によらず、すべての場合において注射時の痛みを著しく軽減することができる。   As described above, the painless external preparation for injection of the present invention can remarkably reduce pain at the time of injection in all cases regardless of the type of injection and the mode of injection.

Claims (3)

上腕部に注射する場合において前腕部に塗布するための無痛注射用外用剤であって、メタノール、エタノール、イソプロパノールおよびノルマルプロパノールから選ばれる、少なくとも１種以上である脂肪族アルコール、並びに、メントールおよび下記（Ｉ）式の化合物の群から選ばれる、少なくとも１種以上であるＴＲＰＭ８受容体活性化チャンネルを刺激する物質を含む、無痛注射用外用剤。
Figure 0004979830
 An external preparation for painless injection for application to the forearm in the case of injection into the upper arm, which is at least one selected from methanol, ethanol, isopropanol and normal propanol , menthol and the following (I) An external preparation for painless injection comprising a substance that stimulates at least one TRPM8 receptor activation channel selected from the group of compounds of formula (I) .
Figure 0004979830
 前記脂肪族アルコール１００質量部に対し、前記ＴＲＰＭ８受容体活性化チャンネルを刺激する物質を１×１０−５〜１００質量部含む、請求項１に記載の無痛注射用外用剤。 The relative fatty alcohol 100 parts by mass, the TRPM8 comprises 1 × 10 -5 to 100 parts by mass of agents that stimulate receptor activation channels, painless injection external preparation according to claim 1. 前記脂肪族アルコール１００質量部に対し、更に水を１０〜２００質量部含む、請求項１または請求項２に記載の無痛注射用外用剤。
 The external preparation for painless injection according to claim 1 or 2, further comprising 10 to 200 parts by mass of water with respect to 100 parts by mass of the aliphatic alcohol.
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Citations (4)

* Cited by examiner, † Cited by third party
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WO1996029062A1 (en) * 1995-03-22 1996-09-26 Teikoku Seiyaku Kabushiki Kaisha Cold sheet
JPH1053527A (en) * 1996-08-09 1998-02-24 Tanabe Seiyaku Co Ltd Percutaneous absorbent preparation containing caffeine
JPH11255659A (en) * 1998-03-11 1999-09-21 Iron:Kk Sheet for wrapping around calf and ankle
JP2001055319A (en) * 1999-08-17 2001-02-27 Pola Chem Ind Inc Dry shampoo sheet

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JPH07157424A (en) * 1993-12-03 1995-06-20 Lintec Corp Gel formulation for local anesthesia
JPH09255565A (en) * 1996-03-26 1997-09-30 Daikyo Yakuhin Kogyo Kk Hydrogel patch for dermal local anesthesia
JP2006137737A (en) * 2004-11-09 2006-06-01 Mizuho Yamabe Local anesthetic liquid having disinfectant effect for skin and liquid medicinal set
DK2101819T3 (en) * 2006-11-20 2013-04-29 Harvard College Methods, compositions and kits for the treatment of pain and pruritis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029062A1 (en) * 1995-03-22 1996-09-26 Teikoku Seiyaku Kabushiki Kaisha Cold sheet
JPH1053527A (en) * 1996-08-09 1998-02-24 Tanabe Seiyaku Co Ltd Percutaneous absorbent preparation containing caffeine
JPH11255659A (en) * 1998-03-11 1999-09-21 Iron:Kk Sheet for wrapping around calf and ankle
JP2001055319A (en) * 1999-08-17 2001-02-27 Pola Chem Ind Inc Dry shampoo sheet

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Kandavel Local anesthesia for cataract surgery

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