KR100446416B1 - Transdermal system for local anesthesia - Google Patents

Abstract

The patch for local anesthesia of the present invention comprises (A) a support layer, (B) a drug-containing matrix layer and (C) a release layer, wherein the drug-containing matrix layer (B) is based on the total weight of the matrix layer ( b ₁ ) 67 to 94% by weight of a pressure-sensitive adhesive selected from natural or synthetic rubbers; (b ₂ ) 5 to 25% by weight local anesthetic; And (b ₃ ) 1 to 8% by weight of a skin permeation enhancer, wherein the N position is 2-pyrrolidone substituted with C _8-12 alkyl, the drug dosage is easily controlled and the transdermal absorption rate of the drug is significantly improved. Expresses faster anesthesia than conventional formulations.

Description

Patch for local anesthesia {TRANSDERMAL SYSTEM FOR LOCAL ANESTHESIA}

Local anesthetics are drugs that act on the peripheral perceptual nerve to block nerve transmission, thereby slowing or losing the pain in the local area. Application methods include subcutaneous injection, which is used as a pretreatment for wound closure or simple treatment, and an occulusive dressing technique, which is used in the form of a cream or gel containing anesthetics when the surgical site is relatively extensive. Recently, drugs made by adding a small amount of a local anesthetic so as to be used for surface anesthesia or premature ejaculation of the genital mucosa are commercially available.

These drugs are formulated in the form of injections, solutions, creams, gels, etc., dual injections are painful when administering, difficult to self-administer, liquids, creams or gels are difficult to adjust the dosage and sticky due to the nature of the formulation Or the coating is contaminated.

U.S. Patent No. 4,529,601 discloses an emulsion or cream formulation using a eutectic mixture of prilocaine base and lidocaine base as a local anesthetic, WO 96/01637 shortens anesthetic expression time, In order to reduce skin irritation and maintain anesthetic effects for a long time, ointments or creams using polar lipids and triacyl glycerol have been disclosed.

U.S. Patent 5,587,167 discloses ointments based on herbal extracts and alcohols. However, these herbal extracts are inconvenient to use and have a problem in that unpleasant odor persists. Korean Patent Laid-Open Publication No. 2000-17706 discloses a gel formulation consisting of a local anesthetic, a gel base, ethanol and water for the purpose of improving the stickiness, which is a disadvantage of the existing formulation, but as in the conventional liquid or cream formulations, the dose control is Difficult and causes coating contamination during use.

In addition, the injections, liquids, creams, and gels immediately after drug administration, the amount of drug delivered rapidly increased and overdosed beyond the proper concentration required for drug expression at the localized site, and thereafter, it rapidly decreased to titrate for drug efficacy. It has a drug delivery characteristic of bone-floor phenomena falling below the concentration, making it difficult to keep the drug concentration constant at the topical site during the period of use.

Japanese Patent Application Laid-Open No. 7-157,424 discloses a gel matrix for local anesthesia by applying and crosslinking a (meth) acrylic acid alkyl ester / (meth) acrylic acid copolymer containing a local anesthetic on a porous support and impregnating it in an aqueous solution. Formulations are disclosed. This formulation has a disadvantage in that the preparation is complicated and the liquid component contained in the porous base is easily released, and it is difficult to obtain a fast anesthetic effect with this formulation alone. Japanese Patent Laid-Open No. 7-145,047 refers to a tape preparation containing myristic acid isopropyl as an anesthetic and a plasticizer, and Japanese Patent Laid-Open No. Hei 1-299,215 discloses a poly (styrene-butadiene) block copolymer, poly An adhesive tape formulation using a local anesthetic agent and an excipient in a self-adhesive matrix made of a (styrene-isoprene-styrene) block copolymer or the like is disclosed. This formulation has the advantages of being easy to use and easy to adjust the dose compared to conventional injections, solutions, creams and gels.However, the simple combination of pressure-sensitive adhesives and local anesthetics makes it difficult to express anesthetic effects faster than creams and ointments. There is a problem.

Korean Patent No. 185,715 discloses a matrix formulation that initially releases a large amount of drug by containing an excess of drug having a maximum solubility in the acrylate pressure sensitive adhesive in order to improve the disadvantage of the matrix formulation and express a rapid effect. In this case, since the shortening of the drug effect expression time is not remarkable and contains an excess of about 40 to 65% by weight of the drug, there is a disadvantage in that the adhesive properties are remarkably lowered and the adhesive residue remains on the skin when the matrix is removed from the skin. However, it is uneconomical to include more drugs than necessary.

Accordingly, an object of the present invention is to solve the problems of conventional formulations such as injections, solutions, creams, ointments, patches, etc., not only easy to apply, but also significantly improved the transdermal absorption of the drug, and thus the rapid effect expression and application. The present invention provides a patch for local anesthesia that can easily adjust drug dosage.

1 is a cross-sectional view of a patch for local anesthesia according to the present invention;

Figure 2 is a graph comparing the drug permeation rate over time of the topical anesthetic patch and the commercial patch of the present invention for human skin.

※ Explanation of codes for main parts of drawing

1: support layer 2: drug-containing matrix layer

3: release layer

In order to achieve the above object, in the present invention, in the patch for local anesthesia comprising the (A) support layer, (B) drug-containing matrix layer and (C) release layer, the drug-containing matrix layer (B) is Regarding the total weight of the matrix layer,

(b ₁ ) 67 to 94% by weight of a pressure-sensitive adhesive selected from natural or synthetic rubbers;

(b ₂ ) 5 to 25% by weight local anesthetic; And

(b ₃ ) 1 to 8% by weight of a skin permeation enhancer, wherein the N position is 2-pyrrolidone substituted with C _8-12 alkyl.

The patch for local anesthesia according to the invention shown in FIG. 1 consists of a support layer 1, a drug containing matrix layer 2 and a release layer 3. Hereinafter, the present invention will be described in detail.

(A) support layer

The support layer (A) used in the patch for local anesthesia of the present invention may be a plastic sheet such as polyethylene, polypropylene, ethylene / vinylacetate copolymer, vinylon, polyester, polyurethane, nylon, and rayon. Nonwoven fabrics, such as polyester, polyester, acrylic, silk, woven fabrics, such as cotton, or these laminated hybrids are preferable.

(B) drug-containing matrix layer

(b ₁ ) Pressure-sensitive adhesive

In general, pressure-sensitive adhesives require adhesion to the skin, compatibility with drugs and other excipients, and such pressure-sensitive adhesives include TSR (Sekisui Chemical Co., osaka, Japan), DuroTak (National) Acrylic pressure-sensitive adhesives such as Starch Chemical Co., Bridgewater, NJ, USA are commercially available. However, when the acrylic pressure sensitive adhesive is used as a matrix for local anesthesia, the drug diffusion in the pressure sensitive adhesive layer is slowed due to the interaction between the drug and the acrylic polymer in the pressure sensitive adhesive layer. It is difficult.

Pressure-sensitive adhesive (b ₁ ) used in the present invention is polyisobutylene, neoprene, polybutadiene, polyisoprene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-butadiene-isoprene copolymer, polyisobutene, Natural or synthetic rubbers selected from the group consisting of silicone rubbers and mixtures thereof can be used. Of these, styrene / butadiene / isoprene copolymer or polyisobutylene is preferred.

The pressure-sensitive adhesive (b ₁ ) is preferably used in an amount of 67 to 94% by weight based on the total weight of the matrix layer. If the content is less than 67% by weight, the physical properties of the matrix layer and the adhesion to the skin are reduced, making it difficult to use as a patch. If the content is more than 94% by weight, the content of the drug and the skin permeation enhancer is expected to be relatively low. It is difficult to obtain a rapid anesthetic effect.

(b ₂ ) local anesthetic

Local anesthetics (b ₂ ) used in the present invention are amide and ester based anesthetics, preferably lidocaine and its hydrochloride, prilocaine and its hydrochloride, tetracaine and its hydrochloride, dibucaine and Hydrochloride, benzocaine and its hydrochloride, cocaine and its hydrochloride, pranoxine and its hydrochloride, diclomine and its hydrochloride, propacacaine and its hydrochloride, and It is selected from the group consisting of two or more kinds thereof, of which lidocaine is more preferred.

The local anesthetic agent (b ₂ ) is dissolved or uniformly dispersed in the pressure-sensitive adhesive, it is preferable to use in an amount of 5 to 25% by weight based on the total weight of the matrix layer. When it is less than 5% by weight, it is difficult to express a desired sufficient anesthetic effect, and when it exceeds 25% by weight, the adhesive physical property is lowered, making it difficult to use as a transdermal administration formulation.

(b ₃ ) Skin Permeation Enhancer

Only the pressure-sensitive adhesive (b ₁ ) containing the local anesthetic agent (b ₂ ) is difficult to express the desired rapid and continuous local anesthetic effect. In order to increase the skin permeability of the drug, the patch for topical anesthesia of the present invention is a skin permeation enhancer containing 1 to 8% by weight of 2-pyrrolidone in which the N position is substituted with C _8-12 alkyl. It includes.

The N-alkyl-2-pyrrolidone is a surfactant in the form of a combination of a hydrophilic pyrrolidone group and a hydrophobic alkyl chain, and has conventionally been used as a dispersant, a wetting agent, a dissolution aid and the like. As an example in which pyrrolidone derivatives are used for the transdermal administration of a drug, Korean Patent Application Publication Nos. 2001-11625 and 1999-63732 disclose an external preparation composition and an estrogen-containing matrix system, respectively. However, in the case of the external preparation, the drug and the formulation are different, in the case of the estrogen-containing matrix, the system used is different, and the amount of pyrrolidone derivative used is also 10 to 16% by weight, which is much higher than the present invention. do.

Preferred examples of the skin permeation enhancer (b ₃ ) used in the present invention include N-dodecyl-2-pyrrolidone, and when the amount of the skin permeation enhancer (b ₃ ) exceeds 8% by weight, The physical properties are lowered and the skin permeation enhancer is leached out of the pressure-sensitive adhesive, making it difficult to use as a transdermal drug.

The drug-containing matrix layer (B) of the present invention may contain crosslinking agents, thickeners, organic or inorganic fillers which are commonly used for controlling the physical properties and adhesion of the matrix, and general additives such as softeners, preservatives, antioxidants, and the like. More may be added.

(C) release layer

The release layer (C) used in the present invention may be applied in a material or a form commonly used in transdermal administration formulations. For example, polyethylene, polyester, polyvinyl chloride, polyvinylidene coated with silicone resin or fluorine resin Films such as chloride, paper or laminates thereof can be used.

The patch of the present invention can be used for surface anesthesia of the skin for the purpose of relieving pain at the time of needle insertion, intravenous needle insertion, or superficial surgical treatment. It can be useful for local anesthesia in patients with premature ejaculation and premature ejaculation.

The invention can be better understood by the following examples, which are intended for the purpose of illustration of the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Example 1

Styrene / butadiene / isoprene copolymer (product name: Duro-Tak? 87-3500) was added to the mixed solvent of toluene / heptane (8/2) in an amount of 54.2% by weight of solid to prepare an adhesive solution, and then lidocaine, N Dodecyl-2-pyrrolidone was added and stirred uniformly. The content of each component is shown in Table 1 below. After applying the obtained drug-containing pressure-sensitive adhesive solution on a polyester release film (trade name: Scotchpak 1022, manufacturer: 3M) coated with a fluorine resin-based release agent, and dried in a hot air dryer to prepare an adhesive layer sheet having a thickness of 100 ㎛, It was laminated with the support of the polyester fabric and cut into 5, 10, 15 cm ² size to prepare a transdermal formulation.

Examples 2-6

A patch was prepared in the same manner as in Example 1, except that the composition of each component constituting the matrix layer was blended as shown in Table 1 below. In this case, as the components, polyisobutylene (Duro-Tak 87-6430, National Starch Co.), silicone pressure sensitive adhesive (Bio-PSA 4302, Dow Corning), prilocaine, colloidal silica (Aerosil R972, Degussa-Huls) And N-octyl-2-pyrrolidone.

Pressure Sensitive Adhesive (b ₁ ) Local anesthetic (b ₂ ) Skin Permeation Enhancer (b ₃ ) ingredient weight% ingredient weight% ingredient weight% Example One Styrene-Butadiene-Isoprene Copolymer (SIBR) 82.0 Lidocaine 12.0 N-dodecyl-2-pyrrolidone 6.0 2 Polyisobutylene 82.0 Lidocaine 12.0 N-dodecyl-2-pyrrolidone 6.0 3 Silicone adhesive 79.0 Lidocaine 12.0 N-dodecyl-2-pyrrolidone 6.0 Colloidal silica 3.0 4 Polyisobutylene 82.0 Prilocaine 12.0 N-dodecyl-2-pyrrolidone 6.0 5 Polyisobutylene 82.0 Lidocaine 12.0 N-octyl-2-pyrrolidone 6.0 6 Polyisobutylene 74.0 Lidocaine 15.0 N-dodecyl-2-pyrrolidone 8.0 Colloidal silica 3.0

Comparative Examples 1 to 16

A patch was prepared in the same manner as in Example 1, except that the composition of each component constituting the matrix layer was blended as shown in Table 2 below.

Pressure Sensitive Adhesive (b ₁ ) Local anesthetic (b ₂ ) Skin Permeation Enhancer (b ₃ ) ingredient weight% ingredient weight% ingredient weight% Comparative Example One SIBR 88.0 Lidocaine 12.0 - - 2 SIBR 78.0 Lidocaine 12.0 N-dodecyl-2-pyrrolidone 10.0 3 Acrylic adhesive 82.0 Lidocaine 12.0 N-dodecyl-2-pyrrolidone 6.0 4 SIBR 82.0 Lidocaine 12.0 Triethanolamine 6.0 5 SIBR 82.0 Lidocaine 12.0 Propylene Glycol Monolaurate 6.0 6 SIBR 82.0 Lidocaine 12.0 Oleic acid 6.0 7 SIBR 82.0 Lidocaine 12.0 Triacetin 6.0 8 SIBR 82.0 Lidocaine 12.0 Dimethyl sulfoxide 6.0 9 SIBR 82.0 Lidocaine 12.0 N-methyl-2-pyrrolidone 6.0 10 SIBR 82.0 Lidocaine 12.0 2-pyrrolidone 6.0 11 SIBR 82.0 Lidocaine 12.0 3-hydroxy-N-methyl-2-pyrrolidone 6.0 12 SIBR 82.0 Lidocaine 12.0 Polyethylene glycol 6.0 13 SIBR 82.0 Lidocaine 12.0 Dodecanol 6.0 14 SIBR 82.0 Lidocaine 12.0 Isopropyl myristate 6.0 15 SIBR 82.0 Lidocaine 12.0 Sorbitan monolaurate 6.0 16 Acrylic adhesive 40.0 Lidocaine 60.0 - -

The transdermal drug preparation prepared in Comparative Example 2 was inadequate as a patch due to weak adhesive strength, and the preparation in Comparative Example 16 was disclosed in Korean Patent No. 185,715, and crystals were produced and adhesive strength was reduced.

Test Example 1: Evaluation of Local Anesthetic Effect

The skin permeation test of the drug for evaluating the local anesthetic effect of the patch prepared in Examples 1 to 6 and Comparative Examples 1 to 16 was performed as follows:

The aqueous phase of the drug permeation test diffusion device [Franzcel] was filled with phosphate buffer at pH 7.4 to maintain the temperature at 32 ± 0.5 ° C., and the skin was prepared in the above Examples and Comparative Examples using human cadaver skin. The prepared matrices were cut and applied to the donor cell size. As time passed, 300 μl of the buffer in which the drug was diffused was taken for each hour, and the drug permeated by liquid chromatography was quantified. On the other hand, for comparison, two commercially available local anesthetics (gels and sprays) were tested under the same conditions in the same amount as the active ingredients. The cumulative permeation amount of two commercially available formulations prepared in Example 1 over time is shown in FIG. 2, and the cumulative drug at 24 hours after drug administration of the two commercially available formulations prepared in Examples and Comparative Examples. The permeation amount is shown in Table 3.

Cumulative Dose (㎍) Cumulative Dose (㎍) Cumulative Dose (㎍) Example 1 282.5 ± 32.5 Comparative Example 3 57.4 ± 5.9 Comparative Example 11 56.8 ± 15.2 Example 2 254.6 ± 27.9 Comparative Example 4 34.6 ± 6.3 Comparative Example 12 25.1 ± 6.8 Example 3 272.4 ± 45.7 Comparative Example 5 42.3 ± 5.5 Comparative Example 13 29.6 ± 10.4 Example 4 304.3 ± 23.1 Comparative Example 6 85.2 ± 11.3 Comparative Example 14 70.1 ± 16.8 Example 5 218.3 ± 32.7 Comparative Example 7 29.1 ± 8.1 Comparative Example 15 39.5 ± 14.1 Example 6 326.8 ± 27.9 Comparative Example 8 46.9 ± 12.4 Comparative Example 16 165.0 ± 19.8 Comparative Example 1 27.3 ± 7.8 Comparative Example 9 92.5 ± 24.6 Commercially available (gel) 92.6 ± 9.8 Comparative Example 2 302.7 ± 47.9 Comparative Example 10 41.4 ± 8.7 Commercially available (product made by spray) 48.2 ± 18.3

2 and Table 3, the drug delivery characteristics of the two commercial local anesthetics shows a typical pulse characteristic that the drug permeation rate is increased after 1 hour after administration and then sharply decreased after 3 hours, while Example 1 of the present invention It can be seen that the drug permeation rate linearly increased up to 2 hours after the administration while maintaining a stable permeation rate for up to 24 hours.

The patch for topical anesthesia according to the present invention is easy to apply to the skin, no stickiness or contamination of the coating, easy to control the dosage of the drug during the application period and significantly improved the transdermal absorption rate of the drug during anesthesia compared to the conventional formulation Expression of the effect has the effect of the invention much faster.

Claims (6)

In the patch for local anesthesia comprising a support layer (A), a drug-containing matrix layer (B) and a release layer (C), the drug-containing matrix layer (B) is based on the total weight of the matrix layer, (b ₁ ) 67 to 94% by weight of a pressure-sensitive adhesive selected from natural or synthetic rubbers; (b ₂ ) 5 to 25% by weight local anesthetic; And (b ₃ ) A patch for local anesthesia, comprising 1 to 8% by weight of N-dodecyl-2-pyrrolidone as a skin permeation enhancer. The method of claim 1, The pressure-sensitive adhesive is a group consisting of polyisobutylene, neoprene, polybutadiene, polyisoprene, styrene / butadiene copolymer, styrene-isoprene copolymer, styrene / butadiene / isoprene copolymer, polyisobutene, silicone rubber and mixtures thereof A patch for local anesthesia, characterized in that selected from. The method of claim 1, Local anesthetics include lidocaine and its hydrochloride, prilocaine and its hydrochloride, tetracaine and its hydrochloride, dibucaine and its hydrochloride, benzocaine and its hydrochloride, cocaine and its hydrochloride, pranoxin and its hydrochloride, dichromine and its hydrochloride Propacocaine and its hydrochloride salt, and a mixture of two or more thereof, characterized in that the patch for local anesthesia. delete The method of claim 1, A pressure-sensitive adhesive is a styrene / butadiene / isoprene copolymer, and the local anesthetic agent is lidocaine, The patch for local anesthesia. The method of claim 1, A patch for topical anesthesia, which is used for surface anesthesia of skin, genital mucosal anesthesia, or local anesthesia in premature ejaculation.