JP6235407B2 - Fentanyl-containing patch - Google Patents

Description

  The present invention relates to a fentanyl-containing transdermal administration tape preparation.

  Fentanyl is the chemical name 1-phenethyl-4-N-propionyl-anilino-piperidine and is a synthetic analgesic used for anesthesia, analgesia and pain relief. In addition to injections, patches have been developed and widely used as preparations containing fentanyl.

  As a fentanyl-containing patch, a transdermal administration tape preparation (Patent Document 1) containing fentanyl or a salt thereof, an adhesive and sodium acetate, and a basic drug salt and a powder average particle diameter is 0.1 to 100 μm. A patch preparation comprising an organic acid salt (Patent Document 2) has been reported.

Japanese Patent Laid-Open No. 10-45570 Japanese Patent Laid-Open No. 11-302161

However, in Patent Document 1, since the solubility of sodium acetate that promotes the absorption of fentanyl is low in the pressure-sensitive adhesive, a large amount of sodium acetate results in a non-uniform preparation, and there is a problem that the adhesiveness decreases. . Patent Document 2 describes that it is necessary to grind in order to reduce the particle diameter in order to uniformly disperse such sodium acetate in the pressure-sensitive adhesive.
Accordingly, an object of the present invention is to provide a fentanyl-containing transdermal administration tape preparation that does not require any pulverization step, has excellent transdermal absorbability, and has no problems such as crystal precipitation.

  Therefore, the present inventors conducted various studies for promoting good percutaneous absorption of fentanyl and seeking good components such as dispersibility in an adhesive, and when fentanyl was combined with an alkali metal caprylate, It was found that the transdermal absorbability was remarkably improved and a stable tape preparation without defects such as crystal precipitation in the adhesive could be obtained without any pulverization process, and the present invention was completed.

  That is, the present invention provides the following [1] to [5].

[1] A transdermal administration tape preparation containing fentanyl or a salt thereof, an alkali metal caprylate and an adhesive.
[2] The transdermal administration tape preparation according to [1], wherein the content molar ratio (A / B) of fentanyl or a salt thereof (A) to an alkali metal caprylate (B) is 0.1-1.
[3] The transdermal area according to [1] or [2], wherein the content molar ratio (A / B) of fentanyl or a salt thereof (A) to an alkali metal caprylate (B) is 0.1 to 0.5. Administration tape formulation.
[4] The transdermal administration tape preparation according to any one of [1] to [3], wherein the content of fentanyl or a salt thereof is 0.5 to 8% by mass with respect to the entire adhesive layer.
[5] The transdermal administration tape preparation according to any one of [1] to [4], wherein the adhesive is a rubber adhesive or an acrylic adhesive.

  The transdermal administration tape preparation of the present invention is superior in transdermal absorbability of fentanyl and is easy to manufacture because it does not require pulverization and the like. Can be supplied.

It is a figure which shows the release rate of fentanyl in this invention tape formulation with time. It is a figure which shows the skin permeation amount of the fentanyl from this invention tape formulation with time. It is a figure which shows the digital microscope image of the coating solution of Example 2 and Comparative Example 2. FIG.

  The transdermal administration tape preparation of the present invention comprises (A) fentanyl or a salt thereof, (B) an alkali metal caprylic acid salt, and (C) an adhesive.

(A) Fentanyl or a salt thereof is an active ingredient of the transdermal administration tape preparation of the present invention and an analgesic. Examples of the salt of fentanyl include inorganic acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as citrate, tartrate, and fumarate. Organic acid salts are preferable, and citrate is particularly preferable. preferable.
(A) The content of fentanyl or a salt thereof is preferably 0.5 to 8% by mass with respect to the mass of the entire pressure-sensitive adhesive layer of the transdermal administration tape preparation of the present invention from the viewpoint of stable blendability and transdermal absorbability. 1-8 mass% is more preferable, and 1-6 mass% is further more preferable.

(B) The alkali metal caprylate is considered to have an action of promoting percutaneous absorption of fentanyl or a salt thereof, and an action of stably dissolving or dispersing fentanyl or a salt thereof in the pressure-sensitive adhesive layer. Examples of the alkali metal caprylate include sodium caprylate and potassium caprylate, and sodium caprylate is particularly preferable from the viewpoint of promoting transdermal absorption of fentanyl or a salt thereof and stability in the pressure-sensitive adhesive layer.
The content of (B) alkali metal caprylate is the molar ratio of (A) and (B) in terms of (A) fentanyl or its salt percutaneous absorption promoting action and stability in the adhesive layer ( A / B) is preferably from 0.1 to 1, more preferably from 0.1 to 0.5, and even more preferably from 0.1 to 0.4.

(C) As an adhesive, a rubber adhesive or an acrylic adhesive is preferable. Examples of rubber adhesives include styrene / isoprene / styrene copolymer (SIS), polyisobutylene rubber (PIB), isoprene rubber, styrene / butadiene / styrene copolymer (SBS), styrene butadiene rubber, and silicone rubber. It is done. Acrylic acid alkyl ester is mentioned as an acrylic adhesive.
0.1-98 mass% is preferable with respect to the whole adhesive layer, as for content of an adhesive, 0.1-70 mass% is more preferable, and 0.1-50 mass% is further more preferable.

  The adhesive layer of the transdermal administration tape preparation of the present invention further comprises a tackifier, a plasticizer, another absorption accelerator, a solubilizer, an antioxidant, an ultraviolet absorber, silicic anhydride, bentonite, polyvinylpyrrolidone ( PVP), hydroxypropyl cellulose (HPC), starch acrylate and the like can be added.

  Examples of the tackifier include rosin resins, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, maleic resins, and the like. Plasticizers include liquid paraffin, polybutene, higher fatty acid esters (isopropyl myristate, isopropyl palmitate, diisopropyl adipate, diethyl sebacate, etc.), triacetin, triethyl citrate, squalane, squalene, vegetable oil (castor oil, jojoba oil, Olive oil, etc.). Other absorption promoters include higher alcohols (oleyl alcohol, myristyl alcohol, stearyl alcohol, etc.), higher fatty acid esters (isopropyl myristate, isopropyl palmitate, diisopropyl adipate, diethyl sebacate, etc.), polyhydric alcohol fatty acid esters, Examples include polyoxyethylene alkyl ether. Examples of the solubilizer include N-methylpyrrolidone, polyhydric alcohol (propylene glycol, glycerin, polyethylene glycol, butanediol, etc.), crotamiton and the like. Examples of the oxidizing agent include dibutylhydroxytoluene (BHT), dibutylhydroxyanisole (BHA), sodium bisulfite, sodium sulfite, ascorbic acids and the like.

  The transdermal administration tape preparation of the present invention preferably has a form having a support and a liner for the pressure-sensitive adhesive layer containing the above components. The support is preferably a polyester film laminated with a nonwoven fabric such as polyester, polypropylene or polyethylene. As the liner, a polyester film having a silicone-based or fluorine-based release coating is preferable.

  The transdermal administration tape preparation of the present invention can be produced by a method (organic solvent method) or hot melt method in which the components constituting the pressure-sensitive adhesive layer containing the above components are dissolved in an organic solvent and applied. The solvent method is preferred from the viewpoint of drug stability. As the organic solvent, toluene, ethyl acetate, heptane, hexane and the like, and a mixed solvent of two or more of these can be used as appropriate.

  The transdermal administration tape preparation of the present invention can be stored by sealing a plurality of sheets in a sealing bag.

  EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.

1. Preparation of formulation samples Example 1:
SIS, PIB, alicyclic saturated hydrocarbon resin, dibutylhydroxytoluene (BHT) and liquid paraffin were added to an organic solvent (appropriate amount) and dissolved to obtain a base solution.
Separately, fentanyl citrate and sodium caprylate were added to crotamiton and dissolved by stirring while heating to about 80 ° C. to obtain an active ingredient solution.
The active ingredient solution was added to the base solution and stirred to obtain a coating solution.
A coating solution was applied and dried on the silicone-treated surface of the polyester film subjected to silicone treatment, and then the support was laminated and cut into a predetermined size as a preparation sample.
As the support, a polyester film laminated with a polyester nonwoven fabric was used.
The coating amount of the coating solution was adjusted so that the amount of fentanyl citrate per formulation sample (40 cm ² ) was 8 mg.

Furthermore, a preparation sample was prepared in the same manner as in Example 1 according to (Table 1).
However, in Comparative Example 1, since sodium caprylate was not added, fentanyl citrate was in a dispersed state in the active ingredient solution.
In Comparative Example 2, sodium acetate was added instead of sodium caprylate.
Sodium acetate used was pulverized with a mortar. In addition, although data are not shown, when sodium acetate is not crushed, fentanyl citrate and sodium acetate do not form an ion pair well, and a sufficiently good preparation is obtained for a release test and a skin permeation test. I couldn't.

2. Release test The Japanese Pharmacopoeia dissolution test method was applied mutatis mutandis and the paddle over disc method was used.
That is, a double-sided tape was applied to the support side so that the adhesive surface was on top, and the preparation was fixed to a disk and used for the test.
500 mL of isotonic phosphate buffer (pH 7.4) was used as the test solution, and the test solution was kept at a constant temperature of 32 ° C. and stirred at 50 rpm.
At a predetermined time after the start of the test, a test solution was collected and used as a sample solution.
Fentanyl citrate in the sample solution was quantified by high performance liquid chromatography to determine the release rate (%) of fentanyl citrate.

3. Skin Permeation Test Male hairless mouse 7-week-old abdominal excised skin was attached to a horizontal diffusion cell (Chem. Pharm. Bull. 37 (5) 1404-1406 1989), and a prescribed preparation sample was applied to the stratum corneum side. .
On the other hand, 2.5 mL of isotonic phosphate buffer (pH 7.4) was applied as a receiving solution to the receiver side (dermis side).
During the test, the receiving liquid was kept at 32 ° C. and stirred using a magnetic stirrer.
1 mL of the receiving solution was collected at a predetermined time and used as a sample solution. Immediately after collecting the sample solution, 1 mL of a new isotonic phosphate buffer was replenished.
Fentanyl citrate in the sample solution was quantified by high performance liquid chromatography to determine the amount of fentanyl citrate permeation (μg / cm ² ).

4). Method for observing crystals in coating solution and preparation The sample was observed using a digital microscope (HIROX KH-8700 type) (magnification 400).

  Table 1 shows the formulation of the preparation sample, release properties (release rate at 8 hours), skin permeability (cumulative penetration amount at 8 hours), and presence or absence of crystals.

  The release rate of fentanyl and the amount of skin permeation are shown in FIGS. Furthermore, the digital microscope image of the coating solution of Example 2 and Comparative Example 2 is shown in FIG.

As is clear from Table 1 and FIGS. 1 to 3, a tape preparation in which an adhesive layer is formed by blending an alkali metal caprylate with fentanyl or a salt thereof has high skin permeability and release properties. Further, a uniform coating solution and a tape preparation without crystals can be obtained without performing a pulverization step.
On the other hand, when sodium acetate is used, even if pulverization is performed, an active ingredient solution in which fentanyl or a salt thereof and sodium acetate are completely dissolved cannot be obtained. When an insoluble substance of fentanyl or a salt thereof and sodium acetate is present in the coating solution, the insoluble substance is caught on the coater in the coating process, so-called drawing occurs, resulting in a decrease in yield. Furthermore, the presence of insoluble matter results in a non-uniform formulation or a formulation with poor adhesion.

Claims (3)

Fentanyl citrate (A) , sodium caprylate (B) and a rubber-based adhesive, and the molar ratio (A / B) of (A) and (B) is 0.1 to 0.5 Skin preparation tape formulation. The transdermal administration tape preparation according to claim 1, wherein the content of fentanyl citrate is 0.5 to 8 mass% with respect to the entire rubber-based pressure-sensitive adhesive layer. Fentanyl citrate (A), sodium caprylate (B) and rubber-based pressure-sensitive adhesive, and the molar ratio (A / B) of (A) and (B) is 0.1 to 0.5 A method for producing a skin administration tape preparation, wherein fentanyl citrate and sodium caprylate are dissolved in an organic solvent and applied.