JP2000044476A - Fentanyl-containing percutaously absorbable administration matrix type patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a newly prepared fentanyl-containing percutaneously absorbable administration matrix type patch including fentanyl or a salt thereof, having easiness for administration and control of adjustment of dosage and also, short percutaneous absorption delay time (time for cutaneous permeation rate to reach its steady state) (within 4 h) and capable of stably maintaining its effects by keeping stable blood concentrations. SOLUTION: This fentanyl-containing percutaneous absorbable administration matrix type patch is obtained by including fentanyl or a salt thereof in a tacky base consisting of a hydrophobic tack agent, a hydrophilic tack agent and N-methyl-2-pyrrolidone. This patch exhibits the percutaneously absorbable delay time for the drug of within 4 h. In the patch, fentanyl or a salt thereof is compounded at 1-10 wt.%; the hydrophobic tack agent at 10-50 wt.%; the hydrophilic tack agent at 5-30 wt.%; and N-methyl-2-pyrrolidone at 2-10 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a transdermal matrix patch containing fentanyl (chemical name: N- (1-phenethyl-4-piperidyl) propionanilide or a salt thereof and having excellent skin permeability. It is used for the purpose of maintaining the effects of anesthesia and analgesia.

[0002]

2. Description of the Related Art Fentanyl or a salt thereof is known as a drug having a high analgesic effect, but has a short biological half-life and thus has no sustained effect. There was no effective administration method for long-term pain such as cancer pain. In the United States, a long-lasting reversal type patch preparation (trade name: DURAGESIC) containing fentanyl base is commercially available, but there is a problem in controlling the dose (dose rate). That is, when the dose is controlled, it is only controlled by an integral multiple of the dose per preparation due to structural restrictions, and fine control cannot be performed. In addition, one application time was as long as 72 hours (3 days), which was not preferable in view of the patient's quality of life (QOL) such as restrictions on bathing. Further, the percutaneous absorption delay time (lag time: time until the skin permeation rate reaches a steady state) is 8 hours (the permeation rate hardly permeates until the fourth hour, and the permeation rate increases in 4 to 8 hours) And for a long time, Journal of Pai
n Management Vol. 7 No. 3 (S
uppl) April 1992 "Transderm
al Fentanyl's Clinical Phar
Because of the complexity of the treatment, which is used as a maintenance therapy after the first intravenous injection in macology, the development of a transdermal absorption matrix patch, which is a simpler dosage form from the viewpoint of compliance, has been developed. Is desired. Since fentanyl citrate has a very low solubility in a non-aqueous base, the skin permeability of the drug is very low in a non-aqueous base transdermal administration tape, and clinical application has been considered impossible.

On the other hand, as a means for solving these drawbacks, attempts have been made with a transdermal absorption matrix type patch. For example, a fentanyl-containing transdermal administration tape containing fentanyl or a salt thereof, a pressure-sensitive adhesive (polyisobutylene and styrene-isoprene-styrene block copolymer), and sodium acetate has been invented (Japanese Patent Application Laid-Open No. Hei 10 (1998)).
-45570). Although this preparation improves skin permeability through the formation of ion pairs with fentanyl citrate by sodium acetate, it is not satisfactory in terms of transdermal absorption delay time.

[0004]

SUMMARY OF THE INVENTION In view of the above-mentioned drawbacks of the prior art, an object of the present invention is to contain fentanyl or a salt thereof, to facilitate the administration method, and to control the adjustment of the dosage. Is simple, has a short transdermal absorption delay time (time until the skin permeation rate reaches a steady state) (within 4 hours), and maintains a stable effect by maintaining a stable blood concentration. It is an object of the present invention to provide a fentanyl-containing transdermal absorption matrix-type patch of a novel formulation which can be used.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies and have found that fentanyl is added to a hydrophobic adhesive, a hydrophilic adhesive and an adhesive base to which N-methyl-2-pyrrolidone is added as a dissolution aid. Alternatively, by incorporating a salt thereof, a percutaneous absorption administration type patch having a sustained and excellent percutaneous permeability of the drug and a short percutaneous absorption delay time (lag time) has been found. It has been completed. Fentanyl or a salt thereof is 1 to 10% by weight,
10 to 50% by weight of the hydrophobic adhesive, 5 to 5% of the hydrophilic adhesive
It is preferable to contain 30% by weight and 2 to 10% by weight of N-methyl-2-pyrrolidone as a solubilizer. When the amount of fentanyl or a salt thereof is less than 1% by weight, sufficient skin permeability cannot be obtained as a transdermal matrix patch, and when it exceeds 10% by weight, the physical properties of the adhesive layer are adversely affected. . It is preferred to use fentanyl citrate as the salt of fentanyl. As the hydrophobic pressure-sensitive adhesive, an (A-B) n-A type elastic polymer is used, and a styrene-butadiene-styrene block copolymer (Califlex TR-1101 manufactured by Shell Chemical), styrene-
Isoprene-styrene block copolymer (Califlex TR-1107, Califlex TR-
Although 1111) is used, a styrene-isoprene-styrene block copolymer is preferably used. The hydrophilic pressure-sensitive adhesive is not particularly limited, but it is preferable to use polyvinylpyrrolidone. In that case, it is blended at a ratio of 5 to 30% by weight based on the weight of the entire pressure-sensitive adhesive layer. When the amount is less than 5% by weight, sufficient skin permeability as a transdermal matrix patch cannot be obtained, and when it exceeds 30% by weight, the physical properties of the pressure-sensitive adhesive layer are adversely affected.

The adhesive layer of the fentanyl matrix type patch of the present invention contains 2 to 10% by weight of N-methyl-2-pyrrolidone as a dissolution aid for fentanyl or a salt thereof. Fentanyl or the like cannot be uniformly dissolved and dispersed in the agent layer. If the amount exceeds 10% by weight, the physical properties of the pressure-sensitive adhesive layer are adversely affected.

In the pressure-sensitive adhesive layer of the preparation of the present invention, in addition to the above, an absorption enhancer can be added as required. As the absorption enhancer, any substance can be used as long as it has a percutaneous absorption promoting effect. For example, as a higher fatty acid ester having 7 or more carbon atoms and a higher aliphatic alcohol, a higher fatty acid ester or a higher aliphatic alcohol obtained from a fatty acid having 6 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms is used. Examples of the fatty acids having 6 to 18 carbon atoms that can form such higher fatty acid esters or higher fatty alcohols include adipic acid, myristic acid, palmitic acid,
Oleic acid, vaccenic acid, linoleic acid, linolenic acid and the like can be mentioned. As an alcohol having 1 to 20 carbon atoms,
Examples include methanol, ethanol, propanol, isopropanol, butanol, hexanol, pentanol, heptanol, octanol, decanol, and cetanol. The higher fatty acid ester includes isopropyl myristate, diisopropyl adipate, diethyl sebacate and the like, and the higher aliphatic alcohol includes myristyl alcohol and oleyl alcohol. One or a combination of two or more of these fatty acid esters and / or aliphatic alcohols may be used. Further, sodium acetate, which is a transdermal absorption enhancer used in the prior art, may be added in a weight ratio of fentanyl or a salt thereof to sodium acetate of 1: 0.01 to 0.1.

The pressure-sensitive adhesive base layer used in the transdermal patch has low tackiness, and therefore, a tackifier may be added to the pressure-sensitive adhesive layer in order to impart tackiness to the preparation. Examples thereof include rosin derivatives (eg, rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester), alicyclic saturated hydrocarbon resins, polyterpene resins, and the like. The tackifier is desirably blended at a ratio of 10 to 60% by weight based on the total weight of the pressure-sensitive adhesive layer of the preparation of the present invention.

In order to adjust the adhesiveness and improve the processability of the transdermal administration matrix type patch of the present invention, a softener may be added to the adhesive base layer. Examples of the softener include petroleum hydrocarbons (liquid paraffin), crotamiton, N
-Methyl-2-pyrrolidone, liquid rubber (eg, polybutene, liquid isoprene rubber), liquid polybutene rubber, and the like. The softening agent is desirably blended at a ratio of 10 to 60% by weight based on the total weight of the pressure-sensitive adhesive layer of the present invention.

The pressure-sensitive adhesive layer having the above composition can be produced by any method. For example, in the case of manufacturing by a dissolution method, the pressure-sensitive adhesive to be blended is dissolved in an organic solvent, uniformly stirred after adding other components, spread on a support, and dried to obtain the present preparation. . In the case of a thermoplastic pressure-sensitive adhesive, the present preparation can be obtained by dissolving the pressure-sensitive adhesive at a high temperature, adding other components, stirring uniformly, and spreading the mixture on a support.

[0011] Further, in the transdermal administration matrix type patch preparation of the present invention, if the composition of the pressure-sensitive adhesive layer is as described above,
The other layers and components constituting them are not particularly limited, and may be composed of any layer. For example, the transdermal administration matrix type patch of the present invention is composed of a support layer, a release liner layer, and the like in addition to an adhesive layer,
As the support, a support usually used for a patch such as a tape or a patch is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate (PET), and plastic vinyl acetate.
Examples include vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polypropylene, polyvinylidene chloride, aluminum, and the like. These are used, for example, as a sheet (film) of a carbon layer or a laminate of two or more layers. As a material other than aluminum, a woven fabric or a nonwoven fabric may be used.

The thickness of the adhesive base layer is related to the flexibility of the adhesive patch and the adhesive strength of the obtained adhesive base layer. When applied to human skin, the adhesive base layer must have a thickness of at least 10 microns, preferably 20 microns or more, in order to impart sufficient adhesive strength. On the other hand, when the thickness of the adhesive base layer is increased, the drug concentration is reduced, and the rate of transfer of the drug to the surface of the adhesive base layer is reduced, so that the drug utilization is also reduced. In the case of manufacturing by a solvent method, residual solvent increases and skin irritation worsens, which causes rash. For this reason, the thickness of the adhesive base layer is 200 microns or less. Preferably it is less than 100 microns.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail with reference to specific embodiments. Hydrophobic pressure-sensitive adhesive (styrene-isoprene-styrene block copolymer and hydrophilic pressure-sensitive adhesive (polyvinylpyrrolidone), dissolution aid (N-methyl-2-pyrrolidone), etc.) having the composition shown in Tables 1 to 3 below are used. After dissolving in a solvent and further adding other components, the mixture is uniformly stirred and spread on a support to a predetermined thickness, and after drying, the formulations of Examples 1 to 9 are obtained. Formulations were prepared without the addition of a water-soluble adhesive and optionally with the addition of sodium acetate as an absorption enhancer, and fentanyl citrate was used as a drug. Are measured and the percutaneous absorption delay time (lag time), the steady skin permeation rate (Flux), and the accumulated permeation amount are shown in Tables 1 to 3.

Test Method After the purchased frozen human skin was thawed to remove the fat layer on the dermis side, water at 37 ° C. was circulated around the outer periphery of the receptor tank containing a magnetic stirrer so that the dermis side became a receptor. Was mounted in a 2-chamber cell. The matrix-type patches obtained in Examples 1 to 9 and Comparative Examples 1 to 3 were stuck on the stratum corneum side, and 2.5 mL of purified water at 37 ° C. was put in a receptor tank, and the receptor solution was stirred by a magnet stirrer. went. 2.0 mL of the receptor solution was contacted at predetermined intervals for 72 hours after the start of the test, and immediately thereafter, 2.0 mL of a new receptor solution was replenished. The drug concentration of the contacted receptor solution was measured by high performance liquid chromatography. Based on the measured amount of fentanyl, steady-state skin permeation rate (Flux) and lag time in human skin were calculated.

[0015]

[0016]

[0017]

[0018]

As described above, according to the matrix-type patch for transdermal administration according to the present invention, it is possible to obtain a preparation having a percutaneous absorption delay time of 4 hours or less, which is not available in the prior art, as well as fentanyl or Since the salt penetrates the skin in a short time and is continuously absorbed, it is an effective treatment for pain patients who have difficulty in oral administration. In addition, the burden on the patient can be reduced as compared with the continuous administration method by infusion. Also, by cutting the preparation, the dosage can be easily adjusted according to the condition of the patient (for example, symptoms, age, weight, sex). Further, the preparation according to the present invention can enable clinical application of fentanyl citrate, which has conventionally been considered to have very low skin permeability.

[Brief description of the drawings]

FIG. 1 is a time chart of 0 to 72 hours showing the accumulated transmission amounts of Examples 1 to 3 and Comparative Example 1.

FIG. 2 is a time chart of 0 to 12 hours showing the accumulated transmission amounts of Examples 1 to 3 and Comparative Example 1.

FIG. 3 is a time chart of 0 to 72 hours showing the accumulated transmission amounts of Examples 4 to 6 and Comparative Example 2.

FIG. 4 is a time chart of 0 to 12 hours showing the accumulated transmission amounts of Examples 4 to 6 and Comparative Example 2.

FIG. 5 is a time chart of 0 to 72 hours showing the accumulated transmission amounts of Examples 7 to 9 and Comparative Example 3.

FIG. 6 is a time chart of 0 to 12 hours showing the accumulated transmission amounts of Examples 7 to 9 and Comparative Example 3.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Shigeru Imoto 3-8-19 Nitta, Adachi-ku, Tokyo Toko Yakuhin Kogyo Co., Ltd. F-term (reference) 4C076 AA74 BB31 CC01 DD41 DD41A DD45A DD60A EE04A EE16A EE48A EE55A FF31 FF68 4C086 AA01 AA02 BC08 BC21 GA14 MA03 MA05 MA32 MA63 NA10 NA12 ZA08 ZA21

Claims (4)

[Claims] 1. Fentanyl or a salt thereof is contained in an adhesive base comprising a hydrophobic adhesive, a hydrophilic adhesive and N-methyl-2-pyrrolidone, and the percutaneous absorption delay time of the drug is within 4 hours. A fentanyl-containing transdermal administration matrix-type patch, characterized in that: 2. Fentanyl or a salt thereof is 1 to 10% by weight, a hydrophobic adhesive is 10 to 50% by weight, a hydrophilic adhesive is 5 to 30% by weight, and N-methyl-2-pyrrolidone is 2 to 2%.
The fentanyl-containing transdermal administration matrix type patch according to claim 1, which is blended so as to be 10% by weight. 3. The fentanyl-containing transdermal administration matrix type patch according to claim 1, wherein the salt of fentanyl is fentanyl citrate. 4. The fentanyl-containing transdermal administration according to claim 1, wherein the hydrophobic adhesive is a styrene-isoprene-styrene block copolymer, and the hydrophilic adhesive is polyvinylpyrrolidone. Matrix type patch.