JP5634679B2 - Local anesthetic patch - Google Patents

Description

  The present invention relates to a local anesthetic patch.

  Various local anesthetic preparations have been developed for the purpose of pain reduction in arteriovenous indwelling needle treatment before surgery, dura mater / lumbar puncture, joint puncture, skin minor surgery, and the like.

  As such a local anesthetic preparation, for example, EMLA (eutectic mixture of local anesthetics) cream (trade name: “Sweden”, manufactured by Astra) is known. This EMLA cream is an oil-in-water emulsion utilizing the property that a 1: 1 eutectic mixture of prilocaine base and lidocaine base (lidocaine-prilocaine eutectic mixture) liquefies at room temperature.

  Also disclosed is a hydrogel patch for local skin anesthesia in which a gel-like gum base in which an oily skin local anesthetic preparation (lidocaine-prilocaine eutectic mixture) is dispersed is molded into a shape having an adhesive surface on the skin. (See Patent Document 1).

  However, with the creamy skin local anesthetic as described above, a dramatic effect is not obtained by simple application, and in order to obtain a sufficient analgesic effect, first, the cream is spread so that the cream is thickly raised on the skin local area. In addition, it is indispensable to perform a sealing and closing method (ODT), and the operation is complicated.

  Further, the above-mentioned skin local anesthetics require operations for preparation preparation such as filling, heating, dissolution, and stirring of materials using three syringes, and are not easy for the user.

  Further, a commercially available lidocaine tape agent (containing 60% by mass of lidocaine (crystal)) is known, but this lidocaine tape agent contains acrylic lidocaine in a supersaturated state in an acrylic pressure-sensitive adhesive. The skin permeability of lidocaine is secured, and it is said that pain relief at the time of venous indwelling puncture is recognized by applying for 30 minutes. As described above, since a conventional local anesthetic preparation such as lidocaine tape contains a solid drug, the release of the drug is slow and it takes time until the anesthetic effect by the drug is exerted. There was such a problem. In particular, in clinical settings, this type of drug is considered effective only after the pain-free state is reliably achieved. Therefore, in the clinical setting of a patch-type local anesthetic preparation such as conventional lidocaine tape. It is said that it is necessary to stick to the affected part for about 90 to 120 minutes. Therefore, conventional patch-type local anesthetic preparations have problems in medication management and patient compliance.

  In addition, the conventional patch-based local anesthetic preparation contains a drug in a supersaturated state, so the amount of the drug in the preparation increases, sufficient adhesive strength cannot be obtained, and adhesion to the skin is insufficient. Met. There is also a problem that the cost increases.

  In addition, it is conceivable to use an amorphous and liquid drug such as lidocaine-prilocaine eutectic mixture. However, when a liquid drug is included in the adhesive layer at room temperature, the cohesive force of the adhesive layer decreases. As a result, sufficient adhesive strength could not be obtained, and adhesion to the skin was insufficient.

JP-A-9-255565

Clinical anesthesia-Vol. 20 (2), p. 195 (1996)

  An object of the present invention is to provide a local anesthetic patch containing a lidocaine-prilocaine eutectic mixture that has good patchability and can exhibit rapid efficacy.

Such an object is achieved by the present inventions (1) to (5) below.
(1) a sheet-like support substrate;
A pressure-sensitive adhesive layer provided on one surface side of the support substrate and including a cross-linked acrylic copolymer as a main agent;
In the cross-linked acrylic copolymer, an amorphous and liquid lidocaine-prilocaine eutectic mixture is added and mixed,
Content of the lidocaine-prilocaine eutectic mixture in the said adhesive layer is 5-30 mass%,
The pressure-sensitive adhesive layer contains isopropyl myristate or liquid paraffin as a transdermal absorption enhancer,
The content of the isopropyl myristate or the liquid paraffin in the pressure-sensitive adhesive layer is 20% by mass or less,
When the content of lidocaine-prilocaine eutectic mixture in the pressure-sensitive adhesive layer is A [mass%] and the content of isopropyl myristate or liquid paraffin in the pressure-sensitive adhesive layer is B [mass%], 0.13 ≦ B A local anesthetic patch characterized by satisfying the relationship of /A≦0.88 .

  (2) The local anesthetic patch according to (1), wherein the lidocaine-prilocaine eutectic mixture is dissolved in the cross-linked acrylic copolymer.

(3) the crosslinked acrylic copolymer state, and are not made of a copolymer of a monomer composition containing an acrylic monomer having no carboxyl group, a monomer having a plurality of polymerizable unsaturated groups,
The adhesive which comprises the said adhesive layer is a local anesthetic patch as described in said (1) or (2) which does not contain the compound which has a carboxyl group .

(4) (meth) acrylic acid alkyl ester having 3 to 8 carbon atoms as alkyl group and (meth) acrylic having 9 to 18 carbon atoms as alkyl group having no carboxyl group local anesthetic patch according to above SL (3) containing the acid alkyl ester.

(5) the copolymer copolymerization ratio of monomers having a plurality of the polymerizable unsaturated group in the body, local anesthetic patch according to Symbol above a 0.00001~0.001mol% (3).

  According to the present invention, it is possible to provide a local anesthetic patch containing a lidocaine-prilocaine eutectic mixture that has good patchability and can exhibit rapid efficacy.

Hereinafter, the local anesthetic patch of the present invention will be described in detail based on preferred embodiments.
The local anesthetic patch of the present invention has a sheet-like support base and an adhesive layer containing a cross-linked acrylic copolymer containing a drug as a main agent.

<Support base material>
A support base material is a sheet-like base material, and has a function which supports the adhesive layer mentioned later. Such a supporting base material is preferably flexible (soft), has a curved surface following property at the time of application, and is suitable for cutting or punching at the time of processing.

  Such a supporting substrate is not particularly limited, and examples thereof include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyester such as polyethylene naphthalate (PEN), polyethylene (PE), polypropylene (PP), and the like. Polyolefin, polyarylate, polyurethane, polycarbonate, polyamide, polyimide, ethylene vinyl acetate copolymer, polyvinyl chloride, polytetrafluoroethylene, silicone, polysulfone, nylon, polylactic acid, rayon, acrylic, etc. It is possible to use knitted fabrics and non-woven fabrics. Furthermore, a laminate sheet of a plastic film and a plastic film, a woven fabric, a knitted fabric, a nonwoven fabric, paper, or the like can be used.

  The average thickness of the supporting base material is preferably 2 to 4000 μm, and more preferably 10 to 300 μm.

<Adhesive layer>
The pressure-sensitive adhesive layer contains a cross-linked acrylic copolymer as a main agent. In addition, an amorphous and liquid lidocaine-prilocaine eutectic mixture is added and mixed in the cross-linked acrylic copolymer.

[Lidocaine-prilocaine eutectic mixture]
Lidocaine-prilocaine eutectic mixture is a 1: 1 eutectic mixture of prilocaine base and lidocaine base, and is an agent that functions as a local anesthetic.

  Since this lidocaine-prilocaine eutectic mixture melts at a temperature lower than the melting point of the component substances due to freezing point depression, it is a liquid component at room temperature.

  In the present invention, the pressure-sensitive adhesive layer contains a cross-linked acrylic pressure-sensitive adhesive as will be described later as a main agent, and a lidocaine-prilocaine eutectic mixture is added to the cross-linked acrylic copolymer. .

  Thus, by using a cross-linked acrylic pressure-sensitive adhesive as described below as the main component of the pressure-sensitive adhesive layer, the cohesive force required for the pressure-sensitive adhesive layer can be obtained even when a lidocaine-prilocaine eutectic mixture that is liquid at room temperature is used. It can be ensured and good pastability can be obtained. Furthermore, the drug release property can be improved, and the rapid efficacy of the anesthetic effect can be improved.

  The lidocaine-prilocaine eutectic mixture may be contained in a crosslinkable acrylic copolymer described later, but is preferably dissolved in the crosslinkable acrylic copolymer. Thereby, the release property of a lidocaine-prilocaine eutectic mixture can be made more excellent, and the rapid effect of an anesthetic effect can be made more excellent.

  The content of the lidocaine-prilocaine eutectic mixture in the pressure-sensitive adhesive layer is preferably 5 to 30% by mass, and more preferably 8 to 25% by mass. Thereby, the adhesiveness with respect to the skin can be further improved while the drug release property is further improved.

[Crosslinked acrylic copolymer]
The cross-linked acrylic copolymer is a main component of the material constituting the pressure-sensitive adhesive layer, and is a component having a function of imparting adhesive force to the pressure-sensitive adhesive layer.

  The crosslinked acrylic copolymer is not particularly limited as long as it is an acrylic copolymer having a crosslinked structure, but includes an acrylic monomer having no carboxyl group and a monomer having a plurality of polymerizable unsaturated groups. It is preferable that it consists of a copolymer of a monomer composition.

  By the way, when a carboxyl group coexists with lidocaine and prilocaine, an acid-base interaction occurs, and lidocaine and prilocaine are held in the pressure-sensitive adhesive layer, and the release property may be lowered. Even in the case of using a monomer having a carboxyl group, the present invention exhibits a sufficient release property, but by using an acrylic monomer having no carboxyl group, the release property of the drug is further increased. The anesthetic effect can be further improved in rapid action.

  Further, by using a monomer having a plurality of polymerizable unsaturated groups, the crosslinked acrylic copolymer is crosslinked by a monomer having a plurality of polymerizable unsaturated groups. As a result, problems such as adhesive residue do not occur, and the resulting adhesive layer can maintain good pastability.

  Examples of the acrylic monomer having no carboxyl group include (meth) acrylic acid esters. In addition, (meth) acrylic acid ester means either acrylic acid ester or methacrylic acid ester, and (meth) shall have the same meaning hereinafter.

  Specific examples of the acrylic monomer having no carboxyl group include, for example, methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, and (meth) acrylic acid. Pentyl, hexyl (meth) acrylate, cyclohexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, dodecyl (meth) acrylate, (meth) acrylic (Meth) acrylic acid alkyl esters such as myristyl acid, palmitic acid (meth) acrylate, stearyl (meth) acrylate, and (meth) acrylic acid aryl esters such as (meth) acrylic acid benzyl ester. Is a combination of one or more of these It can be used Te.

  Among the above-described acrylic monomers having no carboxyl group, (meth) acrylic acid alkyl ester having 3 to 8 carbon atoms in the alkyl group and (meth) acrylic having 9 to 18 carbon atoms in the alkyl group. It is preferable to use an acid alkyl ester. Thereby, the adhesive force of an adhesive layer can be made more moderate.

  Moreover, in the monomer composition excluding the monomer having a plurality of polymerizable unsaturated groups, the monomer ratio of the acrylic monomer having no carboxyl group is not particularly limited, but is preferably 65 to 100 mol%.

  Examples of the monomer having a plurality of polymerizable unsaturated groups include (poly) ethylene glycol, (poly) propylene glycol, (poly) butylene glycol, (poly) pentamethylene glycol, alkylene glycol such as (poly) hexamethylene glycol, Examples include tri-methylolpropane, glycerin polyoxyethylene glycol, polyoxypropylene glycol, di- or tri (meth) acrylates of polyols such as (poly) glycerin, diallyl phthalate, and divinylbenzene. Alternatively, two or more kinds can be used in combination. Among the above-mentioned, since alkylene glycol diacrylate is excellent in the reactivity with another monomer, the cohesion force of the said copolymer can be made high suitably.

  The copolymerization ratio of the monomer having a plurality of polymerizable unsaturated groups in the copolymer is preferably 0.000005 to 0.005 mol%, and more preferably 0.00001 to 0.001 mol%. .

  Moreover, monomers other than the monomers as described above may be included in the monomer composition. Examples of such monomers include N-vinyl-pyrrolidone, vinyl acetate, styrene, acrylonitrile and the like. It is preferable that the monomer ratio in the said monomer composition except the monomer which has multiple polymerizable unsaturated groups of these monomers is 0-35 mol%. Moreover, it is preferable that such a monomer does not have a carboxyl group.

  The pressure-sensitive adhesive layer preferably further contains isopropyl myristate or liquid paraffin. These components are components having a function as a transdermal absorption enhancer that promotes the transdermal absorbability of lidocaine and prilocaine. By including these components, the rapid efficacy of the anesthetic effect can be further increased.

  The content of isopropyl myristate or liquid paraffin in the pressure-sensitive adhesive layer is preferably 20% by mass or less, and more preferably 1 to 10% by mass. Thereby, the rapidity of the anesthetic effect can be further enhanced while improving the adhesive strength of the pressure-sensitive adhesive layer.

When the content of the lidocaine-prilocaine eutectic mixture in the pressure-sensitive adhesive layer is A [mass%] and the content of isopropyl myristate or liquid paraffin in the pressure-sensitive adhesive layer is B [mass%], 0.13 ≦ B / A It satisfies the relationship of ≦ 0.88. By satisfying such a relationship, the rapid efficacy of the anesthetic effect can be improved more efficiently.

  Moreover, it is preferable that the adhesive which comprises an adhesive layer does not contain the compound which has a carboxyl group substantially. Thereby, the release property of the drug can be further increased.

  Moreover, it is preferable that it is 20-500 micrometers, and, as for the average thickness of an adhesive layer, it is more preferable that it is 30-300 micrometers.

  In the local anesthetic patch of the present invention, a release sheet is preferably provided on the pressure-sensitive adhesive layer surface. The release sheet has a function of protecting the adhesive surface of the adhesive layer when the local anesthetic patch is stored (when not used).

  As such a release sheet, for example, laminated paper such as polyethylene laminated paper and polypropylene laminated paper; polyester film such as polyethylene terephthalate; synthetic resin film such as polyolefin film such as polyethylene and polypropylene can be used. Moreover, you may use the peeling sheet by which the peeling process was given to the single side | surface or both surfaces of these materials with the silicone resin etc. as needed.

  Moreover, it is preferable that it is 10-200 micrometers, and, as for the average thickness of a peeling sheet, it is more preferable that it is 15-100 micrometers.

  The preferred embodiments of the local anesthetic patch of the present invention have been described above, but the present invention is not limited to these.

Next, specific examples of the present invention will be described.
[1] Preparation of local anesthetic patch (Example 1)
First, a monomer composition consisting of 2-ethylhexyl acrylate: 79.9999 mol%, 2-ethylhexyl methacrylate: 10 mol%, dodecyl methacrylate: 10 mol%, and hexamethylene glycol diacrylate: 0.0001 mol% was co-polymerized. 100 parts by mass of an ethyl acetate solution (solid content: 40% by mass) of a cross-linked acrylic copolymer obtained by polymerization was prepared.

  Next, 8.05 parts by mass of lidocaine-prilocaine eutectic mixture (lidocaine / prilocaine = 50/50 [mass%]) and 2.26 parts by mass of isopropyl myristate were added to the ethyl acetate solution, and the mixture was stirred. -The prilocaine eutectic mixture was dissolved and the coating liquid for adhesive layer formation was prepared.

  Next, a release liner made of polyethylene terephthalate (PET) as a release sheet (trade name “SP-PET7511” manufactured by Lintec Corporation) is prepared, and the adhesive layer forming coating liquid is dried on the release surface. The average thickness of the coating was applied to be 50 μm. Thereafter, the formed coating film was dried by heating to form an adhesive layer (containing 8% by mass of lidocaine, 8% by mass of prilocaine, and 4.5% by mass of isopropyl myristate).

  Next, a local anesthetic patch is prepared by laminating a PET film (trade name “Lumirror”, manufactured by Toray Industries, Inc.) having an average thickness of 50 μm as a supporting substrate on the adhesive layer formed on the release sheet. did.

(Examples 2 and 3)
A local anesthetic patch was prepared in the same manner as in Example 1 except that the contents of the lidocaine-prilocaine eutectic mixture and isopropyl myristate in the adhesive layer were changed as shown in Table 1.

Example 4
A local anesthetic patch was prepared in the same manner as in Example 1 except that isopropyl myristate was changed to liquid paraffin.

(Comparative Example 1)
A commercially available lidocaine tape (containing 60% by weight of lidocaine (crystal), manufactured by Takeda Pharmaceutical Company Limited, trade name “Penless”) was used.

(Comparative Example 2)
Instead of the cross-linked acrylic copolymer, the monomer composition composed of 2-ethylhexyl acrylate: 80 mol% and acrylic acid: 20 mol% was changed to a non-crosslinked acrylic copolymer having a carboxyl group. A local anesthetic patch was prepared in the same manner as in Example 1 except that.

  Table 1 shows the types and contents of the constituent components of the pressure-sensitive adhesive layer in each Example and each Comparative Example. In Table 1, the lidocaine-prilocaine eutectic mixture was indicated as “LP”, lidocaine as “L”, isopropyl myristate as “MI”, and liquid paraffin as “LP”.

[2] Evaluation [2-1] Local anesthetic effect A test was conducted on 10 healthy adult males. After stimulating the skin of the back of the subject's hand with a needle and selecting a pain point (degree of pain: 3), the local anesthetic patches of each Example and each Comparative Example were applied for 30 minutes, 1 hour and 2 hours, and then local anesthesia Immediately after removing the patch, the pain point was stimulated with a needle, the degree of pain was evaluated according to the following criteria, and the average values of 10 subjects were listed in Table 1.
(Criteria) 0: Painless, 1: Slightly painful, 2: Painful, 3: Very painful

[2-2] Skin patch test When the local anesthetic patch of each Example and each Comparative Example was applied to the outer side of the upper arm of the subject for 1 hour, the local anesthetic patch was peeled off, and the adhesive residue when peeled off after the sticking Was observed and evaluated according to the following criteria.

(Peeling)
A: No peeling occurred.
○: Some peeling was observed, but there was no problem.
X: Peeling was remarkable.

(Adhesive residue)
A: There was no adhesive residue at all.
○: A little adhesive residue was observed, but there was no problem.
X: The adhesive residue was remarkable.
These results are shown in Table 2.

  As is clear from Table 2, the local anesthetic patch of the present invention had excellent adhesive properties and was excellent in an immediate effect of the anesthetic effect. On the other hand, satisfactory results were not obtained in the comparative example.

Claims (5)

A sheet-like support substrate;
A pressure-sensitive adhesive layer provided on one surface side of the support substrate and including a cross-linked acrylic copolymer as a main agent;
In the cross-linked acrylic copolymer, an amorphous and liquid lidocaine-prilocaine eutectic mixture is added and mixed,
Content of the lidocaine-prilocaine eutectic mixture in the said adhesive layer is 5-30 mass%,
The pressure-sensitive adhesive layer contains isopropyl myristate or liquid paraffin as a transdermal absorption enhancer,
The content of the isopropyl myristate or the liquid paraffin in the pressure-sensitive adhesive layer is 20% by mass or less,
When the content of lidocaine-prilocaine eutectic mixture in the pressure-sensitive adhesive layer is A [mass%] and the content of isopropyl myristate or liquid paraffin in the pressure-sensitive adhesive layer is B [mass%], 0.13 ≦ B A local anesthetic patch characterized by satisfying the relationship of /A≦0.88 .   The local anesthetic patch according to claim 1, wherein the lidocaine-prilocaine eutectic mixture is dissolved in the cross-linked acrylic copolymer. The cross-linked acrylic copolymer is a copolymer of a monomer composition containing an acrylic monomer having no carboxyl group and a monomer having a plurality of polymerizable unsaturated groups,
The local anesthetic patch according to claim 1 or 2, wherein the adhesive constituting the adhesive layer does not contain a compound having a carboxyl group.   As the acrylic monomer having no carboxyl group, (meth) acrylic acid alkyl ester having 3 to 8 carbon atoms in the alkyl group and (meth) acrylic acid alkyl ester having 9 to 18 carbon atoms in the alkyl group The local anesthetic patch of Claim 3 containing these.   The local anesthetic patch according to claim 3, wherein a copolymerization ratio of the monomer having a plurality of polymerizable unsaturated groups in the copolymer is 0.00001 to 0.001 mol%.