JPH0533929B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to transdermal preparations such as poultices and tape preparations containing drugs, and/or transmucosal preparations such as oral preparations and eye drops. The present invention particularly relates to transdermal/transmucosal preparations with enhanced drug absorption. (Prior Art) In order to obtain systemic or local medicinal effects, drugs (active substances) can be absorbed through the skin or mucous membranes using transdermal and/or transmucosal dosage forms. It is being said. This transdermal
Transmucosal administration methods have many advantages over traditional oral administration methods. For example, when a drug is orally administered, the drug is absorbed in the intestines, circulates to the liver, and undergoes metabolism, resulting in a considerable amount of the drug being degraded before it exerts its medicinal effects. In contrast, in transdermal/transmucosal administration methods, the absorbed drug does not pass through the liver during its initial circulation in the body. Therefore, the medicinal efficacy is not significantly reduced due to metabolism in the liver. Oral administration of nonsteroidal anti-inflammatory drugs tends to cause gastrointestinal disorders, but transdermal and transmucosal administration is less likely to cause such gastrointestinal disorders. By controlling the absorption of drugs, it is possible to reduce side effects caused by large amounts of drugs being absorbed in a short period of time. If a constant blood concentration can be maintained over a long period of time, the number of drugs and doses can be reduced. However, even when drugs are administered using transdermal/transmucosal preparations, the drugs often have difficulty permeating through the skin and mucous membranes, resulting in low bioavailability. In particular, there is a stratum corneum on the skin surface,
Since the stratum corneum has a barrier function to prevent foreign substances from entering the body, drugs are often not absorbed through the skin in sufficient quantities to exert pharmacological effects. Preparations containing absorption enhancers have been produced to weaken the barrier function of the stratum corneum and allow a sufficient amount of the drug to be absorbed. For example, JP-A-57-9714, JP-A-58-43368, JP-A-58-52216, JP-A-58-79918, JP-A-60-13720.
No. 60-11431 discloses patches in which the adhesive layer contains an absorption enhancer. Among the above absorption enhancers, for example, salicylic acid,
Urea and dimethyl sulfoxide are known to dissolve stratum corneum, but even when these are added, the transdermal absorption of the drug is not necessarily good. Propylene glycol, glycerin, sodium pyrrolidone carboxylate, etc. can cause the stratum corneum to retain water, but they have little effect on promoting drug absorption. Dimethyl sulfoxide and other substances irritate the skin and mucous membranes and tend to cause erythema and rash. When a tape formulation is prepared by incorporating a dicarboxylic acid ester such as diisopropyl adipate or a fatty acid ester into the adhesive layer,
Since the compatibility between the adhesive and the drug decreases, the drug tends to precipitate from the adhesive. Adhesion may also be reduced. Sulfur-containing compounds such as calcium thioglycolate can also cause bad breath. In addition to the above compounds, myristic acid esters, adipate esters, lauryl sulfate esters, polyocoxyethylene alkyl ethers, etc. have also been disclosed, but even if these absorption enhancers are used, the amount of drug absorbed through the skin or mucous membranes is not necessarily reduced. It cannot be said that it is sufficient. As described above, the current situation is that transdermal/transmucosal preparations that can effectively absorb drugs have not yet been obtained. (Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and its purpose is to provide a preparation that can effectively absorb the drug contained therein through the skin and mucous membranes. It is in. Another object of the present invention is a transdermal/transmucosal preparation containing an absorption enhancer that enhances transdermal/transmucosal absorption of the drug contained therein and is non-irritating to the skin and mucous membranes and is safe for living organisms. Our goal is to provide the following. Still another object of the present invention is to provide a transdermal skin containing an absorption enhancer that does not change the properties of the base, does not cause drug precipitation, and does not cause denaturation of the drug contained therein.・
The purpose of the present invention is to provide transmucosal preparations. (Means for Solving the Problems) The transdermal/transmucosal preparation of the present invention is a transdermal/transmucosal preparation containing a drug and an absorption enhancer for the drug, wherein the absorption enhancer is a fatty acid dialkylol. It is an amide, and the fatty acid has 8 to 15 carbon atoms, thereby achieving the above object. The absorption enhancer used in the present invention is a fatty acid dialkylolamide represented by the following formula. Here, R ₁ is an aliphatic hydrocarbon group having 7 to 14 carbon atoms; R ₂ is a saturated hydrocarbon group having 2 to 6 carbon atoms. The fatty acid that can form the above compound has 8 to 15 carbon atoms (the corresponding R ₁ has 7 to 14 carbon atoms), preferably 10 to 14 carbon atoms. When the number of carbon atoms is outside the range of 8 to 15, the absorption of the drug contained in the preparation decreases. Examples of fatty acids include caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, and the like. Two or more of these may be used in combination. Dialkylolamine HN to these fatty acids
Condensation of (R ₂ OH) ₂ yields the above compound.
The saturated hydrocarbon group R ₂ of the dialkylolamine used has 2 to 6 carbon atoms. Within this range, the smaller the number of carbon atoms, the better the absorption of the drug. Examples of the dialkylolamine include diethanolamine, diisopropanolamine, dibutanolamine, and dihexanolamine. Among the absorption enhancers thus obtained, lauric acid diethanolamide, which is a condensation of lauric acid and diethanolamine, exhibits particularly excellent effects. The above-mentioned absorption enhancer is generally contained in the formulation in a proportion of 0.01 to 30% by weight. This ratio is for ointments,
For cream preparations, suppositories, eye drops, etc., the content is shown for the entire preparation, and for example, for adhesive preparations such as tape preparations and plasters, the content for the drug-containing layer is shown. The same applies to the drug content described below. If the amount of absorption enhancer is too small, the effect of promoting absorption of the drug cannot be obtained. Even if the amount is excessive, not only will the absorption of the drug not be further improved, but also, for example, in the case of a tape preparation, the adhesive physical properties will be lowered, and the compatibility with the adhesive may be deteriorated. The drug (physiologically active substance) used is not particularly limited as long as it can permeate biological membranes by transdermal or transmucosal administration. For example, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, vasodilators,
Examples include antiarrhythmic agents, antihypertensive agents, antitumor agents, local anesthetics, hormonal agents, antihistamines, anticoagulants, diuretics, psychotropic agents, sleeping pills, and antibiotics. Non-steroidal anti-inflammatory drugs include salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibuhenac, fenbufen, alclofenamic acid, phenylbutazone, mehenamic acid,
indomethacin, bendazatsuk, piroxicam,
Examples include flurbiprofen. Steroid anti-inflammatory drugs include hydrocortisone, prednisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate,
These include diflucortolon valerate, clobetasol propionate, and fluocinonide. Vasodilators include diltiazem, verabamil, pentaerythritol tetranitrate, dipyridamole, and isosorbide nitrate. Antiarrhythmic agents include propanolol, pindolol, quinidine, ajmaline, pramaline, and alprenolol. Antihypertensive agents include clonidine and the like. As an antitumor agent,
Examples include 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, and mitomycin C. Local anesthetics include benzocaine, procaine, lidocaine, and tetracaine. Hormone drugs include estrogen,
These include steroid hormones such as estradiol, testosterone, and progesterone; peptide hormones such as insulin; and prostaglandins. Antihistamines include cycloheptadine hydrochloride, diphenhydramine, and phenbenzamine. Anticoagulants include hebarin, diuretics include thiazides, and psychotropic drugs include scopolamine and clofluperous. Sleeping pills include phenobarbital and amobarbital; antibiotics include tetracycline and chloramphenicol. The amount of these drugs to be blended varies depending on the type of drug, the purpose of use of the preparation, etc., but the drug is usually contained in the preparation at a ratio of 0.1 to 30% by weight. Among the transdermal/transmucosal preparations of the present invention containing these drugs and the absorption enhancer, examples of transdermal preparations include tape preparations, patches, poultices, ointments, and cream preparations. Transmucosal preparations include suppositories, buccal preparations, nasal drops, and eye drops. Among the above preparations, tape preparations and patch preparations have an adhesive layer containing a drug and an absorption enhancer formed on one side of a support. The base (adhesive) for tape preparations and patch preparations is not particularly limited, as long as it has enough adhesive strength to fix the preparation to the skin surface for a long time at room temperature. For example, acrylic-based, rubber-based, and silicone resin-based adhesives can be used, and acrylic-based and rubber-based adhesives are usually used. For acrylic adhesives, due to their adhesive properties, in particular, (co)polymers of (meth)acrylic acid alkyl esters obtained from aliphatic alcohols having 4 to 18 carbon atoms and (meth)acrylic acid and/or
Alternatively, a copolymer of the above (meth)acrylic acid alkyl ester and other functional monomers is 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, decyl methacrylate, isodecyl methacrylate, methacrylate These include lauryl acid 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 hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate. Examples of monomers having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; and crotonic acid. Maleic anhydride also provides the same (co)polymerization component as maleic acid. Monomers having an amide group include alkyl (meth)acrylamides such as acrylamide, dimethylacrylamide, and diethylacrylamide;
Examples include alkyl ether methylol (meth)acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide. Examples of monomers having an amino group include dimethylamino acrylate. Copolymerizable monomers other than those mentioned above include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylotrile, ethylene, propylene, butadiene, etc., and these may be copolymerized. It is preferable that the adhesive contains 50% by weight or more of (meth)acrylic acid alkyl ester as a (co)polymerization component. Rubber adhesives include natural rubber, polyisoprene, polyisobutylene, polyvinyl ether,
Polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, etc. are used. As the silicone resin adhesive, silicone rubber such as polyorganosiloxane is used. In addition to these, polyvinyl acetate and natural chicle can also be used. The above-mentioned pressure-sensitive adhesive may contain various additives as necessary, such as tackifiers such as rosin resin, polyterpene resin, coumaron-indene resin, petroleum resin, and terpene phenol resin; liquid polybutene, mineral oil lanolin, and liquid polyisoprene. , a plasticizer such as liquid polyacrylate; a filler; and an anti-aging agent. As the support for tape preparations, patches, and poultices described below, supports commonly used for adhesive patches are used. Materials for such supports include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride. , aluminum, etc. These are used, for example, as a single layer sheet (film) or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics. A drug-containing (adhesive) layer containing a drug and an absorption enhancer is formed on the surface of the support to obtain a tape preparation or patch. Various coating methods can be used to form the adhesive layer, such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method. Among these, a solvent coating method is preferably used. To form an adhesive layer using a solvent coating method, for example, the adhesive is diluted with an appropriate solvent, and a drug,
An absorption enhancer and, if necessary, compounding agents are added and mixed uniformly, and the resulting solution is applied to the surface of the support and dried. Instead of applying the solution directly to the surface of the support, it may be applied onto a release paper coated with a silicone resin or the like, and after drying, the solution may be brought into close contact with the support. Such release paper is used to protect the surface of the adhesive layer of the patch until use. Even in coating methods other than solvent coating methods, it is recommended to place a release paper after forming the adhesive layer to protect the surface of the adhesive layer. The thickness of the adhesive layer also varies depending on the purpose of use, but is usually 30 to 200 μm. If the diameter is less than 80 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. If it exceeds 200 μm, the drug contained in the adhesive layer near the support will not be sufficiently diffused, resulting in a decrease in drug release properties. A poultice also has a drug-containing layer containing a drug and an absorption enhancer formed on one side of the support. Usually, it is fixed to the skin surface with a bandage because it has poor adhesiveness compared to tape preparations and patches. A water-soluble polymer is usually used as the main component of the base of the plaster. Such polymers include, for example, gum arabic, gum tragacanth, locust bean gum, guar gum, echo gum, gum karaya, agar, starch, carrageenan, alginic acid, alginates (e.g. sodium alginate),
Propylene glycol alginate, dextran, dextrin, amylose, gelatin, collagen, pullulan, pectin, amylopectin,
Natural polymers such as starch, amylopectin sodium semiglycolate, chitin, albumin, casein, polyglutamic acid, polyaspartic acid; methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, hydroxycellulose, hydroxyalkylcellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, Semi-synthetic polymers such as carboxymethyl starch, alkali metal carboxymethyl cellulose, alkali metal cellulose sulfate, cellulose acetate phthalate, starch-acrylic acid graft polymer, crosslinked gelatin, phthalic anhydride modified gelatin, succinic acid modified gelatin; polyvinyl alcohol, polyvinyl Pyrrolidone, polyvinyl methyl ether, methyl vinyl ester, polyacrylate (e.g. sodium polyacrylate), carboxyvinyl polymer, vinylpyrrolidone-ethyl ocrylate copolymer, vinylpyrrolidone-styrene copolymer, vinylpyrrolidone-vinyl acetate copolymer Polymer, polyvinyl acetate-(meth)acrylic acid copolymer, polyvinyl acetate-crotonic acid copolymer, vinyl acetate-
(meth)acrylic acid copolymer, vinyl acetate-crotonic acid copolymer, polyvinyl sulfonic acid, polyitaconic acid, polyhydroxyethyl acrylate,
Synthetic polymers include polyacrylamide, styrene-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, and acrylamide-acrylic acid copolymer. The above-mentioned water-soluble polymer, water, drug, and absorption enhancer are uniformly mixed to form a drug-containing layer on the surface of the support, in which the drug and absorption enhancer are contained in a water-containing base consisting of the water-soluble polymer and water. The desired poultice is obtained. In addition, a water-containing base is formed by incorporating water into a water-insoluble polymer such as an acrylic polymer, a rubber-based polymer, or a silicone-based polymer other than the above-mentioned water-soluble polymer, and the drug and an absorption enhancer are added to this as necessary. It is also possible to obtain a poultice by adding a water-soluble polymer to form a drug-containing layer. The amount of water contained in the water-containing base is preferably 5-90% by weight, more preferably 5-90% by weight of the formulation containing the base, drug, and absorption enhancer. The agent is composed of This also applies to ointments and cream preparations, which will be described later. When water is contained within the above range, the effect of the drug absorption enhancer is greatly enhanced. If the amount of water is too small, the absorption enhancer of the drug will not be very large, and when the preparation is brought into close contact with the skin surface, the cooling effect due to evaporation of water will not be obtained. Excessive water increases fluidity and makes it difficult to maintain the shape of the formulation. The drug-containing layer further contains a polyhydric alcohol (e.g., glycerin, propylene glycol).
Humectants such as; inorganic fillers such as kaolin, bentonite, zinc white, titanium dioxide; viscosity modifiers; crosslinking agents; anti-aging agents; and the like may be contained. The main components of the base of ointments and creams include beeswax, fats and oils, lanolin, white petrolatum, paraffin, Plastibase, Zelen 50W (trade name), higher fatty acids, higher alcohols, emulsifiers, macrogol, carboxyvinyl polymer, etc. . These compounds are mixed with drugs and absorption enhancers to obtain ointments and cream preparations. When mixing, if necessary, use a fat-soluble solubilizer such as crotamiton, liquid paraffin, isopropyl myristate, diethyl sebacate; purified water; a water-soluble solubilizer such as ethanol or polyhydric alcohol (e.g. glycerin);
PH regulator; etc. are added. When the oral preparation, nasal spray, or eye drop is in the form of an ointment or cream, the base of the ointment or cream preparation described above is used and prepared in the same manner as the ointment or cream preparation. When in the form of a solution (suspension) or jelly, the desired preparation can be obtained by dissolving or suspending the drug or absorption enhancer in, for example, ethanol, purified water, or glycols. In some cases, drugs and absorption enhancers are dissolved or dispersed in a mixture of water and water-soluble polymers such as tragacanth, gum arabic, sodium alginate, gelatin, metal cellulose, and carboxymethyl cellulose (CMC). Among oral preparations, as oral patches, patches in the same form as tape preparations, patches, and poultices can be used. For example, a laminate can be used in which a drug-containing film is prepared by adding a drug and an absorption enhancer to a base, and a water-insoluble film is laminated on the surface of the film to prevent the drug from escaping. As a base for suppositories, oils and fats such as cacao butter, balm oil, coconut oil, and fractionated coconut oil; vaseline, etc. are used. A desired suppository is prepared by uniformly mixing the drug and absorption enhancer with the above base and using a suppository molder. (Effect) When the transdermal/transmucosal preparation of the present invention is brought into close contact with the surface of the skin or mucous membrane, the drug contained therein is easily absorbed through the skin or mucous membrane. Although the detailed mechanism is unknown, it is thought that the absorption enhancer is used on the skin or mucous membranes, denatures their proteins, increases their water content, and softens them. Therefore, it is thought that the stratum corneum on the skin surface, which is difficult for drugs to pass through, is also softened and the drug contained therein is easily absorbed through the skin. Since a sufficient amount of drug to obtain the required drug is easily absorbed, there is no need to include large amounts of drug in the formulation as in the past. In other words, the bioavailability of the drug is high. Such transdermal/transmucosal absorption promoting effects are much higher than when conventional absorption enhancers are used. Furthermore, the absorption enhancer used in the present invention is highly safe as it does not irritate the skin or mucous membranes. It does not denature the drug contained. It also has excellent compatibility with the base. Since the compatibility between the drug and the base is not changed, the drug does not precipitate from the prepared preparation. When used as a tape preparation or patch, the absorption enhancer itself does not adversely affect the physical properties of the adhesive, such as reducing the adhesive function of the adhesive. (Example) The present invention will be described below with reference to Examples. Example 1 (A) Preparation of patch (tape formulation): Acrylic acid 2
Ethylhexyl 40 mol%, butyl acrylate 50
An ethyl acetate solution containing 25% by weight of a copolymer consisting of 10% by mole of vinylpyrrolidone and 10% by mole of vinylpyrrolidone was prepared. To this solution, 8 parts by weight of indomethacin as a drug and 5 parts by weight of lauric acid diethanolamide as a transdermal absorption enhancer were added to 100 parts by weight of the copolymer (solid content). Further, ethyl acetate was added to make the solid content 15% by weight, and the mixture was thoroughly stirred in a closed system stirrer. This was applied onto a polyethylene terephthalate (PET) film, one side of which had been treated with silicone, to a dry thickness of 60 μm, and dried in a gear oven at 70° C. for 20 minutes. A polyethylene film was laminated on the surface of the resulting adhesive layer as a release paper. This release paper is peeled off and removed during use. (B) Performance evaluation of adhesive Drug permeability test: Using the patch obtained in section (A), a drug permeability test was conducted using an in vitro diffusion cell. Drug permeability after 24 hours (%)
are shown in Table 1. The test method is as follows. Drug permeability test method using in vitro diffusion cell: Prepare a Franz-shaped diffusion cell with an opening diameter of 25 cm. Physiological saline adjusted to pH 7.2 is placed in the receptor part of the Franz-shaped diffusion cell, and 37°C warm water is circulated through the outer wall to keep the temperature of the receptor part constant. A test piece of the patch (circular object with a diameter of 20 mm) obtained in section (A) was applied to the epidermis (4 cm x 4 cm) of the depilated flank of a normal male rabbit, and the epidermis was placed in a cell. Installing. Fill the receptor fluid, taking care not to introduce air bubbles between the skin and the receptor fluid level.
After 24 hours, the receptor fluid is sampled, the drug concentration is measured by high performance liquid chromatography using a reversed phase column, and the drug permeability is calculated from the following formula. Drug permeability (%) = drug concentration × receptor capacity / amount of drug contained in the test strip × 100 Drug blood concentration: Using the patch obtained in section (A), in vivo blood concentration was measured as follows. It was done using the method. The results are shown in FIG. In vivo blood concentration measurement method: Cut the patch obtained in section (A) into a size of 5 cm x 7.5 cm and apply it to the skin surface of the depilated back of a normal male rabbit. After 1 hour, 3 hours, 6 hours, 9 hours, and 24 hours, blood was collected from the auricular vein of the rabbit, and the drug concentration in the serum was measured by high-performance liquid chromatography using a reversed-phase column. Measure. From FIG. 1, it can be seen that when the patch obtained in this example is used, the blood concentration of the drug is high and the skin permeability of the drug is excellent. The area under the blood concentration curve (AUC) was 14074±2778, and Comparative Example 5 did not contain the transdermal absorption enhancer described below.
It showed a value about 2.8 times higher than that of 4992±434. Drug release test: Using the patch obtained in section (A), a drug release test was conducted in the following manner. The results are shown in Table 2. Drug release test: Cut the patch obtained in section (A) into a circle with a diameter of 52 mm to obtain a test piece. This test piece was kept at 37℃ in a constant temperature water bath with a pH of 7.0.
Immerse in 250ml of 10mM phosphate buffer and stir. After 10 minutes, 20 minutes, 40 minutes, 60 minutes,
After 120 minutes and 180 minutes, a small amount of the phosphate buffer is collected, and the amount of eluted drug is measured by high performance liquid chromatography using a reversed phase column. Calculate the drug elution rate from the following formula. Drug elution rate (%) = Amount of drug eluted/Amount of drug contained in test piece x 100 Comparative example 1 (A) Preparation of patch (tape preparation): Using oleic acid polyoxyethylamide as a transdermal absorption enhancer The procedure is the same as in Example 1 (A) except for the above. (B) Performance evaluation of adhesive Drug permeability test: Using the patch obtained in section (A) of this comparative example, it was conducted according to section (B) of Example 1. The results are shown in Table 1. Comparative Example 2 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that urea was used as the transdermal absorption enhancer. (B) Production evaluation of adhesive Drug permeability test: Using the patch obtained in Section (A) of this comparative example, it was conducted according to Section (B) of Example 1. The results are shown in Table 1. Drug release test: Using the patch obtained in Comparative Example (A), the test was conducted according to Example 1 (B). The results are shown in Table 2. Comparative Example 3 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that diisopropyl adipate was used as the transdermal absorption enhancer. (B) Performance evaluation of adhesive Drug permeability test: Using the patch obtained in section (A) of this comparative example, it was conducted according to section (B) of Example 1. The results are shown in Table 1. Drug release test: Using the patch obtained in Comparative Example (A), the test was conducted according to Example 1 (B). The results are shown in Table 2. Comparative Example 4 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that propylene glycol was used as the transdermal absorption enhancer. (B) Performance evaluation of adhesive Drug permeability test: Using the patch obtained in section (A) of this comparative example, it was conducted according to section (B) of Example 1. The results are shown in Table 1. Drug release test: Using the patch obtained in Comparative Example (A), the test was conducted according to Example 1 (B). The results are shown in Table 2. Comparative Example 5 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that no transdermal absorption enhancer was added. (B) Performance evaluation of adhesive Drug permeability test: Using the patch obtained in section (A) of this comparative example, it was conducted according to section (B) of Example 1. The results are shown in Table 1. Drug blood concentration: Using the patch obtained in Comparative Example (A), the test was carried out according to Example 1 (B). The results are shown in FIG. Drug release test: Using the patch obtained in Comparative Example (A), the test was conducted according to Example 1 (B). The results are shown in Table 2.

【table】

[Table] It can be seen from Table 1 that the patch of Example 1 exhibits an absorption transmittance that is about 11 times higher than that of the patch of Comparative Example 5 which does not contain a transdermal absorption enhancer. Lauric acid diethanolamide is an excellent transdermal absorption enhancer, showing an extremely high drug permeation rate of more than 5 times compared to conventional patches containing transdermal absorption enhancers (Comparative Examples 1 to 4). One thing is clear.

[Table] Table 2 shows that the patch of Example 1 exhibits almost the same drug release properties as the patch of Comparative Example 5 which does not contain a transdermal absorption enhancer. This is thought to be because the compatibility between the drug and the adhesive hardly changes even when the transdermal absorption enhancer is added. Example 2 (A) Preparation of patch for oral mucosa: Polyvinyl acetate 40
A methyl acetate solution containing 20 parts by weight of hydroxyperopylcellulose and a methanol solution containing 20 parts by weight of hydroxyperopyl cellulose were mixed, 13 parts by weight of heparin and 2 parts by weight of lauric acid diethanolamide (absorption enhancer) were added thereto, and the mixture was mixed with a dissolver using a dissolver. Mixed evenly. This was cast and dried to obtain a film with a thickness of 0.35 mm. A polyvinyl acetate film having a thickness of 0.1 mm was laminated and adhered to this film.
This laminate was punched out to a size of 1.5 cm ² to obtain a patch for oral mucosa. (B) Performance evaluation of the patch for oral mucosa: The patch obtained in section (A) (containing 1050U of heparin) was applied to the oral cavity of a beagle dog, and 0.5 hours after application, 1 hour later,
Two and four hours later, blood was collected from the forelimb vein, and the blood heparin concentration was measured using a Test Team "Heparin" kit. The results are shown in Table 3. Comparative Example 6 (A) Preparation of patch for oral mucosa: Same as Example 2 (A) except that no absorption enhancer was added. (B) Performance evaluation of the patch for oral mucosa: The same procedure as in Example 2 (B) was conducted using the patch obtained in Comparative Example (A). The results are shown in Table 3.

[Table] From Table 3, the preparation of the present invention using fatty acid dialkylolamide as an absorption enhancer (oral mucosal patch)
It can be seen that drug absorption through mucous membranes is superior to formulations without absorption enhancers. Example 3 (A) Preparation of suppositories: diclofenac sodium 5.0
parts by weight, 2 parts by weight of lauric acid diethanolamide (absorption enhancer), and 93 parts by weight of cacao butter were uniformly mixed and formed into a cylindrical shape to obtain a 0.25 g suppository. (B) Performance evaluation of suppositories: The suppositories obtained in section (A) of this example were administered to the anus of domestic rabbits. Blood was collected from the rabbit auricular vein 10, 20, 40, 60, and 120 minutes after administration. Plasma was obtained from this blood, and after extraction with benzene, the extract was subjected to ECD gas chromatography to quantify the drug (diclofenac sodium) in the plasma. The results are shown in Table 4. Comparative Example 7 (A) Preparation of suppositories: Same as Example 3(A) except that no absorption enhancer was added. (B) Performance evaluation of suppositories: The same procedure as in Example 3 (B) was conducted using the suppositories obtained in Comparative Example (A). The results are shown in Table 4.

[Table] Table 4 shows that the formulation (suppository) of the present invention using a fatty acid dialkylolamide as an absorption enhancer has superior drug absorption through mucous membranes compared to a formulation without an absorption enhancer. Recognize. Examples 4, 5, 6 (A) Preparation of patch (tape formulation): Acrylic acid 2
Ethylhexyl 40 mol%, butyl acrylate 50
An ethyl acetate solution containing 2% by weight of a copolymer consisting of 10% by mole of vinylpyrrolidone and 10% by mole of vinylpyrrolidone was prepared. Add to this solution 100 parts by weight of the copolymer (solid content), 8 parts by weight of indomethacin as a drug, and 5 parts by weight of either caprylic acid diethanolamide, capric acid diethanolamide, or myristic acid diethanolamide as a transdermal absorption enhancer. was added. Further, ethyl acetate was added to make the solid content 15% by weight, and the mixture was thoroughly stirred in a closed system stirrer. This was applied onto a polyethylene terephthalate (PET) film, one side of which had been treated with silicone, to a dry thickness of 60 μm, and dried in a gear oven at 70° C. for 20 minutes. Three types of adhesive patches were obtained by laminating a polyethylene film as a release paper on the surface of the resulting adhesive layer. This release paper is peeled off and removed during use. (B) Performance evaluation of patch: Using the patch obtained in section (A), a drug permeability test was conducted using an in vitro diffusion cell. Table 5 shows the drug permeability (%) after 24 hours. The test method was the same as the drug permeability test in Example 1 (B). Comparative Example 8 (A) Preparation of patch (tape preparation): Same as Example 4, 5, and 6(A) except that no absorption enhancer was added. (B) Performance evaluation of patch: Using the patch obtained in Comparative Example (A), the same evaluation as in Examples 4, 5, and 6 (B) was conducted. The results are shown in Table 5.

【table】

[Table] From Table 5, the patches of Examples 4, 5, and 6 were approximately 15
It can be seen that the drug permeability is ~6 times higher. From this, it is clear that diethanolamine caprylate, diethanolamine caprate, and diethanolamine myristate are all excellent absorption enhancers. Example 7 (A) Preparation of patch (pump): 4 parts by weight of gelatin, 8 parts by weight of polyacrylic acid, 2 parts by weight of carboxymethylcellulose, 4 parts by weight of polyvinylpyrrolidone, 3 parts by weight of kaolin, 0.5 parts by weight of aluminum hydroxide. , 10 parts by weight of glycerin, 1 part by weight of indomethacin (drug), 2.5 parts by weight of lauroyl diethanolamide (absorption enhancer) and 65 parts by weight of purified water were uniformly mixed to obtain a paste-like plaster for papules. Place this on the non-woven fabric 0.5mm
The coating was applied to a thickness of 100 mL and then faced with polyethylene film. (B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, a drug permeability test was conducted using an in vitro diffusion cell. Table 6 shows the drug permeability (%) after 24 hours. The test method is the same as in Example 1 (B). Comparative Example 9 (A) Preparation of patch (patch): Same as Example 7(A) except that 0.5 parts by weight of polysorbate 80 was used as an absorption enhancer. (B) Performance evaluation of patch: The same procedure as in Example 7 (B) was conducted using the patch obtained in Comparative Example (A).
The results are shown in Table 6. Example 8 (A) Preparation of patch (pump): Same as Example 7 (A) except that 3.0 parts by weight of ketoprofen was used as the drug and 3.0 parts by weight of capric acid diethanolamide was used as the absorption enhancer. be. (B) Performance evaluation of patch: The patch obtained in Section (A) of this Example was used in the same manner as in Section (B) of Example 7.
The results are shown in Table 6. Comparative Example 10 (A) Preparation of patch (patch): Same as Example 7(A) except that 0.5 parts by weight of polysorbate 80 was used as an absorption enhancer. (B) Performance evaluation of patch: The same procedure as in Example 7 (B) was conducted using the patch obtained in Comparative Example (A).
The results are shown in Table 6.

[Table] Table 6 shows that the formulation (pump) of the present invention using fatty acid dialkylolamide as an absorption enhancer has superior drug permeability through the skin compared to formulations using conventional absorption enhancers. I know that there is. Example 9 (A) Preparation of gel ointment: 5 parts by weight of heparin (drug), 10 parts by weight of Macrogol 400, 1.5 parts by weight of carboxyvinyl polymer, 10 parts by weight of ethanol,
A gel ointment was obtained by uniformly mixing 71.5 parts by weight of purified water and 2 parts by weight of lauroyl diethanolamide (absorption enhancer). (B) Performance evaluation of gel ointment: 100 mg of the gel ointment (containing 770 U of heparin) obtained in section (A) of this example was applied to the inner side of the auricle of a domestic rabbit to a thickness of approximately 4 cm ² .
Cannulae were inserted into the marginal veins (two locations) before and after the application site, and the isotonic solution was refluxed at a rate of approximately 1.5 ml/min. Heparin in this reflux solution was quantified by measuring the absorbance at 405 nm using a Test Team "Heparin" kit (manufactured by Daiichi Kagaku Yakuhin Co., Ltd.). Heparin measurements were taken 0.5 hours, 1 hour, 2 hours, and 4 hours after applying the gel ointment. The results are shown in Table 7. Comparative Example 11 (A) Preparation of gel ointment: Same as Example 9(A) except that no absorption enhancer was added. (B) Performance evaluation of gel ointment: Using the gel ointment obtained in section (A) of this comparative example, evaluation was carried out in the same manner as in section (B) of Example 9. The results are shown in Table 7.

[Table] Table 7 shows that the formulation of the present invention (gel ointment) using fatty acid dialkylolamide as an absorption enhancer has superior drug absorption through the skin compared to an additive without an absorption enhancer. Recognize. Example 10 (A) Preparation of gel ointment: 2 parts by weight of hydrocortisone acetate, 10 parts by weight of Macrogol 400, 1.5 parts by weight of carboxyvinyl polymer, 10 parts by weight of ethanol, 74 parts by weight of purified water, and caproic acid dibutanolamide (to promote absorption). A gel ointment was obtained by uniformly mixing 2.5 parts by weight of the gel ointment. (B) Performance evaluation of gel ointment: Using 100 mg of the gel ointment obtained in section (A) of this example, it was applied to normal domestic rabbits (male).
The drug was applied to the epidermis of the armpits that had been subjected to hair removal treatment, and a drug permeability test using an in vitro diffusion cell was conducted in accordance with Example 1 (B). Table 8 shows drug permeability (%) after 24 hours. Comparative Example 12 (A) Example except that no absorption enhancer was added.
Same as Section 10(A). (B) The same procedure as in Example 10(B) was carried out. The results were as shown in Table 8.

[Table] Example 11 (A) Preparation of patch (tape): Add isosorbide dinitrate (ISDN) to 100 parts by weight of a 10% cyclohexane solution of a mixture of 45 parts by weight of natural rubber and 45 parts by weight of terpene resin. 3.704 parts by weight of a 30% by weight methylene chloride solution was added and further lauric acid dipropanolamide (absorption enhancer)
0.25 parts by weight was added and thoroughly stirred. This was applied onto a polyamide film and dried in a gear oven at 70℃ for 20 minutes until the adhesive layer had a thickness of 50μm.
A patch was obtained. (B) Performance evaluation of patch (tape): this example (A)
10 cm ² of the patch obtained in Section 1 was applied to the back of a depilated Japanese white rabbit, and changes in blood drug concentration over time were measured. The results are shown in Table 9. Comparative Example 13 (A) Example except that no absorption enhancer was added
Same as Section 11(A). (B) The same procedure as in Example 11(B) was carried out. The results were as shown in Table 9.

[Table] Examples 12, 13 and 14 Diclofenac sodium 50 parts, absorption aid 2
1 part and 93 parts of cocoa butter were mixed uniformly and formed into a cylindrical shape to make a suppository. This absorption was evaluated from the blood concentration using domestic rabbits. 0.25 g of the above suppository was administered to rabbits through the anus, and blood was collected from the auricular vein over time after administration to measure the drug concentration in plasma. To measure diclofenac sodium in plasma, extract the plasma with benzene and perform gas clostography (ECD) on the extract.
It was measured with Comparative Example 14 A suppository was prepared in the same manner as in Example 12 except that no absorption aid was added, and its absorbency was evaluated. The results are shown in Table 10.

[Table] (Effects of the Invention) According to the present invention, by incorporating a fatty acid dialkylolamide into the preparation as an absorption enhancer, the preparation has excellent transdermal or transmucosal absorption of the drug. is obtained. Since the drug has excellent absorption properties, it is not necessary to include a large amount of drug during production as in the past in order to obtain the necessary pharmacological effect. The absorption enhancer used is not irritating to the skin or mucous membranes, so it does not cause a rash even when applied for a long time. It does not alter the quality of the drug. Furthermore, the absorption enhancer does not cause the drug to precipitate or deteriorate the adhesive properties of the tape preparation. Such formulations allow various drugs to be absorbed transdermally and transmucosally. Therefore, it can be used for various medical purposes depending on the type of drug contained.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes in drug blood concentration when a tape preparation of the present invention and a tape preparation containing no transdermal absorption enhancer were applied as a patch to the skin surface of a domestic rabbit.

Claims (1)

[Scope of Claims] 1. A transdermal/transmucosal preparation containing a drug and an absorption enhancer for the drug, wherein the absorption enhancer is a fatty acid dialkylolamide, and the fatty acid has 8 to 15 carbon atoms. It is a transdermal/transmucosal preparation. 2. The transdermal/transmucosal preparation according to claim 1, which contains the absorption enhancer in a proportion of 0.01 to 30% by weight. 3. The transdermal/transmucosal product according to claim 1, which is at least one of tape preparations, patch preparations, patch preparations, ointments, cream preparations, oral preparations, nasal drops, eye drops, and suppositories. formulation. 4. The transdermal/transmucosal preparation according to claims 1 to 3, wherein the drug and the absorption enhancer for the drug are contained in an acrylic adhesive or a rubber adhesive. 5 The acrylic pressure-sensitive adhesive is a (co)polymer of (meth)acrylic acid alkyl ester having an alkyl group having 4 to 12 carbon atoms and/or a (co)polymer having 4 to 12 carbon atoms.
It is a copolymer of a (meth)acrylic acid alkyl ester having 12 alkyl groups and another functional monomer, and the (meth)acrylic acid alkyl ester is contained in the adhesive in an amount of 50% by weight or more as a (co)polymerization component. The transdermal/transmucosal preparation according to claim 4, wherein the transdermal/transmucosal preparation is contained in a proportion of . 6. The transdermal/transmucosal preparation according to claims 1 to 3, wherein the drug and the absorption enhancer for the drug are contained in a water-containing base. 7. The transdermal/transmucosal preparation according to claim 6, wherein a drug-containing layer in which the drug and the absorption enhancer are mixed in a water-containing base is provided on one side of the support. 8. The transdermal/transmucosal preparation according to claims 6 to 7, wherein the water-containing base contains water in a proportion of 1 to 90% by weight.