JPS60214732A - Application agent for external use - Google Patents

Abstract

PURPOSE:An easily usable application agent for external use, containing a drug, polyhydric alcohol and adhesive excipient in a water-soluble protein having absorption promoting action, and capable of enhancing the bioavailability of the drug and understanding accurately the dose of the drug. CONSTITUTION:A solt application agent for external use, obtained by incorporating a drug, e.g. analgesic and anti-inflammatory agent, local anesthetic agent or antimicrobial agent, polyhydric alcohol, e.g. glycerol or PEG, and adhesive excipient, e.g. cellulose, polysaccharide or polyvinyl alcohol (PVA), in a water- soluble protein, e.g. gelatin, solubilized collagen or casein, and having individual tackiness to the skin. The incorporation of the water-soluble protein provides the application agent having remarkably improved drug absorbability, lasting property and bioavailability. The above-mentioned agent is produced by a simple and easy process. The resultant agent can be incorporated with even a liquid or low-melting drug which has not been easily incorporated with solid pharmaceuticals in the past.

Description

[Detailed description of the invention] The present invention relates to an external patch.

Conventionally, pharmaceutical preparations applied to the skin include ointments, liquids,
Poultices, tapes, etc. are known, but these preparations depend on setting the appropriate dosage of the drug, release/penetration of the active ingredient, biological effects, and in the case of ointments, the area and thickness to be applied. It has been pointed out that it is difficult to determine the exact dose of the drug, and that systemic effects due to transdermal absorption cannot be expected. 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, although new administration forms called drug delivery systems have recently been developed, they have only been put into practical use for a small number of specific drugs.

In view of the above-mentioned technical situation, the present inventors have conducted intensive research with the aim of developing a topical preparation that solves the problems of the conventional techniques, 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 has increased bioavailability of the drug and allows for precise control of drug dosage. reached.

Ingredients C&'), (b), (C) and (d
) and has skin adhesive properties (hereinafter sometimes simply referred to as "soft patch")
Regarding.

(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; Drugs include both locally applied drugs and systemically applied drugs. Topically applied drugs are used to treat cutaneous and subcutaneous diseases, or to adjust the skin condition to protect the skin, and are mainly drugs that exert their medicinal effects locally. Can be mentioned. In addition, examples of drugs that are applied systemically include drugs that are absorbed through the skin surface where they are applied, pass through the blood, and enter tissues within the body. These drugs, especially drugs that have little or no percutaneous absorption when taken alone, or drugs that have low bioavailability when administered orally (e.g., have low bioavailability) The active ingredients of the soft patch include drugs that have a high side effect (less than 80%), drugs that have many side effects, drugs that must be administered by injection because they are broken down by digestive juices, drugs that are susceptible to the first-pass effect in the liver, etc. It is beneficial to adopt it. Specific examples of drugs incorporated into soft patches are as follows.

°■Analgesic anti-inflammatory agent = 7cetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, creamal salicylate,! - Met/tol, Kan7ar, Mefenamic acid, Flufenamic acid, Indomethacin, Dichlor7
Enatsuku.

Arclo-7en, ibuprofen, ctopro-7en, nagloxen, p-2-nobroaene.

fenoprofen, salindac, 7-emptafene, clidanac, flurbiprofen, indoprofen, butidic acid, fenthiazac t)lumethys tiaprofenic acid, pensatac, 7-emptazone, piroxicam, phenylbutacin, 7-emptazone, clo7
Ezon, pentazocine, meverizolnat: ■ Steroid anti-inflammatory agents: hydrocorcinol, glednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, fludrocorcinol acetate, etc.: ■ Antihistamines or antiallergic agents: chlorpheniramine, glycyrrhizin Acids, diphenhydramine, beriactin, etc.; ■ Local anesthetics: benzocaine, glocaine, zipcaine, lidocaine, etc.; ■ Antimicrobial agents, etc.
(including antibacterial agents, antifungal agents, antifungal agents, and antiviral agents)) tetracyclines such as nioxytetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, amilorites such as kanamycin, chloramphenicol, Iodine compounds, nido-g-furantoin, nyscutin, amphotericin, 7-radiomycin, sulfonamides, pyrrolnidoline, clotrimazole, etc.: Antihypertensive agents: clonidine, d-methyldopa, reserpine, syrosingopine, recinamine, cinnarizine, human 2 Radin, prazosin, etc.; ■ Antihypertensive diuretics: theofylline, trichloromethiazide, 70ceside, tripacid, methyclothiazide, penflucito, hydrothiazide, spironolactone, metolazone, etc.; ■ Cardiac drugs: digitalis, ubidecarenone, Teimoku =
;Dopamine, etc.;■ Coronary vasodilator dinitroglycerin,
Insorbitol cinitrate, erysto-stetranitrate, pentaerythol cyto 2 nitrate,
Diviridamol, dirazep, topidil, trimetazidine, etc.; [Phase] Vasoconstrictors: dihydroergotamine, dihydroergotamine; @β-procaranol, etc.; @calcium antagonists: dilteazem, nifedipine, nicardipine, verapamil, pencicudine, Dirazep, etc.: @Anti-epileptic drugs 22trazepam, meprobamate, phenytoin, etc.: 0 Anti-vertigo drugs: Insulin.

Betahistine, score 2 min, etc.; [phase] tranquilizers:
Diazepam, lorazepam, flunitrazepam, fluphenazine, etc.; [phase] Hypnosedatives: phenoparbital,
Amobarbital, cycloparbital, etc.; ◎ Muscle relaxant nitrivericin.

Baclofen, dantrolene sodium, cyclobenzapyrine, etc.; [Phase] Autonomic nerve agents, niatropine, levodopa, etc.: 0 Respiratory agents: codeine, ephedrine, inproterenol. Dextromethorphan, orciprenaline, ipratropium broside, cromoglycate, etc.; [phase] Hormonal or antihormonal agents: corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, salivary gland hormones, thyroid hormone, adrenal hormone, kallikrein, insulin, oxendron etc.: [phase] vitamins:
Vitamin A, B.

C, Di, and their derivatives, calcheferols, mecobalamin, etc.; @antitumor agents: 5-fluorouracil and its derivatives, krestin, bisibanil,
Ancitapine, cytarabine, etc.; O Enzymes: lysozyme, urokinase, etc.; O Chinese herbal medicine or herbal medicine extracts: licorice, aloe, purple root, etc.; o Anti-ulcer agents, niarantoin, aldioxa, alcloxa, etc.;

Two or more of the above drugs can be used in combination, if necessary. In addition, the above drugs are used in free form, or
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. methanesulfuric acid, lactic acid, a-acid, fumaric acid, maleic acid, acetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid). Examples of the base include organic bases (eg ammonia, triethylamine) and inorganic bases (eg sodium hydroxide, potassium hydroxide). Furthermore, examples of the above esters include alkyl esters, esters, aralkyl esters, and the like.

The amount of the above-mentioned drug to be mixed may be as long as it is sufficient for the expression of the drug's efficacy, and in most cases, the amount is 0.01-20
! The content is preferably about 0.05 to 10% by weight. Furthermore, the dosage may be increased or decreased as appropriate depending on the type of drug, therapeutic purpose, age and weight of the patient, degree of disease progression, etc.

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 examples of natural proteins include animal proteins and vegetable proteins, and examples of non-natural proteins 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 animal proteins include gelatin, solubilized collagen, casein (or its sodium salt),
Examples include glue and their hydrolysates. This gelatin and solubilized co2-gun include soluble proteins obtained by hydrolyzing proteins contained in animal bones, skins, etc. with acid or alkali or treating with hot water, and furthermore, soluble proteins suitable for these substances. Includes those obtained by chemical modification (e.g. succinylation, maleylation, 7-tar formation),
Its molecular weight is about 1 to 100,000. 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. Further, the above-mentioned peptides include peptides obtained by condensing the same or different amino acids by chemical synthesis, fermentation, semi-synthetic means, etc., and the molecular weight thereof is usually in the order of several hundred to several hundred. Therefore, the constituent amino acids of this peptide are neutral.

Basic and acidic amino acids: optically active forms and mixtures with in or soy protein can be used. Furthermore, among the above-mentioned water-soluble proteins, as the polyhydric alcohols, Rohilene glycol for external use according to the present invention, petile/cricol, nrubitol, etc. are frequently used. One or more types of the above polyhydric alcohols are used.

The amount of the above-mentioned polyhydric alcohols cannot be determined unconditionally as it varies depending on the purpose of blending and the types of other ingredients, etc.
Usually 5 to 70% by weight, preferably 1% by weight based on the entire formulation.
About 0 to 65% by weight is blended.

As the above-mentioned tackifier, there is used a substance that imparts tackiness to the skin to the preparation itself.

Such an adhesion agent may not only provide adhesion to the skin, but also maintain the viscosity of the preparation itself. Preferably used are those that have the function of preventing volatilization of other components such as moisture by forming a film on the surface of the agent, such as celluloses, polysaccharides, carboxyvinyl polymers, polyvinyl alcohol,
Contains polyvinyl biryd. Examples of celluloses include alkylcelluloses and hydroxyalkylcelluloses having an average molecular weight of about 40,000 to 200,000 and an alkyl moiety having 1 to 4 carbon atoms (e.g., methylcellulose, ethylcellulose, flobylcellulose, methylglobilcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), carboxymethyl cellulose derivatives (e.g. carboxymethylated starch, hydroxypropyl starch),
Dextrin, Dextra/, chitin, alginic acid or its sodium salt, glycogen, Pur2no (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 900,000 to 3
It includes polyacrylic acid, polymethacrylic acid, and their alkali metal salts, and more specifically, Hibiswako (trade name, Wako Tsumugi #), Carbobol (trade name, Commercially available products such as Gudrich at), Rubiskol (trade name, EASF) 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 be an amount that can achieve the above-mentioned purpose of blending, and is usually 0.1 to 10% by weight, preferably 0. It is about .3 to 8% by weight.

Furthermore, in addition to the above-mentioned components, an appropriate amount of water is added for the purpose of maintaining the soft patch's properties as a vehicle, such as softness and drug absorption. In this case, the amount to be blended is usually 5 to 65% by weight, preferably 10 to 60% by weight, based on the entire preparation, and other substances may be added as necessary to achieve more effective expression. good. Known additives may be used as such additives. A specific example is shown below.

■Absorption aid (promotes softening of keratin, improves water retention or water absorption 2)
Substances that play an auxiliary role in drug absorption, such as expanding pores):
Alkyl ester of monocarboxylic acid (carboxylic acid moiety has 4 to 30 carbon atoms, ester moiety has 1 to 3 carbon atoms)
Something that is 0. Examples: octyldodecyl myristate, inglovir myristate, ethyl laurate), alkyl esters of dicarboxylic acids (carboxylic acid moiety has 4 carbons)
~20, and one ester moiety has 1 to 20 carbon atoms
something that is. Examples: diethyl adibinate, diisoglobil adibinate, diethyl sebacate), urea, salokol, 1-n-dodecyl azocyclohebutan-2-one (trade name Niacin, Nelson, Research and Development Company) ), dimethyl sulfoxide, dodecyl sulfoxide, dimethylformamide, dimethylacetamide, toluic acid diethylamide, tetrahydronerufuryl 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 ester (
parabens), sorbic acid, dehydroacetic acid, etc. When these preservatives are used, the amount added is usually about 0.01 to 2% by weight of the entire preparation.

■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, and lower grades such as ethanol. alcohol, 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.

■Colorants: Water-soluble tar pigments, natural pigments, etc.

In addition, in the present invention, there is no need to use a crosslinking agent (eg, an aldehyde compound) or an astringent (eg, zinc dioxide, kaolin) as in conventionally known upper 2 chin cataplasm agents. Their use may actually impair the softness of the formulation.

The shape of one dosage form of the soft punch composed of the above ingredients may be any size and shape that can be easily applied to the skin surface, and is generally plate-like, five-disc-like,
It is preferable to have a band-like form and an appropriate thickness and two areas (the effective area in contact with the skin surface when applied). In this case, the appropriate thickness is usually about 0.2 to 3 mm, preferably about 0.4 to 2.5 mm, and the area is usually about 0.6 to 200 mm, preferably 0.2 mm.
~160d. In other words, for example, if it is a plate-shaped soft patch, its length x width is usually 0.2 x
0.4-10 x 20 an, preferably 0.4
In addition to being able to be of the order of X 0.5 an -10X 16 cm, various sizes within the above-mentioned area range can 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. In the form of a large plate that can be used several times to several tens of times so that the required amount can be cut off with scissors etc. during use, or a band that is wound up into a roll. It can be done.

In order to use, store, and handle the above-mentioned soft patch, 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 side can be attached to the skin. It is often convenient to keep it in a safe place. Therefore, the soft patch can be constructed in the following forms: 1) One that does not use any packaging film 10 One that has a packaging film on one side: 2) One that has a packaging film on both sides. Examples of such packaging films include synthetic resin JiE (e.g., polyethylene film, polypropylene film, polyester film, phthalene polymer film, isoprene polymer film), and cellophane film with a thickness of about 0.02 to 0.8. It is preferable to use a material that is stretchable, but woven or non-woven fabrics may also be used.

If the soft patch contains volatile ingredients or there is a risk of contamination during storage, store it in an airtight container (e.g. a aluminum bag) before use.

It is best to store it in a polyethylene bag or a moisture-proof paper bag).

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. can be expanded, contracted, and indented (thus,
It feels good when used because it adheres well to the skin.)

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 applied to the skin of various parts of the body for medical purposes depending on the treatment purpose, target, etc. For example, for local application, it is applied directly to the diseased area or its vicinity, and for whole body application, it is applied to areas where the active ingredient is easily absorbed through the skin (e.g., areas where keratin has not developed) and where there is less discomfort. It is best to attach it to the area. 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 (eg, to prevent rough skin and sunburn) by incorporating known cosmetic ingredients.

Various methods can be used to produce the soft patch as long as they do not impede the purpose of the present invention.

For example, suitable modifications can be made to the means conventionally used in the production of pharmaceutical preparations such as layer agents, chewing gum, jelly, confectionery such as chocolate, and food products such as noodles.

This modification is a necessary modification for maintaining softness, improving drug absorption, etc., which are the objectives of the present invention. Typical manufacturing methods include the aforementioned drugs and water-soluble proteins.

A method is adopted in which the polyhydric alcohol and the tackifier are blended in an appropriate order and then molded into a desired size. Specifically, in advance: ■ a mixture of water-soluble protein and water;
■ Prepare a mixture of drug, polyhydric alcohol and water (at this time, add the above-mentioned additives if necessary): and ■ Prepare a mixture of tackifier and water, and then ■ It is often convenient to adopt a process in which the preparations are mixed step by step, stirred until the entire preparation has uniform properties, and then shaped. 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 cutting, punching, etc. operations. 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, and it also Even liquid or low melting point drugs that are difficult to incorporate into mold 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 2 or less containing ifenprodil tartrate,
(The drugs contained are shown in the same way.) According to the prescription in Table 1, 20g of gelatin was mixed with 32g of purified water.
g and dissolved under heating for 50CK; ■ Pullulan@
2g was dissolved in 8.9g of purified water: ■ 0.5g of sodium polyacrylate was dissolved in 10g of purified water; ■ 1g of ifenprodil tartrate and 0.1 of parabens were added to a mixture of 25g of glycerin and 800.5g of polyester rubé.
g was suspended under heating for 50CK; ■Add ■ to the above ■,
Stir in a homomixer at the same temperature; Add ■ to this ■,
Stir in a homomixer at the same temperature; Add ■ to this ■,
The mixture was stirred in a homomixer at the same temperature and then spread in a dredger. After cooling, cut it, thickness x length x width = 0.1 am
A plate-like soft patch (main ingredient content: 28 .mu.m) having a size of 801×6 Gm was obtained.

Example 2 (Grazosin hydrochloride-containing preparation) According to the prescription in Table 1, by the same method as Example 1, thickness x length x width =
0. A plate-shaped soft patch (main ingredient content: 14 wg) measuring 1 cm X 4 cts X 6 Gm was obtained.

Example 3 (Indomethacin-containing preparation) According to the prescription in Table 1, by the same method as Example 1, thickness x length x width =
A plate-shaped soft patch measuring 0.101 x 8 cm x 121 cm (base ingredient content: 110 .mu.m) was obtained.

Example 4 (Dibiridamole-containing preparation) According to the prescription in Table 1, the same method as in Example 1 was used. Example 5 (Clonidine hydrochloride-containing preparation) According to the prescription in Table 1, in the same manner as in Example 1, the thickness x Length x width = 0.1 aIIX 4
A plate-like soft patch (main ingredient content: 28q) measuring cm x 12 cn was obtained.

Example 6 (Pentazocine hydrochloride-containing preparation) According to the formulation in Table 1, a plate-like product with thickness x length x width = O, l cm x 4 cm x 5 cm (base ingredient TT24■) was prepared in the same manner as in Example 1. Soft Patch and Thickness Example 7 (Clidanac-containing preparation) According to the formulation in Table 1, the drug substance obtained by the same method as in Example 1 was packaged in polyethylene packaging 0, 2 aII.
It was molded into a plate-like product measuring 10 x 6 x 11 x 6 x 11 x 6.

Example 1 (Preparation containing triamcinolone acetonite) According to the prescription in Table 1, ■ Gelatin 20 g K'! fl
Add 30 g of 1M water to 0 g of humidified water and dissolve at 50C by heating: ■ Dissolve 2 g of K hydroxyethyl cellulose in 7 g of full 1 m water; ■ Dissolve 5 g of sodium caseinate in 10 g of nm water: ■ 25 g of glycerin, 800.2 g of polysorbate. , parabens o, sg, and 0.5 g of triamcinolone acetonide were mixed uniformly under heating at 50C: ■ Added ■ to the above ■, and mixed them at 500 °C in an Omomixer.
■ Added ■ to this ■, and stirred at the same temperature in a homomixer; ■ Added ■ to this ■, stirred at the same temperature in a homomixer, and then spread it into a molding machine. After cooling, the resulting drug substance was coated with a polyethylene packaging film, and further cut into a circle with a thickness of 0.1 cm and a diameter of 2 cm.
The lining was a disc-shaped soft patch. Note that sodium caseinate is used also as an adhesive/thickener.

1[fl12 (preparation containing dihydroergotamine methanesulfonate)] According to the formulation in Table 1, by the same method as Example 1,
The obtained drug substance has a thickness of O, l cm and a length of 2° an
Formed into a plate-like object with a width of 15 am, and further formed into a crystal surface Example 1
3-19 (Clidanac-containing preparation) 1g 1 According to the prescription in the table, the obtained drug substance was prepared in the same manner as in Example 1 to a thickness of 0.1 an x 13 cn x 10 x 10
011 plate shape.

Examples 20 to 21 (Clidanac-containing preparation) In 70 g of ethanol, according to the recipe in Table 1, /lin, hydroxyglobil cellulose, Clidanac and parabens were sequentially added and dissolved, and then sodium caseinate was added and the entire mixture was dissolved. It was spread to a uniform thickness. Furthermore, at room temperature 2
By drying for 4 hours, ethanol was evaporated and a plate-shaped soft plate measuring 12 cm in length and 10 cm in width was obtained.

Example 22 (Piroxicam-containing preparation) According to the prescription in Table 1, by the same method as Example 1, thickness x length x width =
0.1 an X 6 an X 4 c! A plate-shaped soft batch of m was obtained.

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 also feels good when used, has no side effects such as clogging even when 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) Compared to conventional topical preparations such as ointments, it is easier to use and the dosage can be more easily determined.

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.
More appropriate measures can be taken depending on the target disease.

(b) Excellent transdermal absorption of active ingredients such as drugs is provided. Therefore, not only local efficacy but also systemic efficacy is expected.

(...) Because it is a soft formulation, it has good elasticity, adhesion to the skin, and feels good when used.

(d) Drugs that have problems with side effects (gastrointestinal disorders, etc.) and bioavailability using other administration methods such as oral administration can be effectively improved (metabolism delays, etc.).

(e) When oral administration is performed several times a day, if the patient forgets to take the dose or dislikes taking it, or if it is necessary to take multiple doses and doses, the patch of the present invention can be used once or twice a day. It has a long-lasting medicinal effect and is easy to use for patients.
Moreover, 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 stickiness) The soft patch of Example 1 from which the drug was removed was used as a sample, and "New Edition Sensory Test Handbook" pages 356 to 366 (published by Japan Science and Technology Association) was used as a sample. Based on Scheffe's method as described,
The test was conducted twice on each subject for 10 adults. That is, the above sample was applied to the left and right upper arms, and removed after 2 hours.
The feeling of application on the left and right arms was judged based on the following criteria: Very good (+3
), Certainly good (+2), Somewhat good (+1)
) r No difference (0), somewhat bad (-1), definitely bad (2) #very bad (-3).

As a result, the usability of the above soft patch was +2.15±0
．． It was 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 these results, the subjects pointed out that the soft patch had a particularly soft feel, which was not found in conventional external patches.

Test Example 2 (Drug release test) (Method) Indomethacin-containing soft batch of Example 3 (diameter 3.
5 an
/15 phosphate buffer (m5.5; 37c) 200 ut was attached to an artificial membrane (Miyopore Filter 5SWPO4'700, Millibore M) placed in contact with the solution surface, and passed through this artificial membrane. The amount of indomethacin released into the buffer was determined by HPLC (high performance liquid chromatography). That is, 1 m of this buffer
1 aliquots were collected over time, extracted with 5 ml of dichloromethane, the solvent was then distilled off from the extract, and the resulting residue was extracted with 7 ml of dichloromethane.
A solution dissolved in 0.2 mL of 5% acetonitrile was used as a measurement sample. In the HPLC, Nucleosil 01B was used as a column.
Quantification was carried out by measuring the absorbance at 318 nm in the ultraviolet region using acetonitrile and 10.01 M potassium dihydrogen phosphate (75:25) as the mobile phase at a flow rate of 2 ml/Zmin.

(Result no The above results are shown in Table 2.

Table 2 Test Example 3 (Preparation containing iaenprodil tartrate) (Method) The back coat of white male domestic rabbits (body weight 2.8-3.1 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 shaved site until the final blood collection and fixed with a bandage. Separately, (B
) Ifenbrodil tartrate aqueous solution was orally administered using a catheter. The dosage of iaenprodil tartrate in the four groups (A) and (B) above was 1 cIO /
- was set.

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. 2 ml of each serum was extracted with ether, the extract was reacted with pentafluorobenzylbromide in the presence of a strong alkali, and then with bis-(trimethylsilyl)trifluoroacetamide, and the resulting derivative was subjected to EC'D gas chromatography. Quantification was carried out using a graphography device (63Ni).

(Results) The results are shown in Table 3. From this table, (E) Crnax (maximum serum concentration) in the oral administration group is approximately 29.4
ng/m, Tfnaz (time to reach maximum serum concentration) was approximately 0.5 hours, (A) cma in the transdermal administration group
It is observed that x is approximately 20.2 ng/ml, Tma treatment is 2 to 3 hours, and there is a clear difference in the change in serum concentration of ienprodil between the two groups. That is, (B)
In the administration group, serum iaenprodil continued to decrease after 0.5 hours after administration, whereas in the administration group (A), the concentration remained at a nearly constant level for 1 to 6 hours after administration. , and showed CmaX comparable to oral administration, and further extended the drug elimination half-life (t 1/2) [(B)
1 hour in (A), approximately 4.8 hours in (A)] and AUG
(Area above serum concentration) was confirmed to increase (approximately 2.1 times).

The above results indicate that the use of soft patches significantly improves and sustains the transdermal absorption of drugs, and ultimately improves the bioavailability of drugs.

It is understood that drug metabolism and decomposition due to the hepatic first-pass effect upon oral administration is suppressed.

Test Example 4 (Preparation containing pentazocine hydrochloride) (Method) The dorsal area of white male rabbits (body weight 2.8-3.5 kg, 3 rabbits per group) was electrically shaved in the same manner as in Test Example 3 above, and (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 a capsule for oral administration was orally administered together with 30 ml of water. The doses of pentazocine hydrochloride in the above administration groups (A) and (B) were both K 20 mg and 7 kg.

After administration of the 100 drugs, 5 ml of blood was collected at appropriate times for 1 to 8 hours in the (A) administration group, and 0.25 to 5 ml of blood was collected in the (B) administration group.
Blood was collected at appropriate times up to 6 hours, and 3ffLL was centrifuged. Using the serum obtained, Berkowitz's method [C
11nical Pharmacology and
Therapy.

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 in the (B) administration group, the drug absorption was relatively fast, but the serum concentration after 'rmα rapidly decreased, whereas in the (A) administration group, drug absorption was slow in the initial stage of administration. However, the serum concentration remained relatively high even after TAE, and the concentration remained high even 8 hours after administration.

From the above results, it is understood that the soft batch has excellent drug absorption, persistence, and significant improvement in bioavailability.

Test Example 5 (Pharmacological test of prazosin hydrochloride-containing preparation) (Method) Depilated male SD rats (body size Jizoo~300
g, 6 to 8 animals per group) Attach (A) the soft batch of Example 2 to the back and securely tape it on.The dosage is as follows:
Both drugs were administered at a dose of 20 μ/kg once a day for 3 consecutive days. 24 hours after the last dose, bentoparbital sodium (
Norepinephrine (3 μg/kg) was administered intravenously under anesthesia at a dose of 4” Otl@/kg (intraperitoneal administration), and the pressor response at this time was observed and compared with an untreated control group.

(Results) The above results are shown in Table 5. From this result, it is understood that although the soft patch is administered transdermally, it exhibits medicinal efficacy (suppression of pressor response) comparable to oral administration.

Table 5 *: 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) White male rabbits (body weight 2
．． 5-2.9 kg) On the back surface, apply the soft patch of Example 5 at 0.5 kg. A plate of I X 8 X 10 aa (containing clonidine hydrochloride 471'@) was applied and fixed with tape (7 hours after application, the soft patch was removed and the remaining drug on the skin was removed with absorbent cotton. (I wiped it off). 0.5 to 24 hours after application, 3 ml of blood was collected at appropriate times, and the plasma was collected by centrifugation.
The method of nd et al. (Acta Pharmacol.

Toxicol, vol. 40, p. 145 (1977)
] After treatment, clonidine was quantified using an ECD-gas chromatography device.

(Results) The above results are shown in Table 6. From this result, prompt and sustained transdermal absorption of the drug was confirmed.

Table 6 Test Example 7 (Piroxicam-containing preparation) (Method) On the back of shaved male rats (body weight 425 to +7 og),
The soft patch of Example 22 was used at a dose of piroxicam of 0.
It was attached so that it became 5Q/body, and the top was fixed with tape. Blood was collected at appropriate times 1 to 4 hours after application, and serum was collected by centrifugation.

Using 0.21 m of this serum, Hobbs et al.'s method [To
urnalof C11nical Pharmaco
Piroxicam was quantified by a fluorescence method according to 3, Vol. 19, p. 27o (1979).

(result) The above results are shown in Table 7.

Table 7 Procedural amendments February 13, 1985 Manabu Shiga, Commissioner of the Patent Office1, Indication of the case 1982 Patent Application No. 667102, Title of the invention Topical patch 3 Person making the amendment Relationship to case 2 Patent Applicant address: 3-3-9 Nozawa, Setagaya-ku, Tokyo jH'”
(1,) Grelan Pharmaceutical Co., Ltd. Representative Sho Yanagisawa 4, Agent 〒532 6 Number of inventions increased by amendment 0 7, Subject of amendment tl+ In Table 1 on page 25 of the specification, Example 9 The amount of purified water, which is a blended ingredient, is "59.8"
5s, s, jK correction.

that's all

Claims (1)

[Claims] The following components (a), (b), (c) and (d)
), and has its own skin-adhesive properties. (a) Drugs (b) Water-soluble proteins that exhibit an absorption-promoting effect (c) Polyhydric alfurs (d) Adhesive agents