JP3280711B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption preparation of morphine hydrochloride or morphine sulfate, and more particularly to a percutaneous absorption preparation of morphine hydrochloride or morphine sulfate to which a percutaneous absorption enhancer is added.

[0002]

2. Description of the Related Art Morphine hydrochloride or morphine sulfate is a drug having a medicinal effect such as analgesic, antitussive and anti-photophoric activity, and has conventionally been administered to patients in the form of oral preparations, injections, suppositories and the like. However, the efficacy of oral preparations does not last for a long time, and the pain given to patients by needle sticks is great in injections, and suppositories improve the above two disadvantages to some extent but are not sufficient. There was discomfort due to the unique route of administration.

[0003] In recent years, in order to improve the drawbacks of the above administration routes,
Research on percutaneous absorption of morphine hydrochloride has been actively conducted. For example, it has been reported that morphine hydrochloride is dissolved in a solvent of l-menthol-ethanol-water and applied to the skin for percutaneous absorption ( Abstracts of the 6th Annual Meeting of the Pharmaceutical Society of Japan, The 7th Annual Meeting of the Pharmaceutical Society of Japan, Abstracts of the 6th Symposium on Transdermal Preparations). However, it is difficult to handle a solution obtained by dissolving morphine hydrochloride in water or ethanol, and it has not been possible to uniformly supply morphine to the human body by transdermal absorption for a long period of time.

[0004]

SUMMARY OF THE INVENTION In view of the above drawbacks, an object of the present invention is to provide a transdermal absorption preparation which can supply morphine hydrochloride or morphine sulfate uniformly over a long period of time and is easy to handle. I do.

[0005]

The support used in the present invention is preferably a material which is impermeable or hardly permeable to a drug and is flexible. Examples of the support include cellulose acetate, ethyl cellulose, polyethylene, polypropylene, and the like. Polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, polybutylene terephthalate, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene- A resin film such as a butyl acrylate-carbon monoxide copolymer, an aluminum sheet, or the like is used, and these may be a laminated sheet, or may be laminated with a woven or nonwoven fabric.

The base in the present invention comprises an adhesive, a transdermal absorption enhancer and morphine hydrochloride or morphine sulfate.
The pressure-sensitive adhesive only needs to be pharmaceutically acceptable, and examples thereof include pressure-sensitive adhesives at room temperature, such as acrylic pressure-sensitive adhesives and rubber pressure-sensitive adhesives.

[0007] The acrylic pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of an alkyl (meth) acrylate polymer, and is a functional monomer, a polyfunctional monomer, or a vinyl compound copolymerizable with the alkyl (meth) acrylate. And the like.

Examples of the above alkyl (meth) acrylate include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. Examples include acrylate, octyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, and stearyl (meth) acrylate.
In these alkyl (meth) acrylates, when the number of carbon atoms in the alkyl group is reduced, the cohesive strength is improved but the cohesive strength is reduced. Conversely, when the number of carbon atoms is increased, the cohesive strength is improved but the cohesive strength is reduced. Those having 2 to 18 carbon atoms are preferred.

Examples of the functional monomer copolymerizable with the alkyl (meth) acrylate include (meth) acrylic acid, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, butylmalate, and maleic acid. , Maleic anhydride, fumaric acid, crotonic acid and the like. The cohesion of the pressure-sensitive adhesive is improved by copolymerization with these functional monomers.

[0010] Examples of the polyfunctional monomer copolymerizable with the alkyl (meth) acrylate include, for example,
1,6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, diallyl phthalate, diallyl maleate, diallyl adipate, diallyl glycolate, triallyl isocyanurate, diethylene glycol bisallyl carbonate And the like. These polyfunctional monomers are copolymerized to improve the cohesive strength of the pressure-sensitive adhesive.

Further, as the vinyl compound copolymerizable with the alkyl (meth) acrylate, for example, ethylene, vinyl chloride, propylene, acrylonitrile, N-
Vinyl-2-pyrrolidone, vinyl acetate, styrene, α-
Methyl styrene, butadiene and the like can be mentioned. The cohesive force of the pressure-sensitive adhesive is improved by these vinyl compounds.

The acrylic pressure-sensitive adhesive has an alkyl (meth) acrylate as a main component, and other components are appropriately determined according to required performance. In the case of a functional monomer, it is generally copolymerized in an amount of 20% by weight or less in the pressure-sensitive adhesive, preferably 1 to 10% by weight. Moreover, in the case of a polyfunctional monomer, generally, 0.005 to
0.5% by weight is copolymerized. Further, in the case of a vinyl compound, it is generally copolymerized in an adhesive at 50% by weight or less, preferably at 40% by weight or less.

In particular, 2-ethylhexyl acrylate 5
5-89.5% by weight, polyfunctional monomer 0.005-
0.5% by weight and N-vinyl-2-pyrrolidone 10-4
5% by weight of the copolymer is preferred.

Further, a tackifier, a filler or the like may be added to the acrylic pressure-sensitive adhesive within a pharmaceutically acceptable range.

The rubber-based pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of a rubber elastic material, and generally contains a tackifier, and may optionally contain a softener and the like.

As the rubber elastic body, for example, cis-
1,4-isoprene, trans-1,4-isoprene,
Polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer,
Styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-
Examples include a styrene block copolymer, a styrene-olefin-styrene block copolymer, a styrene-isoprene-butylene block copolymer, and silicone rubber.

Examples of the tackifier include rosin, hydrogenated rosin, disproportionated rosin, rosin polymer, rosin ester, terpene resin, terpene phenol resin, petroleum resin, alkyl-phenol resin, xylene resin,
Coumarone resins, coumarone-indene resins, and the like.

Examples of the softener include process oil, palm oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, safflower oil, and coconut oil. And oil such as castor oil, polybutene, liquid isobutylene, liquid polyacrylate, beeswax, carnauba wax, lanolin and the like.

The above-mentioned percutaneous absorption enhancer has 2 to 2 carbon atoms.
8 oxycarboxylic and dicarboxylic acids are used.
When the number of carbon atoms is 9 or more, the absorption promoting effect is reduced, so that the number of carbon atoms is limited to 2 to 8, and examples of the oxycarboxylic acid include lactic acid, glyceric acid, tartaric acid, and citric acid.

The dicarboxylic acids include, for example, saturated aliphatic linear dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid and suberic acid, and fumaric acid and maleic acid. Saturated aliphatic linear dicarboxylic acids, phthalic acid, isophthalic acid, aromatic dicarboxylic acids such as terephthalic acid, and malic acid.

When the amount of the transdermal absorption enhancer is small, the effect of promoting the transdermal absorption of the drug is insufficient when the amount is small, and when the amount is large, the compatibility with the adhesive decreases. Medium 0.
1-10% by weight is preferred.

When the amount of morphine hydrochloride or morphine sulfate is decreased, the medicinal effect is reduced. On the contrary, when the added amount is increased, the sticking property of the pressure-sensitive adhesive is decreased.
% By weight is preferred.

In the transdermal absorption preparation of the present invention, crospovidone is further added to the base. This crospovidone is a cross-linked homopolymer of N-vinyl-2-pyrrolidone, as described in the United States Pharmacopeia NF XVII (official title), containing 11.0-12.8% by weight (anhydrous state). It is a substance containing a nitrogen atom in the range.

Examples of commercially available crospovidone include Kollidon CL (registered trademark) and Kollidon CL-M (registered trademark) manufactured by BASF, polyplasdone XL (registered trademark) manufactured by GAF, and polyplasdone. INF-10 (registered trademark), and the like. Also, methods for producing these compounds are described in U.S. Pat. Nos. 3,759,880 and 3,933,766.
No. 3,689,439, No. 4,139,688 and No. 4
180633.

Crospovidone has a moderate swelling property in water. Therefore, when a preparation containing crospovidone is administered to the skin, it absorbs water such as sweat and swells, thereby improving drug release. When the amount of crospovidone is small, the effect of promoting release of the drug is not sufficiently obtained when the amount is small, and when the amount is large, the adhesive property of the adhesive is reduced. Is preferred.

The thickness of the base layer is not particularly limited. However, if the base layer is thin, the medicinal effect cannot be obtained unless a large amount of drug is added, and the sticking property of the pressure-sensitive adhesive decreases. Conversely, if the thickness is too large, the drug in the formulation will not be effectively used, and the cost will only increase, and no improvement in performance can be expected. Therefore, 20 to 200 μm
Is more preferable, and more preferably 30 to 100 μm.

The composition of the percutaneous absorption preparation of the present invention is as described above. For example, the method of producing the percutaneous absorption preparation is to mix a pressure-sensitive adhesive, a drug, a percutaneous absorption enhancer and, if necessary, a crospovidone. A method of coating on a body and drying, or a method of coating on a release paper, drying and transferring to a support, or the like is used.

[0028]

Next, embodiments of the present invention will be described. Hereinafter, “parts” means “parts by weight”. (Synthesis of Adhesives A and B) A predetermined amount of monomer and 400.0 parts of ethyl acetate shown in Table 1 were supplied to a separable flask equipped with a stirrer and a cooling device, and the temperature was raised to 60 ° C. while stirring and purging with nitrogen. did. A solution prepared by dissolving 2.0 parts of lauroyl peroxide in 100.0 parts of cyclohexane was divided into 10 parts, and one of them was added to a separable flask to initiate polymerization. Thereafter, the remaining 9 was added one by one every one hour, and 240.0 parts of ethyl acetate was gradually added to carry out a polymerization reaction for 12 hours. After completion of the reaction, the mixture was cooled to a solid
Ethyl acetate was added to a weight percent.

[0029]

[Table 1]

(Examples 1 to 8, Comparative Examples 1 to 6) A predetermined amount of an adhesive, Kollidone CL, a transdermal absorption enhancer shown in Table 1,
The morphine hydrochloride was supplied to the dissolver, and the solid content concentration was 30.
Ethyl acetate was added to give a weight%, and the whole was uniformly mixed. The obtained liquid mixture is applied onto a silicon-treated polyethylene terephthalate film (thickness: 48 μm), dried to form an adhesive layer having a thickness of 80 μm, and then to a polyethylene terephthalate-ethylene · thickness of 38 μm.
It was transferred onto the ethylene / vinyl acetate copolymer layer of the vinyl acetate copolymer laminated film to obtain a transdermally absorbable preparation.

[0031]

[Table 2]

Using the obtained preparation, the amount of skin permeation (μg) was measured using the diffusion cell 1 shown in FIG. The diffusion cell 1 is composed of a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 arranged on the tank 2.
An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the bottom wall extends in the peripheral direction and is provided with a flange 5. A flange 6 is provided on the upper part of the receptor tank 2, and a sampling port 7 protruding laterally is attached to a side wall. The flange 5 and the flange 6 are overlapped facing each other, and the donor tank 3 and the receptor tank 2 are airtightly and concentrically stacked. A magnetic stirrer 9 is placed inside the receptor tank 2.

After a hairless mouse (6 weeks old, male) was killed by cervical dislocation, the skin on the back was immediately peeled off, and the subcutaneous fat and muscle layer were removed to obtain a skin piece 8 of about 5 cm × 5 cm.
The obtained skin piece 8 was sandwiched between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor layer 3 was completely closed by the skin piece 8. The obtained transdermal absorption preparation 10 was circular (3.
It was cut into 14 cm ² ) and attached to the center of the skin piece 8 so that the adhesive layer was in contact with the skin piece 8.

The receptor layer 2 was filled with a receptor solution, placed in a thermostat maintained at a temperature of 37 ° C., and stirred by rotating a magnet stirrer 9 with a magnet stirring device. Twenty-four hours after the start of the test, 1 ml of the receptor solution was collected from the sampling port 7, and the amount of the drug in the collected receptor solution was measured by high-performance chromatography. Upon collection of the receptor liquid, the receptor liquid was replenished after collection. The test was performed with n = 2, and the average value was calculated.
The results are shown in Table 2.

The receptor solution was NaH ₂ PO ₄ 5 × 10 ^-4
mol, Na ₂ HPO ₄ 2 × 10 ^-4 mol, NaCl 1.5 × 10 ^-1 mol and gentamicin 10 mg were dissolved in 500 ml of distilled water.
After adjusting the pH to 7.2 with a 0.1N aqueous solution, the volume was adjusted to 1000 ml with distilled water.

[0036]

The composition of the percutaneous absorption preparation of the present invention is as described above. It can be easily produced and can be easily used, and morphine hydrochloride or morphine sulfate is supplied uniformly over the skin having keratin for a long period of time. It is possible. In addition, the percutaneous absorption preparation of the present invention contains at least one transdermal absorption enhancer selected from the group consisting of oxycarboxylic acids and dicarboxylic acids having 2 to 8 carbon atoms. It has excellent absorbability, and when crospovidone is added, more excellent transdermal absorbability is obtained.

Therefore, the percutaneous absorption preparation of the present invention provides pain,
It can be effectively applied to patients presenting symptoms such as cough and diarrhea.

[Brief description of the drawings]

FIG. 1 is a perspective view showing a diffusion cell.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Diffusion cell 2 Receptor tank 3 Donor tank 4 Opening 5, 6 Flange 7 Sampling port 8 Skin piece 9 Magnetic stirrer 10 Transdermal absorption preparation

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-104516 (JP, A) JP-A-2-56429 (JP, A) JP-A-4-217926 (JP, A) JP-A-61- 254532 (JP, A) JP-A-62-181226 (JP, A) JP-A-62-126119 (JP, A) JP-A-6-40947 (JP, A) (58) Fields investigated (Int. ⁷ , DB name) A61K 31/485 A61K 9/70 A61K 47/12 A61P 29/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A pressure-sensitive adhesive , having 2 to 2 carbon atoms, on one surface of a support.
And one or more percutaneous absorption enhancer selected from the group consisting of 8-hydroxy carboxylic acids and dicarboxylic acids, Kurosupobi
Don and, morphine hydrochloride or transdermal absorption preparation of the morphine sulfate, comprising base from which are stacked.