JP2002193795A - Local anesthetic tape - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a local anesthetic tape having a certain level of rigidity to prevent the mutual adhesion of the plasters caused by the bending of the plaster by its own weight in pasting and free from the problems of the increase in production cost and the safety to the skin caused by the use of an unnecessarily large amount of local anesthetic agent, the lowering of the percutaneous absorption caused by the crystallization of the drug in the distribution stage and the lowering of the production efficiency and to facilitate the confirmation of the presence of the tape or the peeling of the tape at the medical treatment site by coloring the substrate in a conspicuous color such as white color. SOLUTION: A plaster containing 5-30 wt.% local anesthetic agent, 10-50 wt.% rubber-based tacky agent, 10-50 wt.% tackifier and 10-50 wt.% liquid paraffin as main components is supported on a substrate and the laminate is made to have moderate followability to the skin and a moderate rigidity to prevent the mutual adhesion of the plasters by the bending of the laminate by its own weight in pasting.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention can be used for local anesthesia prior to skin microsurgery, such as during injection on the skin surface or removal of varicella, at the time of puncture of an indwelling needle, dura or lumbar spine or joint puncture. , A tape containing a local anesthetic for the purpose of pain relief during treatment, especially a tape for local anesthesia with excellent percutaneous absorbability and excellent handling properties with less drug content than before, with less side effects It relates to the agent.

[0002]

2. Description of the Related Art Various external preparations containing an amide-type local anesthetic such as lidocaine for application to skin or mucous membranes have been studied, and ointments and liquid preparations have been proposed.

[0003] These are mainly used for surface anesthesia. However, since the skin permeability of the amide-type local anesthetic is low, it is difficult to obtain a sufficient drug effect. At the time of lumbar spine or joint puncture or local anesthesia before skin minor surgery, satisfactory effects have not been obtained. In addition, ointments and liquid preparations have drawbacks such as soiling of fingers during administration and soiling of clothes after administration, and as a result, drugs adhering to skin or mucous membranes other than the administration site may cause sensation in those parts. Inconveniences such as paralysis sometimes occurred.

Further, JP-A-60-16916, JP-A-60-185713, JP-A-63-93714, JP-A-4-208229, JP-A-6-145051, etc. disclose the base in the base. There are disclosed a transdermal patch in which the drug concentration is increased and crystals of the drug are precipitated, and a transdermal patch in which the drug is present in a supersaturated state exceeding the saturation solubility in the base.

[0005] However, in the case of a base in which a drug is present in a supersaturated state, there is a problem that drug crystals precipitate during the distribution stage of the product, and the transdermal absorbability of the drug is reduced.

In a transdermal patch in which drug crystals are precipitated, the drug must be contained at a supersaturated concentration or higher.
There has been a problem that the amount of drug per preparation increases and the cost increases. Particularly, in JP-A-4-208229 and JP-A-6-145051, the content of the transdermally absorbable drug in the pressure-sensitive adhesive polymer (specifically, acrylic pressure-sensitive adhesive) is 40% by weight. In the following, it is difficult to achieve a local anesthetic effect in a short time, which is expected from a local anesthetic, and a preparation having a drug content of 40 to 65% by weight is disclosed. Also, JP-A-11-496
No. 70 describes the following.

"Recently, a lidocaine tape preparation containing 60% by weight of lidocaine has been marketed as a local anesthetic for application. This lidocaine tape preparation supersaturates lidocaine in an acrylic pressure-sensitive adhesive. As a result, the skin permeability of lidocaine is ensured,
It is reported that pain after venous indwelling puncture is alleviated by application for a minute. However, in a clinical setting, this kind of drug is judged to be effective only after a painless state is reliably achieved. Therefore, as a conventional method of using a lidocaine tape agent in a clinical setting, 90- It is said that it is necessary to apply for about 120 minutes (Clinical anesthesia-V
ol. 20 (2), p. 195 (1996)). Therefore, the conventional lidocaine tape preparation has problems in medication management and patient compliance. "

In the case of a transdermal patch in which drug crystals are gradually precipitated after reaching a supersaturated concentration level, there is a problem that the production efficiency is significantly reduced due to the time required for the precipitation. In addition, the high concentration of the drug and the presence of crystals lead to a decrease in the adhesive strength, and the application of the high concentration of the drug is also undesirable from the viewpoint of skin safety.

JP-A-7-126157 and JP-A-7-2
No. 15850 or JP-A-11-49670 discloses a technique of increasing the skin permeability of a drug by blending an absorption promoter such as isopropyl myristate, isopropyl palmitate, crotamiton or N-methyl-2-pyrrolidone. It has been disclosed. However, incorporation of these absorption enhancers generally raises the skin permeability of the drug, while causing irritation to the skin and safety.

Japanese Patent Application Laid-Open No. Hei 7-233504 discloses that a rubber-based pressure-sensitive adhesive extracts a lipid component from the skin, and this lipid component is transferred into the pressure-sensitive adhesive base, and an anesthetic is added thereto. It says that as a result of dissolution and an increase in the dissolution rate, the skin permeability of the anesthetic increases, and a sufficiently high drug effect can be obtained quickly. However, it is hard to say that a small amount of intradermal lipid component provides such an effect. In addition, there are individual differences in human skin, and therefore, the migration of lipid components of the skin into the pressure-sensitive adhesive base varies depending on the human or the application site, resulting in a large change in the skin permeability of anesthetics There was a problem of doing. Furthermore, it takes a long time for the lipid components in the skin to migrate into the pressure-sensitive adhesive base and increase the permeability of the anesthetic to the skin, so that the immediate effect of the anesthetic action was insufficient.

[0011] Although the publication discloses that a tackifier and liquid paraffin, which are optionally contained in the component composition of the plaster of the present invention, can be contained as a base, examples are also provided. In addition, there was no description suggesting an excellent local anesthetic effect developed when liquid paraffin was used. Furthermore, the preparations obtained from the examples have no tackiness due to their composition and are difficult to adhere to the skin, so that they have poor drug absorption.

Japanese Patent Application Laid-Open No. Hei 10-147521 describes a part of the composition of the plaster of the present invention. However, the gazette discloses the persistent pain of herpes zoster or postherpetic neuralgia. The present invention relates to a patch for sustained pain relief which can be used for the reduction of pain, and which can stably and percutaneously absorb the medicinal ingredient over a long period of time, and has a local anesthetic effect as disclosed in the present invention. There was no suggestion of immediate effect.

[0013] In addition, the drawback of handling properties of the conventional preparations is that the preparations are too soft and easily bend when the release liner is removed or pasted, and the adhesive surfaces adhere to each other, making it unusable. There was something. Even if the adhered adhesive surfaces were peeled off from each other, the adhesive surface was destroyed and reuse was difficult.

[0014]

[Problem to be Solved by the Invention] A local anesthetic is contained in a smaller amount or at a lower concentration, the skin is less irritating, and regardless of the condition of the skin, it has a safe skin permeability of the local anesthetic, and It is an object of the present invention to obtain a tape preparation for local anesthesia which is excellent in handleability and is a problem.

[0015]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that by blending a local anesthetic in the following tape preparation, a lower concentration, higher safety, higher production efficiency and higher production cost, The present inventors have found that a tape preparation for local anesthesia having excellent handleability can be obtained, and completed the present invention.

One of the advantages of the tape for local anesthesia of the present invention is that it can be used as a softening agent for a plaster composed of a rubber-based pressure-sensitive adhesive composition without using a special percutaneous absorption enhancer as in the prior art. Is also used, and has the effect of inadvertently enhancing the local anesthetic effect of liquid paraffin with little irritation.

Another excellent point of the tape for local anesthesia of the present invention is that the composition in which the plaster is supported on the support has an appropriate rigidity. When sticking, it is a point which does not bend by an own weight and adhesive surfaces adhere. Further, since the pressure-sensitive adhesive has an appropriate cohesive property, even if the pressure-sensitive adhesive surfaces adhere to each other, the pressure-sensitive adhesive can be easily peeled off and reused.

The tape for local anesthesia of the present invention comprises 5 to 30% by weight of a local anesthetic and a rubber-based adhesive 10 on a flexible support.
It is characterized in that it supports a plaster body containing 〜50% by weight, 10-50% by weight of a tackifier and 10-50% by weight of liquid paraffin as main components, and its constituent body has appropriate rigidity.

The support used in the tape preparation for local anesthesia of the present invention may be a woven fabric, nonwoven fabric, sheet made of a high molecular compound such as polyethylene, polypropylene, rayon, cotton polyester, polyvinyl alcohol or the like, or a laminate of these films. Are used.
In particular, in the present invention, in order to improve the handleability at the time of pasting,
It is necessary to select a support that maintains the rigidity of the preparation from which the release liner has been removed, at least so that the preparation does not easily bend and the adhesive surfaces do not adhere to each other. For example, it is preferable to use a support having a drape coefficient of 0.20 to 0.65 as the stiffness in the JIS general textile test method. If it is less than 0.20, the preparation, which is too soft and the release liner is removed, may be easily bent and the adhesive surfaces may adhere to each other. If it is more than 0.65, it may be difficult to follow the skin. In addition, it is desirable that the color of the support be a conspicuous color such as white, for example, so that the presence or absence of sticking and peeling of the preparation can be easily confirmed at the medical site.

The rubber-based pressure-sensitive adhesive which is a base component used in the tape for local anesthesia of the present invention includes, for example, styrene-isoprene-styrene block copolymer (SIS),
One or more of polyisobutylene polymer, styrene-butadiene block polymer, polybutene, polyisoprene, butyl rubber, natural rubber and the like are used.
The used amount is 10 to 50% by weight, preferably 20 to 30% by weight in total. If the amount is too small, the cohesive strength is reduced and cohesive failure of the pressure-sensitive adhesive is caused to deteriorate the quality or leave adhesive. It is not preferable because it causes skin contamination, and when it is too much, it becomes too hard and a proper adhesive strength cannot be obtained.

The tackifier used in the tape for local anesthesia of the present invention is a resin that produces tackiness only when combined with an adhesive base. If the tackifier is not contained, no adhesive force is generated and the adhesive cannot function as a patch. For example, one or more kinds of alicyclic saturated hydrocarbon resins, terpene resins, rosin resins and the like can be blended. The compounding amount is 10 to 50% by weight, preferably the total is 20 to 45% by weight. If the amount is too small, a sufficient adhesive force cannot be obtained, and if it is too large, the adhesive force is too large to exfoliate the keratin. It causes physical irritation to the skin, such as causing skin irritation, which is not preferable.

Liquid paraffin, which acts as a softening agent and as a local anesthetic release modifier used in the plaster of the tape for local anesthesia of the present invention, is usually incorporated in an amount of 10 to 50.
%, Preferably 15 to 45% by weight. If the amount is too small, appropriate follow-up properties to the skin, the adhesion and the effect of promoting the release of the local anesthetic are not obtained. It is not preferable because it causes skin contamination such as waking up, deterioration of quality and adhesive residue.

The local anesthetic used in the present invention is usually 5
It is preferred to use ３０30% by weight. If it is less than this, a desired local anesthetic effect cannot be expected. Further, even if the amount is more than this, since crystals of the local anesthetic start to precipitate, further improvement in drug release characteristics cannot be expected. Moreover, an unnecessary increase in the drug concentration in the preparation not only leads to a decrease in adhesive strength, but is also undesirable from the viewpoint of skin safety.

In the above plaster composition, a filler may be added to keep the plaster thickness or the like or to prevent the plaster from becoming too soft and penetrating into the support. Examples of the filler include kaolin, titanium oxide, talc, zinc oxide, calcium carbonate, silicate, aluminum silicate hydrate, barium sulfate, calcium sulfate, and the like.

The plaster composition of the present invention may contain an antioxidant such as dibutylhydroxytoluene and a fragrance such as peppermint oil which are used in general patches, if necessary.

An example of the method for producing the composition of the present invention is as follows. A mixture of a styrene-isoprene-styrene block copolymer, a tackifier, a liquid paraffin, a filler to be added as required, and an optional component is heated and melted. Stir and mix. The local anesthetic was melted in this solution, mixed uniformly with stirring, the resulting solution was uniformly applied on a plastic film subjected to peeling treatment, and the resulting solution was bonded to a non-woven fabric serving as a support for the device. A percutaneous absorption preparation is obtained by cutting to a predetermined size. In addition, the production method is not particularly limited to the above method, and the production can be carried out even if the mixing order, the stirring method, the materials, and the like are changed.

[0027]

Conventionally, in order to obtain a satisfactory effect on puncture of a venous indwelling needle, dural or lumbar spine or joint puncture, and local anesthesia before skin minor surgery, percutaneous absorption with drug crystals precipitated. Percutaneous absorption patches in which the drug is present in a supersaturated state with respect to the drug and the base have been studied. In contrast, there were problems such as a decrease in transdermal absorbability due to the precipitation of drug crystals or a decrease in production efficiency, whereas the tape preparation for local anesthesia of the present invention exhibited a desired effect with a smaller amount of drug, and showed an increase in production efficiency. Thus, a preparation having excellent skin safety can be obtained. In addition, it has excellent characteristics that have never been used before.

[0028]

【Example】

Hereinafter, the present invention will be further described by showing Examples, Comparative Examples and Test Examples.

Based on the formulations shown in Table 1, the following methods were used to prepare Examples 1 to 4, Comparative Example 1, and JP-A-7-233054.
Comparative Example 3 (not including a softener, a tackifier, etc.) based on the example described in No. 1 was manufactured.

[0031]

[Table 1]

(Production method of Examples 1 to 4 and Comparative example 1)
The styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, liquid paraffin and antioxidant were heated and melted and stirred, and then lidocaine was melted and uniformly stirred and mixed. A plastic film uniformly coated with this solution was bonded to a polypropylene nonwoven fabric and cut into a size of about 3 × 5 cm to produce a tape.

(Production method of Comparative Example 3) After the styrene-isoprene-styrene block copolymer was heated and melted, lidocaine was melted and uniformly stirred and mixed. A tape preparation containing 10% by weight of lidocaine was produced from this solution in the same manner as in the example.

Test Example 1 (In Vitro Skin Permeation Test) Five kinds of Examples 1-4 and Comparative Example 2 (commercially available lidocaine tape (containing 60% lidocaine)) were used as samples, and the skin permeability of lidocaine was determined by the following method. Was evaluated. The test results are shown in FIG.

(Experimental Method) The abdominal skin of a hairless mouse was attached to a horizontal diffusion cell such that the stratum corneum was on the donor side, and each sample was attached to the skin surface on the donor side.
Put the receptor solution (saline) on the receptor side,
While maintaining the temperature at 7 ° C., the receptor solution was collected over time, and the amount of lidocaine permeating the skin of the hairless mouse was measured by the HPLC method.

As a result, as shown in FIG. 1, Example 1 (lidocaine concentration 5%) showed lower permeability than Comparative Example 2, but Examples 2, 3 and 4 showed skin permeability comparable to Comparative Example 2. Showed sex. From these results, Example 2 of the product of the present invention,
3 and 4 were expected to have the same effect as Comparative Example 2, and it was thought that Example 2 could obtain almost the same effect at a drug concentration of only 1/9 of Comparative Example 2.

Test Example 2 (Local anesthetic action on guinea pig back skin) Using Example 3, Comparative Example 1 and Comparative Example 2 as samples, the local anesthetic effect of lidocaine was evaluated by the following method.

(Test Method) Each sample (2.5 cm × 3 cm) was applied to a site where a dehaired guinea pig was stimulated with a mandolin line and a clear skin contraction reaction occurred. 30
After 10 minutes, the sample was removed, and after 10 minutes from the removal, the removal site was stimulated with a mandolin line at 5 points per location every 10 minutes, and the number of skin contraction reactions (Pain score) at that time was performed.
e; 0-5) were recorded.

As a result, as shown in FIG. 2, the local anesthetic action of Example 3 was almost the same as that of Comparative Example 2 although the drug concentration was 1/6 that of Comparative Example 2.

Test Example 3 (Efficient Surface Anesthetic Action) Using the five types of Examples 1-3, Comparative Example 2 and Comparative Example 3 as samples, the local anesthetic effect of lidocaine was evaluated by the following method.

(Test Method) The study was conducted on 20 healthy adult males. After stimulating the back skin of the subject with a mandolin line and selecting a pain point (degree of pain: 3), the pain point on the dominant arm and the back skin opposite to the dominant arm is 30 minutes for each of Example 3 or Comparative Example 2 for 30 minutes. For a short time. Immediately after removing the sample, the pain point was stimulated with a mandolin line, and the degree of pain was evaluated according to the following criteria.

(Criteria for judging anesthetic effect) 0: Painless 1: Slightly painful 2: Painful 3: Very painful

As a result, as shown in Table 2, the local anesthetic effect of Example 3 was almost equivalent to that of Comparative Example 2. It was also found that the local anesthetic effect was sufficiently exhibited in Examples 1 and 2, though the effect was slightly inferior to Comparative Example 2. In addition, about Comparative Example 3, Example 3
Less effective than That is, it was confirmed that the tape preparation for local anesthesia of the present invention was also excellent in terms of immediate effect.

[0044]

[Table 2]

Test Example 4 (Usability test with commercially available product) Using Example 3 and Comparative Example 2, a usability test was performed on 20 subjects. It was examined whether or not the subjects could apply both formulations without fail, without being instructed on the specific application method. Further, with respect to the preparation after removal of the liner, it was tested whether the adhesive surfaces were intentionally adhered to each other, peeled off again and applied. As a result, as shown in Table 3, all of the 20 patients were able to correctly adhere to Example 3 whereas 9 of Comparative Example 2 failed (although the formulation after liner removal had no rigidity). , It was bent by its own weight when pasted, and the adhesive surfaces were stuck together.) Further, in Example 3, the re-peeling and re-applying were possible after all the 20 persons adhered the adhesive surfaces to each other. However, in Comparative Example 2, the paste was destroyed for the preparation of 15 persons, and the re-peeling was performed. After that, it could not be pasted.

[0046]

[Table 3]

Test Example 5 (Skin safety test) 30 healthy adult volunteers (24 men, 6 women:
Example 3 was applied to the inner side of the upper arm for 2 hours and 4 hours. In addition, white petrolatum was used as a control. The determination was performed twice, 1 hour and 24 hours after the preparation was removed and cleaned 2 hours and 4 hours after application. The criteria were determined according to the following criteria, and the skin irritation index was determined by scoring according to Sugai as a standard indicating the safety of the preparation.

(Judgment Criteria) Judgment Score -0: No response ± 0.5: Light erythema +1: Erythema ++ 2: Erythema + swelling +++ 3: Erythema + swelling + papules to vesicles +++ 4: Large blister

(Calculation method of skin irritation index) Skin irritation index = (total score of one with strong irritation after 1 hour and 24 hours after removal) / (number of test examples) × 100

As a result, as shown in Tables 4 and 5,
In the time affixing, 1 hour after removal, a reaction was observed in 1 out of 30 cases in Example 3, but no reaction was observed in all 30 cases 24 hours after removal. In addition, in the case of sticking for 4 hours, there was no reaction in all 30 cases both 1 hour after removal and 24 hours after removal. The skin irritation index is 1 according to the evaluation criteria for a preparation applied to adult normal skin by Sugai.
Although less than 5.0 was regarded as a safe product, Example 3 of the present invention was 1.7, which was determined to be safe.

[0051]

[Table 4]

[0052]

[Table 5]

Test Example 6 (Local anesthetic effect on pain at the time of venous indwelling needle puncture) Preparation of Example 3 or Comparative Example 2 for 60 patients to be treated aged 20 to 76 who need venous indwelling needle puncture 3
It was stuck for 0 minutes, punctured with a venous indwelling needle after exfoliation, the degree of pain at that time was asked, and the following five levels were evaluated.

0. It doesn't hurt It hurts a little 2. It hurts Very painful 4. Pain assessment not possible 1) Failure to puncture the indwelling needle (impossible to re-puncture the same site) 2) No puncture

Table 6 shows the results. In the group to which Example 3 was applied, 5 cases were “not painful”, 20 cases were “slightly painful”, and 25 cases (83.3%) were “slightly painful” or more. In the comparative example 2 application group, 5 cases were “not painful”, 21 cases were “slightly painful”, and 26 cases were “slightly painful” or more (8 cases).
9.7%). Mann about "slightly painful" and more
As a result of the -Whitney U test, no significant difference was observed between the two groups. “I hurt” is 5 in Example 3.
Example and Comparative Example 2 were 3 cases, and "very painful" was not recognized between both groups.

[0056]

[Table 6]

[0057]

According to the present invention, an excellent local anesthetic effect can be obtained at a low concentration. In addition, it is excellent in handling, manufacturing efficiency,
It can be said that the preparation is extremely useful in terms of production cost.

[Brief description of the drawings]

FIG. 1 is a diagram comparing skin permeability of hairless mice of Examples 1 to 4 and Comparative Example 2.

FIG. 2 is a view showing the local anesthetic action on the skin of the guinea pig back in Example 3, Comparative Example 1 and Comparative Example 2.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 47/46 A61P 23/02 A61M 35/00 A61J 1/00 370C A61P 23/02 A61M 35/00 Z ( 72) Inventor Hiromi Koga 2596 No. 1, Nobomi, Kashima City, Saga Prefecture F-term (reference) 4C076 AA74 AA81 BB31 CC01 DD34A EE58A FF68 4C167 AA72 BB13 BB23 CC01 GG08 GG10 GG30 H206 DB43 GA18 GA31 KA01 MA03 MA05 MA29 MA52 MA83 ZA21 ZA89

Claims (3)

[Claims] Claims 1. A local anesthetic 5 to 30 on a flexible support.
% By weight, 10 to 50% by weight of rubber-based adhesive, tackifier 1
It carries a plaster containing 0 to 50% by weight and 10 to 50% by weight of liquid paraffin as main components, and its constituents have an appropriate follow-up property to the skin, and bend by its own weight at least when applied. It has an appropriate rigidity such that plasters do not adhere to each other, and is used for reducing pain at the time of injection on the skin surface, or for local anesthesia at the time of venous indwelling needle or joint puncture. Local anesthetic tape 2. The local anesthetic tape preparation according to claim 1, wherein the local anesthetic is at least one selected from the group consisting of lidocaine, tetracaine, procaine and salts thereof. 3. The tape preparation for local anesthesia according to claim 1, wherein a support having a drape coefficient of 0.20 to 0.65 is used as the stiffness in the JIS general textile test method. .