JP6371073B2 - Patch used to introduce anesthetic (local anesthetic) by iontophoresis - Google Patents

Description

  The present invention relates to a patch used when a local anesthetic for pain during puncture is transdermally administered by iontophoresis.

In the medical field, injection is frequently performed intradermally, subcutaneously, intramuscularly, intravenously, and the like. The injection action is performed for temporary administration of a drug or blood collection for blood tests. In some cases, the needle is continuously placed in the body such as infusion, blood donation, hemodialysis and the like.
The puncture in the injection causes the mental and physical pain of the patient. Therefore, the pain at the time of the puncture can be alleviated to improve the quality of life (QOL) of the patient and smoothly perform the medical practice.

In Japan, lidocaine tape (Penless Tape (registered trademark), Patent Document 1) and the like are sold in Japan for the purpose of reducing pain during puncture. For the same purpose, a cream (EMLA (registered trademark)) containing lidocaine and prilocaine is sold in the United States. However, these have a slow onset of action and require administration time of the preparation (drug) for at least 30 minutes or more before puncture, and there is concern about congestion in the medical field.
Therefore, a method for administering a local anesthetic percutaneously and rapidly has been desired in the treatment for alleviating pain during puncture.

On the other hand, iontophoresis is a method of promoting permeation of mainly ionic physiologically active substances from the skin or mucous membrane using electrical energy. Specifically, for two patches arranged on the skin at an interval, the anode of the current generator (power supply device) is connected to one patch, the cathode is connected to the other patch, and microamperes per cm ² Is applied for several minutes to several hours, and an ionic physiologically active substance is introduced into the living body from the skin or mucous membrane by the current (Patent Documents 2 and 3).
According to this iontophoresis, a large amount of local anesthetic such as lidocaine can be introduced into the skin in a short period of time, so that a local anesthetic effect can be expected in a short time, without requiring a long time for puncture pretreatment, immediately Puncture and medical treatment can be performed.

Currently, in the United States, local anesthetics (a combination of lidocaine and epinephrine) administered using iontophoresis are on the market for the purpose of pain relief at the time of puncture and pain at the time of minor surgery such as laser treatment ( Product name: Lidosite (registered trademark)). Generally, during minor surgery, it is necessary to continuously relieve the pain associated with this. Therefore, in this preparation, a vascular astringent (epinephrine) is blended as a sustained action agent for maintaining the local anesthetic effect of lidocaine.
If epinephrine is used, it is thought that the action of an anesthetic can be maintained for 60 minutes or more by reducing the blood flow volume of the skin surface layer and keeping the local anesthetic under the skin for a long time (Patent Document 4). 5).

  However, when an iontophoresis preparation containing epinephrine is used, the duration of the local anesthetic effect is too long, and this is not preferable particularly for pain relief at the time of puncture where the duration of the local anesthetic effect is not so required. . If the duration is too long, it may result from puncture or medication such as nerve damage caused by puncture, damage to the administration site due to injection, fluid leakage during injection or infusion, internal bleeding during blood donation or hemodialysis, etc. The detection of side effects may be delayed, so it is necessary to prevent it.

Japanese Patent Laid-Open No. 06-145051 U.S. Pat. No. 4,141,359 Japanese Patent Laid-Open No. 02-200302 JP-T-2004-501727 JP 2000-219623 A

The present invention was devised in view of the above problems, and its purpose is to promptly develop a local anesthetic effect after iontophoresis, and to quickly lose the local anesthetic effect after puncture. It is an object of the present invention to provide a patch for iontophoresis that can be performed (the anesthetic effect does not last unnecessarily long).
That is, the present invention is not intended to provide a long-term anesthetic effect for minor surgery or the like, and to perform the puncture treatment without pain and to prevent delays in finding side effects due to the puncture procedure. The purpose is to eliminate the anesthetic effect in a relatively short time (about 20 minutes).

As a result of intensive studies on the above problems, the inventors of the present invention have determined the concentration of lidocaine, which is a local anesthetic, based on a predetermined mathematical formula when manufacturing a patch for use in introducing a local anesthetic into the skin by iontophoresis. And determined that the intended purpose can be achieved.
That is, when the patch production method of the present invention produces a patch containing polyvinyl alcohol as a main base and lidocaine as a local anesthetic, the concentration Y (weight%) of lidocaine is set to 2.0 to 5.0 mA · It is set to be equal to or higher than the concentration obtained by the formula Y = 0.110X + 0.028 with respect to a predetermined amount of electricity X (per cm ² ) at the time of introduction in a range of min / cm ² .
Moreover, it was confirmed by the “additional test example” described later that the amount of electricity X is effective in the range of 1.6 to 5.0 mA · min / cm ² .

When a local anesthetic is introduced into the skin by iontophoresis using the patch produced by the method of the present invention, anesthesia effectively acts in the introduction region for approximately 5 to 20 minutes after the end of energization. After that, the anesthetic effect disappears. As a result, pain at the time of puncture can be sufficiently relieved and the anesthetic effect disappears thereafter, so that it is possible to effectively prevent the discovery of side effects due to the puncture treatment from being delayed.

The graph which shows the result of the local anesthetic effect by the difference in an electric quantity in the pin prick test (Test Example 1) using a guinea pig. In Test Example 3, when the electrical quantity of 2.0 mA · min / cm ^2, a graph showing the results indicating the rat skin in lidocaine concentration due to differences in the formulation lidocaine concentration. In Test Example 3, when the electrical quantity of 1.0 mA · min / cm ^2, a graph showing the results indicating the rat skin in lidocaine concentration due to differences in the formulation lidocaine concentration. In Test Example 3, when the electrical quantity of 5.0 mA · min / cm ^2, a graph showing the results indicating the rat skin in lidocaine concentration due to differences in the formulation lidocaine concentration. The graph which shows the relationship between the threshold value of the lidocaine density | concentration in a formulation, and the electric quantity obtained in Test Example 3. In Experiment 4, the graph which shows the result of the local anesthetic effect with respect to a human volunteer. The graph which shows the result of the local anesthetic effect by the presence or absence of an epinephrine in the pin prick test of the reference test example using a guinea pig. The graph which shows the result of the local anesthetic effect by the difference in an electric quantity in the pin prick test (additional test example) using a guinea pig.

≪Patch configuration≫
The patch according to one embodiment of the present invention is a gel-like patch comprising a hydrophilic gelling agent as a main base and containing a local anesthetic. A local anesthetic is introduced into the human body by iontophoresis using this patch. The patch of the present invention does not contain a sustained action agent that maintains the anesthetic effect of the local anesthetic.

  As the main base used in the gel-like patch of the present invention, hydrophilic gelling agents such as polyvinyl alcohol, polyvinyl pyrrolidone, agar, gelatin, carboxymethyl cellulose and the like are used. In particular, it is preferable to use polyvinyl alcohol as the main base.

  The drug contained in the gel patch of the present invention is only a local anesthetic. Do not add vascular astringents or vasoconstrictors (epinephrine, naphazoline, phenylephrine, etc.) that maintain the anesthetic effect.

  The local anesthetic used in the present invention is itself a commonly used local anesthetic. Examples thereof include lidocaine, dibucaine, tetracaine, oxybuprocaine, procaine, bupivacaine, and salts thereof. These local anesthetics are preferably formulated in the form of a salt form such as hydrochloride or sulfate in consideration of solubility in the preparation, but when the local anesthetic is formulated in the form of a base. Acidic additives such as hydrochloric acid or sulfuric acid may be added to the preparation.

In the present invention, the size of the gel patch is not particularly limited. The gel part in which the local anesthetic is blended is in contact with the skin, and determines the surface area of the part to be punctured. Therefore, the size of the gel patch, for the medical personnel familiar to puncture, although considered sufficient 2.5 cm ^2, generally, may be about the area 2.5~5.0cm ^2.

≪Concentration of local anesthetics≫
The compounding concentration of the local anesthetic in the preparation is 0.25% by weight or more, but commercially, the compounding ratio of 0.25 to 2.0% by weight is considered in consideration of the stability and manufacturing accuracy of the drug. good.
Although depending on the amount of electricity, the local anesthetic effect expected to be less than 0.25% by weight of the local anesthetic cannot be provided. On the other hand, even if the content of the local anesthetic is increased, a dramatic effect cannot be expected, and only the number of drugs that are not used increases, which is economically disadvantageous.

≪Applicable amount of electricity≫
The amount of electricity applied to the iontophoresis patch of the present invention is adjusted to 2.0 to 5.0 mA · min / cm ² . The following amount of electricity is the amount of electricity per 1 cm ² .
It is impossible to obtain the desired effect even if an electric quantity of less than 2.0 mA · min / cm ² is applied, and conversely, an electric quantity exceeding 5.0 mA · min / cm ² is an electric Large irritation and large amount of electricity may cause burns.

≪Energization time≫
The energization is completed after the determination or diagnosis that injection, infusion, or blood collection is necessary or before the puncture is actually performed. The energization time is assumed to be 5 to 30 minutes. The
If the energization time is within 5 minutes, the amount of electricity in the present invention will increase the current, apply a load to the power supply, increase the current and voltage flowing to the human, and feel pain. If the energization time is longer than 30 minutes, the original medical treatment such as injection or blood collection is delayed, which hinders the original medical treatment.

≪Duration of anesthetic effect targeted by the present invention≫
In a puncture action at a medical site, after anesthesia is performed on a patient, a certain puncture preparation time is required before puncture, such as confirmation of a puncture site and disinfection, and this takes 5 to 20 minutes. . That is, alleviation of pain at the time of puncture by a local anesthetic only needs to last for 5 to 20 minutes after the administration of the local anesthetic is completed.
If the effect of the local anesthetic is less than 5 minutes, the local anesthetic effect may have already disappeared at the time of puncture when time is spent for puncture preparation.
In addition, if the effect of the local anesthetic continues for 20 minutes or more, there is a possibility that detection of side effects due to puncture or drugs will be delayed. This is because the patient cannot perceive side effects due to the anesthetic effect. In order to prevent this and enable early detection and treatment of side effects, it is desirable that the local anesthetic effect disappears quickly after a certain time after iontophoresis.

  Thus, an object of the present invention is to alleviate pain at the time of puncture and to provide an anesthetic effect duration of about 5 to 20 minutes in order to prevent the discovery of side effects from being delayed. Since it does not give a long-term anesthetic effect for minor surgery or the like, it is important that the anesthetic effect disappears in about 20 minutes.

As an index of the effect and persistence of local anesthetics, animal or human pin prick tests are known. In the pin prick test, the skin is stimulated with a sharp instrument such as a mandolin wire, and the presence or absence of a reaction to it is checked. If there is no response, anesthesia is “effective”. If there is a response, anesthesia is “ineffective”.
In the present invention, the state having a completely local anesthetic effect is defined as 100%, the local anesthetic effect is 50% or more until 5 minutes after the end of energization, and the local anesthesia is displayed after 20 minutes after the end of energization. With the goal of achieving an effect of less than 50%, preferably around 0%, the prescription composition of the gel-like patch necessary for this purpose was determined by experiments.
[Example 1 and Test Example 1]

（単位：ｇ）

試験例１
イオントフォレシスにおいて、「実施例１のパッチ」とともに使用する対極用のパッチとして、生理食塩水で作製した１５％ポリビニルアルコールゲルのパッチ（以下、「生食パッチ」と呼ぶ）を作製した。
両パッチをモルモットの除毛した背部にそれぞれ貼付し、「実施例１のパッチ」に直流電源の陽極を、「生食パッチ」に陰極を接続し、０．１、０．２、および０．４ｍＡ／ｃｍ^２で１０分間通電した（電気量１．０、２．０、および４．０ｍＡ・分／ｃｍ^２）。

６匹のモルモットに対して、通電終了後「実施例１のパッチ」から局所麻酔薬を導入した部位を、マンドリン線で刺激し、脊髄反射の有無を観察した（ピンプリック試験）。刺激による反射が無い場合を局所麻酔効果がある「有効」と判断した。各モルモットに対して刺激を５回与え、無反応回数を試行回数（５回）で除して、有効率（無反応率）を算出した。

その結果を図１のグラフに示した。グラフから分かるように、通電終了直後の局所麻酔効果は、電気量４．０ｍＡ・分／ｃｍ^２では、１００％の有効率が得られ、電気量２．０ｍＡ・分／ｃｍ^２では７５％の有効率が得られた。また、これらの場合、５０％以上の有効率を示す時間は通電終了後５〜１５分であり、通電終了後２０分には麻酔効果がほとんど消失した。
一方、電気量１．０ｍＡ・分／ｃｍ^２の場合には、通電終了直後の有効率こそ４０％であったが、効果は持続しなかった。 Example 1
Lidocaine 0.43 g was dissolved in dilute hydrochloric acid 0.67 g to prepare a lidocaine solution. The liquid was mixed with a mixed liquid of 10 g of glycerin and about 74 g of purified water, and 15 g of polyvinyl alcohol was further added to this liquid and dissolved by heating. After cooling, purified water was added to make the total weight 100 g and stirred to prepare a gel solution.
This gel solution was poured into a patch-like support made of silver foil and foam tape, molded into a disk shape, and further subjected to gel crosslinking at room temperature to produce a gel-like patch of Example 1. The gel composition is shown in Table 1 below.

<< Table 1: Composition of gel patch of Example 1 >>

(Unit: g)

Test example 1
In iontophoresis, a patch of 15% polyvinyl alcohol gel prepared with physiological saline (hereinafter referred to as “saved patch”) was prepared as a counter electrode patch used together with the “patch of Example 1”.
Both patches were affixed to the back of the guinea pig, and the positive electrode of the DC power source was connected to the “patch of Example 1”, and the negative electrode was connected to the “saline patch”, 0.1, 0.2, and 0.4 mA. / Cm ² for 10 minutes (electricity 1.0, 2.0, and 4.0 mA · min / cm ² ).

For 6 guinea pigs, the site where the local anesthetic was introduced from the “patch of Example 1” after the end of energization was stimulated with a mandolin line and the presence or absence of spinal cord reflex was observed (pin prick test). The case where there was no reflex due to stimulation was judged as “effective” with local anesthetic effect. Stimulation was given 5 times to each guinea pig, and the number of no reactions was divided by the number of trials (5 times) to calculate the effective rate (no response rate).

The results are shown in the graph of FIG. As can be seen from the graph, a local anesthetic effect immediately after the energization ends, the quantity of electricity 4.0 mA · min / cm ^2, 100% of the effective rate can be obtained, the quantity of electricity 2.0 mA · min / cm ² at 75% An effective rate was obtained. Moreover, in these cases, the time showing an effective rate of 50% or more was 5 to 15 minutes after the end of energization, and the anesthetic effect almost disappeared 20 minutes after the end of energization.
On the other hand, when the amount of electricity was 1.0 mA · min / cm ² , the effective rate immediately after the end of energization was 40%, but the effect was not sustained.

From this, it is considered that the amount of drug introduced in iontophoresis and the drug effect resulting therefrom depend on the amount of electricity. In this test example, the local anesthetic effect obtained at an electric charge of 2.0 mA · min / cm ² or more is obtained, and at an electric charge of 4.0 mA · min / cm ² , the effective rate is 100%, and a suitable local anesthetic effect is obtained. It was thought that.
[Example 2, Comparative Examples 1 and 2 and Test Example 2]

（単位：ｇ）

試験例２
実施例１、２および比較例１、２の各ゲル状パッチを用いて、試験例１と同様の実験を行った。なお、電気量は、２．０ｍＡ・分／ｃｍ^２とした。
その結果、通電終了直後の有効率は、実施例１、２および比較例２で、いずれも７５％前後を示し、一方、比較例１では、６３％にとどまった（表３）。
このことから、イオントフォレシスにおいては、電気量が同じであれば、局所麻酔効果は、製剤中のリドカイン濃度にあまり依存しないと考えられた。なお、比較例１は、以下の試験例３に述べるが、電流によって皮膚中へ導入される薬物が製剤中に十分なかったため、局所麻酔効果が減じたと考えた。

≪表３：通電終了直後における麻酔の有効率≫

［実施例３、比較例３〜６および試験例３］ A gel patch in which the content of lidocaine was changed with respect to “Example 1” was produced in the same manner as in Example 1. Each gel-like patch is referred to as “Example 2”, “Comparative Example 1”, and “Comparative Example 2”, and the compositions are shown in Table 2 below.

<< Table 2: Composition of gel patches of Example 2 and Comparative Examples 1 and 2 >>

(Unit: g)

Test example 2
Using the gel patches of Examples 1 and 2 and Comparative Examples 1 and 2, the same experiment as in Test Example 1 was performed. The amount of electricity was 2.0 mA · min / cm ² .
As a result, the effective rate immediately after the end of energization was about 75% in Examples 1 and 2 and Comparative Example 2, while it was only 63% in Comparative Example 1 (Table 3).
From this, it was considered that in iontophoresis, if the amount of electricity is the same, the local anesthetic effect does not depend much on the lidocaine concentration in the preparation. In Comparative Example 1, as described in Test Example 3 below, it was considered that the local anesthetic effect was reduced because there was not enough drug in the formulation to be introduced into the skin by electric current.

<Table 3: Effective rate of anesthesia immediately after energization>

[Example 3, Comparative Examples 3 to 6 and Test Example 3]

試験例３
リドカイン濃度の異なる実施例１〜３および比較例１〜６の各ゲル状パッチと、生食パッチをラットの除毛した背部にそれぞれ貼り、ゲル状パッチを直流電源の陽極に、生食パッチを陰極に接続した。電気量を「２．０ｍＡ・分／ｃｍ^２」、「１．０ｍＡ・分／ｃｍ^２」、「５．０ｍＡ・分／ｃｍ^２」とした３つの場合について、通電終了後の貼付部位の皮膚を摘出し、その摘出皮膚中のリドカイン量を高速液体クロマトグラフ法で測定した。
図２Ａは「２．０ｍＡ・分／ｃｍ^２」の電気量で試験した結果を示している。図２Ａにおいて、皮膚中リドカイン濃度は、比較例５、１、および６（リドカイン濃度：０．０４３、０．０８７、および０．１７％）の製剤中リドカイン濃度と良い相関が見られた。また、皮膚中リドカイン濃度は、実施例１、３、および２（リドカイン濃度：０．４３、０．８７、および１．７％）の製剤中リドカイン濃度と良い相関が見られた。
そして、これらの相関式の共通解（それら回帰直線の交点）の製剤中リドカイン濃度は、０．２３％であった。このことから、この製剤中濃度を境（閾値）に薬物が皮内へ導入される状態が変化すると考えられた。

同様に行った電気量「１．０ｍＡ・分／ｃｍ^２」と「５．０ｍＡ・分／ｃｍ^２」の試験でも、同じ関係が見られ、電気量「１．０ｍＡ・分／ｃｍ^２」の場合における閾値は、０．１５％であった（図２Ｂ）。電気量「５．０ｍＡ・分／ｃｍ^２」の場合における閾値は、０．５８％であった（図２Ｃ）。これら製剤中リドカイン濃度閾値（Ｙ）と電気量（Ｘ）には良い相関（Ｒ^２＝０．９９７）が得られた（図３）。 A gel patch in which the content of lidocaine was changed with respect to “Example 1” was produced in the same manner as in Example 1. Each gel patch is referred to as “Example 3”, “Comparative Example 3”, “Comparative Example 4”, “Comparative Example 5”, and “Comparative Example 6”, and the compositions are shown in Table 4 below.

Test example 3
The gel patches of Examples 1 to 3 and Comparative Examples 1 to 6 having different lidocaine concentrations, and the raw food patch were applied to the back of the rat, and the gel patch was used as the anode of the DC power source and the raw food patch was used as the cathode. Connected. The quantity of electricity "2.0 mA · min / cm ^2", "1.0 mA · min / cm ^2", for the three cases was "5.0 mA · min / cm ^2", skin application site after application end And the amount of lidocaine in the extracted skin was measured by high performance liquid chromatography.
FIG. 2A shows the result of testing with an electric quantity of “2.0 mA · min / cm ² ”. In FIG. 2A, the lidocaine concentration in the skin showed a good correlation with the lidocaine concentration in the preparations of Comparative Examples 5, 1, and 6 (lidocaine concentrations: 0.043, 0.087, and 0.17%). Moreover, the lidocaine density | concentration in skin showed the good correlation with the lidocaine density | concentration in a formulation of Example 1, 3, and 2 (lidocaine density | concentration: 0.43, 0.87, and 1.7%).
And the lidocaine density | concentration in a formulation of the common solution (intersection of those regression lines) of these correlation formulas was 0.23%. From this, it was considered that the state in which the drug was introduced into the skin was changed at the concentration (threshold) in the preparation.

Similarly, the amount of electricity that went with "1.0mA · min / cm ^2" is also a test of "5.0mA · min / cm ^2", the same relationship is observed, the amount of electricity of "1.0mA · min / cm ^2" The threshold in the case was 0.15% (FIG. 2B). The threshold value in the case of the amount of electricity “5.0 mA · min / cm ² ” was 0.58% (FIG. 2C). A good correlation (R ² = 0.997) was obtained between the lidocaine concentration threshold (Y) in these preparations and the electric quantity (X) (FIG. 3).

From this result, the following can be considered. That is, the threshold of lidocaine concentration in the drug product is determined by the amount of electricity, and in the low drug concentration region up to that threshold, there is a shortage of drug amount commensurate with the amount of electricity due to energization. When the amount of drug introduced is increased, and the concentration in the formulation is higher than the threshold value, the drug is sufficiently affected by the amount of electricity, so the effect of the drug concentration is small.
Therefore, in order to realize a stable drug introduction amount that is less affected by the drug concentration in iontophoresis, the lidocaine concentration (Y) to be blended in the preparation is Y = 0.110X + 0 depending on the amount of electricity (X) to be energized. It is considered necessary that the concentration is equal to or higher than the concentration obtained by the equation of .028.
[Test Example 4: Human test]

The “gel patch of Example 1” and the “raw food patch” were affixed to the forearms of five human volunteers, and energized with an electric charge of 1.0 or 2.0 mA · min / cm ² . After energization, the administered site was stimulated 5 times with a mandolin line, and the number of trials (5 times) where pain was not felt was divided by the number of trials (5 times) to calculate the effective rate (painless rate).
As a result, a local anesthetic effect with an effective rate of 100% was observed immediately after the end of energization with an electric amount of 2.0 mA · min / cm ² , and after an effective rate of 50% or more lasted for 15 minutes, The anesthetic effect almost disappeared. On the other hand, with an electric charge of 1.0 mA · min / cm ² , the effective rate was only about 50% even immediately after the end of energization, and the local anesthetic action disappeared rapidly after 5 minutes after administration (FIG. 4). .
From both human tests and guinea pig tests, it was found that the amount of electricity required 2.0 mA · min / cm ² or more.
[Prescription Examples 1 and 2 and Reference Experiment Examples]

（単位：ｇ）

参考試験例
イオントフォレシスにおいて、「処方例１のパッチ」と「生食パッチ」を作製した。両パッチをモルモットの除毛した背部に貼付し、「処方例１のパッチ」に直流電源の陽極を、「生食パッチ」に陰極を接続し、０．３５ｍＡ／ｃｍ^２の電流密度で１０分間通電した（電気量３．５ｍＡ・分／ｃｍ^２）。「処方例２のパッチ」についても同様の試験を行い、両者を比較した。
６匹のモルモットに対して、処方例１および処方例２のパッチにより局所麻酔剤を導入した部位をマンドリン線で刺激し、脊髄反射の有無を観察した（ピンプリック試験）。刺激による反射が無い場合を局所麻酔効果がある「有効」と判断した。各モルモットに対して刺激を５回与え、無反応回数を試行回数（５回）で除して、有効率（無反応率）を算出した。
その結果、エピネフリン配合の処方例２では、５０％以上の有効率が６０分以上続いたが、エピネフリンが配合されていない処方例１では、１５分も続かなかった。このことは、処方例２の場合、イオントフォレシス終了から６０分間に生じるかもしれない副作用の発現を見逃す可能性があることを示している（図５）。
すなわち、通電終了後、約５〜２０分程度に限って麻酔効果を得ることを目的とする場合には、エピネフリン等の麻酔作用持続剤を配合すべきでないことが確認できた。
In this experimental example, a gel-like patch (formulation example 1) containing no epinephrine (anesthetic action-sustaining agent) and a gel-like patch containing it (formulation example 2) are prepared and subjected to a comparative test. Thus, it has been confirmed that the local anesthetic effect can be prevented from being unnecessarily prolonged for a long time when no epinephrine is added to the gel patch.

Formulation Example 1
9.24 g of lidocaine hydrochloride and 10 g of glycerin were dissolved in about 65 g of purified water, and 15 g of polyvinyl alcohol was added and dissolved by heating. After cooling, purified water was added to make the total weight 100 g and stirred to prepare a gel solution. The gel solution was poured into a patch-like support made of silver foil and foam tape, molded into a disk, and freeze-thawed to produce a gel-like patch of Formulation Example 1. Thus, the gel-like patch of Formulation Example 1 does not contain epinephrine.

Formulation example 2
Similarly to Formulation Example 1, lidocaine hydrochloride and glycerin were dissolved in purified water, and polyvinyl alcohol was added and dissolved by heating. After cooling, 0.1 g of epinephrine (0.182 g as epinephrine hydrogen tartrate) and purified water were added to make a total weight of 100 g, and dissolved and stirred to prepare a gel solution. Thereafter, a gel-like patch of Formulation Example 2 was produced in the same manner as Formulation Example 1. The gel patch of Formulation Example 2 is different from Formulation Example 1 in that it contains epinephrine. Table 5 shows the compositions of Formulation Example 1 and Formulation Example 2.

<< Table 5: Composition of gel-like patches of Formulation Examples 1 and 2 >>

(Unit: g)

Reference Test Example In “iontophoresis”, “patch of prescription example 1” and “saline patch” were prepared. Affix both patches to the back of the guinea pig, and connect the anode of the DC power source to the “Patch of Prescription Example 1” and the cathode to the “Savored Patch” and energize for 10 minutes at a current density of 0.35 mA / cm ^2. (Electric quantity 3.5 mA · min / cm ² ). A similar test was performed for “Patch of Prescription Example 2”, and the two were compared.
Six guinea pigs were stimulated with a mandolin line at the site where the local anesthetic was introduced by the patches of Formulation Example 1 and Formulation Example 2, and the presence or absence of spinal cord reflex was observed (Pinprick test). The case where there was no reflex due to stimulation was judged as “effective” with local anesthetic effect. Stimulation was given 5 times to each guinea pig, and the number of no reactions was divided by the number of trials (5 times) to calculate the effective rate (no response rate).
As a result, in Formulation Example 2 containing epinephrine, an effective rate of 50% or more lasted for 60 minutes or more, but in Formulation Example 1 containing no epinephrine, it did not last for 15 minutes. This indicates that in the case of Formulation Example 2, there is a possibility that the onset of side effects that may occur 60 minutes after the end of iontophoresis may be missed (FIG. 5).
In other words, it was confirmed that an anesthetic action-sustaining agent such as epinephrine should not be added when the purpose is to obtain an anesthetic effect only for about 5 to 20 minutes after the end of energization.

《Additional test example》
Furthermore, the following tests were conducted using “patch of Example 1” and “saline patch” similar to Test Example 1 as additional test examples. The meaning of this additional test is as follows. That is, according to the above-described Test Examples 1 to 4, the lidocaine concentration (Y) is obtained by the equation of Y = 0.110X + 0.028 in the range of 2.0 to 5.0 mA · min / cm ^{2 in} the electric quantity (X). It has been confirmed that it should be more than the value that can be achieved. An additional test is aimed at exploring an effective further electric charge range for an electric charge (X) of less than 2.0 mA · min / cm ² .

FIG. 6 shows the result of the pin prick test performed under the same condition setting as in Test Example 1. As can be seen from the graph of FIG. 6, it was confirmed here that the local anesthetic effect immediately after the end of energization and its persistence depend on the amount of electricity. The effective rate 5 minutes after the end of energization was 50% or more when the amount of electricity was 1.6 mA · min / cm ² or more, but less than 50% when the amount of electricity was 1.4 mA · min / cm ² or less. The effective rate 20 minutes after the end of energization was less than 50% for any amount of electricity.
As a result of consideration by combining the previous Test Example 1-4 Toko results of additional tests, the quantity of electricity 1.6 mA · min ^/ cm 2 ^~5.0mA · min / cm ^2, the local anesthetic effect sought It can be concluded that it can be obtained.

  For pain relief at the time of puncture, we provide an efficient and safe iontophoresis preparation at the medical site, which can be used widely from injection of medicine to vaccination, blood collection, blood donation, dialysis, etc. It can also be used by patients who dislike injections, especially children.

Claims (2)

A method for producing a patch comprising lidocaine as a local anesthetic and introducing the local anesthetic into the skin by iontophoresis ,
For a predetermined amount of electricity X (per 1 cm ² ) at the time of introduction in a range of 2.0 to 5.0 mA · min / cm ^2, the concentration of lidocaine exceeds the concentration obtained by the formula Y = 0.110X + 0.028 . A method for producing a patch, characterized in that a density Y (% by weight) is set .
A method for producing a patch comprising lidocaine as a local anesthetic and introducing the local anesthetic into the skin by iontophoresis ,
With respect to the amount of electricity X (per 1 cm ² ) at the time of introduction determined in the range of 1.6 to 5.0 mA · min / cm ^2, the concentration of lidocaine is higher than the concentration obtained by the formula Y = 0.110X + 0.028 . A method for producing a patch, characterized in that a density Y (% by weight) is set .

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