JPH09255565A - Hydrogel patch for dermal local anesthesia - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a hydrogel patch for dermal local anesthesia applicable by only a simple operation. SOLUTION: This virtually flat-shaped hydrogel patch with dermal application face is obtained by dispersing an oily dermal local anesthetic preparation in a gel-like gum base. The local anesthetic preparation consists of a eutectic mixture of a base-type prilocaine and lidocaine, and the gum base contains, other than the preparation, <=3wt.% of a sucrose fatty acid ester and <=20wt.% of ethanol. Because the above eutectic mixture can be liquefied at room temperature, it is easily mixed with the gum base, being effective for homogeneous dispersion in the gum base, and there is no concern for getting hard for the preparation to be absorbed transdermally due to its crystallization in the gum base. This hydrogel patch has dermal local anesthetic effect at least comparable to those of conventional PL cream and is easier to apply.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hydrogel patch for local anesthesia of the skin.

[0002]

2. Description of the Related Art There are many medical treatments in a hospital that cause pain to a patient, such as drug administration by injection, blood collection or venous cannulation. Therefore, avoiding pain is an important issue not only for the patient but also for the doctor to facilitate the medical treatment.

Particularly in children, the pain may be difficult to treat, and an effective preparation for further reducing the pain is desired. In recent years, various medical-related research and development facilities have investigated more effective local anesthetic preparations and reported their effects.

Among them, an applied drug effective for alleviating pain caused by injection, simple surgery, laser or dry ice treatment, etc. has been developed. For example, EMLA (eutectic mixture of commercially available products in Europe and America) has been developed. local an
Esthetics) cream (trade name; manufactured by Astra, Sweden) has been found to be useful.

The characteristic of EMLA cream is that it facilitates the preparation of an oil-in-water emulsion by utilizing the property that a eutectic mixture of prilocaine base: lidocaine base = 1: 1 liquefies at room temperature. In addition, there is a characteristic that the amount of drug in the oil droplets is four times that of lidocaine alone.

[0006]

Since such EMLA cream is difficult to obtain outside of Europe and the United States, the present inventors have decided to use PL (Prilocain / Lidokaine) cream as a skin local anesthetic similar to EMLA cream. Has been independently adjusted and clinically used, and it has already been reported that this PL cream is highly effective in relieving pain during resection of molluscum contagiosum in children.

However, the above-mentioned creamy local topical anesthetic does not have a dramatic effect by simple application, and in order to obtain a sufficient analgesic effect, first of all, thicken the cream locally on the skin. It was indispensable to spread and then apply the closed closure method (ODT), and the operation was complicated.

In view of the above problems, it is an object of the present invention to obtain a hydrogel patch for local skin anesthesia which is easier to apply than the conventional coating type.

[0009]

In order to achieve the above object, in the hydrogel patch for local skin anesthesia according to the invention described in claim 1, a gel-like gum base in which an oily local skin anesthesia preparation is dispersed, It is formed in a shape having a surface to be attached to the skin.

Further, in the hydrogel patch for local skin anesthesia according to the invention described in claim 2, in the hydrogel patch for local skin anesthesia according to claim 1, the oily skin local anesthesia preparation is a basic prilocaine and lidocaine. Is a eutectic mixture with.

The hydrogel patch for local skin anesthesia according to the invention of claim 3 is the hydrogel patch for local skin anesthesia according to claim 1 or 2.
The gum base is 3% or less of sucrose fatty acid ester,
And 20% or less of ethanol.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is a hydrogel patch in which an oily skin local anesthetic preparation is dispersed in a gel-like gum base. The anesthetic can be applied only by a simple operation of placing the anesthetic on.

When the tape is fixed to the affected area with a tape or a bandage as necessary, the conventional coating type such as cream covers the skin so that it does not move or fall off on the skin while maintaining the required thickness. However, the hydrogel patch of the present invention does not have such difficulty in handling, and the fixing work can be efficiently performed in a short time.

The shape of the hydrogel patch has a sticking surface having an area corresponding to the area to be anesthetized, and has a thickness such that the anesthetic preparation to be dispersed / included is at least the amount necessary for anesthetic application. To do. Since the hydrogel patch of the present invention is used on the skin surface, it is thought that it is mainly formed into a flat shape in many cases, but the shape may be appropriately set according to the usage.

As the oily skin local anesthetic preparation, for example, as described in claim 2, a eutectic mixture of basic prilocaine and lidocaine can be used. As described above, since the eutectic mixture of prilocaine base and lidocaine base has the property of liquefying at room temperature, it is easy to mix with the gum base in preparing the hydrogel patch, and the uniform dispersion in the gum base is achieved. Is effective for. Also,
There is also no problem of making dermal absorption difficult by crystallization in the base.

In addition to lidocaine and prilocaine, various local anesthesia agents such as procaine hydrochloride, oxybuprocaine hydrochloride and diethylaminoethyl parabutylaminobenzoate hydrochloride have been conventionally used. The present invention is not limited to the eutectic mixture of basic prilocaine and lidocaine as a skin local anesthetic formulation, and other various drugs conventionally used as described above can be utilized and crystallized in the base. It suffices if it is prepared in a uniformly dispersible state without performing.

The basic composition of the gum base is, for example,
Various gums derived from microorganisms or secreted from plants, fruits, bark and the like, and mixtures of these gums are subjected to treatments such as dissolution and heating to give gels. It is desirable that this gel-like gum base be capable of easily uniformly dispersing an anesthetic preparation, have good shape and retention of the preparation during storage as a hydrogel patch, and can release the preparation appropriately during use. .

Then, as a result of various studies, it became clear that the inclusion of sucrose fatty acid ester as an emulsifier in the base material contributes to the uniform dispersion in the gel of the preparation.
However, excessive addition leads to an increase in the apparent solubility of the oily preparation in the base, and as a result, the release from the base may be suppressed. It is desirable to add an appropriate content rate to the base after setting an appropriate content rate.

This sucrose fatty acid ester is permitted as a food additive and is known to be completely harmless orally. In addition, its properties are often tasteless, odorless, and colorless, and mucous membranes. No irritation to skin or eyes. Furthermore, it is highly biodegradable and does not cause any specific physiological change to the living body at least orally or transdermally. From the above, sucrose fatty acid ester is a preferred surfactant for use as an emulsifier in the base of hydrogel patches that come into direct contact with the skin.

It is known that addition of ethanol promotes skin absorption of drugs. The mechanism of the ethanol skin absorption promotion is to enhance lipid fluidity in the horny layer, degreasing action to extract lipids such as sterol and ceramide, which are the main barrier function of the stratum corneum, protein structure change, and the skin of ethanol itself. Examples include cotransportation associated with permeation. In addition, it was reported by Hatanaka et al. That ethanol promotes the skin permeability of fat-soluble drugs by increasing the diffusivity of the drug in the lipid pathway, which is the main passage for fat-soluble drugs. (See Pharmacology, 52, 215-223, 1992), this report suggests that at low concentrations only lipid pathways reduce permeation resistance of both lipid pathways and pore pathways. There is.

It has been revealed that the addition of ethanol also promotes the skin absorption of prilocaine and lidocaine. By adding ethanol to the gel-like gum base of the present invention, the skin of the local topical anesthetic preparation of hydrogel patch can be obtained. It can promote absorption. However,
If the content of ethanol is excessive, water separation phenomenon of the hydrogel patch will occur during storage. Therefore, it is desirable to add ethanol to the base after setting an appropriate content rate.

As an example of a suitable content rate of the sucrose fatty acid ester and ethanol, for example, as described in claim 3, in the case of the content rate of the prilocaine-lidocaine eutectic mixture which is about the same as that of the conventional PL cream. , That is,
When the gum base contains 5% prilocaine-lidocaine eutectic mixture, the content of sucrose fatty acid ester is 3% or less, and the content of ethanol is 20% or less.

In addition to the above, any agent that promotes skin absorption of the skin local anesthetic preparation can be added to the gel gum base. However, it is needless to say that it is necessary to appropriately select the combination and the concentration thereof so as not to adversely affect the human body and exclude the shape of the hydrogel patch and the good maintenance of the drug.

For example, monotenpenes such as L-menthol are believed to interact with lipid moieties in the corneum, thereby increasing the fluidity of lipid pathways and contributing to enhanced absorption. It was also reported by Okabe et al. That the action was enhanced by ethanol (see Drag Design and Delivery, 6,229-238, 1990).

This L-menthol was also found to have an effect of promoting skin absorption in prilocaine and lidocaine. Therefore, although it may be contained in the gel gum base of the present invention, since menthol has some irritation, whether or not it is contained in consideration of the balance such as application time and skin sensitivity of the patient, or how much. It is desirable to appropriately set whether to contain.

From the viewpoint of promoting skin absorption of the drug, pH
Adjustment of the value is also one method and can be used for the gel-like gum base of the present invention. That is, the pH value affects the ratio between the molecular type and the dissociative type of the drug, and as is already known, the increase in the molecular type contributes to the increase in the skin absorption of the drug, and therefore, the transdermal absorption is likely It is conceivable to set so that the ratio of molecular types increases.

[0027] For example, since both prilocaine and lidocaine are basic substances, the proportion of the molecular form increases as the pH value of the base increases, and the pH range in which skin tissue is not impaired is 1-10. In consideration of the above, by setting the pH value of the gel gum base itself constituting the hydrogel patch of the present invention to a higher value with the upper limit being pH 10, it is possible to further promote the transdermal absorption of the anesthetic preparation. It will be possible.

[0028]

EXAMPLES The present invention will be described below with reference to examples. (Example 1) As a first example of the present invention, the microorganism Xanthomonas campestri (Xanthomonas campestri) is used.
s) xanthan gum, which is obtained by fermenting glucose to produce extracellularly produced gum and then powdering it, and using a gum mixture of locust bean gum obtained by crushing legume seeds as a base material, oily The case where a hydrogel patch is prepared using a syringe using a basic prilocaine-lidocaine eutectic mixture as a skin local anesthetic preparation is shown below.

It should be noted that sucrose fatty acid ester, ethanol and L-menthol were added at various contents,
Nine kinds of hydrogel patches were prepared, and the composition of each hydrogel patch A to I is as shown in Table 1.

[0030]

[Table 1]

In obtaining the eutectic mixture of base type prilocaine and lidocaine, since the base type prilocaine is not commercially available, it was first adjusted with prilocaine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.). That is, oily basic prilocaine is released by adding 39 mL of 1N-NaOH to a solution of 10 g of prilocaine hydrochloride in 50 ml of purified water. After adding 40 mL of ether in a separating funnel and extracting oily prilocaine to the ether layer, the ether layer was separated and further ether was removed by an evaporator to obtain basic prilocaine.

Lidocaine (manufactured by Wako Pure Chemical Industries, Ltd.) was added to the basic prilocaine in a ratio of 1: 1 to obtain a basic prilocaine-lidocaine eutectic mixture.

Next, as xanthan gum, echo gum (trade name: manufactured by Dainippon Pharmaceutical Co., Ltd., weight average molecular weight of about 2,000,000, viscosity 0.5% aqueous solution 500 cps) and locust bean gum (manufactured by Dainippon Pharmaceutical Co., Ltd., average molecular weight of 30 to 310,000, viscosity 0.5). % Aqueous solution 200c
ps) was sieved and then mixed with a mortar / pestle at a compounding ratio of 1: 1 to obtain a gum mixture.

As shown in FIG. 1, in the first syringe 1,
100 mg of this gum mixture, 500 mg of eutectic mixture, and 1.0 mL of ethanol were put, purified water was put in the second syringe 2, and after evacuating each, these two first and second syringes (1, 2 ) Are joined together via the silicon connector 4.

By operating the piston of the second syringe 2,
Purified water was sent to the syringe 1 all at once. The purified water added at this time is the total with the contents of the first syringe 1.
Adjust to 10 mL. Further, the entire contents were moved from the first syringe 1 to the second syringe 2.

The contents were uniformly mixed by repeating the operation of moving the contents between the first syringe 1 and the second syringe 2 10 times or more. After mixing, the contents are collected in one of the first syringes 1 (or the second syringes 2), the syringe connector 4 is removed, and the tip of the first syringe 1 (or the second syringe 2) in which the contents are collected I put a cap on.

This first syringe 1 was placed in a hot water bath at 80 ° C. and 30
The contents were dissolved by heating under the condition of minutes. Using the syringe connector 4 again, the first syringe 1 and another third syringe (not shown) are joined together at their tip portions, and the contents are 4-5.
After reciprocating in both syringes (1, 3) about once to make them uniform, 1.2 mL each was filled into a plurality of new molding syringes 3. Finally, each molding syringe 3 was capped and stored in a refrigerator at 6 ° C. for 24 hours to obtain a flat hydrogel patch A having a diameter m of 28 m and a thickness of 2.0 mm.

Hereinafter, in the case of the above hydrogel patch A,
Hydrogel patches B to H were produced by the same steps except for the composition of the contents put in the first syringe. That is, in the hydrogel patch B, the composition of the hydrogel patch A was further added to DK ester F as sucrose fatty acid ester.
-160 (trade name: manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) with 50 mg added, hydrogel patch C has a composition of A and DK ester 100
hydrogel patch D with 300 mg of DK ester added to the composition of A, hydrogel patch E with 100 mg of DK ester added to the same amount of gum mixture and eutectic mixture as A, and ethanol added What did not do, Hydrogel Patch F is 0.5% ethanol in E composition.
The hydrogel patch G was prepared by adding 2 mL of ethanol to the composition of E, and the hydrogel patch H was prepared by adding 100 mg of L-menthol to the composition of G.
Further, the hydrogel patch I has the same composition as H and is a hydrogel patch having a relatively high pH value, in which purified water adjusted to pH 9.0 is put in the second syringe.

By the above-mentioned operations, nine flat hydrogel patches A to I each having a diameter of 28 mm and a thickness of 2.0 mm, which were cooled in a syringe, were obtained. These hydrogel patches were subjected to a rat skin absorption test of an anesthetic preparation described below and a skin local anesthetic effect test in healthy volunteers (using a conventional PL cream as a control).

Here, adjustment of the PL cream will be described below. The composition of the PL cream is as shown in Table 2 below. On a hot water bath, add ethyl paraoxybenzoate to 100 mL of purified water.
After dissolving 50 mg, Carbopol 934P (BFGoodri, USA)
ch company) was added and further dissolved by stirring. After cooling, 2N-NaOH
The pH was adjusted to 9.0 with to obtain a cream base.

Separately, lidocaine is added to basic prilocaine to prepare a eutectic mixture on a hot water bath, and HCO-60 (trade name: Nikko Chemicals Co., Ltd.) as polyoxyethylene hydrogenated castor oil is added and melted. The eutectic mixture was emulsified in a cream base using a mortar and pestle to give a PL cream.

[0042]

[Table 2]

(Embodiment 2) Next, as a second embodiment of the present invention, the hydrogel patches A to A obtained in the above Embodiment 1 will be described.
For I, an in vivo drug absorption test was attempted. This was done using hairless rats and PL cream as a control. The procedure of the rat skin absorption test of this anesthetic preparation is as follows.

First, under anesthesia, the necessary number of hairless rats' abdomen was shaved with hair clippers. Each sample was attached to the center of the abdomen after hair removal. That is, hydrogel patch A
Samples I to I were taken out from the syringe, placed on the abdomen, and then subjected to ODT treatment using a cattleep (trade name: Nichiban).
The PL cream was filled in a container having the same volume as the hydrogel patch, spread on the abdomen, and similarly treated with ODT.
The application time of each drug containing each hydrogel patch is 60
Minutes, and for some, 30 and 45 minutes.

After application of the drug, the formulation remaining on the skin surface of each application site was washed and removed with a saline solution, and about 0.3 g of the skin of each drug application site was extracted and subjected to measurement of drug concentration in skin.

The determination of prilocaine and lidocaine in rat skin was performed by the method of A. Brodin et al. (J, Parm. Sci., 73, 481-4).
84, 1984)). That is, after homogenizing 0.3 g of each extracted skin, add 2 mL of methanol,
The drug in the skin was extracted for 24 hours. 0.5 mL of the internal standard substance methanol solution (2-ethyl-hexyl parahydroxybenzoate 400 μg / mL) was added to 0.5 mL of each extract, and the mixture was centrifuged and used with Echrodisc 3CR (product name: German Man Science Japan). The filtered product was used as a sample.

The amount of drug in each sample was analyzed by HPLC under the following conditions.
It measured by the method and calculated | required by the calibration curve created beforehand. The column is LiChrosorb RP-8 (10 μm, 4.6 mm × 200 mm, Cica-M
ERCK), mobile phase is methanol and phosphate buffer (pH 8.
A mixed solution (65:35) of 0, 1/3 M) was used. Ultraviolet detector (LC-3A, Shimadzu) is used for detection, and the wavelength is 24
The test was performed at 6 mm and a flow rate of 1.0 mL / min. Rats 3-4 per group
The number of animals was set to be the average value.

The results are shown in bar graphs in FIGS. 2, 3 and 4. In each figure, the black-painted portion shows the amount of prilocaine in the sample converted to 1 g of rat skin, and the white-painted portion shows the amount of lidocaine in the sample converted to 1 g of rat skin, Therefore, the height of the bar graph is the total amount of both drugs (μg / g) per gram of rat skin.

First, FIG. 2 shows the drug amounts in the samples of hydrogel patches A to D from the viewpoint of the influence of the sucrose fatty acid ester content on the drug percutaneous absorption of the hydrogel patch. That is, hydrogel patch A,
B, C, and D had sucrose fatty acid ester contents of 0%, 0.5%, 1%, and 3%, respectively, and the other compositions were the same, and the content was 60% in the rat abdomen.
After application for a minute, the amount of drug extracted from the skin by the above operation was shown per 1 g of rat skin.

As is clear from FIG. 2, the measured / converted drug amounts were 724 μg / g, 822 μg / g, and 857 μg / g in order.
, And 850 μg / g, and there was no significant difference in transdermal drug absorption between hydrogel patches with different sucrose fatty acid ester contents. But,
The hydrogel patch A, which does not contain any additives, can be adjusted, but compared to a sucrose fatty acid ester content of 0.5% or more, the gel surface is oily and an oily anesthetic preparation is uniformly dispersed in the gel. It is suggested that it is not possible. On the other hand, it has been pointed out that the excessive addition of the surfactant leads to an increase in the apparent opening for dissolving the eutectic mixture with respect to the base, and as a result, the release from the base may be suppressed.

Further, the content of sucrose fatty acid ester, which had the highest skin absorption of the drug, was 1%, and when the content became 3%, the skin absorption slightly decreased. It is considered that the addition of sucrose fatty acid ester in excess of 3% is not preferable. In the hydrogel patch in this Example, 1% is a more suitable content rate of sucrose fatty acid ester.

FIG. 3 shows the drug amount in the samples of hydrogel patches C and E to G from the viewpoint of the influence of the ethanol content on the drug percutaneous absorption of the hydrogel patch. That is, hydrogel patches E, F, C,
G has an ethanol content of 0%, 5%, and 10%, respectively.
% And 20%, and the other compositions were the same as each other (content of sucrose fatty acid ester was 1%), and each was applied to the abdomen of the rat for 60 minutes, and then extracted from the skin by the above operation. The drug amount was shown per 1 g of rat skin.

As is clear from FIG. 3, the measured / converted drug amounts were 678 μg / g, 708 μg / g, and 857 μg / g in order.
g, 954 μg / g, and it was found that the higher the ethanol content, the greater the skin absorption of both drugs.
The mechanism of ethanol for promoting skin absorption by drugs is to enhance lipid fluidity in the corneum, defatting action, protein structure change, cotransport associated with permeation of ethanol by the skin itself, and increase diffusivity of drug in lipid pathway. Various things can be considered, such as promotion of skin permeability of fat-soluble drugs, and in the concentration range examined in this Example, it is unclear which absorption promoting mechanism is involved, but addition of ethanol includes prilocaine and It was suggested to accelerate the skin absorption of lidocaine.

In the hydrogel patch having an ethanol content of more than 20%, a water separation phenomenon was observed during storage, and it was difficult to add 20% or more of ethanol with the increase of the water separation tendency. Therefore, it is desirable to suppress the content of ethanol added to accelerate drug absorption into the skin to 20% or less, especially in view of quality.

FIG. 4 shows addition of ethanol and L-menthol to percutaneous absorption of a hydrogel patch.
From the viewpoint of the effect of adjusting the pH value, the amount of the drug in the samples of the hydrogel patches GI and PL cream is shown. That is, hydrogel patch G (containing 20% ethanol) containing no L-menthol and hydrogel patch H (20% ethanol) containing 1% L-menthol and the same composition as G (containing L-menthol). No, 20%
Hydrogel patch I prepared with purified water (pH 9.0) was applied to the abdomen of each rat for 60 minutes, and the amount of drug extracted from the skin by the above-mentioned operation was adjusted to 1 g of rat skin. The results are shown in comparison with PL cream (containing neither L-menthol nor ethanol).

As is apparent from FIG. 4, the measured / converted drug amount is PL cream, hydrogel patch G, I,
In the order of H, 926μg / g, 954μg / g, 1180μg / g, 1460
It was μg / g. First, the hydrogel patch G containing 20% ethanol showed a drug skin absorption similar to that of PL cream. In contrast, Hydrogel Patch I containing 20% ethanol and prepared with pH 9.0 purified water showed significantly higher drug skin absorption.

This is because an increase in the molecular type increases the skin absorption of the drug, but the pH value, which is one of the environmental factors in which the drug exists, affects the ratio of the molecular form and the dissociation type of the drug, Since both prilocaine and lidocaine used as the skin local anesthetic formulation in this example are basic substances,
It is considered that by adjusting the pH of the base to a high level, the proportion of molecular forms that are easily transdermally absorbed increased.

From the above results, also taking into consideration that the pH range in which skin tissue is not damaged is 1 to 10,
In order to promote the skin absorption of the drug, it is desirable that the pH of the hydrogel patch itself is set higher than the upper limit of pH10.

Further, with respect to the above hydrogel patch I whose pH value was adjusted to be high, 1% L- was added to 20% ethanol.
Hydrogel Patch H containing menthol showed higher drug skin absorption. This is because in the absorption of prilocaine and lidocaine, L-menthol interacts with the lipid moiety in the horny layer to increase the fluidity of lipid pathway, which is the main permeation passage for fat-soluble drugs, thereby increasing drug skin absorption. This is probably because ethanol promoted and further enhanced the action of L-menthol.

Next, with respect to the hydrogel patch H and the hydrogel patch I, the results of examining the effect of the application time on the skin absorption of the drug are shown in FIG.
Shown in Hydrogel patch H and hydrogel patch I and PL cream were applied to the abdomen of rats for 30 minutes and 45 minutes, respectively.
After application for 60 minutes, the amount of drug extracted from the skin at each application time by the above operation was converted to 1 g of rat skin, and each time was shown in a diagram. In the figure, the PL cream measurement results are shown by white circles, the hydrogel patch I measurement results by black circles, and the hydrogel patch H measurement results by black squares.

As is clear from FIG. 5, first, regarding the PL cream, the drug content in the skin increased linearly with the extension of the application time. On the other hand, both hydrogel patches I and H tend to show a rapid increase in absorption rate after the application time of 45 minutes.
In that case, the tendency was remarkably observed. As a result, with respect to PL cream, hydrogel patch I had a significant difference at an application time of 60 minutes, and hydrogel patch H had a significant difference already from around the application time of 45 minutes.

Although ethanol is weaker than octanol, it has a degreasing action for extracting lipids such as sterol and ceramide, which are the main body of the barrier function of the stratum corneum,
It is known that the formation of new pores increases the drug permeability.However, octanol has a strong and rapid degreasing effect, whereas ethanol has a higher application concentration and application time. It is also known that the degreasing effect is enhanced. This tendency is in good agreement with the tendency of the absorption promoting effect, and it is suggested that the concentration-dependent and time-dependent transdermal absorption promoting effect of ethanol may be due to its degreasing effect.

Therefore, as shown in FIG. 5, the increase in absorption rate after application time of 45 minutes in hydrogel patches I and H occurred not in the PL cream but in the hydrogel patches. It is considered that this is due to the above-described degreasing effect of existing ethanol.

In the series of rat skin drug absorption tests in this example, the amount of drug in the skin was higher in the hydrogel patch and PL claim than in lidocaine in both cases. This is because prilocaine has a higher tissue affinity than lidocaine,
It is known that liver metabolism is also fast, which is considered to contribute to the difference between the amounts of both drugs detected in the skin.

(Example 3) Next, as a third example of the present invention, the hydrogel patch H and the hydrogel patch prepared in Example 1 and having high measurement results in the rat skin absorption test of Example 2 were obtained. About I, healthy volunteers 11
A skin local anesthetic effect test was performed on the name. Here, PL cream and commercially available lidocaine tape were used as controls.

The lidocaine tape is a plaster solution prepared by dissolving an acrylic adhesive and lidocaine in ethyl acetate, applied as a thin film and dried, and then formed as a plaster layer on a polyester film support. It is a thing. With this lidocaine tape, lidocaine is crystallized in the plaster layer, and if this crystal is not dissolved once it is not absorbed by the skin, so it takes time to obtain the drug effect, and the adhesive concentration is maintained. Therefore, there is a limit to the concentration of lidocaine that can be contained, so that a great drug effect cannot be expected. Further, this lidocaine tape was difficult to adhere to the rat abdomen,
The drug rat skin absorption test was not performed.

The procedure of the local skin anesthesia effect test is as follows. First, inside the upper arm of each of the 11 subjects,
The hydrogel patch H and the hydrogel patch I were placed on the skin with their sticking surfaces in contact with each other, and then fixed with a tape.
The cream was filled in a dedicated container and fixed on the skin with tape, and lidocaine tape was directly applied to the application site, and application of each drug was started.

From the start of application, elapsed time is 30 minutes, 45 minutes and
A pain test was performed at the drug application site for each subject at three 60 minutes. The pain test is the pinprick method, that is,
It was performed by pressing the needle of the syringe device shown in FIG.
In this device, an inner syringe 22 having a small diameter is slidably inserted into the outer syringe 21 instead of a piston, and an appropriate weight 24 is inserted into the inner syringe 22. The inner syringe 22 slides inside the outer syringe 21 toward the tip side by the load of the weight 24,
The needle 25 attached to the tip of the inner syringe 21 passes through a guide 23 provided at the tip of the outer syringe 21 and projects outward.

This device is installed so that the tip of the outer syringe 21 comes into contact with the skin of the subject, and a load is applied to the inner syringe 22.
Pressurizes the skin of the subject by means of the needle 25 that moves toward the skin side and is projected. At the time of this pressurization, the degree to which the subject felt pain was measured. For the measurement, each subject was subjected to pressurization five times for each site to which the preparation was applied. The anesthetic effect was judged in three levels of pain = 1 point, slight pain = 0.5 point, and no pain = 0 point, and a total score of 5 times was calculated.

The total measured points for each preparation are shown as a pain score in the diagram of FIG. In the figure, white triangles for lidocaine tape, white circles for PL cream,
The case of hydrogel patch H is shown by a black square, and the case of hydrogel patch I is shown by a black circle. The significance test of the obtained results is based on the Wilcoxon rank sum test method (Reference: Bulletin of Dermatology, 89,267-271,1944, Anesthesia, 39,473-
477, 1990).

As can be seen from FIG. 7, the commercially available lidocaine tape had a high pain score of 2.2 even at the application time of 60 minutes,
Regarding the minimum pain score, only 2 out of 11 patients showed 0.5, and none of them had a pain score of 0. Compared to such lidocaine tape, hydrogel patch H and hydrogel patch I showed significantly lower pain scores from application time of 30 minutes and PL cream from application time of 45 minutes.

However, no significant difference was observed between the hydrogel patch H and the hydrogel patch I and PL creams. In addition, looking only at the subjects who showed a minimum pain score of 0, the application time was 30 minutes for PL cream for 2 persons, 45 minutes for 4 persons, and 60 minutes for 4 persons. In the case of person H, it takes 30 minutes for 2 people, 45
There were 2 in 60 minutes and 5 in 60 minutes. In the case of Hydrogel Patch I, there were 0 at 30 minutes, but there were 5 at 45 minutes and 6 at 60 minutes. From the above results, it was revealed that the hydrogel patch H and the hydrogel patch I can be expected to have an effect equal to or higher than that of the conventional PL cream.

On the other hand, the drug absorption amount in the rat skin absorption test conducted in Example 2 was in the order of hydrogel patch H> hydrogel patch I> PL cream over the application time of 30 to 60 minutes. In the evaluation of the local skin anesthesia effect by the Pinprick method for healthy persons, the order was hydrogel patch I> PL cream> hydrogel patch H except for the application time of 30 minutes, which was not necessarily correlated with the results of the rat skin absorption test.

This is to judge the anesthesia effect in a relatively shallow area up to about 1 mm subcutaneously under the conditions of the Pinprick method performed in this example, and does not reflect the anesthesia effect in a deeper area under the skin. It could be considered as one of the factors.

Actually, with the hydrogel patch H, two subjects who showed a pain score of 0 at the application time of 60 minutes tried subcutaneously about 2 mm of needle stick, but no pain was felt at all. This time, we have not examined the depth of the anesthetic effect from the skin surface, but it is possible that there is a difference in the anesthetic effect up to the subcutaneous depth between the preparations prepared this time.

In the rat skin absorbability test of the hydrogel patch containing prilocaine-lidocaine in the above Example 2, the hydrogel patch H containing 20% ethanol and 1% L-menthol was the best, but in Example 3 The effect of local anesthesia on healthy subjects was not always correlated with the results of animal experiments, but hydrogel patch H and hydrogel patch I were
It was found that an effect equal to or higher than that of cream can be expected.

However, the hydrogel patch H containing L-menthol was complained of tingling sensation on the skin from all the subjects for a while after application, and redness at the application site was also observed in some cases. Therefore, in actual use, regarding L-menthol, it is desirable to devise some means of usage in consideration of the influence on the patient. Looking at this point,
Speaking only of the hydrogel patches A to I prepared this time,
Hydrogel Patch I may be desirable for most clinical use.

In the above examples, the hydrogel patch prepared by using the syringe was described, but the present invention is not limited to this, and it is possible to uniformly mix the base material and the drug, and to form the hydrogel patch well. If so, various manufacturing processes can be used.

[0079]

As described above, the hydrogel patch of the present invention has an effect that it can be applied more easily while having a local skin anesthetic effect equal to or higher than that of the conventional PL cream.

[Brief description of drawings]

FIG. 1 is an explanatory view showing a manufacturing process of a hydrogel patch according to a first embodiment of the present invention.

FIG. 2 is a bar graph showing the results of a drug rat skin absorption test of a hydrogel patch in a second example of the present invention for hydrogel patches A to D, and 1 g of rat skin.
The amount of the drug detected per hit (white-painted part: lidocaine, black-painted part: prilocaine) is shown respectively.

FIG. 3 is a bar graph showing the results of a drug rat skin absorption test of a hydrogel patch in the second example of the present invention for hydrogel patches C and EG, in which the amount of drug detected per 1 g of rat skin (white Painted part: Lidocaine,
Black-painted part: Prilocaine).

FIG. 4 is a bar graph showing the results of a drug absorption test on the skin of a hydrogel patch for a rat in the second embodiment of the present invention, using PL cream as a control for hydrogel patches G to I, and the drug detected per 1 g of rat skin. The amounts (white painted part: lidocaine, black painted part: prilocaine) are shown respectively.

FIG. 5 is a diagram showing the results of a drug rat skin absorption test of a hydrogel patch in a second example of the present invention with respect to hydrogel patches H and I with PL cream as a control over time.

FIG. 6 is a schematic configuration diagram illustrating a syringe device used for a local anesthesia effect test on the skin of a healthy person for hydrogel patches H and I according to the third embodiment of the present invention.

FIG. 7 is a diagram showing the results of a local anesthesia effect test on a healthy human skin for hydrogel patches H and I in a third example of the present invention over time (horizontal axis: application time (min), vertical axis: pain score). (Total points)).

[Explanation of symbols]

 1: First Syringe 2: Second Syringe 3: Molding Syringe 4: Syringe Connector 5: Cap A: Hydrogel Patch A 21: Outer Syringe 22: Inner Syringe 23: Syringe Guide 24: Weight 25: Needle

Claims (3)

[Claims] 1. A hydrogel patch for local skin anesthesia, characterized in that a gel-like gum base in which an oily local skin anesthesia preparation is dispersed is formed into a shape having a surface for sticking to the skin. 2. The hydrogel patch for local anesthetic of skin according to claim 1, wherein the oily local anesthetic preparation is a eutectic mixture of basic prilocaine and lidocaine. 3. When the gum base contains a 5% base type prilocaine-lidocaine eutectic mixture part, it further contains 3% or less of sucrose fatty acid ester and 20% or less of ethanol. The hydrogel patch for local skin anesthesia according to claim 2.