JPH0436133B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an external patch. Conventionally, ointments, liquids, poultices, tapes, etc. have been known as pharmaceutical preparations applied to the skin, but these preparations require careful attention to the setting of an appropriate dose of the drug, release and penetration of the active ingredient, and There are problems with bioavailability, usability, etc. For example, in the case of ointments, it has been pointed out that it is difficult to determine the exact dosage of the drug depending on the area and thickness to be applied, and that systemic effects due to transdermal absorption are not expected to be very effective. Furthermore, in comparison with other administration methods such as oral preparations, external preparations still have problems such as the skin acting as a barrier to drug absorption and extremely low bioavailability. On the other hand, a new form of administration called a drug delivery system has recently been developed, but it has only been put into practical use for a small number of specific drugs. In view of the above technical situation, the present inventors have conducted extensive research with the aim of developing a topical preparation that solves the problems in the conventional technology, and have found that a topical preparation containing water-soluble protein has excellent transdermal absorption. As a result of further investigation based on this knowledge, we have completed the present invention as an easy-to-administer, easy-to-use external preparation that increases the bioavailability of the drug and allows accurate determination of drug dosage. I've reached it. In order to achieve the above-mentioned purpose, such a preparation of the present invention contains specific ingredients mainly consisting of water-soluble proteins. That is, the topical patch of the present invention is a soft patch for topical use that contains the following components (a), (b), (c), and (d) and is self-adhesive to the skin (hereinafter simply referred to as a "soft patch"). (sometimes abbreviated as ). (a) Drugs (b) Water-soluble proteins that exhibit an absorption-promoting effect (c) Polyhydric alcohols (d) Adhesive agents The above drugs are not particularly limited as long as they can be absorbed transdermally; This includes both locally applied drugs and systemically applied drugs. Topically applied drugs include:
Alternatively, drugs that are used for the purpose of adjusting the condition of the skin so as to protect the skin and mainly exert medicinal effects locally can be mentioned. In addition, as a drug that is applied systemically, it is absorbed through the skin surface where it is applied, passes through the bloodstream, and reaches tissues and organs within the body.
Mainly drugs that exert systemic medicinal effects are mentioned.
Among these drugs, there are drugs that have little or no percutaneous absorption when taken alone, or drugs that have a low bioavailability when administered orally (e.g., a bioavailability of 80%). The following drugs), drugs with many side effects, drugs that must be administered by injection because they are broken down by digestive fluids, drugs that are susceptible to the first-pass effect in the liver, etc. are used as active ingredients in soft patches. is beneficial. Specific examples of drugs incorporated into soft patches are as follows. Analgesic and anti-inflammatory agents: acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, l-menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, planoprof Ene, phenoprofen, saridac, fuenbufuen, clidanac, flurbiprofen, indoprofen, putizic acid, fentiazac, tolmetin, tiaprofunic acid, penzadac, pufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, meperizole, etc.; steroids Anti-inflammatory agent:
Hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, fludrocortisone acetate, etc.; Antihistamines or antiallergic agents: chlorpheniramine, glycyrrhizic acid, diphenhydramine, periactin, etc.; Local anesthetics: benzocaine , procaine, dibucaine,
Lidocaine, etc.; Antimicrobial agents, etc. (including antibacterial agents, antifungal agents, antifungal agents, and antiviral agents): tetracyclines such as oxytetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin , macrolides such as erythromycin, chloramphenicol, iodine compounds, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, pyrrolnitrin, clotrimazole, etc.;
Antihypertensive agents: clonidine, α-methyldopa, reserpine, syrosingopine, recinamine, cinnarizine, hydralazine, prazosin, etc.; antihypertensive diuretics: theophylline, trichloromethiazide,
Furoseside, tripacid, methyclothiazide, penfluzide, hydrothiazide, spironolactone, metolazone, etc.; Cardiac agents: digitalis, ubidecarenone, dopamine, etc.; Coronary vasodilators: nitroglycerin, isosorbitol dinitrate, erystose tetranitrate,
Pentaerytol tetranitrate, dipyridamole, dirazep, trapidil, trimetazidine, etc.; Vasoconstrictors: dihydroergotamine, dihydroergotoxin, etc.; β-blockers or antiarrhythmic agents: pindolol, propranol, etc.; Calcium antagonists: diltiazem,
Nifedipine, nicardipine, verapamil, benciclane, dirazep, etc.; antiepileptic drugs: nitrazepam, meprobamate, phenytoin, etc.;
Anti-vertigo drugs: isoprenaline, betahistine,
Scopolamine, etc.; tranquilizers: diazepam,
Lorazepam, flunitrazepam, fluphenazine, etc.; Hypnosedatives: phenobarbital, amobarbital, cyclobarbital, etc.; Muscle relaxants: triperisone, baclofen, dantrolene sodium, cyclobenzapyrine, etc.; Autonomic agents: atropine, levodopa, etc.; Respiratory tract Medications: codeine, efuedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium proside, cromoglycic acid, etc. Hormones or antihormones: corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, salivary gland hormones, thyroid hormones , adrenal hormones, kallikrein, insulin, oxendron, etc.; vitamins: vitamins A, B, C,
D, E, K and their derivatives, calcieferols, mecobalamin, etc.; Antitumor agents: 5-
Fluorouracil and its derivatives, Krestin, Picibanil, Ancitabine, Cytarabine, etc.; Enzymes: Lysozyme, Urokinase, etc.;
Chinese herbal medicine or herbal medicine extracts: licorice, aloe, purple root, etc.; Anti-ulcer agents: allantoin, aldioxa, alcloxa, etc.; Diabetic agents, etc. Two or more of the above drugs can be used in combination, if necessary. In addition, the above-mentioned drugs can be used in a free state, those capable of forming salts can be used in the form of acid or base salts, and those having a carboxylic acid group can be used in the form of their esters. The above acids include organic acids (e.g. methanesulfonic acid, lactic acid,
tartaric acid, fumaric acid, maleic acid, acetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid)
However, bases also include organic bases (eg, ammonia, triethylamine) and inorganic bases (eg, sodium hydroxide, potassium hydroxide). Further, examples of the esters include alkyl esters, aryl esters, aralkyl esters, and the like. The amount of the above-mentioned drug may be sufficient as long as it is sufficient for the drug to be effective, and in many cases,
It is blended in an amount of about 0.01 to 20% by weight, preferably about 0.05 to 10% by weight. In addition, the type of drug, the purpose of treatment,
Depending on the patient's age, weight, and stage of disease,
It will be increased or decreased as appropriate. The above-mentioned water-soluble protein is not particularly limited as long as it exhibits an absorption promoting effect on the drug to be mixed. Such water-soluble proteins are natural or non-natural proteins, and natural ones include:
Animal proteins and vegetable proteins, and non-natural ones include artificially obtained peptides. Although there are technical fields in which peptides are distinguished from proteins, in the present invention they are included in proteins in view of their operational effects. Specific examples of the above-mentioned animal proteins include gelatin, solubilized collagen, casein (or its sodium salt), glue, and hydrolysates thereof. This gelatin and solubilized collagen include soluble proteins obtained by hydrolyzing proteins contained in animal bones, skins, etc. with acid or alkali or by treating them with hot water, and also by appropriate chemical modification ( Examples: succinylation, maleylation, phthalation) and their molecular weights range from tens of thousands to hundreds of thousands. Typical examples of the above-mentioned vegetable proteins include soybean protein (eg, obtained by precipitating and enzymatically treating the water-soluble portion of defatted soybean soapstock) and soybean casein.
Furthermore, the above-mentioned peptides include peptides obtained by condensing the same or different amino acids by chemical synthesis, fermentation, semi-synthetic means, etc.
Its molecular weight is usually on the order of several hundred to tens of thousands. Therefore, the constituent amino acids of these peptides are:
Various amino acids can be employed, including neutral, basic and acidic amino acids; optically active and racemic amino acids; natural and synthetic amino acids. In the present invention, one or more of the above water-soluble proteins are used. For example, gelatin alone or a mixture of gelatin and casein or soybean protein can be used. Furthermore, among the above-mentioned water-soluble proteins, gelatin, solubilized collagen, casein, soybean protein, etc. are generally preferred in consideration of drug absorption promoting action, compatibility or dispersibility with other ingredients, difficulty in obtaining them, etc. used as. The amount of the water-soluble protein blended may be any amount sufficient to achieve the purpose of the present invention, and preferably,
A sufficient amount is used to facilitate absorption of the drug through the skin. For this purpose, water-soluble protein is often used in an amount comparable to or greater than that of the drug, usually 5 to 70% by weight of the entire formulation.
Preferably, about 10 to 60% by weight is blended. The above-mentioned polyhydric alcohols are not particularly limited as long as they suit the purpose of adjusting and maintaining the softness of the topical patch of the present invention, ensuring compatibility or dispersibility with other ingredients, and wettability during application. Various types are used. Such polyhydric alcohols include glycols, triols, and polyols. As a specific example of the glycol, carbon number 2
-6 glycol (e.g. ethylene glycol, propylene glycol, butylene glycol), polyethylene glycol (average molecular weight: 200-8000,
Typical examples of the triol include glycerin and trimethylolpropane, and typical examples of the polyol include sorbitol and polybilylpyrrolidone. One or more types of these polyhydric alcohols are used, for example,
Glycerin alone or a mixture of glycerin and butylene glycol can be used. Among the above polyhydric alcohols, those that are suitable for the above purpose, have low volatility, and have plasticity are generally preferred, and in this sense, glycerin, propylene glycol, butylene glycol, sorbitol, etc. are frequently used. One or more types of the above polyhydric alcohols are used. The blending amount of the above polyhydric alcohols is based on the purpose of blending,
Although it cannot be absolutely limited as it varies depending on the types of other ingredients, it is usually blended in an amount of about 5 to 70% by weight, preferably about 10 to 65% by weight, based on the entire formulation. As the above-mentioned tackifier, there is used a substance that imparts tackiness to the skin to the preparation itself. As such an adhesion agent, it is preferable to use an agent that has functions such as imparting adhesion to the skin, maintaining the viscosity of the preparation itself, and preventing volatilization of other components such as moisture by forming a film on the surface of the preparation. For example,
Includes celluloses, polysaccharides, carboxyvinyl polymers, polyvinyl alcohol, and polyvinylpyrrolidone. These celluloses include alkylcelluloses and hydroxyalkylcelluloses with an average molecular weight of about 40,000 to 200,000, and the number of carbon atoms in the alkyl moiety is 1 to 4 (e.g., methylcellulose, ethylcellulose, propylcellulose, methylpropylcellulose, hydroxymethylcellulose). , hydroxyethylcellulose, hydroxypropylcellulose), carboxymethylcellulose or its alkali metal salts. Specific examples of the above polysaccharides include starch and its derivatives (e.g. carboxymethylated starch,
hydroxypropyl starch), dextrin,
Dextran, chitin, alginic acid or its sodium salt, glycogen, pullulan (trade name,
Examples include single polysaccharides such as those manufactured by Hayashibara, and complex polysaccharides such as mannan, pectin, and gum arabic. The carboxyvinyl polymer has an average molecular weight of about 900,000 to 3,000,000, and includes polyacrylic acid, polymethacrylic acid, and alkali metal salts thereof.More specifically, Hiviswako (trade name) Commercially available products such as Carbopol (trade name, manufactured by Gutsudoritsuchi), Rubiscoll (trade name, manufactured by BASF) are advantageously used. One or more of the above tackifiers may be used. In the present invention, when using the above-mentioned tackifier, the amount to be blended is selected to achieve the above-mentioned purpose of blending, and is usually 0.1% of the total formulation.
~10% by weight, preferably about 0.3~8% by weight. Furthermore, in addition to the above-mentioned components, an appropriate amount of water is added in order to maintain the formulation properties of the soft patch, such as softness and drug absorption. In this case, the amount to be added is usually 5 to 65% by weight based on the entire preparation.
Preferably 10 to 60% by weight, more preferably 20 to 60% by weight
It is about 55% by weight. In addition to the above-mentioned components, other substances may be added as necessary in order to more effectively express the characteristics of the soft patch. Known additives may be used as such additives. A specific example is shown below. Absorption aids (those that play an auxiliary role in drug absorption, such as promoting the softening of keratin, improving water retention or water absorption, and expanding pores): Alkyl esters of monocarboxylic acids (carboxylic acid moieties have 4 to 30 carbon atoms, The ester moiety has 1 to 30 carbon atoms.
Examples: octyldodecyl myristate, isopropyl myristate, ethyl laurate), alkyl esters of dicarboxylic acids (carboxylic acid moiety has 4 to 20 carbon atoms, and one ester moiety has 1 to 20 carbon atoms. Examples) : diethyl adipinate, diisopropyl adipinate, diethyl sebacate), urea, salokol, 1-n
- Dodecylazocycloheptan-2-one (Product name: Azone, Nelson, Research &
Depropment Co., Ltd.), dimethyl sulfoxide,
Dodecyl sulfoxide, dimethylformamide, dimethylacetamide, toluic acid diethylamide, tetrahydrofurfuryl alcohol, dodecylpyrrolidone, methylpyrrolidone, etc. When these absorption aids are used, the amount added is usually about 0.5 to 5% by weight of the entire formulation. Preservatives (those with functions such as preventing deterioration caused by microorganisms and preservatives): paraoxybenzoic acid alkyl esters (parabens), sorbic acid,
such as dehydroacetic acid. When using these preservatives, the amount added is usually 0.01 to 2
It is about % by weight. Emulsifier/dispersant (those with functions such as uniform dispersion of ingredients): Nonionic surfactants such as polyoxyethylene fatty acid ester and polysorbate 80, anionic surfactants such as sodium lauryl sulfate, lower alcohols such as ethanol, etc. , acetone, etc. When these emulsifying/dispersing agents are used, the amount added is usually about 0.1 to 5.0% by weight, with a final concentration based on the entire formulation. Coloring agents: water-soluble tar pigments, natural pigments, etc. In addition, in the present invention, there is no need to use a crosslinking agent (eg, aldehyde compound) or an astringent (eg, zinc oxide, kaolin) as in conventionally known gelatin plasters. Their use may actually impair the softness of the formulation. The shape of one dosage form of the soft patch composed of the above-mentioned ingredients may be any size and shape that can be easily applied to the skin surface.
In general, it is preferable to have a plate-like, disc-like, band-like shape, etc., and to have an appropriate thickness and area (effective area in contact with the skin surface when applied). In this case, the above thickness is usually 0.2 to 3 mm, preferably 0.4 to 2.5 mm.
The area is usually about 0.08 to 200 cm ² , preferably about 0.2 to 160 cm ² . In other words, for example, if it is a plate-shaped soft patch, its length x width is usually 0.2 x 0.4 to 10 x 20.
cm, preferably about 0.4 x 0.5 cm to 10 x 16 cm, and various sizes within the above-mentioned area range can also be adopted, such as a disk shape or a band shape. Which shape to adopt among these shapes is arbitrarily selected depending on the administration site, therapeutic purpose, etc. Soft patches having the above shape are generally separated into individual dosage forms, but in some cases, for convenience of use, a cutting groove is provided to distinguish one dosage form. There are many types of products, such as those that are made into a large plate made up of several to several tens of times so that the required amount can be cut off with scissors etc. during use, or those that are wound into a roll. It can be in the form of For use, storage, and handling of the soft patch mentioned above, if one or both sides of the soft patch are covered with a suitable packaging film, the packaging film can be removed at the time of use and the exposed drug surface can be attached to the skin. It is often convenient to do so. Soft patches can therefore be constructed in the following forms: without any packaging film; with packaging film on one side; with packaging film on both sides. Such packaging films include synthetic resin films (e.g., polyethylene films, polypropylene films, elastomer films, butadiene polymer films, isoprene polymer films), cellophane films, etc. with a thickness of about 0.02 to 0.8 mm, and are elastic. It is preferable to use a woven fabric or a non-woven fabric. In addition, if the soft patch contains volatile components or there is a risk of contamination during storage, store it in a sealed container (e.g., aluminum pack, polyethylene bag, moisture-proof paper bag) before use. It's a good idea to save it. The external patch of the present invention is generally soft. Specifically, it has flexibility and viscoelasticity, as evidenced by its softness that allows it to be slightly deformed without damage to its shape.For example, it can be easily deformed by applying some external force. It can be expanded and contracted and dented (therefore, it adheres well to the skin and feels good when used). Incidentally, cases where the softness of the preparation is increased by applying water to the surface of the soft patch during application are also included in the concept of softness in the present invention. The soft patch having the above-mentioned structure is used for medical purposes and is applied to the skin of various parts of the body depending on the treatment purpose, target, etc. For example, for topical application, it is applied directly to the diseased area or its vicinity, and for systemic application, it is applied to areas where it is easy to absorb the active ingredient through the skin (e.g., areas where keratin is not developed).
It is best to apply it to areas where you feel less discomfort. In addition to the skin, it can also be applied to mucous membranes (oral cavity, nasal cavity, rectum, vagina). Furthermore, it is also possible to use it for cosmetic purposes (for example, as a countermeasure against rough skin and sunburn) by incorporating known cosmetic ingredients. Various methods can be used to manufacture the soft patch, as long as they do not impede the purpose of the present invention. For example, it can be used by adding appropriate modifications to the means conventionally used for manufacturing pharmaceutical preparations such as suppositories, chewing gums, jellies, confectionery such as tiyocholate, and foods such as noodles. The modification maintains the softness which is the objective of the present invention,
This is a necessary modification to improve drug absorption. A typical manufacturing method is to mix the above-mentioned drug, water-soluble protein, polyhydric alcohol, and adhesive agent in an appropriate order, and then mold the product into a desired size. Specifically, a mixture of water-soluble protein and water in advance;
A mixture of drugs, polyhydric alcohol and water (adding the above-mentioned additives if necessary);
It is convenient to adopt a process of preparing a mixture of a tackifying agent, a tackifying agent, and water, and then step-by-step mixing in approximately this order, stirring until the entire preparation has uniform properties, and then molding. There are many things. In this molding process, the drug substance obtained in this process is usually spread into a container with an appropriate thickness and size, or compression molded using an appropriate mold. It may be subdivided into dosage form sizes by operations such as cutting, punching, etc. Other manufacturing methods include using other liquid ingredients (e.g. polyhydric alcohols) in place of water, or grinding or kneading the ingredients with or without adding water. After that, a method of compressing and molding in a suitable mold may be adopted. During or after the above steps, the above-mentioned packaging film can be applied as necessary. The above manufacturing method consists of simple and convenient operations and processes, so it is advantageous for implementation on an industrial scale, and it is possible to obtain soft patches of various shapes and forms depending on the purpose. Even liquid or low-melting point drugs that are difficult to incorporate into pharmaceutical preparations can be incorporated. Examples of the method for producing the external patch of the present invention are shown below. Further, Table 1 shows the prescriptions of each example. Example 1 (Preparation containing ifenprodil tartrate:
(The drugs contained are shown in the same way below.) According to the formulation in Table 1, 20 g of gelatin was wetted with 32 g of purified water and dissolved while heating at 50°C; 2 g of pullulan was dissolved in 8.9 g of purified water; Polyacrylic 0.5g of sodium chloride dissolved in 10g of purified water; 25g of glycerin and 80g of polysorbate
1 g of ifenprodil tartrate and 0.1 g of parabens were suspended in 0.5 g of the mixture while heating at 50°C; the above was added and stirred in a homomixer at the same temperature; this was added and homogenized at the same temperature. The mixture was stirred in a mixer; the mixture was added, stirred in a homomixer at the same temperature, and then spread in a molding machine.
After cooling, cut into pieces, thickness x length x width = 0.1cm x 8cm x 6
A plate-shaped soft patch (main ingredient content: 28 mg) of cm was obtained. Example 2 (Prazosin hydrochloride-containing preparation) According to the prescription in Table 1, a plate-shaped soft patch (base ingredient content: 14 mg) with thickness x length x width = 0.1 cm x 4 cm x 6 cm was prepared using the same method as in Example 1. Obtained. Example 3 (Preparation containing indomethacin) A plate-shaped soft patch (base ingredient content: 110 mg) with thickness x length x width = 0.1 cm x 8 cm x 12 cm was obtained according to the prescription in Table 1 and in the same manner as in Example 1. Ta.

【table】

[Table] Example 4 (Dipyridamole-containing preparation) A plate-shaped soft patch (base ingredient content: 29 mg ) was obtained. Example 5 (Preparation containing clonidine hydrochloride) According to the prescription in Table 1, a plate-shaped soft patch (base ingredient content: 28 mg) with thickness x length x width = 0.1 cm x 4 cm x 12 cm was prepared. Obtained. Example 6 (Preparation containing pentazocine hydrochloride) A plate-shaped soft patch with thickness x length x width = 0.1 cm x 4 cm x 5 cm (base ingredient content: 24 mg) was prepared according to the prescription in Table 1 and in the same manner as in Example 1. Thickness x
Two types of disc-shaped soft patches with a diameter of 0.1 cm x 1.7 cm (main ingredient content 2.8 mg) were prepared. Example 7 (Clidanac-containing preparation) According to the recipe in Table 1, a drug substance obtained in the same manner as in Example 1 was spread on a polyethylene packaging film to a thickness of 0.1 cm, and then cut. Vertical 6
A plate-shaped soft patch measuring cm x width 4 cm was manufactured. Example 8 (Soft patch containing oxendrone) A drug substance obtained in the same manner as in Example 1 according to the prescription in Table 1 was punched and cut to determine the thickness.
A disc-shaped soft patch measuring 0.15 cm x 2.5 cm in diameter was manufactured. Example 9 (Pindolol-containing preparation) According to the formulation in Table 1, the drug substance obtained in the same manner as in Example 1 was molded into a strip having a thickness of 0.1 cm and a width of 2.0 cm. After applying a packaging film to this product, it was wound into a coil. Example 10 (Ubidecarenone-containing preparation) According to the formulation in Table 1, the obtained drug substance was cut into a thickness by the same method as in Example 1.
It was molded into a plate-like product measuring 0.2 cm x 10 cm x 6 cm. Example 11 (Preparation containing triamcinolone acetonide) Purified water was added to 20 g of gelatin according to the formulation in Table 1.
30g was added, moistened, and dissolved under heating at 50°C;
2 g of hydroxyethylcellulose was dissolved in 7 g of purified water; 5 g of sodium caseinate was dissolved in 10 g of purified water.
25 g of glycerin, 0.2 g of polysorbate 80, 0.3 g of parabens and 0.5 g of triamcinolone acetonide were uniformly mixed under heating at 50°C;
This was added and stirred at the same temperature in a homomixer; this was added and stirred at the same temperature in a homomixer, and then spread in a molding machine. After cooling, the resulting drug substance was coated with a polyethylene packaging film and further cut into a circular shape to produce a disc-shaped soft patch with a thickness of 0.1 cm and a diameter of 2 cm. In addition, sodium caseinate is sticky and
It is also used as a thickener. Example 12 (Preparation containing dihydroergotamine methanesulfonate) According to the recipe in Table 1, the obtained drug substance was prepared in the same manner as in Example 1, with a thickness of 0.1 cm and a length of 20 cm.
This product was formed into a plate-like product measuring 15 cm wide, and grid-like score lines were provided on the entire surface of the product at intervals of 4 cm long and 5 cm wide. (During use, the required number of sheets can be cut out along this score line.) Examples 13 to 19 (Clidanac-containing preparations) Preparations obtained according to the formulations in Table 1 and in the same manner as in Example 1. The thickness of the original material is 0.1cm
It was formed into a plate shape of 13 cm long and 10 cm wide. Examples 20 to 21 (Clidanac-containing preparation) Glycerin, hydroxypropyl cellulose, Clidanac and parabens were added and dissolved in 70 g of ethanol according to the recipe in Table 1 in order, and then sodium caseinate was added and the whole was homogenized. After stirring thoroughly, the mixture was spread into a glass flat plate with a thickness of about 1 mm. Furthermore, by drying at room temperature for 24 hours, the ethanol is evaporated and the
A 10 cm plate-shaped soft patch was obtained. Example 22 (Piroxicam-containing preparation) A plate-shaped soft patch with thickness x length x width = 0.1 cm x 6 cm x 4 cm was obtained according to the prescription in Table 1 and in the same manner as in Example 1. The external patch of the present invention obtained by the above method can be stored in a stable state, and when used, has appropriate adhesion and adhesiveness to the skin and mucous membranes of the human body. It is easy to use, has no side effects such as rash even if it is applied for a long time, and can be easily removed after use. Such a preparation of the present invention has the following characteristics and is therefore very useful medically and industrially. (b) It is easier to use and the dosage can be easily determined than conventional topical preparations such as ointments. Therefore, it is possible to avoid the occurrence of side effects due to overdosage, loss of drug, and failure to achieve drug efficacy due to underdosage, and more appropriate measures can be taken depending on the therapeutic purpose and target disease. (b) Excellent transdermal absorption of active ingredients such as drugs is achieved. Therefore, not only local efficacy but also systemic efficacy is expected. (c) Since it is a soft preparation, it has good elasticity, adhesion to the skin, and feels good when used. (d) Drugs that have side effects (gastrointestinal disorders, etc.) and bioavailability problems (delayed metabolism, etc.) can be effectively improved using other administration methods such as oral administration. (E) Oral administration several times a day may result in forgetting to take the drug or
If you dislike taking it or need to take it in various types and in large quantities, the patch of the present invention can be used once or twice a day to provide long-term medicinal effects.
It is easy for patients to use, and it is easy for doctors to manage both the disease and drug efficacy. Next, test examples of the formulation of the present invention will be described. Test Example 1 (Sensory test regarding feeling of use such as adhesion and tackiness) The soft patch of Example 1 from which the drug was removed was used as a sample, and the "New Edition Sensory Test Handbook" No. 356 was used.
Based on the Sietsufue method described on pages 366 to 366 (published by Japan Society of Science and Technology), the test was performed twice on each of 10 adults. That is, the above sample was pasted on the left and right upper arms, removed after 2 hours, and the feeling of pasting on the left arm and right arm was judged based on the following criteria: Very good (+3), Definitely good. (+2), somewhat better (+1), no difference (0), somewhat worse (-1), definitely worse (-
2), very poor (-3). As a result, the usability of the above soft patch was +2.15
It was ±0.84. For reference, a commercially available poultice that was tested at the same time had a value of -0.76±0.81.
Furthermore, in addition to this result, the subjects pointed out that the soft patches had a particularly soft feel.
This point was not found in conventional external patches. Test Example 2 (Drug release test) (Method) The indomethacin-containing soft patch of Example 3 (disc-shaped with a diameter of 3.5 cm and a thickness of 0.1 cm) was
It was attached to an artificial membrane (Millipore Filter SSWPO4700, manufactured by Millipore) placed in contact with the solution surface of 200 ml of M/15 phosphate buffer (PH5.5, 37°C), and the solution was poured into the above buffer through this artificial membrane. The amount of indomethacin released was determined by HPLC (high performance liquid chromatography). That is, 1 ml of this buffer solution was collected over time, extracted with 5 ml of dichloromethane, and then the solvent was distilled off from the extract.
A solution of the obtained residue in 0.2 ml of 75% acetonitrile was used as a measurement sample. Its HPLC
In this, we used Nucleosil C18 as a column and acetonitrile/0.01M potassium dihydrogen phosphate (75:25) as a mobile phase at a flow rate of 2 ml/min, and measured the absorbance at 318 nm in the ultraviolet region for quantitative determination. Summer. (Results) The above results are shown in Table 2.

[Table] Test Example 3 (Preparation containing ifenprodil tartrate) (Method) The back coat of white male domestic rabbits (weight 2.8 to 3.1 kg, 3 birds per group) was shaved with electric clippers and an electric razor; (A) The soft patch obtained in Example 1 was applied to the site until the final blood collection and fixed with a bandage. Separately, (B) ifenprodil tartrate aqueous solution was orally administered using a catheter. In addition, (A) above,
(B) The dose of ifenprodil tartrate in both administration groups was set at 10 mg/Kg. In the (A) administration group, 5 ml of blood was collected at appropriate times from 1 to 8 hours after administration, and in the (B) administration group, from 0.25 to 4 hours after administration, and serum was collected by centrifugation. 2ml each of this serum
was extracted with ether, the extract was reacted with pentafluorobenzyl bromide in the presence of a strong alkali, and then reacted with bis-(trimethylsilyl)trifluoroacetamide, and the resulting derivative was subjected to ECD.
- Determined by gas chromatography ( ^63Ni ). (Results) The results are shown in Table 3. From this table, (B) C _nax (maximum serum concentration) in the oral administration group is approximately
29.4ng/ml, T _nax (time to reach maximum serum concentration) approximately 0.5 hours, (A) C _nax in the dermal administration group approximately
20.2 ng/ml, T _nax for 2 to 3 hours, and a clear difference in the serum concentration course of ifenprodil between the two groups. In other words, in the (B) administration group, serum ifenprodil continued to decrease from 0.5 hours after administration, whereas in the (A) administration group, it remained almost constant for 1 to 6 hours after administration. level of concentration and comparable to oral administration
C _nax , and further increases the drug elimination half-life (t1/2) [approximately 1 hour in (B) and approximately 4.8 hours in (A)] and increases AUC (area under serum concentration) (approximately 2.1 times).
was confirmed. The above results show that when using soft patches, the percutaneous absorption of drugs is significantly improved, sustained, and
It is understood that this results in an improvement in the bioavailability of the drug, and at the same time, the metabolism and decomposition of the drug due to the hepatic first-pass effect upon oral administration is suppressed.

[Table] Test Example 4 (Preparation containing pentazocine hydrochloride) (Method) Inject (A ) The soft patch obtained in Example 6 was applied and fixed with a bandage until the final blood collection. Separately, (B) pentazocine hydrochloride filled into capsules for oral administration was orally administered together with 30 ml of water. The doses of pentazocine hydrochloride in the above (A) and (B) administration groups were both 20
mg/Kg. After administration of both drugs, 5 ml of blood was collected at appropriate times from 1 to 8 hours in the (A) administration group, and 0.25 to 5 ml of blood was collected in the (B) administration group.
3 ml of blood was collected at appropriate times for up to 6 hours, centrifuged, and the serum obtained was used to perform Berkowitz's method [Clinical Pharmacology and Therapy, Vol.
10, p. 320 (1969)], the serum concentration of pentazocine was measured by a fluorescence assay. (Results) The results are shown in Table 4. From this table, it can be seen that while the (B) treatment group showed relatively fast drug absorption,
After T _nax , the serum concentration quickly decreased, but
In the (A) administration group, although drug absorption was slow at the initial stage of administration, the serum concentration remained relatively high even after T _nax , and the concentration remained high even 8 hours after administration. From the above results, it is understood that the soft patch has excellent drug absorption, persistence, and significant improvement in bioavailability.

[Table] Test Example 5 (Pharmacological test of prazosin hydrochloride-containing preparation) (Method) Depilated male SD rats (body weight 200-300
g, 6 to 8 animals per group) The soft patch of (A) Example 2 was attached to the back, and the top was fixed with tape.
Separately, (B) a 1% gum arabic suspension of prazosin hydrochloride was orally administered. The dose in both groups (A) and (B) was 20 mg/Kg once a day, and the administration was continued for 3 days. 24 hours after the final administration, 3 μg/Kg of norepinephrine was administered intravenously under anesthesia with sodium pentobarbital (dose 40 mg/Kg; intraperitoneal administration), and the pressor response at this time was observed. compared with. (Results) The above results are shown in Table 5. from this result,
Although the soft patch is administered transdermally, it is understood that it exhibits medicinal efficacy (suppression of pressor response) comparable to oral administration.

[Table] *: There is a significant difference compared to the control group with a risk rate of 5%. (There is no significant difference between groups A and B.)
Test Example 6 (Preparation containing clonidine hydrochloride) (Method) A 0.1 x 8 x 10 cm plate of the soft patch of Example 5 was placed on the back of a white male rabbit (weight 2.5-2.9 kg) whose hair was shaved 24 hours before drug administration. (containing 47 mg of clonidine hydrochloride) was applied to the skin, and the patch was fixed with tape (7 hours after application, the soft patch was removed and the drug remaining on the skin was wiped off with absorbent cotton). 0.5 to 24 hours after application, 3 ml of blood is collected at appropriate times and plasma collected by centrifugation is used.
The method of Edlund et al. [Acta Pharmacol. Toxicol.
40, p. 145 (1977)], ECD
- Clonidine was determined by gas chromatography equipment. (Results) The above results are shown in Table 6. from this result,
Rapid and sustained transdermal absorption of the drug was observed.

[Table] Test Example 7 (Piroxicam-containing preparation) (Method) The soft patch of Example 22 was applied to the back of shaved male rats (body weight: 425-470 g) so that the dose of piroxicam was 0.5 mg/body; was fixed with tape. Blood was collected at appropriate times 1 to 4 hours after application, and serum was collected by centrifugation. Using 0.2 ml of this serum, Hobbs et al.'s method [Tournal
of Clinical Pharmacology, vol. 19, p. 270 (1979
Piroxicam was quantified by fluorescence method according to [2013]. (Results) The above results are shown in Table 7.

【table】

Claims (1)

[Scope of Claims] 1. A soft patch for external use which contains the following components (a), (b), (c) and (d) and is self-adhesive to the skin. (a) Drug (b) 5 to 70% by weight of the entire formulation, a water-soluble protein that exhibits an absorption promoting effect (c) Polyhydric alcohol, 5 to 70% by weight of the entire formulation (d) The entire formulation 0.1-10% by weight of tackifier