JPH04202140A - Percutaneously absorbable preparation - Google Patents

Abstract

PURPOSE:To obtain a percutaneously absorbable preparation containing an ester compound having a long-chain hydrocarbon group in the molecule, capable of effectively absorbing a medicine and reducing the irritancy to skin. CONSTITUTION:The objective percutaneously absorbable preparation for giving a required medicine into circulatory organ system by penetrating through in vivo membranes when applied externally and usable as a tape, patch, cataplasm, cream, ointment, etc., consisting of a viscous or non-viscous base, medicines and a compound expressed by formula wherein R is 7-17C hydrocarbon group; X is H or alkali metal, e.g. 2-stearoyloxy-propane-1,2,3-tricarboxylic acid, and as necessary, further containing percutaneous absorbing agents such as ethanol and glycerol. The compound expressed by the formula has a moderating action on skin irritancy caused by perspiration induced by medicines, absorbation promotors used in combination or sealing thereby with bandages. The mixing ratio of the compound is within the range of 0.5-30wt% based on the total amount of the preparation.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to tapes and patches that are applied to the skin and used to deliver the required drug to the body's circulatory system through biological membranes. , percutaneous absorption preparations such as poultices, creams, and ointments.

(Prior art) Traditionally, oral preparations, injections, suppositories, etc. have been adopted as appropriate dosage forms for administering drugs into the body, but in recent years, the development of transdermal absorption preparations has become more active due to the following advantages: It is progressing. In other words, in transdermal absorption preparations, ■Drugs absorbed into the body do not pass through the liver during the first circulation; therefore, as in the case of oral administration, drugs absorbed in the intestines circulate to the liver where they are metabolized and their medicinal efficacy increases. There is no disadvantage of decreasing

■Less mental burden and physical pain on patients compared to injections.

■It is easy to maintain the blood concentration at the required level for a long period of time, and continuous administration over a long period of time is possible.

■Administration can be easily interrupted as necessary, such as when a concentration that causes side effects is reached.

By the way, this type of transdermal absorption preparation administers the drug to the body's circulatory system via the stratum corneum of the skin, which has a barrier function to prevent foreign substances from entering the body, so it does not achieve the desired drug efficacy. It is not always possible to administer a sufficient amount of drug to induce the expression of symptoms.

Conventionally, as a countermeasure against impaired drug absorption by the skin, for example, occlusive bandage therapy has been performed, in which the skin at the site of administration of the drug is covered with a non-moisture permeable material. This method involves covering the skin with a moisture-impermeable material to prevent moisture from evaporating from the skin and making the stratum corneum on the skin's surface hydrated and looser, thereby promoting transdermal absorption of drugs.

In addition, various absorption enhancers have been developed as a method for promoting transdermal absorption of drugs to a higher degree, and many transdermal absorption preparations containing these have been proposed. For example, those using (polyhydric) alcohols as absorption enhancers (JP-A-62-2
30710, JP-A-1-68323, JP-A-1-2
68648), products using natural moisturizing factors and their derivatives (see JP-A-62-187415), keratin emollients, aprotic solvents, oils and fats.
Those using essential oils (see JP-A-1-1868''24 and JP-A-1-228920), those using surfactants (JP-A-62-132828, JP-A-6)
3-208537), those using fatty acids (see JP-A-63-313731), and those using fatty acid esters (JP-A-1-25720,
(see JP-A No. 1-174355), those using 1-dodecyl azacyclohebutan-2-one (see JP-A No. 62-61918), and those using similar substances (see JP-A No. 62-61918). No. 62-164662, JP-A-63-6
6172 and Japanese Patent Laid-Open No. 63-215665).

(Problem to be Solved by the Invention) However, with the above-mentioned prior art transdermal absorption preparation, when trying to increase the amount of drug absorbed through the skin, the drug may irritate the skin during the period of application of the transdermal absorption preparation. There is a problem of receiving.

That is, in occlusive bandage therapy, skin irritation occurs due to sweating. In general, absorption enhancers do have the effect of promoting transdermal absorption of drugs, but since they exert some kind of effect on the skin, they all have the disadvantage of being highly irritating to the skin. In particular, absorption enhancers that are highly effective in promoting percutaneous absorption tend to cause strong skin irritation. Furthermore, absorption enhancers may cause a phenomenon in which the drug itself becomes irritating due to its high concentration in the skin as a result of promoting absorption of the drug. As described above, the current situation is that a transdermal absorption preparation that allows drugs to be efficiently absorbed and causes less skin irritation has not yet been developed.

In view of the above-mentioned circumstances, an object of the present invention is to enable transdermal absorption of a sufficient amount of a drug to exert the desired medicinal effect, and to reduce skin irritation caused by an absorption enhancer as much as possible. To provide transdermal absorption preparations.

(Means for Solving the Problems) As a result of repeated studies to achieve the above object, the present invention has revealed that when a specific compound is added to a preparation, transdermal permeability of the drug improves and there is little to no skin irritation. It was completed with the knowledge that it would disappear.

That is, the transdermal absorption preparation according to the present invention comprises a base, a drug, and the general formula % (wherein R means a hydrocarbon group having 7 to 17 carbon atoms, and X means a hydrogen atom or an alkali metal atom, respectively). ) (hereinafter referred to as "ester compound (I)").

As the base for the transdermal absorption preparation according to the present invention, an adhesive base is used in the case of tapes and poultices, and a non-adhesive base is used in the case of ointments, creams and patches.

Further, the transdermal absorption preparation according to the present invention may further contain an absorption enhancer, if necessary.

a) In the transdermal absorption preparation according to the present invention, the ester compound (I) has surfactant ability due to its characteristic molecular structure of having a long-chain hydrocarbon group in the molecule, and itself has good effects on the skin. It is a substance that exhibits excellent absorbency. Ester compound (1) also has the effect of reducing skin irritation caused by sweating due to drugs, absorption enhancers, or occlusive bandage therapy.

In the ester compound (1), the hydrocarbon group represented by R is limited to those having 7 to 17 carbon atoms. The reason is that when the number of carbon atoms is less than 7, the hydrophilicity of the molecule is too strong and the absorption into the skin is poor, and the above effects are not expressed.
On the other hand, if the number of carbon atoms exceeds 17, the effect of inhibiting the fluidity of skin lipids appears, which adversely affects the transdermal absorption of the drug. The hydrocarbon group represented by R has 11 carbon atoms.
Particularly preferred are those in the range of 13 to 13.

Ester compound (1) can be synthesized by a known method. For example, U.S. Pat.
3-) IJ carboxylic acid), and R is CH(CH2)1
4 (2-palmitoyloxy-propane-
1,2,3-4 recarboxylic acids), for example, the latter is said to be produced by reacting balmitoyl chloride and citric anhydride in ether.

Ester compound (1) contained in the transdermal absorption preparation of the present invention
), the concentration of the adhesive or non-adhesive base, the drug, the ester compound (I), and the absorption enhancer, humectant, inorganic filler, viscosity modifier, crosslinking agent, Additives such as anti-aging agents, solubilizers, pH adjusters, etc.
A range of 0.5 to 30% by weight is preferred in Sτ-mass@-sum. If the concentration of the ester compound (I) is too high, the proportion of the base in the above-mentioned total will be too small, and if the concentration of the ester compound (1) is too low, the effect will not appear, so either case is preferable. do not have.

b) Other absorption enhancers may be used in combination with the ester compound (1) depending on the absorption amount of the drug.

Ester compound (I) is effective in reducing skin irritation caused by absorption enhancers.

The absorption enhancer used in combination with ester compound (I) may be any conventionally known one and is not particularly limited.

Examples of absorption enhancers include ethanol, isostearyl alcohol, oleyl alcohol, propylene glycol, 1,3-butanediol, glycerin,
-pyrrolidone, 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone,
1-methyl-2-pyrrolidone-5-carboxylic acid, pyrrolidone carboxylic acid alkyl ester, ethyl lactate, myristyl lactate, urea, salicylic acid, dimethyl sulfoxide,
Decyl methyl sulfoxide, olive oil, castor oil, polyoxyethylene lauryl ether, polyoxyethylene lauryl ether sulfate, polyoxyethylene lauryl ether phosphate, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, N-lauroyl sarcosine, lauric acid jetanolamide, oleic acid, linoleic acid, lylunic acid, isopropyl myristate,
Examples include isopropyl palmitate, diethyl sebacate, diethyl adipate, and diisopropyl adipate. Two or more of these absorption enhancers may be used in combination.

When used together with an absorption enhancer, the concentration of the absorption enhancer is determined by the adhesive or non-adhesive base, the drug, the ester compound (I), the absorption enhancer, and the humectant added as necessary as described below.
One tablet of additives such as inorganic fillers, viscosity modifiers, crosslinking agents, anti-aging agents, solubilizers, pH adjusters, etc.
A range of 0.01 to 30% by weight is preferred during the summation.

If the concentration of the absorption enhancer is too high, the proportion of the base in the above-mentioned total will be too small, and if the concentration of the absorption enhancer is too low, the effect will not be manifested, so either case is not preferable.

C) The drug (physiologically active substance) used in the transdermal absorption preparation of the present invention is not particularly limited as long as it can permeate biological membranes transdermally. Examples of drugs include antipyretic and antiinflammatory analgesics, steroid anti-inflammatory agents, vasodilators, hypertension and
Arrhythmia agents, antihypertensive agents, antitussive expectorants, anti-inflammatory agents,
Local anesthetics, hormones, asthma/nasal allergy treatments,
Antihistamines, anticoagulants, antispasmodics, cerebral circulation/metabolism improvers, antidepressants/anxiolytics, vitamin D preparations, hypoglycemic agents,
Examples include antiulcer agents, sleeping pills, and antibiotics.

Examples of antipyretic and antiinflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminof-11-ene, diclofenac sodium, ibuprofen,
Examples include sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac 1 phenylbutacine, mefenamic acid, pendazac, piroxicam, flurbiprofen, pentazocine, buprenorphine hydrochloride, butorphanol tartrate.

Examples of steroidal anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fluorousiltide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethacin, betamethasone acetate, diflucortolon valerate, clobetasol propionate, and fluocinonide. Examples include.

Examples of vasodilators include diltiazem, verapamil,
Examples include pentaerythritol tetranitrate, dipyridamole, isosorbide nitrate, nifedipine, and nitroglycerin.

Examples of agents for hypertension and arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and sisopyramide.

Examples of antihypertensive agents include clonidine hydrochloride, captopril, prazosin hydrochloride, penbutolol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, elanabril maleate, atenolol hydrochloride, bunitrol hydrochloride, and the like.

Examples of antitussive and expectorant agents include procaterol hydrochloride, terbutaline sulfate, phenotyrol hydrobromide, tubuterol hydrochloride, amproxol hydrochloride, pirbutyol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride, and formotyol fumarate. It will be done.

Antitumor agents include 5-fluorouracil, 1-(2-
Examples include (tetrahydrofuryl)-5-fluorouracil, mitomycin C, and the like.

Examples of local anesthetics include pensicaine, prophylaxis, lidocaine, and tetracaine.

Examples of hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone, and prostaglandin, and peptide hormones such as insulin.

Examples of therapeutic agents for asthma and nasal allergies include ketotifen fumarate, azelastine hydrochloride, and sodium cromoglycate.

Examples of antihistamines include cyclohebutadine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, and mequitazine.

Examples of anticoagulants include heparin.

Examples of antispasmodics include scopolamine and clofluperol.

Examples of cerebral circulation/metabolism improving agents include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, provincamine fumarate, dihydroergotoxin mesylate, isosemprodil tartrate, isoxsuprine hydrochloride, and the like.

Examples of antidepressants and anxiolytics include maprotiline hydrochloride, etizolam, diazepam, promazepam, amitributyline hydrochloride, mianserin hydrochloride, and the like.

Examples of vitamin D preparations include alfacalcidol,
Examples include ergocalciferol.

Examples of hypoglycemic agents include glibenclamide, gliclacit, and the like.

Examples of anti-ulcer agents include levobride malate, famotidine, glycopyrronium bromide, and the like.

Examples of sleeping pills include phenobarbital, amobarbital, and the like.

Examples of antibiotics include tetracycline and chloramphenicol.

The blending amount of these drugs varies depending on the type of drug and the purpose of use of the transdermal absorption preparation, but it usually includes an adhesive or non-adhesive base, a drug, an esthetics level regulator, a crosslinking agent, an anti-aging agent, A0 information on additives such as solubilizers and pH adjusters! al
The amount is in the range of 0.1 to 30% by weight in the total composition.

d) Dosage forms of the transdermal absorption preparation of the present invention include tapes, batches, poultices, creams, and ointments.

Among these dosage forms, tape preparations contain a drug, an ester compound (1), and an absorption enhancer added as necessary in an adhesive as an adhesive base. The batch agent consists of a reservoir layer (non-adhesive base layer) and an adhesive layer, and the reservoir layer contains a drug, an ester compound (1), and an absorption enhancer added as necessary. This is what was given. This reservoir layer is applied to the skin via an adhesive layer, and the drug in the reservoir layer is transdermally absorbed through the adhesive layer. However, the drug, ester compound (1), etc. in the reservoir layer may also be included in the adhesive layer.

d-1) As the non-adhesive base for the reservoir layer of the batch agent, conventionally known external bases can be used, such as white vaseline, silicone oil, carboxyvinyl polymer,
Examples include polyvinyl alcohol, polyethylene glycol, and liquid paraffin.

d-2) The adhesive base of the tape preparation and the adhesive of the adhesive layer of the batch preparation should have excellent compatibility with the absorption enhancer and have adhesive strength that can fix the preparation to the skin surface for a long time at room temperature. It is not particularly limited as long as it has. Preferred adhesives include:
Acrylic adhesives, rubber adhesives, silicone adhesives, etc. are used.

As the acrylic pressure-sensitive adhesive, in particular (
Homopolymers or copolymers of alkyl meth)acrylates and/or copolymers of the alkyl (meth)acrylates and other functional monomers are preferably used.

The above (meth)acrylic esters include butyl acrylate, isobutyl acrylate, hexyl acrylate,
Octyl acrylate, 2-ethylhexyl acrylate,
Isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, meth, acrylic acid Examples include decyl, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like. Examples of monomers having a hydroxyl group include 2-hydroxyethyl (meth)acrylate, hydroxypropyl (
Hydroxyalkyl (meth) such as meth)acrylates
An example is acrylate. Monomers having a carboxyl group include α-acrylic acid, methacrylic acid, etc.
Examples include β-unsaturated carboxylic acid: maleic acid monoalkyl ester such as butyl maleate, maleic acid, fumaric acid, crotonic acid, and the like. Maleic anhydride also provides the same (co)polymerization component as maleic acid. Examples of monomers having an amide group include alkyl (meth) such as acrylamide, dimethylacrylamide, diethylacrylamide, etc.
Acrylamide: Examples include alkyl ether methylol (meth)acrylamide such as butoxymethylacrylamide and ethoxymethylacrylamide, diacetone acrylamide, and the like. Examples of monomers having an amino group include dimethylaminoethyl acrylate and vinylpyrrolidone.

As copolymerizable monomers other than those mentioned above, vinyl acetate, vinyl alcohol, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, etc. can also be used. It is preferable that the adhesive contains at least 50% by weight of (meth)acrylic acid alkyl ester as a (co)polymerization component.

If necessary, a polyfunctional monomer is further added to the acrylic pressure-sensitive adhesive and copolymerized with other monomer components. The addition of this polyfunctional monomer causes very slight crosslinking between the resulting polymers, thereby increasing the internal cohesive strength of the adhesive. Therefore, the so-called adhesive residue phenomenon when the patch is removed can be almost eliminated, regardless of the properties of the skin to which it is applied or the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on drug release properties or low skin irritation. Examples of such polyfunctional monomers include di(meth)acrylate, tri(meth)acrylate, and tetra(meth)acrylate.
It is not limited to this. More specifically, di(meth)acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth)acrylic acid; and polyalkylene glycols such as polyethylene glycol and polypropylene glycol. Di(meth)acrylate obtained by combining with (meth)acrylic acid; trimethylolpropane tri(meth)acrylate and glycerin tri(meth)acrylate
and tetra(meth)acrylates such as pentaerythritol tetra(meth)acrylate. These polyfunctional monomers may be used in combination of two or more types. The polyfunctional monomer is used in an amount of 0.005 to 0.5% by weight based on the total monomers used in the production of the adhesive. When the amount of polyfunctional monomer used is less than 0.005% by weight,
The effect of improving internal cohesive force due to crosslinking is small, and
When the weight percentage exceeds 21, the adhesive obtained by polymerization is
= Easily causes gelation, which also affects drug diffusion and release.

As a rubber adhesive, adhesive (=J A composition containing 20 to 200 parts by weight of a preservative and an appropriate amount of a softener, a stabilizer, etc. is used.

As the silicone adhesive, one whose main component is polydimethylsiloxane or the like is used.

The above adhesives include tackifiers such as rosin resins, polyterpene resins, coumaron-indene resins, petroleum-based resins, and terpene-phenol resins; liquid polybutene, mineral oil, lanolin', liquid polyisoprene, and liquid polyacrylates. Compounding agents such as plasticizers; fillers and anti-aging agents are added as necessary.

d-3) As a support for tapes and patches, it is flexible but imparts self-supporting properties to transdermal absorption preparations, and an adhesive base layer (adhesive base, drug, ester compound (■)
, and absorption enhancers added as necessary, moisturizers, inorganic fillers, viscosity modifiers, crosslinkers, anti-aging agents,
Among additives such as solubilizers and pH adjusters, layered materials consisting of non-volatile components are used, which serve to prevent volatilization and migration of the drug in the middle and reservoir layers. Materials for the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, There are aluminum, etc. These materials are used, for example, as a single layer sheet or film or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics. As the support, one made of a material that has conformability to the skin surface is suitably used, and a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is particularly preferred. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

A tape preparation is constructed by forming an adhesive base layer on the surface of the support. The patch agent is constructed by sequentially laminating a reservoir layer and an adhesive layer on the surface of the support. A suitable control membrane may be present between the adhesive layer and the adhesive layer in the patch.

d-4) A normal adhesive tape manufacturing method can be applied to form the adhesive base layer. A typical example is the solvent coating method, and in addition to this, there are hot melt coating methods, electron beam curing emulsion coating methods, etc. The obtained solution or dispersion is directly applied to the surface of the support and dried to form an adhesive base layer of a required thickness. Alternatively, this solution or dispersion may be applied onto a protective release paper, and after drying, the resulting adhesive base layer may be brought into close contact with the support. The thickness of the adhesive base layer varies depending on the purpose of use, but is usually 30 to 2
It is in the range of 00 μm. If the thickness is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. If the thickness exceeds 200 μm, the drug contained in the adhesive base layer near the support will not be sufficiently diffused, resulting in a decrease in drug release properties.

d-5) The tape usually has a release paper on its application surface to protect the surface of the adhesive base layer until use. The batch agent has a release paper in the adhesive layer. As the release paper, a material obtained by siliconizing a polyethylene terephthalate film is often used, but the release paper is not limited to this. The thickness of the release paper is 100 μm or less, preferably 5 to 50 μm.

e) A poultice is a drug-containing paste containing an adhesive base, a drug, an ester compound (I), and an absorption enhancer added as necessary, and is less sticky than a supporting tape or batch. Therefore, it is fixed to the skin surface with a bandage, etc. Poultice bases include, for example, natural polymers such as alkali metal alginates, gelatin, corn starch, and gum tragacanth; cellulose polymers such as methyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose; starch polymers such as dextrin and carboxymethyl starch. Synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone are used.

To produce poultices, the adhesive base, drug, ester compound (■), and absorption enhancer added if necessary are mixed uniformly, and the resulting drug-containing paste is spread on one side of the support. Apply in layers. The drug-containing paste further contains purified water, humectants, inorganic fillers, viscosity modifiers, crosslinkers,
It may also contain anti-aging agents and the like. As the humectant, glycerin, propylene glycol, etc. are used, and as the inorganic filler, kaolin, bentonite, zinc white, titanium dioxide, etc. are used.

f) Creams and ointments are drug-containing pastes made by uniformly mixing a non-adhesive base, a drug, an ester compound (1), and an absorption enhancer added as necessary. As the base, beeswax, fats and oils, lanolin, white petrolatum, paraffin, plastibase, higher fatty acids, higher alcohols, emulsifiers, macrogol, carboxyvinyl polymers, etc. are used.

Creams and ointments contain fat-soluble solubilizers, purified water,
A water-soluble solubilizer, pH adjuster, etc. may also be contained. As the fat-soluble dissolving agent, liquid paraffin, isopropyl myristate, diethyl sebacate, etc. are used, and as the water-soluble dissolving agent, ethanol, glycerin, propylene glycol, etc. are used.

g) The transdermal absorption preparations in various dosage forms thus obtained are:
Usually for the purpose of administering drugs transdermally into the body's circulatory system.
Applied directly to the skin surface. Furthermore, this transdermal absorption preparation may be pasted or applied to the skin for the purpose of treating diseased areas of the skin.

(Function) (a) Since the transdermal absorption preparation according to the present invention contains the ester compound (I), a sufficient amount of drug can be absorbed transdermally to exert the desired medicinal effect. I can do it.

The mechanism of action of ester compound (1) on the skin is thought to be as follows. Ester compound (1) has a characteristic molecular structure in which it has a long-chain hydrocarbon group within its molecule, and thus has surface-active ability and itself exhibits good absorption into the skin.

This compound therefore acts as a non-irritating absorption enhancer, allowing sufficient amounts of the drug to be absorbed through the skin.

(b) Ester compound (I) reduces skin irritation caused by sweating caused by drugs, absorption enhancers, or occlusive bandage therapy, although its mechanism of action is not clear.

(C) Skin irritation caused by absorption enhancers for promoting drug absorption is alleviated by the ester compound (1) as described above, so depending on the required absorption amount of the drug, other absorption enhancers may be used. Can be used together without any problems.

(Examples) Next, in order to specifically explain the present invention, several examples corresponding to the present invention and comparative examples for comparison therewith will be given, and furthermore, the obtained transdermal absorption preparations will be described. The performance test is shown below.

(a) Production Example 1 of transdermal absorption preparation 1) 2-Lauroyloxy-propane-1; 2.3-
Synthesis of tricarboxylic acid (referred to as ester compound (a)) Ester compound (a) was obtained as a compound of general formula (1) by performing operations according to the synthesis method described in U.S. Patent No. 2,636,887. .

That is, 12.5 g of citric acid was dissolved in 120 ml of tetrahydrofuran while heating, and when the liquid temperature reached 50°C, 14.2 g of lauroyl chloride was added, and the temperature was increased to 6.
Refluxing was carried out at 7°C for 2 hours. Then, 90 g of benzene was added and the reaction solution was cooled to room temperature. The obtained white crystals were filtered, washed once each with benzene and n-hexane, and dried.

Thus, ester compound (a) Log was prepared.

if) Preparation of acrylic adhesive 37 g of 2-ethylhexyl acrylate, 317 g of 2-ethylhexyl methacrylate and 51 g of dodecyl methacrylate were placed in a separable flask, and further 174 g of ethyl acetate was added to adjust the monomer concentration to 70% by weight. did.

This solution was heated to a temperature of 70° C. under a nitrogen atmosphere, and a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane and 220 g of ethyl acetate were added little by little, and a polymerization reaction was carried out for 12 hours.

In this way, an ethyl acetate solution of an acrylic pressure-sensitive adhesive having a solid content concentration of 45% by weight was obtained. 1ff) Preparation of Coating Solution To the obtained adhesive solution, an ethyl acetate solution containing isosorbide nitrate as a drug and a tetrahydrofuran solution containing the ester compound (a) obtained in step i) were added to the obtained adhesive solution to adjust the solid content (
The total weight concentration of the adhesive, drug, and ester compound (a) is 35% by weight, and the solid concentrations of isosorbide nitrate and ester compound (a) are 6% and 5% by weight, respectively. The entire solution was mixed uniformly using a day silver.

A coating solution containing the patch formulation was thus prepared.

jv) Preparation of tape 38 μm thick polyethylene terephthalate (PET)
Step i
j+) was applied and dried at 60°C for 30 minutes to form an 80 μm thick adhesive base layer. about,
Copolymer of PET and ethylene-vinyl acetate (PET-E
A support with a thickness of 34 μm made by laminating VA) was brought into close contact with the adhesive base layer. In this way, a tape preparation was prepared as a transdermal absorption preparation.

Comparative Example 1 In step fit) of Example 1, the ester compound (a
) was not used, but other operations were carried out in the same manner as in Example 1 to prepare a tape preparation.

Comparative Example 2 In step 1ii) of Example 1, the ester compound (a
), lauric acid was used as an absorption enhancer at a blending ratio of 5% by weight in solid content, and other operations were carried out in the same manner as in Example 1 to prepare a tape preparation.

Example 2 1) 2-octanoyloxy-propane-1°2.3
-Synthesis of tricarboxylic acid (referred to as ester compound (b)) Octanoyl chloride is used instead of lauroyl chloride.
8 g of ester compound (b) was prepared using the same procedure as in step i) of Example 1 except for using the following procedure.

ii) Preparation of acrylic adhesive 470 g of 2-ethylhexyl acrylate.

A separable flask was charged with 50 g of vinylpyrrolidone and 0.762 g of a 10% by weight solution of hexanediol dimethacrylate in ethyl acetate, and then 520 g of ethyl acetate was added.
g was added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60° C. under a nitrogen atmosphere, and a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane and 349 g of ethyl acetate were added little by little, and a polymerization reaction was carried out for 12 hours.

In this way, an ethyl acetate solution of an acrylic pressure-sensitive adhesive having a solid content concentration of 35% by weight was obtained. -1゛1゛mount) Preparation of coating solution Add estradiol as a drug to the obtained adhesive solution.
A tetrahydrofuran solution containing lauric acid jetanolamide as an absorption enhancer and the ester compound (b) obtained in step 1) was mixed with solid content (weight sum of adhesive, drug, absorption enhancer, and ester compound (b)). concentration is 25
% by weight, and the solid concentrations of estradiol, lauric acid jetanolamide, and ester compound (b) are 10% by weight, 5% by weight, and 8% by weight, respectively.
% by weight, and the entire liquid was uniformly mixed using a day silver.

A coating solution containing the patch formulation was thus prepared.

iv) Preparation of tape preparation: By the same operation as in step iv) of Example 1, an adhesive base layer was formed on a release paper made of silicone-treated PET, and a = 34- support made of PET-EVA was added to this layer. A tape preparation was prepared as a transdermal absorption preparation.

Comparative Example 3 In step 1ij) of Example 2, the ester compound (b
) in place of acetyl citric acid at a solid concentration of 8% by weight.
A tape preparation was prepared by using the following blending ratio and performing other operations in the same manner as in Example 2.

Example 3 1) Synthesis of 2-oleyloxy-propane-1,2°3-tricarboxylic acid (referred to as ester compound (C))], 2.5 g of citric acid and 19.5 g of oleoyl chloride were mixed in 2001 Mix with diethyl ether and boil the mixture for 30
The mixture was stirred for 3 days under reflux at °C. The diethyl ether was then removed under reduced pressure and the resulting viscous liquid was washed twice with ethanol.

In this way, 1 g of ester compound (c) was prepared.

ji) Preparation of rubber adhesive Natural rubber (manufactured by Japan Synthetic Rubber Co., Ltd.) 100 as a rubber elastic body
Based on the parts by weight, 60 parts by weight of terpene resin (manufactured by Yasushi Kogyo Co., Ltd., YS Resin Pxl15-:300) as a tackifier, and liquid polybutene (manufactured by Nisseki Chemical Co., Ltd., H
V-300) 140 parts by weight were each dissolved in 1200 parts by weight of tetrahydrofuran to give a solid content concentration of 20% by weight.
A tetrahydrofuran solution of a rubber adhesive having the following properties was obtained.

Hi) Preparation of coating liquid Indomethacin as a drug, polyoxyethylene (2) lauryl ether as an absorption enhancer, and the ester compound (C) obtained in step 1) are added to the obtained adhesive solution.
solid content (weight sum of adhesive, drug, absorption enhancer, and ester compound (c))
so that the concentration is 15% by weight, and indomethacin,
The solid concentration of polyoxyethylene (2) lauryl ether and ester compound (C) is 3% by weight, respectively.
They were added in amounts of 2% by weight and 10% by weight, and the entire liquid was uniformly mixed using a day silver.

A coating solution containing the patch formulation was thus prepared.

iv) Preparation of tape By the same operation as in step iv) of Example 1, an adhesive base layer is formed on a release paper made of silicon-treated PET, and a support made of PET-EVA is brought into close contact with this layer. A tape preparation was prepared.

Comparative Example 4 In step i'i+) of Example 3, the ester compound (
A tape preparation was prepared in the same manner as in Example 3 except that C) was not used.

Comparative Example 5 In step jN) of Example 3, the ester compound (C)
A tape preparation was prepared in the same manner as in Example 3 except that polyoxyethylene (2) lauryl ether was not used.

Example 4 1) 2-lauroyloxy-propane-1°2.3-
Synthesis of sodium tricarboxylate (referred to as ester compound (d)) 2 g of ester compound (a) obtained in step i) of Example 1
0.1 N Na while stirring in 200 ml of distilled water.
159 ml of OH aqueous solution was added in portions. The reaction solution was then heated to dryness under reduced pressure.

In this way, 2.3 g of ester compound (d) was prepared.

if) Preparation of ointment Plastibase (manufactured by Nippon Squibb Co., Ltd., external gelling hydrocarbon Plastibase 50W) as a non-adhesive base
Piroxicam as the drug, lauroylsarcosine as the absorption enhancer, and the powder of the ester compound (d) obtained in step l) were added to the non-adhesive base, the drug, the absorption enhancer, and the ester compound (d). ) were added so that the respective concentrations in the total sum were 2.5% by weight, 1% by weight and 5% by weight, and the formulations were evenly mixed in a mortar.

Thus, an ointment was prepared.

Comparative Example 6 In step if) of Example 4, the ester compound (d)
An ointment was prepared in the same manner as in Example 4 except that the ointment was not used.

Comparative Example 7 In step ++) of Example 4, ester compound Cd)
An ointment was prepared in the same manner as in Example 4 except that lauroylsarcosine was not used.

(b) Performance evaluation of transdermal absorption preparations i) Rat skin transfer test For each tape preparation obtained in Examples 1 to 3 and Comparative Examples 1 to 5, drug transfer to rat skin was performed using the method shown in Test 1. A sex test was conducted.

Test 1 A circular test piece of tape (area: 3° 14 cm2) was applied to the depilated back of a rat (Wistar strain, male, 7 weeks old), and after 24 hours it was peeled off and collected. The number of repetitions was 5 for each tape.

These recovered test pieces were extracted with methanol, and the remaining amount of the drug in the tape was measured by high performance liquid chromatography. The difference between the initial amount of drug in the tape and the amount remaining after the test was defined as the amount of drug transferred to the rat skin over 24 hours, and the ratio of the transferred amount to the initial amount of drug was defined as the transdermal absorption rate.

Table 1 summarizes the transdermal absorption rates for each tape preparation.

ii) Rat skin permeability test For each of the ointments obtained in Example 4 and Comparative Examples 6.7, a drug permeability test on excised rat skin was conducted using the method shown in Test 2.

Test 2 First, a diffusion cell (1) shown in the attached drawing was prepared. The diffusion cell (1) consists of a bottomed cylindrical tank (2) on the lower side and a bottomed cylindrical donor tank (3) placed above this. An opening (4) is provided in the center of the bottom wall of the donor tank (3), and an upper flange (5) and a lower flange (6) are provided at the lower end of the donor tank (3) and the upper end of the receptor tank (2), respectively. ) are provided, and an upper flange (5) and a lower flange (6).
Donor tank (3)
and a receptor tank (2) are stacked airtightly and concentrically. A laterally protruding sampling port (A) is attached to the side of the receptor tank (2), and a magnetic stirrer (9) is placed inside the receptor tank (2).

Rat with hair removed from the back (Wistar strain, male, 7 weeks old)
After sacrificing the animal by cervical dislocation under ether anesthesia, the depilated skin was immediately peeled off and the subcutaneous fat and subcutaneous layer were removed.
A piece of skin measuring cm×4 cm was obtained. This piece of skin (8) is attached to the upper flange (5) and lower flange (6) of the diffusion cell (1).
) to completely close the opening (4) of the donor tank (3) with the skin piece (8).

PET-EVA punched into a circular shape with an area of 3.14cm2
100 mg of ointment (jO) was applied to the PET side of the film, and it was attached to the upper surface of the skin piece (8). The receptor tank (2>) was filled with a receptor solution prepared by the following method.

Then, the diffusion cell (1) was placed in a constant temperature bath maintained at a temperature of 37° C., and the receptor liquid was stirred using a magnetic stirring device. 24 hours after the start of the test
7), and the amount of drug permeated into this receptor fluid was measured by high performance liquid chromatography. The ratio of the amount of permeation to the initial amount of drug in each ointment was defined as the percutaneous absorption rate.

Table 1 summarizes the percutaneous absorption rates for each ointment.

Preparation of receptor fluid Na H2P 04 (5X 10-' mol),
Na 2HPO4 (2xlO-' mol), NaCl
(1°5 x 10-' mole) and centamine 10
Dissolve mg in 500 ml of distilled water, and the pH of the resulting solution
was adjusted to 7.2 with a 0.1N NaOH aqueous solution, and then the volume was adjusted to 10100O with distilled water.

Ni) Rat skin irritation test The tapes and ointments obtained in Examples 1 to 4 and Comparative Examples 1 to 7 were tested for irritation to rat skin by the method shown in Test 3.

Test 3 For the tape preparations of Examples 1 to 3 and Comparative Examples 1 to 5, the skin of rats treated in the same manner as Test 1 was
One hour after the tape was removed, the state of erythema on the skin was visually observed. For the ointments of Example 4 and Comparative Example 6.7, PE punched in a circular shape with an area of 3.14 cm
100 mg of the ointment was applied to the T-EVA film and applied to the depilated back of the rat. After 24 hours, the ointment was removed, and the state of erythema on the skin after removal was visually observed.

The number of repetitions was 5 for each formulation.

The degree of erythema was evaluated using the following 5-grade criteria from 0 to 4.

0: No erythema 1: Mild erythema that can be barely discerned 2: Obvious erythema 3: Moderate erythema 4: Deep red erythema The skin irritation score for each transdermal absorption preparation is , the average value calculated by dividing the sum of scores for each round by the number of repetitions, 5, was displayed. The obtained evaluation results are summarized in Table 1.

(Margins below) Table 1 In Table 1, from a comparison of Example 1 and Comparative Example 1, the tape preparation of Example 1 has about 1.4 times the transdermal absorption compared to the tape preparation of Comparative Example 1 containing only the drug. It can be seen that the skin irritation judgment point is rather small. Therefore, it is recognized that the ester compound (a') contained in the tape preparation of Example 1 has an effect of promoting drug absorption and also has an effect of reducing the skin irritation of the preparation.

Furthermore, from the comparison between Example 1 and Comparative Example 2, the ester compound (a) contained in the tape preparation of Example 1 is superior to the absorption enhancer (lauric acid) contained in the tape preparation of Comparative Example 2. The tape preparation of Example 1 was found to have a low skin irritation effect.

From the comparison between Example 2 and Comparative Example 3, ester compound (1)
It is recognized that if the number of carbon atoms in R is too smaller than the required value, the above effect will not be exhibited.

From the comparison of Example 3 and Comparative Example 4.5 and the comparison of Example 4 and Comparative Example 6.7, it was found that the ester compound (I) reduces the skin irritation of the absorption enhancer and further has an absorption promoting effect. is recognized.

As mentioned above, as is clear from Table 1, ester compound (1)
is recognized to effectively reduce skin irritation caused by absorption enhancers or drugs, and also to exhibit an absorption promoting effect itself.

(Effects of the Invention) (a) Since the transdermal absorption preparation according to the present invention contains the ester compound (1), a sufficient amount of the drug can be absorbed through the skin to exert the desired medicinal effect. .

The detailed mechanism of action of ester compound (I) on the skin is considered as follows. The ester compound (1) is
Due to its characteristic molecular structure of having a long-chain hydrocarbon group within the molecule, it has surfactant ability and is therefore easily absorbed into the skin. Therefore, this compound acts as a less irritating absorption enhancer and allows a sufficient amount of the drug to be absorbed through the skin. Therefore, it is not necessary to contain a large amount of drug as in the conventional case. In addition, even if the local drug concentration in the skin becomes high, the ester compound (1)
The drug-induced irritation is reduced due to its good absorption promoting properties.

(b) The ester compound (1) reduces skin irritation caused by sweating due to its effect on occlusive bandage therapy.

Therefore, transdermal absorption preparations such as tapes and patches can be applied to the skin for a long period of time.

(C) Since the skin irritation caused by the absorption enhancer is alleviated by the ester compound (I) as described above, other absorption enhancers can be used together with the ester compound (1) without any problem. Therefore, an absorption enhancer can be contained in an amount sufficient to enhance drug absorption depending on the required absorption amount of the drug. As a result, the use of absorption enhancers allows the effective blood concentration of the drug to be maintained over a long period of time and increases the bioavailability of the drug.

(d) Thus, according to the transdermal absorption preparation of the present invention, a sufficient amount of drug can be absorbed transdermally to produce the desired drug effect, and the absorption enhancer can stimulate the skin. It is possible to provide transdermal absorption preparations in various dosage forms with reduced

BRIEF DESCRIPTION OF THE DRAWINGS The drawing is a perspective view of a diffusion cell used to test the skin permeability of drugs contained in transdermal formulations. Patent applicant Sekisui Chemical Co., Ltd.

Claims (2)

[Claims] (1) Base, drug, and general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R means a hydrocarbon group with 7 to 17 carbon atoms, and X means a hydrogen atom or an alkali metal atom, respectively. A transdermal absorption preparation characterized by comprising an ester compound represented by (2) The transdermal absorption preparation according to claim 1, further comprising an absorption enhancer.