KR20030021418A - Transdermal fentanyl matrix patch - Google Patents

Abstract

PURPOSE: A matrix formulation for transdermally administering fentanyl that consists basically of an impermeable protecting layer, polymeric adhesive layer and release paper is provided which prolongs the duration while at the same time drastically accelerating the achievement of drug action by controlling permeation kinetics and thus exerts quick and excellent effects on controlling pain. CONSTITUTION: The matrix formulation for transdermal administration of fentanyl contains an impermeable protecting layer(a), a polymeric adhesive layer(b) having a thickness of 10 to 500μm and a release layer(c), wherein the polymeric adhesive layer is (i) a polymeric adhesive, (ii) a base or salt of fentanyl or fentanyl derivatives as a drug and (iii) a permeation controller and contains one or two or more mixed solvents selected from the group consisting of solvents having a melting point of 120deg.C or less.

Description

Fentanyl transdermal formulations {Transdermal fentanyl matrix patch}

The present invention relates to matrix transdermal formulations containing bases or salts of fentanyl or fentanyl analogs (hereinafter referred to as fentanyl).

Fentanyl (Fentanyl; N-phenyl-N [1- (2-phenylethyl) -4-piperidinyl] propanamide) is a potent narcotic analgesic that is 50 to 100 times more potent than morphine and can cause cancer, postoperative pain, It has been used to alleviate chronic pain or to induce anesthesia. Effective blood concentrations for analgesic effects vary, but generally have a therapeutic index of about 1 to 3 ng / ml, a short biological half-life, and serious side effects such as respiratory depression during intravenous injections for analgesia. Therefore, despite its potent analgesic effect, it cannot be administered by traditional methods of administration such as muscle, subcutaneous injection, and its use has been limited.

Recently, controlled release formulations have been developed and used to address these pharmaceutical disadvantages, which are transdermal dosage forms designed to release fentanyl continuously through the skin. Transdermal dosage forms can maximize drug efficacy and minimize side effects by maintaining a constant blood concentration due to the nature of the formulation, bypass the first-pass effect in the liver, and determine drug dosage relatively accurately. In addition, since the administration method is simple and convenient, and the formulation is easily removed, there is an advantage that the drug can be easily removed when discontinuation of the drug is required.

The already commercially available transdermal dosage form of fentanyl is a reservoir type formulation as known in US Pat. No. 4,588,580, which is a system in which fentanyl is mixed and dissolved in a liquid drug storage layer consisting of ethanol and water. Disadvantages of the patch formulations include disadvantages such as complicated manufacturing process, poor skin adhesion, and the appearance of the drug after 12 hours.

U.S. Patent No. 4,822,802 attempts to shorten the time to reach steady state by intravenously injecting an amount of fentanyl at the same time as the transdermal formulation is attached to compensate for the late drug efficacy of the transdermal formulation.

In another attempt to shorten the lag time, U.S. Pat.No. 5,186,939 discloses a high viscosity and low solubility of fentanyl as a polymer adhesive to induce rapid release of drugs in matrix fentanyl patch formulation designs. Formulations using amine-resistant polydimethylsiloxane are described. However, in this case, although there is some effect on increasing the initial release, the solubility of the drug in the polymer adhesive layer used is so low that the drug cannot be delivered for a long time. Therefore, fentanyl is released for at least 3 days, it is difficult to continuously exhibit analgesic effect.

Other transdermal formulation formulations of fentanyl have prior art patents relating to skin permeation control compositions for controlling drug release or enhancing skin permeability, but lasting at least 3 days, preferably at least 7 days, effectively reducing the initial delay time. There is no prior art related to a system for releasing a drug.

An object of the present invention is to provide a fentanyl transdermal formulation having both rapid and initial expression of efficacy. It is still another object of the present invention to provide a new fentanyl transdermal formulation which is improved in fit by being designed in a thin and flexible matrix.

BRIEF DESCRIPTION OF THE DRAWINGS It is sectional drawing which shows the structure of the monolayer matrix type transdermal administration formulation of this invention. a represents an impermeable protective layer, b represents a polymer adhesive layer, and c represents a release paper.

The present invention relates to matrix transdermal formulations containing bases or salts of fentanyl or fentanyl analogs (hereinafter referred to as fentanyl). More specifically, the present invention comprises (a) an impermeable protective layer, (b) a polymer adhesive layer and (c) a release paper as a basic structure, wherein the polymer adhesive layer comprises (i) a polymer adhesive, (ii) a drug. And a base or salt of fentanyl or a fentanyl analog and (iii) a permeation control agent, wherein the monolayer matrix transdermal agent comprises at least one solvent selected from the group of solvents having a boiling point of 120 ° C. or less or two or more mixed solvents.

In the monolayer matrix type transdermal drug delivery system of the present invention, a drug and a skin permeation control agent are mixed in a polymer adhesive layer, that is, an adhesive polymer matrix, so that the skin permeation control agent is permeated through the skin before the drug at least 12 hours after skin adhesion. By reversibly deforming the skin, it induces rapid penetration of the drug and disappears in the polymer adhesive layer and the body, and after a certain time, only the drug is continuously released at a constant rate to maintain effective blood concentration. As much of the drug is permeated.

The skin permeation control agent used in the present invention is designed to act only at the beginning, and disappears after disappearing through the body from the mid to the end, the reason why the role of the skin permeation control agent is not required after the mid Fentanyl has a small dose and a high flow rate of the drug that penetrates the skin, so that designing a suitable transdermal formulation can reach pharmacologically effective blood levels without additional permeability control agents. The flow rate of the active substance penetrating the skin is defined as the unit area of the skin and the amount of active substance per unit time [μg / cm 2 / hour] and reaches a steady-state after the initial stage. For fentanyl the skin permeation flow rate is typically in the range from 0.5 to 5.0 μg / cm 2 / hour.

Skin permeation modifiers available are solvents, fatty acids, fatty alcohols, fatty acid esters, ionic / nonionic surfactants that are miscibility with the adhesive and do not degrade the solubility in the drug matrix and do not interact with the drug. And urea. However, it is preferable to select among solvents having excellent skin permeation control effect on fentanyl by reversibly converting the lipid structures of the polymer adhesive layer and the stratum corneum of the skin in order to induce drug inflow more quickly in the early stage. Among these are low alcohols, polyhydric alcohols, ethyl acetate, pyrrolidone, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, triacetin, transcurol and the like. Low-cost alcohols include aromatic alcohols such as C3 to C10 aliphatic alcohols such as ethanol, propanol, isopropanol, butanol, pentanol, nucleic acidol, heptanol, and benzyl alcohol. Polyhydric alcohols include propylene glycol, butanediol, glycerin, low molecular weight polyethylene glycol and the like. The most effective skin permeation modulators are ethanol (bp 78 ° C), 2-propanol (bp 82 ° C), 1-propanol (bp 97 ° C), 1-butanol (bp 118 ° C), 2-butanol (bp 98 ° C), 1-pentanol (bp 118 ° C) ethyl acetate (bp 76 ° C) solvents with boiling points below 120 ° C, extracting polar fats in the stratum corneum and reversibly changing the structure It acts to regulate skin permeation. In addition, they are small in molecular weight and very fast in the stratum corneum and dermal layer, so that they are lost early after skin permeation. 2-pyrrolidone (bp 245 ° C), N-methylpyrrolidone (bp 202 ° C), dimethylsulfoxide (bp 189 ° C), N-methylformamide (bp 198 ° C), N-dimethyl Solvents with high boiling points such as formamide (bp 153 ° C), triacetin (bp 258 ° C), and transcurol (bp 199 ° C) have a relatively slow diffusion rate in the polymer adhesive layer and skin and act on the skin. As this is continuous, it is not what is expected in the present invention. Skin permeation modifiers selected from fatty acids, fatty acid alcohols, fatty acid esters, and ionic / nonionic surfactants have a slower and more sustained effect on skin permeation than solvents, leading to an initial excess release of the drug and thus to an effective blood concentration. It is not suitable for the purpose of the present invention to be reached quickly.

In the present invention, the skin permeation control agent may be used in an amount of 1 to 50% by weight, preferably 5 to 30% by weight based on the total weight of the polymer adhesive layer, and may be used as a mixed solvent in any ratio. If the content is too small, it is difficult to expect sufficient initial permeation of fentanyl due to deterioration of the skin permeation control action. If the content is too high, the fentanyl permeation is excessively increased, resulting in a risk of side effects and a decrease in physical properties of the pressure-sensitive adhesive layer. These solvent-type skin permeation regulators are mostly lost from the polymer adhesive layer within 24 hours after adhesion, so that the solubility of the drug in the adhesive layer is reduced to form a saturation state, thereby maintaining a constant thermodynamic activity and thus exhibiting a constant release rate.

In general, transdermal dosage forms are divided into reservoir and matrix types depending on the form. The reservoir type is a formulation in which a liquid reservoir containing a drug, a skin permeation control agent, a gelling agent, etc. is placed on the adhesive layer, and the edge is sealed by heat fusion as described in US Patent No. 4,588,580. There is a disadvantage, but it is easy to encapsulate a low boiling point solvent-type skin permeation control agent. In contrast, the matrix-type transdermal dosage form is formed by forming a protective layer with a thin polymer film after containing a drug in the adhesive layer. The method has a simple manufacturing method and a comfortable fit when attaching the skin. There are restrictions on compatibility and usage, and in particular, solvents having a boiling point of 120 ° C or lower are limited as a skin permeation regulator because hot air of 100 ° C or more is applied in the process of evaporating and removing the pressure-sensitive adhesive solvent.

The transdermal administration agent of the present invention adopts a matrix type composed of a single layer of adhesive and exhibits a good fit when attaching the skin, and at the same time, unlike the conventional matrix type transdermal administration agent, a solvent having a boiling point of 120 ° C or less is included as a skin permeation regulator. have. That is, in the present invention, by first preparing a matrix composed of drugs and adhesives, and then laminating the skin permeation regulator with an impermeable protective layer without applying heat by evaporating, absorbing, or spraying the matrix layer, the boiling point is 120 ° C or less. Solvents can be used.

One example of the matrix formulation according to the present invention may be a form composed of an impermeable protective layer (a), a polymer adhesive layer (b), and a release paper (c) as shown in FIG. 1.

The impermeable protective layer has the effect of preventing the loss of fentanyl, skin permeation control agents and other additives from the formulation during storage or adhesion to the skin, and polyethylene, polypropylene, polyolefin, polyurethane, polyvinyl chloride, ethylene vinyl It can be chosen from acetate copolymer films. The protective layer is preferably to have a suitable thickness to give a shape to the formulation, and may usually have a thickness of 10 to 300 ㎛, more preferably 25 to 100 ㎛ to give flexibility to the formulation.

The polymer adhesive layer is preferably prepared in a thickness of 10㎛ to 500㎛, more preferably 30㎛ to 150㎛ thickness.

The polymer adhesive layer is a layer that serves to attach the formulation to the skin at the same time as the reservoir of the drug. As a polymeric adhesive which forms the frame | skeleton of such a polymeric adhesive layer, 1 or more types of components chosen from the polyacrylate type | system | group, silicone type, and polyisobutylene type which are adhesives used normally can be used. The polymer adhesive used in the present invention has good compatibility with the solvent-type skin permeation control agent, and even after the skin permeation control agent is lost by diffusion from the adhesive layer, the solubility in fentanyl is sufficiently high so that the crystallization of the drug does not occur and the drug storage layer. It is preferable to select from the polyacrylate type | system | group adhesive which stability is maintained as. More preferably, it can select from the polyacrylate adhesive whose solubility of fentanyl to an adhesive is 10-300 micrograms / ml. If the solubility is too low, ethanol can be crystallized after the alcohol permeation agent exits the matrix, and if it is too high, the thermodynamic activity is lowered and the skin permeation rate is lowered.

In the conventional matrix formulation, the polymer adhesive layer is prepared by coating the adhesive solution dissolved in the solvent on a release paper and then evaporating and drying the solvent at a high temperature of 100 ° C. to 140 ° C. However, in the present invention, boiling points such as ethanol (bp 78 ° C), 2-propanol (bp 82 ° C), and 1-propanol (bp 97 ° C), which are used as skin permeation regulators, are evaporated and removed together with the adhesive solvent when dried. It may be preferable to manufacture in two steps as follows. In the first step, a pressure-sensitive adhesive solution is first coated on a release paper, and then the solvent is evaporated to dry to form a polymer adhesive layer. Then, in the second step, the coating and lamination process is completed by encapsulating the skin permeation control agent on the adhesive layer prepared in step 1 by evaporating, absorbing, spraying or discharging, and laminating the protective layer. Fentanyl, plasticizer, antioxidant and other additives may be mixed with the pressure-sensitive adhesive solution and coated, or first, the pressure-sensitive adhesive layer may be coated or dried and then discharged or sprayed together with the permeation control agent. Encapsulate in layers.

The monolayer matrix transdermal administration agent of the present invention is effective in transdermal administration of fentanyl in combination with rapid initial expression and sustainability. The design of such formulations of the present invention is accomplished by the selection and preparation of suitable skin permeation control agents that only increase the initial skin permeation rate without affecting the rate of drug permeation after mid-dose administration. In addition, the monolayer matrix transdermal formulation of the present invention can provide a new fentanyl transdermal formulation with improved fit when attached by designing a thin and flexible matrix.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1 Preparation of Polymer Adhesive Layer in Matrix Transdermal Formulation: Use of Polyacrylate Adhesive Polymer and Ethanol

A commercial product Durotax 87-4098 (National Starch & Chemical Ltd., New Jersey, USA) was selected as a polymer adhesive to prepare a transparent solution in which the fentanyl was added so that the drug content was 4.0% by weight after drying. . The pressure-sensitive adhesive solution was applied on a silicone-coated polyester (100 μm thick) film, and left at room temperature for 12 hours, followed by drying for 6 hours under vacuum reduced pressure to obtain a transparent adhesive film having a thickness of 65 μm. Matrix transdermal formulations made from DuroTak's tacky polymer showed a uniform and transparent surface. After drying, the adhesive film has a high adsorption property in air, and was stored in a petri dish at low temperature (4 ° C.).

The ethanol, the permeation control agent, was first poured into a petri dish container, and then the lid was closed and allowed to stand at room temperature for 24 hours to saturate the ethanol in air and then adhere the drug-containing polymer adhesive layer cut into squares (2 cm x 2 cm). It was performed by attaching a double-sided adhesive to the top of the inside of the petri dish lid with the side facing down and standing for a predetermined time.

Examples 2-12. Preparation of Polymer Adhesive Layer in Matrix Transdermal Formulation

According to the formulation of Table 1 below, the polymer pressure-sensitive adhesive layer of Examples 2 to 12 were prepared in the same manner as in Example 1 by changing only the type of the polymer adhesive and the permeation control agent and the exposure control agent.

Preparation of Polymer Adhesive Layer in Matrix Transdermal Formulation Polymer adhesive Permeation regulator Exposure time to penetration control agent (hours) Example 1 Polyacrylate: Durotax 87-4098 ¹⁾ ethanol 0.5 Example 2 Silicone: Bio-PSA 4302 ²⁾ ethanol 0.5 Example 3 Polyisobutylene: Durotax 87-6430 ¹⁾ ethanol 0.5 Example 4 Polyacrylate: Durotax 87-4098 Propanol 0.5 Example 5 Silicone: Bio-PSA 4302 Propanol 0.5 Example 6 Polyisobutylene: Durotax 87-6430 Propanol 0.5 Example 7 Polyacrylate: Durotax 87-4098 ethanol One Example 8 Silicone: Bio-PSA 4302 ethanol One Example 9 Polyisobutylene: Durotax 87-6430 ethanol One Example 10 Polyacrylate: Durotax 87-4098 Propanol One Example 11 Silicone: Bio-PSA 4302 Propanol One Example 12 Polyisobutylene: Durotax 87-6430 Propanol One Example 13 Polyacrylate: Durotax 87-4098 ethanol 1.5 Example 14 Silicone: Bio-PSA 4302 ethanol 1.5 Example 15 Polyisobutylene: Durotax 87-6430 ethanol 1.5 Example 16 Polyacrylate: Durotax 87-4098 Propanol 1.5 Example 17 Silicone: Bio-PSA 4302 Propanol 1.5 Example 18 Polyisobutylene: Durotax 87-6430 Propanol 1.5 Example 19 Polyacrylate: Durotax 87-4098 ethanol 2 Example 20 Silicone: Bio-PSA 4302 ethanol 2 Example 21 Polyisobutylene: Durotax 87-6430 ethanol 2 Example 22 Polyacrylate: Durotax 87-4098 Propanol 2 Example 23 Silicone: Bio-PSA 4302 Propanol 2 Example 24 Polyisobutylene: Durotax 87-6430 Propanol 2 Example 25 Polyacrylate: Durotax 87-4098 ethanol 2.5 Example 26 Silicone: Bio-PSA 4302 ethanol 2.5 Example 27 Polyisobutylene: Durotax 87-6430 ethanol 2.5 Example 28 Polyacrylate: Durotax 87-4098 Propanol 2.5 Example 29 Silicone: Bio-PSA 4302 Propanol 2.5 Example 30 Polyisobutylene: Durotax 87-6430 Propanol 2.5 Example 31 Polyacrylate: Durotax 87-4098 ethanol 3 Example 32 Silicone: Bio-PSA 4302 ethanol 3 Example 33 Polyisobutylene: Durotax 87-6430 ethanol 3 Example 34 Polyacrylate: Durotax 87-4098 Propanol 3 Example 35 Silicone: Bio-PSA 4302 Propanol 3 Example 36 Polyisobutylene: Durotax 87-6430 Propanol 3

1) National Starch & Chemical Ltd., New Jersey, USA

2) Dow Corning Products (Dow Corning, Michigan, USA)

Example 13. Preparation of Matrix Transdermal Formulations

A commercially available product, Durotak 87-4098 (National Starch & Chemical Ltd., New Jersey, USA) was selected as a polymer adhesive, and a polyester (100 μm thick) film coated with silicon was used as a release paper in the same manner as in Example 1. The ethanol-encapsulated polymer adhesive layer was prepared and laminated using a rubber roller together with a polyethylene film (Cotran 9720, 3M, USA) which is an impermeable protective layer. The prepared transdermal formulation is cut into the required size to remove the release paper and attached to the skin.

Comparative Examples 1-15. Preparation of Polymer Adhesive Layer in Matrix Transdermal Formulation

According to the formulation of Table 2, only the type of permeation control agent and the method of encapsulation were changed and the polymer adhesive layers of Comparative Examples 1 to 15 were prepared in the same manner as in Example 1. First, after the fentanyl and the permeation control agent was dried in the polymer adhesive solution, the content was uniformly mixed so as to be 4.0 wt% and 15.0 wt%, respectively, and a polymer adhesive layer was prepared by coating and drying in the same manner as in Example 1.

Preparation of Polymer Adhesive Layer in Matrix Transdermal Formulation Polymer adhesive Permeation regulator Comparative Example 1 Polyacrylate: Durotax 87-4098 - Comparative Example 2 Silicone: Bio-PSA 4302 - Comparative Example 3 Polyisobutylene: Durotax 87-6430 - Comparative Example 4 Polyacrylate: Durotax 87-4098 N-methylpyrrolidone Comparative Example 5 Polyacrylate: Durotax 87-4098 Glycerol Monooleate Comparative Example 6 Polyacrylate: Durotax 87-4098 Glycerol Monolaurate Comparative Example 7 Polyacrylate: Durotax 87-4098 Sorbitan monooleate Comparative Example 8 Polyacrylate: Durotax 87-4098 Sorbitan monolaurate Comparative Example 9 Polyacrylate: Durotax 87-4098 Propylene Glycol Monooleate Comparative Example 10 Polyacrylate: Durotax 87-4098 Ethyl oleate Comparative Example 11 Polyacrylate: Durotax 87-4098 Isopropyl myristate Comparative Example 12 Polyacrylate: Durotax 87-4098 Pyrrolidone laurate Comparative Example 13 Polyacrylate: Durotax 87-4098 Methyl laurate Comparative Example 14 Polyacrylate: Durotax 87-4098 Oleic acid Comparative Example 15 Polyacrylate: Durotax 87-4098 Dodecanol

Experimental Example 1. Experiment of encapsulation amount of permeation control agent

For the polymer adhesive layers prepared in Examples 1 to 36, the ethanol loading amount was determined from the weight increase amount before and after exposing the polymer membrane to the permeation control agent.

The results are shown in Table 3 as the average value of the three experiments, it was confirmed that the amount of permeation control agent increases with exposure time up to 3 hours.

Loading amount of permeation control agent Ethanol loading amount (% by weight) Propanol loading (% by weight) Example 1 16 Example 2 8 Example 3 6 Example 4 14 Example 5 9 Example 6 7 Example 7 28 Example 8 13 Example 9 8 Example 10 22 Example 11 11 Example 12 9 Example 13 40 Example 14 19 Example 15 12 Example 16 26 Example 17 18 Example 18 14 Example 19 42 Example 20 25 Example 21 14 Example 22 32 Example 23 24 Example 24 17 Example 25 45 Example 26 29 Example 27 15 Example 28 36 Example 29 28 Example 30 22 Example 31 49 Example 32 31 Example 33 18 Example 34 42 Example 35 30 Example 36 24

Experimental Example 2. Skin Permeation Experiment Ⅰ

The skin permeation test of fentanyl was carried out for the polymer adhesive layers prepared in Comparative Examples 1-3 and Examples 1-12. The prepared polymer adhesive layer was attached to a Franz diffusion cell (Franz diffusion cell, Crown Glass, Model FDC-400, USA) and then carried out at 32 ° C. A 50 mM phosphate buffer solution (pH = 6.0) was used as the release solution, and the percutaneous dosage form was attached to the skin collected from the back of the hairless mouse, and fixed at the center of the apparatus, and the release solution was stirred at 600 rpm. Samples of 0.4 ml each of the discharge solution were taken at regular intervals, and fresh solutions were replenished by the same amount. Fentanyl in the collected samples was analyzed under the following conditions using liquid chromatography, and the permeation amount was determined from the calibration curve.

<Liquid chromatography analysis conditions>

Column: Capcell Pak C8 UG120, 4.6mmx250mm (Shiseido CO., LTD., Japan)

Developing solvent: 0.23v / v% perchloric acid / acetonitrile (65:35 v / v%)

UV: 206 nm

Solvent Flow Rate: 0.5 ml / min

Sample loop: 100 ml

The transmission rates with time obtained from the results are shown in Tables 4 and 5. In all three types of adhesives, the initial permeation rate increased markedly within 12 hours with the addition of ethanol, and the increase in permeation rate was proportional to the ethanol content. After 24 hours, ethanol disappeared, resulting in a rate of penetration similar to that of the ethanol-free transdermal formulation. Propanol was used instead of ethanol as a permeation control agent.

Fentanyl Penetration Rate Through Skin from Ethanol-Containing Polymeric Adhesive Layer Polymer adhesive Ethanol content (% by weight) Average permeation rate per hour (mg / cm ² / hour) 0-6 hours 6-12 hours 12-24 hours 24 to 48 hours 48-72 hours Comparative Example 1 Polyacrylate 0 9.8 27.8 30.1 17.2 7.1 Example 1 16 32.1 43.6 31.1 19.7 9.2 Example 7 28 64.1 54.6 32.8 18.6 6.9 Comparative Example 2 silicon 0 9.5 22.5 26.8 11.7 9.2 Example 2 8 25.6 52.3 30.6 12.7 8.1 Example 8 13 37.5 53.3 39.1 9.3 9.3 Comparative Example 3 Polyisobutylene 0 2.7 9.3 12.4 6.8 3.8 Example 3 6 9.0 18.5 16.1 9.3 3.6 Example 9 8 16.3 25.8 22.8 11.7 4.3

Fentanyl permeation rate through the skin from the polymer adhesive layer containing propanol Polymer adhesive Propanol content (% by weight) Average permeation rate per hour (mg / cm ² / hour) 0-6 hours 6-12 hours 12-24 hours 24 to 48 hours 48-72 hours Comparative Example 1 Polyacrylate 0 9.8 27.8 30.1 17.2 7.1 Example 4 14 28.3 36.5 31.4 13.2 8.3 Example 10 22 43.6 48.5 29.2 15.3 5.6 Comparative Example 2 silicon 0 9.5 22.5 26.8 11.7 9.2 Example 5 9 23.5 46.3 28.2 11.9 7.3 Example 11 11 30.2 50.3 31.1 13.2 10.1 Comparative Example 3 Polyisobutylene 0 2.7 9.3 12.4 6.8 3.8 Example 6 7 8.3 19.2 15.8 8.1 4.2 Example 12 9 12.1 26.3 18.2 7.4 3.7

Experimental Example 3. Skin Permeation Experiment Ⅱ

In order to clearly confirm the skin permeation control function only at the beginning of the low boiling point solvents selected in the present invention, the skin permeation rate of the drug was compared with the polymer adhesive layers of Comparative Examples 4 to 15 prepared using other skin permeation control agents. Observed. Experimental method was the same as the skin permeation experiment of Experimental Example 2. Comparative Example 1, which did not use a permeation control agent, was used as a control.

The experimental results are shown in Table 6. Although there was a difference according to the type of permeation control agent, the skin absorption promoting effect was observed in all cases, and the skin permeability was improved in all time domains rather than the permeation pattern to improve initial permeation only. This has been shown to be inconsistent with the purpose of the present invention to effectively reduce only lag time for fast drug expression.

Fentanyl Permeation Rate Through Skin from the Polymeric Adhesive Layer of Comparative Example Permeation regulator Average permeation rate per hour (mg / cm ² / hour) 0-6 hours 6-12 hours 12-24 hours 24 to 48 hours 48-72 hours Comparative Example 1 - 9.8 27.8 30.1 17.2 7.1 Comparative Example 4 N-methylpyrrolidone 12.2 33.3 32.5 23.2 11.2 Comparative Example 5 Glycerol Monooleate 11.2 31.3 31.4 23.8 16.2 Comparative Example 6 Glycerol Monolaurate 9.2 26.8 32.9 18.3 9.1 Comparative Example 7 Sorbitan monooleate 13.1 32.9 34.3 22.1 13.2 Comparative Example 8 Sorbitan monolaurate 8.3 29.6 32.1 19.3 11.1 Comparative Example 9 Propylene Glycol Monooleate 9.7 28.3 29.4 18.6 8.2 Comparative Example 10 Ethyl oleate 9.3 28.2 30.4 17.8 9.1 Comparative Example 11 Isopropyl myristate 12.0 33.1 32.9 19.4 7.4 Comparative Example 12 Pyrrolidone laurate 10.6 30.5 34.1 21.3 11.6 Comparative Example 13 Methyl laurate 8.6 29.3 30.6 16.3 7.8 Comparative Example 14 Oleic acid 11.5 28.4 33.4 18.2 8.4 Comparative Example 15 Dodecanol 12.6 32.6 35.1 18.6 12.2

According to the present invention, by selecting an appropriate skin permeation control agent and controlling the permeation kinetics, the drug expression time is markedly increased and the duration is extended, so that fentanyl transdermal can exert a rapid and excellent effect in controlling moderate to severe pain. Dosage formulations are provided.

Claims (8)

(a) an impermeable protective layer, (b) a polymer adhesive layer and (c) a release paper as a basic structure, wherein the polymer adhesive layer comprises (i) a polymer adhesive, (ii) a base of a fentanyl or fentanyl analog as a drug, or A monolayer matrix transdermal agent comprising a salt and (iii) a solvent or a mixture of two or more solvents selected from the group of solvents having a boiling point of 120 ° C. or lower as a permeation control agent. 2. The solvent according to claim 1, wherein the permeation control agent is selected from the group consisting of ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and ethyl acetate Phosphorus monolayer matrix transdermal agent. The method of claim 1 or 2, wherein the permeation control agent is a monolayer matrix type transdermal agent containing 1 to 50% by weight based on the total weight of the polymer adhesive layer. 4. The monolayer matrix transdermal agent according to claim 3, wherein the content of the permeation control agent is 5 to 30% by weight based on the total weight of the polymer adhesive layer. The method of claim 1, wherein the polymer adhesive is a monolayer matrix type transdermal drug delivery agent selected from the group of polyacrylate-based, silicone-based, and polyisobutylene-based adhesives. The monolayer matrix transdermal agent according to claim 1, wherein the polymer adhesive layer has a thickness of 10 µm to 500 µm. 7. The monolayer matrix transdermal agent according to claim 6, wherein the polymer adhesive layer has a thickness of 30 µm to 150 µm. 1) coating the pressure-sensitive adhesive solution on the release paper, and evaporating and drying the solvent to form a polymer adhesive layer; and 2) encapsulating the protective layer by encapsulating the polymer permeation layer by evaporation, absorption, spraying or discharging the skin permeation control agent. The manufacturing method of the monolayer matrix type transdermal preparation of Claim 1 containing the process.